sildenafil-citrate and Hypertension--Pulmonary

The optimal treatment strategy using pulmonary vasodilators in pulmonary arterial hypertension associated with CHD (PAH-CHD) remains controversial. We aimed to compare the efficacy and safety of pulmonary vasodilators in PAH-CHD. PubMed and EMBASE databases were searched through May 2022 and a network meta-analysis was conducted. The primary outcomes were mean difference of changes in 6-minute walk distance, NYHA functional class, and N-terminal pro-brain natriuretic peptide. The secondary outcomes included pulmonary vascular resistance, mean pulmonary arterial pressure, and resting oxygen saturation. We identified 14 studies, yielding 807 patients with PAH-CHD. Bosentan and sildenafil were associated with a significant increase in 6-minute walk distance from baseline compared with placebo (MD 48.92 m, 95% CI 0.32 to 97.55 and MD 59.70 m, 95% CI 0.88 to 118.53, respectively). Bosentan, sildenafil, and combination of bosentan and sildenafil were associated with significant improvement in NYHA functional class compared with placebo (MD -0.33, 95% CI -0.51 to -0.14, MD -0.58, 95% CI -0.75 to -0.22 and MD -0.62, 95% CI -0.92 to -0.31, respectively). Bosentan and sildenafil were also associated with significant improvements in secondary outcomes. These findings were largely confirmed in the subgroup analysis. Various adverse events were reported; however, serious adverse event rates were relatively low (4.8-8.7%), including right heart failure, acute kidney injury, respiratory failure, hypotension, and discontinuation of pulmonary vasodilators. In conclusion, bosentan and sildenafil were the most effective in improving prognostic risk factor such as 6-minute walk distance and NYHA class. Overall, pulmonary vasodilators were well tolerated in PAH-CHD.

Topics: Antihypertensive Agents; Bosentan; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Network Meta-Analysis; Pulmonary Arterial Hypertension; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vasodilator Agents

Sildenafil was first prescribed for angina pectoris and then for erectile dysfunction from its effects on vascular smooth muscle relaxation and vasodilatation. Recently, sildenafil has been proposed for congenital heart diseases induced pulmonary hypertension, which constitutes a huge burden on children's health and can attribute to fatal complications due to presence of unoxygenated blood in the systemic circulation. Therefore, our meta-analysis aims to further investigate the safety and efficacy of sildenafil on children population.. We searched the following electronic databases: PubMed, Cochrane CENTRAL, WOS, Embase, and Scopus from inception to April 20th, 2022. Randomized controlled trials that assess the efficacy of using sildenafil in comparison to a placebo or any other vasodilator drug were eligible for inclusion. The inverse variance method was used to pool study effect estimates using the random effect model. Effect sizes are provided in the form of mean difference (MD) with 95% confidence intervals (CI).. Our study included 14 studies with (n = 849 children) with a mean age of 7.9 months old. Sildenafil showed a statistically significant decrease over placebo in mean and systolic pulmonary artery pressure (PAP) with MD -7.42 (95%CI [-13.13, -1.71], P = 0.01) and -8.02 (95%CI [-11.16, -4.88], P < 0.0001), respectively. Sildenafil revealed a decrease in mean aortic pressure and pulmonary artery/aortic pressure ratio over placebo with MD -0.34 (95%CI [-2.42, 1.73], P = 0.75) and MD -0.10 (95%CI [-0.11, -0.09], P < 0.00001), respectively. Regarding post corrective operations parameters, sildenafil had a statistically significant lower mechanical ventilation time, intensive care unit stay, and hospital stay over placebo with MD -19.43 (95%CI [-31.04, -7.81], s = 0.001), MD -34.85 (95%CI [-50.84, -18.87], P < 0.00001), and MD -41.87 (95%CI [-79.41, -4.33], P = 0.03), respectively. Nevertheless, no difference in mortality rates between sildenafil and placebo with OR 0.25 (95%CI 0.05, 1.30], P = 0.10) or tadalafil with OR 1 (95%CI 0.06, 17.12], P = 1).. Sildenafil is a well-tolerated treatment in congenital heart diseases induced pulmonary hypertension, as it has proven its efficacy not only in lowering both PAP mean and systolic but also in reducing the ventilation time, intensive care unit and hospital stay with no difference observed regarding mortality rates.

Topics: Child; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Randomized Controlled Trials as Topic; Sildenafil Citrate; Vasodilator Agents

The prognosis of patients with untreated pulmonary arterial hypertension (PAH) has historically been poor. Previous studies have recommended that sildenafil was beneficial, but the dose varies greatly. In this study, we aimed to evaluate the safety and effectiveness of sildenafil [dose: 20 mg/three times a day (TID)] for adult Asian PAH patients.. Electronic databases (MEDLINE, Embase, Web of Science, the Cochrane Library, CBM, CNKI, and Wanfang Data) were searched from their inception to January 2022. We recruited all randomized controlled trials and non-randomized studies of interventions that compared sildenafil (20 mg/TID) versus placebo or symptomatic treatment for adult Asian PAH patients.. A total of 10 studies involving 480 participants were included. Compared to symptomatic treatment, sildenafil-treated patients were more likely to walk 57.68 meters further in six-minute walk distance [mean difference (MD) =57.68 m, 95% confidence interval (CI): 41.55 to 73.81], achieve an improvement in systemic arterial oxygen saturation (MD =2.48%, 95% CI: 1.26 to 3.71), and increase the score of the Borg scale for dyspnea (MD =-0.99 points, 95% CI: -1.45 to -0.53). The total number of patients with World Health Organization class III and IV also exhibited a downtrend. Compared to the placebo, sildenafil was associated with a reduction in the mean pulmonary artery pressure (MD =-4.13 mmHg, 95% CI: -6.52 to -1.74) and the level of brain natriuretic peptide (MD =-86.16 pg/mL, 95% CI: -103.39 to -68.93). The most common adverse events were headache, flushing, dyspepsia, and diarrhea, which were relatively mild.. Sildenafil at a dose of 20 mg/TID is well tolerated in adult Asian PAH patients, and is associated with statistically significant improvements in exercise capacity, cardio-pulmonary function, and haemodynamic indices. The long-term prognosis still needs to be evaluated and confirmed by further trials.

Topics: Adult; Dyspnea; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Quality of Life; Sildenafil Citrate; Treatment Outcome

The efficacy and safety profile of phosphodiesterase-5 inhibitors (PDE-5i) in pregnancy are unclear from the few relatively small diverse studies that have used them.. To assess the safety profile and clinical outcomes of PDE-5i use in pregnancy.. We searched Embase, PubMed, CENTRAL, Prospero and Google Scholar to identify randomised controlled trials (RCTs) reporting the use of any PDE-5i in pregnancy up to September 2021.. RCTs reporting obstetric or perinatal outcomes or maternal adverse outcomes in women taking PDE5i in pregnancy.. Risk ratios (RR), 95% confidence intervals (95% CI) and 95% prediction intervals were calculated and pooled for analysis.. We identified 1324 citations, of which 10 studies including 1090 participants met the inclusion criteria. Only tadalafil and sildenafil were reported as used in pregnancy. Two studies using tadalafil and eight sildenafil. Nine of ten studies were assessed at having of low risk of bias. PDE-5i use was associated with an increased risk of headaches (RR 1.41, 95% CI 0.97-2.05), flushing (RR 2.59, 95% CI 0.69-9.90) and nasal bleeding (RR 10.53, 95% CI 1.36-81.3); an increase in vaginal birth when used for non-fetal growth restriction (FGR) indications (RR 1.24, 95% CI 1.00-1.55) and a reduction in risk of operative birth for intrapartum fetal compromise (RR 0.58, 95% CI 0.38-0.88). There was no evidence of any increase in risk of perinatal death (RR 0.89, 95% CI 0.56-1.43). However, use for the treatment of FGR increased the risk of persistent pulmonary hypertension of the newborn (PPHN) (RR 2.52, 95% CI 1.00-6.32).. This meta-analysis suggests PDE-5i use in pregnancy is associated with mild maternal side effects and lower risk of operative birth for intrapartum fetal distress. Prolonged use for the treatment of FGR may increase the risk of PPHN.. PDE-5i use in pregnancy is associated with mild maternal side effects, lower operative birth for intrapartum fetal distress and a possible increase in persistent pulmonary hypertension of the newborn when used for the treatment of fetal growth restriction.

Topics: Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Fetal Distress; Fetal Growth Retardation; Humans; Hypertension, Pulmonary; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Pregnancy; Sildenafil Citrate; Tadalafil

Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology.

Topics: Female; Fetal Growth Retardation; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pre-Eclampsia; Pregnancy; Sildenafil Citrate

The combination of pulmonary fibrosis and emphysema (CPFE) has been recently defined as a syndrome, it is radiologically recognized and is characterized by the simultaneous coexistence of emphysema of superior pulmonary location and fibrosis predominantly in lower lobes.. We present three patients with CPFE, who underwent right cardiac catheterization for pulmonary hemodynamic assessment, finding mean pulmonary artery pressure (mPAP) between 37-52 mm Hg (mean 45 mm Hg), who received treatment with specific vasodilators for pulmonary arterial hypertension (PAH).. The three patients had higher mPAP than expected for Group III (Pulmonary hypertension due to lung disease and/or hypoxia) of the classification of pulmonary hypertension (PH) by the World Health Organization (WHO), in whom the use of Sildenafil was justified by the presence of progressive dyspnea, and no symptoms suggestive of infectious exacerbation associated with right ventricular failure.

Topics: Cardiac Catheterization; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pulmonary Emphysema; Pulmonary Fibrosis; Sildenafil Citrate; Vasodilator Agents

There is significant controversy relating to whether chronic thromboembolic pulmonary hypertension (CTEPH) can be treated with pulmonary arterial hypertension- (PAH-) targeted therapies and which therapy is the optimal choice for patients. A large number of randomized controlled trials (RCTs) have compared PAH-targeted therapies with placebo or conventional therapies. In this study, we aimed to compare all of the PAH-targeted medications that are used to treat CTEPH and rank their efficacy by the application of network meta-analysis (NMA).. We searched PubMed, EMBASE, Web of Science, the Cochrane Central Register, https://clinicaltrials.gov, and who.int/trialsearch/, for relevant RCTs published up to January 2020. In addition to traditional meta-analysis, we also performed NMA in our systematic review, as deployed in a previous protocol (PROSPERO: CRD42020173765).. Our study identified eight eligible RCTs that evaluated seven PAH-targeted therapies in 703 patients with CTEPH. NMA revealed that riociguat was ranked first as the most optimized therapy for ameliorating the 6-minute walk distance with a probability of 80.4%. Bosentan was significantly better than others with regard to reducing brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide with a probability of 84.3%. Sildenafil was identified as the best drug in terms of improving the New York Heart Association/World Health Organization functional class with a probability of 87.3%. Treprostinil and macitentan were more beneficial than other drugs in reducing pulmonary vascular resistance and lowering the incidence of clinical worsening with probabilities of 86.2% and 79.2%, respectively.. Analysis revealed positive advantages for the use of PAH-targeted drugs in patients with CTEPH. Overall, treprostinil and riociguat were superior to all other PAH-targeted medications in most of the outcomes investigated.

Topics: Antihypertensive Agents; Bosentan; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Network Meta-Analysis; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. IMPACT: PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Cardiac Catheterization; Cardiac Surgical Procedures; Echocardiography; Endothelin Receptor Antagonists; Heart Failure; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Magnetic Resonance Imaging; Nitric Oxide; Oxygen Inhalation Therapy; Prostaglandins I; Sildenafil Citrate; Tomography, X-Ray Computed; Tricuspid Valve Insufficiency; Vascular Resistance; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) is a significant clinical problem characterized by refractory and severe hypoxemia secondary to elevated pulmonary vascular resistance resulting in right-to-left extrapulmonary shunting of deoxygenated blood. PPHN is associated with diverse cardiopulmonary disorders and a high early mortality rate for infants with severe PPHN. Surviving infants with PPHN have an increased risk of long-term morbidities. PPHN physiology can be categorized by (1) maladaptation: pulmonary vessels have normal structure and number but have abnormal vasoreactivity; (2) excessive muscularization: increased smooth muscle cell thickness and increased distal extension of muscle to vessels that are usually not muscularized; and (3) underdevelopment: lung hypoplasia associated with decreased pulmonary artery number. Treatment involves adequate lung recruitment, optimization of cardiac output and left ventricular function, and pulmonary vasodilators such as inhaled nitric oxide. Infants who fail to respond to conventional therapy should be evaluated for lethal lung disorders including alveolar-capillary dysplasia, T-box transcription factor 4 gene, thyroid transcription factor-1, ATP-binding cassette A3 gene, and surfactant protein diseases.

Topics: Bosentan; Epoprostenol; Humans; Hypertension, Pulmonary; Hypoxia; Infant; Infant, Newborn; Infant, Premature; Lung; Milrinone; Nitric Oxide; Oxygen; Persistent Fetal Circulation Syndrome; Pulmonary Alveoli; Pulmonary Surfactants; Risk; Sildenafil Citrate; Vascular Resistance; Vasodilator Agents

Pediatric pulmonary hypertension (PAH) is a rare disease that carries a poor prognosis if left untreated. Although there are published guidelines for the treatment of children with pulmonary hypertension, due to the limited number of robust pediatric clinical trials, recommendations are often based on limited data or clinical experience. Furthermore, many practical aspects of care, particularly for the pediatric patient, are learned through experience and best navigated with a multidisciplinary team. While newer PAH therapies have been approved for adults, there is still limited but expanding experience in pediatrics. This new information will help improve the targets of goal-oriented therapy. Lastly, this review highlights practical aspects in the use of the different therapies available for the treatment of pediatric pulmonary hypertension.

Topics: Adolescent; Adult; Bosentan; Calcium Channel Blockers; Child; Child, Preschool; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infant, Newborn; Phenotype; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Prognosis; Pulmonary Arterial Hypertension; Pyridazines; Pyrimidines; Receptors, Endothelin; Sildenafil Citrate; Sulfonamides; Tadalafil; Young Adult

Pulmonary arterial hypertension (PAH) is a rare disease in children, with significant mortality. Because of the limited research on pediatric PAH, first, systematic review of related drugs is conducted, and then economic evaluation of PAH drug treatment programs is conducted, which to provide a reference for the choice of more cost-effective treatment options.. The search includes electronic databases such as Pubmed, ScienceDirect, and Embase. Through inclusion and exclusion criteria, screen high-quality randomized controlled trials. We used TreeAge Pro 2011 software to construct the markov model, that to simulate the total medical cost and quality-adjusted life years (QALYs), and to calculate the incremental cost-effectiveness ratio. Sensitivity analysis of transfer probability, utility, and cost was carried out.. Incorporate two studies that meet the criteria, one compared the therapeutic effects of bosentan and placebo on pediatric PAH, the other compared therapeutic effects of sildenafil and placebo on pediatric PAH, both articles were of good quality. Compared with the sildenafil group (3.38QALYs and $161,120.14), the QALY of the bosentan treatment group (3.33QALYs and $257,411.29) was reduced by 0.05, and the cost increased by $96,291.15. The estimated improvement to quality of life and reduced costs result in an estimate of economic dominance for sildenafil over bosentan. This dominant result persisted probabilistic analyses.. Based on this model, a more cost-effective treatment drug for PAH in children is sildenafil.

Topics: Bosentan; Child; Cost-Benefit Analysis; Humans; Hypertension, Pulmonary; Pharmaceutical Preparations; Pulmonary Arterial Hypertension; Quality of Life; Sildenafil Citrate

To provide an updated review and meta-analysis on the efficacy and safety of sildenafil for treating persistent pulmonary hypertension in neonates (PPHN).. PubMed/Medline, SCOPUS, Cochrane Central Register of Controlled Trials, and Web of Science were searched from the inception of publication to January 2021. The principal outcomes include oxygenation parameters, hemodynamic metrics and echocardiographic measurements, as well as adverse outcomes.. A total of eight studies were included with 216 term and premature neonates with PPHN. Compelling evidence showed the use of sildenafil could improve the prognosis of PPHN neonates, compared with baseline or placebo in neonates with PPHN, and a time-dependent pattern of the improvements can be observed. After 24 h of treatment, the Oxygenation index suggested a steady decrease (SD: -1.80, 95% confidence interval [CI]: -2.92, -0.67) and sildenafil exerted peak effects after 72 h of treatment (SD: -4.02, 95% CI: -5.45, -2.59). No clinically significant side effects were identified. Egger's test and funnel plots of the major outcomes were performed, and the publication bias was not significant.. Improvements were shown in oxygenation index, pulmonary arterial pressure, and adverse outcomes after using sildenafil for PPHN in neonates. However, future research with robust longitudinal or randomized controlled design is still needed.

Topics: Humans; Hypertension, Pulmonary; Infant, Newborn; Sildenafil Citrate

Pulmonary hypertension (PH) is a severe and prevalent complication of chronic obstructive pulmonary disease (COPD), with low quality of life and poor prognosis. This study was designed to evaluate the efficacy and safety of Sildenafil in the treatment of PH caused by COPD (COPD-PH) and provide reference for clinical treatment.. We systematically searched PubMed, EMBASE, Cochrane Library, Clinical Trials.gov databases, Wanfang Data and CNKI for comprehensive literature reporting Sildenafil for randomized controlled trials (RCT) of COPD-PH. Quality assessment, data analysis used the modified Jadad scale and RevMan5.3 software.. A total of 9 RCTs involving 579 patients were included in our study. The primary outcome measure was Six minutes walking distance (6MWD). Secondary observations were Pulmonary artery systolic pressure (PASP), Borg dyspnea index, and Survey scale (SF-36). Our data demonstrate that Sildenafil can improve 6WMD [29.64, 95% CI (13.78, 45.50), P < 0.00001] and PASP [-7.86, 95% CI (-11.26, -4.46) P < 0.00001] of COPD-PH, compared with the control group. However, SF-36 [2.64, 95% CI (-6.85, 12.14) P = 0.59] and Borg dyspnea index [-0.28, 95% CI (-1.08, 0.52) P = 0.49] have no significant difference between those two groups. Adverse reactions in the Sildenafil treatment group were tolerated headaches and digestive symptoms, which were relatively safe.. Available clinical evidence indicates that Sildenafil seems to be safe and effective for COPD-PH and can improve the patients' 6WMD. However, large-sample, high-quality multicenter RCTs are still needed to provide stronger evidence-based medical evidence.

Topics: Humans; Hypertension, Pulmonary; Pulmonary Disease, Chronic Obstructive; Sildenafil Citrate; Treatment Outcome

Pulmonary arterial hypertension is a multifactorial nosological entity that increases neonatal mortality as a result of heart failure. Pulmonary vasodilators are the cornerstone of treatment, of which sildenafil is the most commonly used drug. Therefore, the results of a recently updated Cochrane systematic review are summarized, in which the efficacy and safety of sildenafil for the treatment of pulmonary hypertension in neonates was evaluated.. La hipertensión arterial pulmonar es una enfermedad multifactorial que incrementa la mortalidad en el neonato como consecuencia de falla cardiaca. Los vasodilatadores pulmonares son la piedra angular del tratamiento, de los cuales el ­sildenafil es el fármaco más empleado. A continuación, se resumen los resultados de una revisión sistemática Cochrane en la que se evaluaron la eficacia y la seguridad del sildenafil para el tratamiento de la hipertensión arterial pulmonar en neonatos.

Topics: Humans; Hypertension, Pulmonary; Infant, Newborn; Randomized Controlled Trials as Topic; Sildenafil Citrate; Vasodilator Agents

Efficacy of sildenafil in treating paediatric pulmonary arterial hypertension is controversial. This systematic review aimed to explore the safety and effect of sildenafil on treating paediatric pulmonary arterial hypertension (PAH) through meta-analysis.. In this study, the electronic databases, including the Cochran Library database, EMBASE, and MEDLINE were systemically retrieved to identify the related randomised controlled trials (RCTs). Two reviewers had independently completed study selection, data collection, and assessment of the bias risk. Amongst 938 articles researched according to our retrieval strategy, 15 papers that involved 673 cases had been screened. Relative to control group, the sildenafil group had markedly reduced mortality (RR = 0.25, 95% CI: 0.12-0.51; p < 0.0001), but difference within the mortality was not statistically significant between high- and low-dose sildenafil groups (p = 0.152). Nonetheless, difference of the mean pulmonary arterial pressure between sildenafil as well as control group was of no statistical significance. Differences in the length of hospital stay and the incidences of pulmonary hypertensive crisis between children with PAH and controls were of no statistical significance. However, the summary estimate favoured that sildenafil reduced the duration of mechanical ventilation time, as well as the length of ICU stay and inotropic support.. Sildenafil therapy reduces the mortality of PAH patients, but its effects on the haemodynamic outcomes and other clinical outcomes are still unclear.

Topics: Child; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Randomized Controlled Trials as Topic; Respiration, Artificial; Sildenafil Citrate

Pulmonary arterial hypertension (PAH) is severe and often times rapidly progressive disease with fatal outcome. The concept of initial combination of PAH-specific therapies in high risk patients at baseline was first described in the European guidelines on pulmonary hypertension (PH) in 2009, and in low or intermediate risk patients at baseline in 2015. Interestingly, that in Cologne Experts Consensus, and then in the 6th World Symposium on PH medical community started considering initial combination therapy as one of the most important pillars in PAH treatment algorithms in 2018. As of August 2020, as many as 8 formulations of 7 reference PAH-specific drugs are licensed for medical use in the Russian Federation. On top of that, 6 abbreviated drugs (generics) have also become available few years ago. Unfortunately, intravenous and subcutaneous prostacyclin analogs (PCA) and tadalafil are not approved for PH patients treatment in the Russian Federation. In this narrative review paper we attempted to describe studies on initial dual combination therapy with PAH-specific drugs registered in Russia, i.e. ambrisentan and riociguat, macitentan and riociguat, macitentan and sildenafil in low or intermediate risk patients at baseline, as well as iloprost inhaled and sildenafil, iloprost inhaled and bosentan in high risk patients. Some beneficial pharmacological effects due to the synergy between ambrisentan plus riociguat, and inhaled iloprost plus sildenafil appear to be interesting and require further clinical confirmation. Other initial combinations of PAH-specific agents require large-scale clinical trials as well.. Аннотация Легочная артериальная гипертензия (ЛАГ) тяжелое и, часто, быстропрогрессирующее заболевание с фатальным исходом. Возможность начальной комбинированной ЛАГ-специфической терапии у пациентов исходно высокого риска впервые закреплена в Европейских рекомендациях по легочной гипертензии (ЛГ) в 2009 г., а у пациентов исходно низкого и промежуточного риска в 2015 г. В 2018 г. Кельнский консенсус экспертов, а затем 6-й Всемирный симпозиум по ЛГ повысили роль начальной комбинированной терапии в алгоритмах лечения ЛАГ. В Российской Федерации зарегистрированы 8 лекарственных форм 7 оригинальных ЛАГ-специфических препаратов. Помимо оригинальных зарегистрировано 6 генерических препаратов. К сожалению, внутривенные и подкожные простаноиды, а также тадалафил для лечения ЛГ в РФ не одобрены. В обзоре проанализированы исследования, посвященные начальной двойной комбинированной ЛАГ-специфической терапии зарегистрированными в РФ препаратами: амбризентаном и риоцигуатом, мацитентаном и риоцигуатом, мацитентаном и силденафилом у пациентов исходно низкого и промежуточного риска, а также ингаляционным илопростом и силденафилом, ингаляционным илопростом и бозентаном у пациентов исходно высокого риска. Благоприятные фармакологические эффекты, обусловленные синергией амбризентана и риоцигуата, а также ингаляционного илопроста и силденафила, требуют дальнейшего клинического подтверждения. Требуют изучения и другие начальные комбинации ЛАГ-специфических препаратов.

Topics: Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Russia; Sildenafil Citrate

Topics: Bosentan; Disease Progression; Endothelin Receptor Antagonists; Enzyme Activators; Humans; Hypertension, Pulmonary; Hypoxia; Idiopathic Pulmonary Fibrosis; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Circulation; Pulmonary Diffusing Capacity; Pulmonary Ventilation; Pyrazoles; Pyrimidines; Sildenafil Citrate; Treatment Failure; Vascular Remodeling; Vasoconstriction

The perioperative management of patients with pulmonary hypertension requires an in-depth knowledge of the underlying disease, its related pathophysiology, effects of anaesthesia and surgery, as well as the appropriate pharmacotherapy. With respect to preoperative assessment, it is essential to review all available diagnostic findings, evaluate the patient's physical state, and to plan the anaesthetic procedure. Intraoperatively, the prevention of increases in pulmonary resistance and right ventricular decompensation appears essential. For this purpose, stress, hypothermia, decreased systemic perfusion, hypercapnia, hypoxemia, acidosis, and invasive mechanical ventilation should be avoided. If the pulmonary artery pressure exacerbates, application of inhaled nitric oxide or prostacyclins (iloprost), phosphodiesterase-III-inhibitors (milrinone) and phosphodiesterase-V-inhibitors (sildenafil), reflect first-line treatment options. In order to support the right ventricle, inotropes (adrenalin, dobutamine, levosimendan) or inodilators (milrinone) increase its contractility. Dependent on severity of disease and the magnitude of surgical intervention, patients with pulmonary hypertension require a specific continuous monitoring as well as trained staff in the postoperative period.. Das perioperative Management von Patienten mit pulmonaler Hypertonie erfordert von den behandelnden Anästhesisten fundierte Kenntnisse über die zugrunde liegenden Ursachen, die Pathophysiologie, den Einfluss anästhesiologischer und chirurgischer Maßnahmen wie z. B. die mechanische Beatmung sowie intraoperative Behandlungsoptionen. In der präoperativen Vorbereitung gilt es, alle vorliegenden Befunde zu evaluieren, die Belastbarkeit des Patienten zu erheben und die bestehende Dauermedikation zu kennen. Die Basis für einen sicheren intraoperativen Verlauf stellt die Vermeidung einer pulmonalarteriellen Druckerhöhung und Rechtsherzdysfunktion dar. Hierbei gilt es Hypoxie, Hyperkapnie, Azidose, Hypothermie, Stress und eine koronare Hypoperfusion zu verhindern. Bei einem Anstieg des pulmonalarteriellen Drucks können sowohl inhalative, selektive pulmonale Vasodilatatoren, wie Stickstoffmonoxid oder Prostazykline, als auch intravenös Phosphodiesterase-3-Inhibitoren und Phosphodiesterase-5-Inhibitoren eingesetzt werden. Bei einer rechtsventrikulären Dysfunktion oder Dekompensation sollte mittels inotroper Substanzen und Inodilatoren die Herzfunktion unterstützt werden. Abhängig vom Ausmaß der Operation und dem Schweregrad der pulmonalen Hypertonie erfordert die postoperative Betreuung vor allem Expertise und Strukturen, die ein kontinuierliches Monitoring zulassen.

Topics: Anesthesia, General; Anesthetics; Humans; Hypertension, Pulmonary; Milrinone; Nitric Oxide; Sildenafil Citrate; Vasodilator Agents

Recent guidelines recommend riociguat, a soluble guanylate cyclase (sGC) stimulator, and the type 5 phosphodiesterase inhibitor (PDE5i) tadalafil or sildenafil as treatments for pulmonary arterial hypertension. We compared the safety profiles of sildenafil, tadalafil, and riociguat in pulmonary hypertension.. We combined two approaches. First, we performed a meta-analysis of safety data extracted from randomized controlled trials. Second, we conducted a disproportionality analysis of data from VigiBase, the World Health Organization's global database of individual case safety reports, to compare the safety profiles with real-life data.. In the meta-analysis, a significant difference between the three drugs was only detected for gastrointestinal disorders, in disfavor of riociguat (P < .01 for interaction). In the disproportionality analysis, the use of riociguat was associated with fewer reports of visual disorders but increased reporting of gastrointestinal, hemorrhagic, and musculoskeletal disorders compared with sildenafil and tadalafil. Pharmacovigilance signals of hearing/vestibular disorders were heterogeneous: vestibular disorders (dizziness) were reported more frequently for riociguat, whereas hearing disorders (deafness) were reported less frequently compared with PDE5is.. The safety profiles of PDE5is and sGC stimulators significantly differ in pulmonary hypertension. Accordingly, there is a safety rationale in switching between PDE5is and sGC stimulators because of their different side effects.. PROSPERO; No.: CRD42016051986; URL: https://www.crd.york.ac.uk/prospero/.

Topics: Adverse Drug Reaction Reporting Systems; Clinical Trials as Topic; Humans; Hypertension, Pulmonary; Pharmacovigilance; Phosphodiesterase 5 Inhibitors; Pulmonary Wedge Pressure; Sildenafil Citrate; Tadalafil; World Health Organization

Congenital diaphragmatic hernia is rare birth defect, which can be easily corrected after birth. The main problem is that herniation of viscera during fetal life impairs lung development, leading to a 30% mortality and significant morbidity. In isolated cases the outcome can be accurately predicted prenatally by medical imaging. Cases with a poor prognosis can be treated before birth; clinically this is by fetoscopic endoluminal tracheal occlusion. Obstruction of the airways triggers lung growth. This procedure is currently being evaluated in a global clinical trial for left sided cases; right sided cases with poor prognosis are offered the procedure clinically. The search for more potent and less invasive therapies continues. Prenatal transplacental sildenafil administration will in due course be tried clinically, with the aim to reduce the occurrence of persistent pulmonary hypertension, either alone or in combination with fetal surgery. Other medical approaches are in an earlier translational phase.

Topics: Female; Fetal Therapies; Fetoscopy; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pregnancy; Prognosis; Sildenafil Citrate

Congenital diaphragmatic hernia (CDH) is the result of incomplete formation of the diaphragm that occurs during embryogenesis. The defect in the diaphragm permits the herniation of abdominal organs into the thoracic cavity contributing to the impairment of normal growth and development of the fetal lung. In addition to the hypoplastic lung, anomalies of the pulmonary arterioles worsen the pulmonary hypertension that can have detrimental effects in severe cases. Most cases of CDH can be effectively managed postnatally. Advances in neonatal and surgical care have resulted in improved outcomes over the years. When available, extracorporeal membrane oxygenation can provide temporary cardiorespiratory support for those not effectively supported by mechanical ventilation. In spite of these advances, very severe cases of CDH still carry a very high mortality and morbidity rate. Advances in imaging and evaluation now allow for early and accurate prenatal diagnosis of CDH, thereby identifying those at greatest risk who may benefit from prenatal intervention. This review article discusses some of the surgical and non-surgical prenatal interventions in the management of isolated severe congenital diaphragmatic hernia.

Topics: Female; Fetoscopy; Glucocorticoids; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Pregnancy; Prenatal Diagnosis; Prognosis; Sildenafil Citrate; Trachea; Tretinoin; Ultrasonography, Prenatal; Vasodilator Agents

Sildenafil is a pulmonary artery hypertension (PH)-targeted drug that finds an increased indiscriminate use in children with PH secondary to congenital heart disease (CHD).We performed a meta-analysis to evaluate the effects of sildenafil on pediatric patients with PH secondary to CHD during perioperative period.PubMed, EMBASE, the Cochrane Library, and the Google Scholar were searched up to May 2016 for randomized controlled trials (RCTs) assessing the perioperative treatment of sildenafil in pediatric patients with PH secondary to CHD. Major clinical outcomes were mortality before discharge, length of ICU stay, and length of hospitalization. The outcomes were analyzed as continuous and dichotomized variables by using fixed or random effect model, and we computed the pooled RR and MD with 95% confidence interval.Five RCTs involving 238 pediatric patients with PH experienced CHD operation were included. Sildenafil was used in all trials. We observed no differences in mortality before discharge (RR 0.35; 95% CI 0.06-2.10; χ

Topics: Adolescent; Child; Child, Preschool; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Length of Stay; Perioperative Care; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Treatment Outcome

After ascent to high altitude (≥2500 m), the inability of the human body to adapt to the hypobaric and hypoxia environment can induce tissue hypoxia, then a series of high altitude illnesses including acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE) would develop. Symptoms of AMS include headache, dizziness, nausea, and vomiting; HAPE is characterized by orthopnea, breathlessness at rest, cough, pink frothy sputum, and results in obvious pulmonary edema that poses significant harm to people; HACE is characterized by ataxia and decreased consciousness, leading to coma and brain herniation which would be fatal if not treated promptly. This review article provides a current understanding of the pathophysiology of these three forms of high altitude illness and elaborates the current prevention and treatment measures of these diseases.

Topics: Acetazolamide; Acute Disease; Altitude Sickness; Calcium Channel Blockers; Carbonic Anhydrase Inhibitors; Cytokines; Dexamethasone; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Inflammation Mediators; Nifedipine; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Alveoli; Sildenafil Citrate

Although many studies have reported on the cost-effectiveness of bosentan for treating pulmonary arterial hypertension (PAH), a systematic review of economic evaluations of bosentan is currently lacking. Objective evaluation of current pharmacoeconomic evidence can assist decision makers in determining the appropriate place in therapy of a new medication.. Systematic literature searches were conducted in English-language databases (MEDLINE, EMBASE, EconLit databases, and the Cochrane Library) and Chinese-language databases (China National Knowledge Infrastructure, WanFang Data, and Chongqing VIP) to identify studies assessing the cost-effectiveness of bosentan for PAH treatments.. A total of 8 published studies were selected for inclusion. Among them were two studies comparing bosentan with epoprostenol and treprostinil. Both results indicated that bosentan was more cost-effective than epoprostenol, while the results of bosentan and treprostinil were not consistent. Four studies compared bosentan with other endothelin receptor antagonists, which indicated ambrisentan might be the drug of choice for its economic advantages and improved safety profile. Only two economic evaluations provided data to compare bosentan versus sildenafil, and the results favored the use of sildenafil in PAH patients. Four studies compared bosentan with conventional, supportive, or palliative therapy, and whether bosentan was cost-effective was uncertain.. Bosentan may represent a more cost-effective option compared with epoprostenol and conventional or palliative therapy. There was unanimous agreement that bosentan was not a cost-effective front-line therapy compared with sildenafil and other endothelin receptor antagonists. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed.

Topics: Antihypertensive Agents; Bosentan; Cost-Benefit Analysis; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sildenafil Citrate; Vasodilator Agents

Topics: Adolescent; Age Factors; Child; Child, Preschool; Drug Approval; Drug Development; Government Regulation; Health Policy; Humans; Hypertension, Pulmonary; Infant; Patient Safety; Pediatrics; Phosphodiesterase 5 Inhibitors; Policy Making; Risk Assessment; Risk Factors; Sildenafil Citrate; Treatment Outcome; United States; United States Food and Drug Administration; Vasodilator Agents

Persistent pulmonary hypertension in the neonate (PPHN) is associated with high mortality. Currently, the therapeutic mainstay for PPHN consists of assisted ventilation and administration of inhaled nitric oxide (iNO). However, nitric oxide is costly, and its use may not be appropriate in resource-poor settings. Approximately 30% of patients fail to respond to iNO. High concentrations of phosphodiesterases in the pulmonary vasculature have led to the use of phosphodiesterase inhibitors such as sildenafil or milrinone.. To assess the efficacy and safety of sildenafil for treatment of pulmonary hypertension in neonates.. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 3), MEDLINE via PubMed (1966 to 18 April 2017), Embase (1980 to 18 April 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 18 April 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.. We included randomised and quasi-randomised controlled trials of sildenafil compared with placebo or other pulmonary vasodilators, irrespective of dose, route, and duration of administration, in neonates with pulmonary hypertension, if investigators reported any of the prespecified outcomes.. We assessed the methodological quality of trials regarding how bias was minimised at study entry, during study intervention, and at outcomes measurement. We extracted data on relevant outcomes; we estimated the effect size and reported it as risk ratio (RR), risk difference (RD), or mean difference (MD), as appropriate. We applied the I. For this update, we identified two additional studies, for a total of five eligible trials that enrolled 166 infants. The methodological quality of these studies ranged from low to high risk of bias. Three studies were performed in resource-limited settings, where iNO and high-frequency ventilation were not available at the time of the study. One study compared sildenafil versus active controls, and another study evaluated sildenafil as adjuvant therapy to iNO. When comparing sildenafil with placebo, investigators noted significant reduction in mortality in the sildenafil alone group (three studies, 77 participants; typical RR 0.20, 95% confidence interval (CI) 0.07 to 0.56; I. Sildenafil used for treatment of pulmonary hypertension has potential for reducing mortality and improving oxygenation in neonates, especially in resource-limited settings where iNO is not available. However, large-scale randomised trials comparing sildenafil versus active controls (other pulmonary vasodilators) and providing follow-up for survivors are needed to assess the comparative effectiveness and long-term safety of sildenafil versus other pulmonary vasodilators.

Topics: Bronchodilator Agents; Cause of Death; Humans; Hypertension, Pulmonary; Infant, Newborn; Nitric Oxide; Randomized Controlled Trials as Topic; Sildenafil Citrate; Vasodilator Agents

Pulmonary hypertension (PH) is a syndrome that is of growing concern to pediatricians worldwide. Recent data led to concerns about the safety of phosphodiesterase type 5 (PDE5) inhibitors in children and a US Food and Drug Administration safety advisory. Our objective is to provide insight into therapies for PH in children and to systematically review the comparative effectiveness and safety of PDE5 inhibitors in the management of pediatric patients with PH. We searched the following databases through February 2015: Medline, Embase, SCOPUS, and the Cochrane Central Register of Controlled Trials. We included studies that examined PDE5 inhibitor use in children with PH. Allowed comparators were either no medication or other classes of medication for management of PH. Study inclusion was via a 2-stage process with 2 reviewers and a predesigned form. Of 1270 papers identified by the literature search, 21 were included: 8 randomized controlled trials and 13 observational studies (9 retrospective, 4 prospective). There is strong evidence that PDE5 inhibitor use improves echocardiography measurements, cardiac catheterization parameters, and oxygenation compared with baseline or placebo in pediatric patients with PH. Evidence suggests that low- and moderate-dose sildenafil are safe regimens for children. There are a relatively small number of randomized controlled trials that address use of PDE5 inhibitors in pediatric patients with PH. PDE5 inhibitors are effective agents for cardiovascular and oxygenation end points in pediatric PH and important components of a multimodal pharmacotherapeutic approach to this growing challenge. Additional studies are needed to define optimal PH therapy in childhood.

Topics: Blood Flow Velocity; Cardiac Catheterization; Cardiac Output; Cardiotonic Agents; Child; Dose-Response Relationship, Drug; Echocardiography; Exercise Tolerance; Humans; Hypertension, Pulmonary; Length of Stay; Off-Label Use; Oxygen; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Pulmonary Circulation; Respiration, Artificial; Sildenafil Citrate

Pulmonary hypertension (PH) in infants is a life-threatening disease with a high mortality. It is treated with different drugs that act upon the three different pathways involved in its development. Studies on the drug pharmacodynamics are sparse, however.. This review reports a search on the currently available literature in English on drug pharmacodynamics in infants with PH. The search yielded 2499 citations in the EMBASE, MEDLINE, COCHRANE, Web of Science, PubMed Publisher and Google Scholar databases since 1961. Of these, 1691 did not meet the research question. Eventually, 655 articles were of interest, including 44 randomized controlled trials on PH in infants. These articles cover all PH medications used in infancy.. Mortality of PH in infancy has dropped considerably over the past years. iNO is widely used, followed by sildenafil - both orally and intravenously in contrast to the exclusively oral use in adults. In adults, the pharmacodynamic effects of the different medications are tested using the 6-minute walking test, changes in the NYHA classification, or by invasive measurement of pulmonary pressure. Reliable data of pharmacodynamics tested in adequate series or in randomized controlled trials in children are lacking, however, for most of these medications.

Topics: Administration, Inhalation; Animals; Drug Design; Exercise Test; Humans; Hypertension, Pulmonary; Infant; Nitric Oxide; Sildenafil Citrate; Vasodilator Agents

Pulmonary arterial hypertension (PAH), as a life-threatening disease with no efficient cure, may impose a tremendous economic burden on patients and healthcare systems. However, most existing studies have mainly emphasised epidemiology and medications, while large observational studies reporting on the economic burden are currently lacking.. To review and evaluate evidence on the costs of PAH and the cost effectiveness of PAH treatments, and to summarise the corresponding cost drivers.. Systematic literature searches were conducted in English-language databases (PubMed, Web of Science, ScienceDirect) and Chinese-language databases (China National Knowledge Infrastructure, Wanfang Data, Chongqing VIP) to identify studies (published from 2000 to 2014) assessing the costs of PAH or the cost effectiveness of PAH treatments. The search results were independently reviewed and extracted by two reviewers. Costs were converted into 2014 US dollars.. Of 1959 citations identified in the initial search, 19 papers were finally included in this analysis: eight on the economic burden of PAH and 11 on economic evaluation of PAH treatments. The economic burden on patients with PAH was rather large, with direct healthcare costs per patient per month varying from $2476 to $11,875, but none of the studies reported indirect costs. Sildenafil was universally reported to be a cost-effective treatment, with lower costs and better efficacy than other medications. Medical costs were reported to be the key cost drivers.. The economic burden of patients with PAH is substantial, while the paucity of comprehensive country-specific evidence in this area and the lack of reports on indirect costs of PAH warrant researchers' concern, especially in China.

Topics: Cost of Illness; Cost-Benefit Analysis; Health Care Costs; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Pulmonary arterial hypertension (PAH) is a disease that imposes a significant burden on patients. Although multiple treatment options for PAH are available, head-to-head comparisons are difficult to conduct. Network meta-analysis (NMA) can be a useful alternative for direct comparison to estimate the relative effectiveness of multiple treatments. The objective of the present study was to conduct a systematic review and NMA to evaluate the relative effectiveness among oral PAH medications.Data collection was performed by searching the Cochrane Central Register of Controlled Trials (CENTRAL) and Ichushi-Web. Randomized controlled trials (RCTs) assessing at least 1 of the following 3 outcome measurements; 6-minute walk distance test (6MWD), WHO functional class (WHOFC), and mean pulmonary artery pressure (mPAP) were included (PROSPERO registration number: CRD42015016557). Outcomes were evaluated by estimating the differences in the mean change from baseline or by estimating the odds ratios. Analyses were performed using WinBUGS 1.4.3.Seven double-blind RCTs were eligible. NMA results showed similar improvements in 6MWD for all medications assessed. Bosentan and sildenafil caused a statistically significant improvement in WHOFC compared to other medications.The relative effectiveness of oral PAH medications could be compared using NMA, which suggested the superiority of bosentan and sildenafil in the improvement of WHOFC.

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vasodilator Agents

To identify suitable end points and surrogates for pediatric pulmonary arterial hypertension (PAH) as the lack of developmentally appropriate end point and clinical trials contribute to the unmet medical need.. Reviewed the efficacy end points and surrogates for all trials (1995 to 2013) that were submitted to the Food and Drug Administration (FDA) to support the approval of PAH therapy and conducted literature search.. An increase in the 6 min walking distance (6MWD) was used as a primary end point in 8/9 adult PAH trials. This end point is not suitable for infants and young children because of performance limitations and lack of control data. One adult PAH trial used time to the first morbidity or mortality event as a primary end point, which could potentially be used in pediatric PAH trials. In the sildenafil pediatric PAH trial, the change in pulmonary vascular resistance index or mean pulmonary artery pressure was used as a surrogate for the 6MWD to assess exercise capacity. However, two deaths and three severe adverse events during the catheterizations made this an unacceptably high-risk surrogate. The INOmax persistent pulmonary hypertension of the newborn trial used a reduction in initiation of extracorporeal membrane oxygenation treatment as a primary end point, which is not feasible for other pediatric PAH trials. A Literature review revealed none of the existing noninvasive markers are fully validated as surrogates to assess PAH efficacy and long-term safety.. For pediatric PAH trials, clinical end points are acceptable, and novel validated surrogates would be helpful. FDA seeks collaboration with academia, industry and parents to develop other suitable and possibly more efficient efficacy end points to facilitate pediatric PAH drug development.

Topics: Biomarkers; Child; Child, Preschool; Clinical Trials as Topic; Endothelin Receptor Antagonists; Exercise Test; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Oxygen Consumption; Pyrimidines; Reference Standards; Reproducibility of Results; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

Sildenafil (Revatio®) and tadalafil (Adcirca®) are specific inhibitors of the phosphodiesterase-5 enzyme and produce pulmonary vasodilation by inhibiting the breakdown of cyclic guanosine monophosphate (cGMP) in the walls of pulmonary arterioles.. We focus on the efficacy and safety of sildenafil and tadalafil in the treatment of pulmonary hypertension (PH) in children through a PubMed literature search.. Although used since 1999 in the treatment of PH in children, it is only in the past few years that robust evidence for the use of sildenafil has emerged principally in the pivotal STARTS-1 study. The open-label extension of this study, STARTS-2, has revealed safety concerns substantiated by FDA post marketing surveillance leading to recommendations to use lower doses. More recently, tadalafil has been introduced allowing once daily dosing with apparently similar efficacy to sildenafil in children. Recently there have been suggestions that sildenafil and tadalafil may have a place in treating muscular dystrophy.

Topics: Animals; Child; Cyclic GMP; Dose-Response Relationship, Drug; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil

There is no cure for pulmonary hypertension due to left heart disease (PH-LHD), but the rationale for using sildenafil to treat pulmonary arterial hypertension with heart failure with reduced ejection fraction (HFrEF) has been supported by short-term studies. We performed a meta-analysis to evaluate the effectiveness of sildenafil for PH-LHD with HFrEF. A systematic literature search of PubMed, EMBASE and the Cochrane Central Register of Controlled Trials was conducted from inception through October 2014 for randomized trials and for observational studies with control groups, evaluating the effectiveness of sildenafil to treat PH-LHD with HFrEF. Sildenafil therapy decreased pulmonary arterial systolic pressure both at the acute phase and at the 6-month follow-up (weighted mean difference (WMD): -6.03 mm Hg, P=0.02; WMD: -11.47 mm Hg, P<0.00001, respectively). Sildenafil was found to reduce mean pulmonary artery pressure (WMD: -3 mm Hg, P=0.0004) and pulmonary vascular resistance (WMD: -60.0 dynes cm(-5), P=0.01) at the 3-month follow-up. Oxygen consumption at peak significantly increased to 3.66 ml min(-1) kg(-1) (P<0.00001), 3.36 ml min(-1) kg(-1) (P<0.00001) and 2.60 ml min(-1) kg(-1) (P=0.03) at 3, 6 and 12 months, respectively. There were significant reductions in ventilation to CO2 production slope of -2.00, -4.68 and -7.12 at 3, 6 and 12 months, respectively (P<0.00001). Sildenafil was superior to placebo regarding left ventricular ejection fraction at the 6-month follow-up (WMD: 4.35, P<0.00001), and it significantly improved quality of life. Sildenafil therapy could effectively improve pulmonary hemodynamics and cardiopulmonary exercise testing measurements of PH-LHD with HFrEF, regardless of acute or chronic treatment.

Topics: Exercise Test; Heart Failure; Humans; Hypertension, Pulmonary; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Quality of Life; Sildenafil Citrate; Stroke Volume; Ventricular Function, Left

Pulmonary hypertension is a disease with diverse etiology. According to the New ESC guidelines, pregnancy is contraindicated for a patent with pulmonary hypertension and qualify such patent to class IV NYHA, regardless of the reason of hypertension. Pregnancy is revived for a patient with pulmonary hypertension despite of the fact that recent treatment methods including specific therapy with the endothelin receptor antagonistst (bosentan), phosphodiesterase inhibitors (sildenafil) and prostacyclin analogs (iloprost) were introduced. In the case of coincidence of pregnancy and pulmonary hypertension, patients should be managed in a center with expertise in pulmonary hypertension with all therapeutic options available.

Topics: Antihypertensive Agents; Bosentan; Female; Humans; Hypertension, Pulmonary; Iloprost; Phosphodiesterase Inhibitors; Pregnancy; Pregnancy Complications; Sildenafil Citrate; Sulfonamides

Numerous medications are used off-label in term and premature infants, with limited safety or efficacy data. Although sildenafil is approved by the US Food and Drug Administration for the treatment of pulmonary hypertension in adults, it is not approved for use in children. However, sildenafil use in term and premature infants with pulmonary hypertension is increasing. The goal of this study was to review controlled trials evaluating the efficacy of sildenafil use in: (1) term infants with pulmonary hypertension; (2) premature infants at risk for developing bronchopulmonary dysplasia (BPD); and (3) premature infants with BPD-associated pulmonary hypertension.. MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts databases were searched for citations related to sildenafil use in term or near-term infants with pulmonary hypertension or premature infants at risk for BPD or with BPD-associated pulmonary hypertension. Randomized and nonrandomized controlled trials were searched for that evaluated sildenafil use in term and premature infants compared with placebo or inhaled nitric oxide alone. Included studies were limited to English or Spanish language. Risk of bias was determined by using the Cochrane risk of bias tool.. Five trials (4 full-text articles and 1 abstract) of the 802 screened citations met the criteria for inclusion. All 5 trials were randomized controlled trials; the largest had 51 participants. Four of the trials (with a total of 137 subjects) evaluated the use of sildenafil versus placebo for term or near-term infants with persistent pulmonary hypertension of the newborn in low-resource settings in which inhaled nitric oxide was unavailable; there were no trials of sildenafil in areas in which inhaled nitric oxide is routinely available. The trials showed improvements in oxygenation index and a reduction in mortality in the sildenafil groups (5.9% vs 44%). One trial evaluated early sildenafil use (after day 7 of life) in premature infants for the prevention of BPD (n = 20). More premature infants in the sildenafil group died, were exposed to postnatal steroids, and had higher right-sided ventricular pressures later during hospitalization; these differences were not statistically significant. No trials evaluated sildenafil versus placebo in premature infants with BPD-associated pulmonary hypertension.. There is currently little evidence to support the use of sildenafil in term or near-term infants with persistent pulmonary hypertension of the newborn in areas in which inhaled nitric oxide is available. More data are needed to determine the effectiveness and dosing of sildenafil in improving outcomes for term and premature infants. Sildenafil dosing and safety studies are needed, especially among premature infants, before efficacy trials are performed.

Topics: Administration, Inhalation; Bronchopulmonary Dysplasia; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Nitric Oxide; Randomized Controlled Trials as Topic; Sildenafil Citrate; Vasodilator Agents

Phosphodiesterase (PDE) enzymes are widely distributed throughout the body, having numerous effects and functions. The PDE type 5 (PDE5) inhibitors are widely used to treat erectile dysfunction (ED). Recent, intense preclinical and clinical research with PDE5 inhibitors has shed light on new mechanisms and has revealed a number of pleiotropic effects on the cardiovascular (CV) system. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary arterial hypertension, and both sildenafil and tadalafil are approved for this indication. However, current or future PDE5 inhibitors have the potential of becoming clinically useful in a variety of CV conditions such as heart failure, coronary artery disease, and hypertension. The present review discusses recent findings regarding pharmacologic treatment of ED and its interaction with the CV system and highlights current and future clinical applications beyond ED.

Topics: Animals; Carbolines; Cardiovascular Diseases; Cardiovascular System; Erectile Dysfunction; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil

To evaluate the safety and efficacy of using sildenafil for ≥ 12 weeks to treat pulmonary arterial hypertension (PAH).. Randomized controlled trials (RCTs) of sildenafil therapy in patients with PAH published through May 2013 were identified by searching PubMed, the Cochrane Library, Embase, relevant websites, and reference lists of relevant studies. Two reviewers independently assessed the quality of the trials and extracted information.. Meta-analysis was carried out with subsets of 4 trials involving 545 patients. Sildenafil therapy significantly reduced clinical worsening of PAH compared to placebo (RR 0.39, 95% CI 0.21-0.69) and improved the 6-min walk distance (MD 31.3 m, 95% CI 18.01-44.67), WHO functional class, hemodynamic variables and health-related quality of life (HRQoL). Sildenafil did not, however, improve all-cause mortality (RR 0.29, 95% CI 0.02-4.94) or Borg dyspnea score relative to placebo, nor did it significantly affect the incidence of serious adverse events. In fact, sildenafil was associated with higher total incidence of adverse events, but these additional events were mild to moderate in severity and were tolerable.. Sildenafil therapy lasting ≥ 12 weeks improves multiple clinical and hemodynamic outcomes in patients with PAH, but it appears to have no effect on mortality or serious adverse events. The long-term efficacy and safety of sildenafil therapy in PAH requires further study based on large and well-designed RCTs.

Topics: Exercise Tolerance; Familial Primary Pulmonary Hypertension; Health Status; Humans; Hypertension, Pulmonary; Piperazines; Purines; Quality of Life; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Increased indiscriminate use of pulmonary artery hypertension-targeted drugs has been observed in patients with pulmonary hypertension (PH) secondary to heart failure. We performed a meta-analysis to evaluate the chronic effects of using phosphodiesterase 5 (PDE5) inhibitors to treat patients with PH secondary to chronic systolic heart failure.. PubMed, EMBASE, and the Cochrane Library were searched up to October 2013 for randomized controlled trials (RCTs) assessing PDE5 inhibitor treatments in PH patients secondary to chronic heart failure. Six RCTs involving 206 chronic systolic heart failure patients with PH complications were included. Sildenafil was used in all trials. Sildenafil treatment resulted in fewer hospital admissions compared with the placebo treatment (3.15% vs. 12.20%; risk ratio 0.29; 95% confidence interval 0.11-0.77). Various haemodynamic parameters were improved with additional sildenafil treatment, including reduced mean pulmonary artery pressure [weighted mean difference (WMD) -5.71 mmHg, P<0.05] and pulmonary vascular resistance (WMD -81.5 dynes/cm(-5), P<0.00001), increased LVEF (WMD 3.95%, P<0.01), and unchanged heart rate and blood pressure. The exercise capacity improved (oxygen consumption at peak exercise, WMD 3.20 mL/min(-1)/kg(-1), P<0.00001; ventilation to CO2 production slope, WMD -5.89, P<0.00001), and the clinical symptoms were relieved based on the breathlessness (WMD 7.72, P<0.00001), fatigue (WMD 2.28, P<0.05), and emotional functioning (WMD 5.92, P<0.00001) scores.. Additional sildenafil treatment is a potential therapeutic method to improve pulmonary exercise capacity and quality of life by ameliorating PH in patients with chronic systolic heart failure.

Topics: Blood Pressure; Exercise Tolerance; Heart Failure, Systolic; Heart Rate; Humans; Hypertension, Pulmonary; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfonamides

In view of the recent U.S. Food and Drug Administration's warning against the use of sildenafil in pediatric patients, we aimed to provide an updated overview of the dosing and safety of sildenafil in infants and to explore the relevance of the present safety concerns to the infant population.. The National Library of Medicine PubMed and Cochrane Database of Systematic Reviews were searched using the following terms: Sildenafil AND (infant OR infants OR newborn OR newborns OR child OR children OR childhood OR pediatric OR pediatrics OR paediatric OR paediatrics).. Studies presenting original clinical data regarding the dosing, use, or safety of sildenafil in infants with pulmonary hypertension would be included.. Of the 49 included studies, case reports and case series were the most common type of publications (n = 25). The identified trials included 625 children, with more than 140 infants. Persistent pulmonary hypertension of the newborn and pulmonary hypertension associated with other conditions were the most common underlying diagnoses.. There is currently no evidence of serious adverse event in infants exposed to sildenafil. Present safety concerns regarding the use of sildenafil in pediatric patients should be further explored before being applied to infant population. Sildenafil remains a valuable option for the treatment of pulmonary hypertension in young infants. Prospective studies should be designed in such a way that they include a safety assessment to evaluate potential adverse outcomes of sildenafil therapy in this population.

Topics: Blood Coagulation Disorders; Cardiovascular Diseases; Eye Diseases; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Nervous System; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

High altitude illness can be life-threatening if left untreated. Acute mountain sickness and high altitude pulmonary hypertension are two syndromes of high altitude illness. Recent clinical studies showed the beneficial effects of phosphodiesterase type 5 (PDE-5) inhibitors on the treatment of pulmonary hypertension. In this report, we performed a meta-analysis to evaluate the clinical efficacy of PDE-5 inhibitors on high altitude hypoxia and its complications.. Randomized controlled trials evaluating the efficacy of PDE-5 inhibitor in the setting of high altitude were identified by searching Cochrane Central Register of Controlled Trials (September 2013), PubMed (from 1990 to September 2013), and EMBASE (from 1990 to September 2013). Extracted outcomes from selected studies for meta-analysis included arterial oxygen saturation, pulmonary artery systolic pressure, heart rate, and Lake Louise Consensus AMS symptom score. Weighted mean differences with 95% confidence intervals were presented for the continuous outcomes.. Five clinical trials that met the selection criteria were identified for the meta-analysis. All of these studies used sildenafil as the PDE-5 inhibitor. A total of 60 subjects received sildenafil, and 72 subjects were given placebo. In accordance with previous report, short-term treatment with sildenafil (1-2 days) significantly reduced pulmonary artery systolic pressure at rest (MD -4.53; 95% CI -6.72, -2.34; p<0.0001). However, treatment with sildenafil (1-2 days) did not improve oxygen saturation after exposure to high altitude (MD 0.07; 95% CI -1.26, 1.41; p=0.91). Moreover, no significant difference was observed in heart rate between sildenafil and placebo-treated group (MD 6.95; 95% CI -3.53, 17.43; p=0.19). AMS score did not improve after treatment at different time points.. Short-term treatment with sildenafil can attenuate the altitude-induced high pulmonary systolic arterial pressure, but has no significant beneficial effects on arterial oxygen saturation, heart rate, and acute mountain sickness.

Topics: Altitude; Altitude Sickness; Heart Rate; Humans; Hypertension, Pulmonary; Hypoxia; Oxygen; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones

Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Carbolines; Endothelin Receptor Antagonists; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Purines; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Tadalafil; Vascular Resistance; Vasodilator Agents

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Bosentan; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Mice; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Rats; rho-Associated Kinases; Signal Transduction; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but debilitating and life-threatening complication of acute pulmonary embolism. CTEPH results from persistent obstruction of pulmonary arteries and progressive vascular remodelling. Not all patients presenting with CTEPH have a history of clinically overt pulmonary embolism. The diagnostic work-up to detect or rule out CTEPH should include ventilation-perfusion scintigraphy, which has high sensitivity and a negative predictive value of nearly 100%. CT angiography usually reveals typical features of CTEPH, including mosaic perfusion, part or complete occlusion of pulmonary arteries, and intraluminal bands and webs. Patients with suspected CTEPH should be referred to a specialist centre for right-heart catheterisation and pulmonary angiography. Surgical pulmonary endarterectomy remains the treatment of choice for CTEPH and is associated with excellent long-term results and a high probability of cure. For patients with inoperable CTEPH, various medical and interventional therapies are being developed.

Topics: Angioplasty, Balloon; Bosentan; Chronic Disease; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Embolism; Purines; Pyrazoles; Pyrimidines; Sildenafil Citrate; Sulfonamides; Thromboembolism

Pulmonary hypertension, including pulmonary arterial hypertension (PAH), is a serious disease in children, but few clinical studies have been conducted to evaluate treatment regimens in this population. Currently, treatment of children with PAH is mostly based on clinical studies conducted in adults and a few dedicated pediatric studies. Sildenafil, a phosphodiesterase type 5 inhibitor, has an established efficacy and safety profile for the treatment of adults with PAH. In May 2011, sildenafil received approval for the treatment of pediatric patients aged 1-17 years in the EU; however, pediatric use is not approved in the USA. This systematic literature review summarizes the clinical data available on the use of sildenafil to treat children with PAH and pulmonary hypertension.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Drug Approval; Humans; Hypertension, Pulmonary; Infant; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

The treatment of pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants has evolved in recent years, improving both quality of life and survival for patients. One of the potential agents for this condition is sildenafil, a phosphodiesterase-V inhibitor with proven efficacy within the idiopathic PH population. However, only limited evidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. This review summarises the evidence base for sildenafil alone and in combination with other recognised therapeutic agents for ameliorating paediatric PH in the presence of BPD. It also examines the suitability for current practice with the aim of clarifying regimens that produce improved patient outcomes. We conclude that sildenafil is both safe and effective in this utility. Doses should be started at 0.5 mg/kg every 8 h before titrating up towards 2 mg/kg every 6 h to effect reductions in pulmonary vascular resistance and arterial pressure. Evidence suggests that if continued until PH resolution, this improves survival from 61% to 81% at 12 months. Furthermore, there are also data suggesting that in treatment refractory PH cases, the addition of endothelin antagonists and prostacyclin analogues to sildenafil therapy can also be considered.

Topics: Bronchopulmonary Dysplasia; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Sildenafil citrate is a potent, selective phosphodiesterase type 5 inhibitor approved for the treatment of pulmonary arterial hypertension (PAH) and plays an important role in the management of the disease.. In this review, we focus on the current available information on the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of sildenafil citrate in PAH through a MEDLINE literature search. Comparison of sildenafil citrate with tadalafil, another phosphodiesterase type 5 inhibitor was also performed.. In the last few years, considerable progress has been made in the understanding and treatment of PAH. Sildenafil citrate has multiple advantages and whether it is first-line treatment alone or in combination for the mild form of the disease, it is one of the treatments of choice. In terms of its future use, more studies are still needed to better evaluate the benefit/risk balance of sildenafil citrate in pediatric populations.

Topics: Adult; Animals; Carbolines; Child; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Tadalafil

Some patients with chronic obstructive pulmonary disease (COPD) have pulmonary hypertension (PH) that adversely affects survival. We performed a systematic review and meta-analysis to assess whether PH-specific therapies have an effect for stable COPD. Data sources were Medline, EMBASE, Cochrane Central Register of Controlled Trials, Korea med and references from relevant publications. Randomized prospective trials that compared PH specific therapy in COPD for more than 6 weeks with placebo were included. The outcomes were the exercise capacity and adverse events. Four randomized controlled trials involving 109 subjects were included in the analysis. Two trials involved bosentan, one sildenafil and one beraprost. The studies varied in duration of treatment from 3 to 18 months. In a pooled analysis of four trials, exercise-capacity was not significantly improved with PH-specific treatment for COPD (risk ratio, -5.1; 95% CI, -13.0 to 2.8). COPD with overt PH significantly improved the exercise capacity (mean difference, 111.6; 95% CI, 63.3 to 159.9) but COPD with PH unknown did not (mean difference, 26.6; 95% CI, -24.3 to 77.5). There was no significant difference in hypoxemia (mean difference, 2.6; 95% CI, -3.7 to 8.8). PH specific treatments have a significant effect in improving exercise capacity in COPD with overt PH.

Topics: Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Databases, Factual; Epoprostenol; Humans; Hypertension, Pulmonary; Hypoxia; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Risk Factors; Sildenafil Citrate; Sulfonamides; Sulfones; Surveys and Questionnaires

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition that historically has a poor outcome with supportive medical treatment. Pulmonary endarterectomy (PEA) is the treatment of choice and offers the only chance of cure. A significant proportion of patients is either not suitable due to the distal distribution of the disease or has persistent pulmonary hypertension (PH) after PEA. Despite the lack of licensed therapies for CTEPH, the similarities in pathobiology of pulmonary arterial hypertension (PAH) and CTEPH has led to the compassionate use of PAH therapies in CTEPH patients. This article reviews the pathobiology of CTEPH and summaries the available evidence for the use of PAH-targeted drugs in CTEPH.

Topics: Antihypertensive Agents; Bosentan; Chronic Disease; Compassionate Use Trials; Endarterectomy; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Embolism; Purines; Pyrazoles; Pyrimidines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

The development of orally active pulmonary vasodilators has been a major breakthrough in the treatment of pulmonary arterial hypertension (PAH). Orally active medications greatly enhanced patient access to PAH treatment and increased an interest in the diagnosis and treatment of this disease that still continues. Four different orally active drugs are currently available for the treatment of PAH and several more are undergoing evaluation. This article discusses the mechanisms by which endothelin receptor antagonists and phosphodiesterase-5 inhibitors mitigate pulmonary hypertensive responses, and reviews the most recent data concerning their efficacy and limitations in the treatment of PAH.

Topics: Administration, Oral; Carbolines; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil

Pulmonary arterial hypertension is a rare and devastating disease characterized by vascular proliferation and remodeling. Epoprostenol, the drug counterpart of the eicosanoid prostacyclin, produced by the vascular endothelial cells, is the drug of choice for this disease. Its capacity to act rapidly and to significantly improve survival prospects in severe pulmonary hypertension patients has been supported by a wealth of evidence. Intravenous epoprostenol was believed to require therapy of indefinite duration. Since 2001, oral drugs have been approved for specific treatment. The availability of newer and less invasive drug therapies for pulmonary arterial hypertension led physicians to withdraw epoprostenol in carefully selected patients. We report a case of successful intravenous epoprostenol interruption in a patient with idiopathic disease. A literature review on epoprostenol withdrawal in pulmonary hypertension in adult patients is also provided.

Topics: Acenocoumarol; Anticoagulants; Antihypertensive Agents; Bosentan; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents; Withholding Treatment

Phosphodiesterase-5 inhibitors (PDE5Is) improve erectile function by enhancing nitric oxide availability in the penis and its supplying vasculature, resulting in vasodilation and increased blood flow. PDE5Is might benefit cardiovascular diseases because phosphodiesterase-5 is also located elsewhere in the body, including the pulmonary and systemic vasculature and in hypertrophied myocardium. PDE5Is are approved for pulmonary arterial hypertension, given that they improved several hemodynamic and clinical parameters in large randomized trials. Initial evidence suggests that PDE5Is benefit patients with congestive heart failure and secondary pulmonary hypertension. PDE5Is seem to improve hemodynamic and clinical parameters in patients with high-altitude pulmonary edema (HAPE) and high-altitude pulmonary hypertension. In climbers with prior episodes of HAPE, PDE5Is prevented HAPE in 2 small randomized trials. In small randomized trials of PDE5Is, patients with Raynaud's phenomenon demonstrated improved blood flow, fewer symptoms and frequency of attacks, and resolution of digital ulcers. In addition to enhancing vasodilation, PDE5Is seem to protect the myocardium through complex pathways that involve nitric oxide, cyclic guanosine monophosphate, protein kinase G, extracellular-signal-regulated kinase, B-cell lymphoma protein-2, and Rho kinase inhibition. In animal models of acute myocardial infarction, PDE5Is consistently reduced infarct size indicating cardioprotection and PDE5Is also promote reverse remodeling and reduce myocardial apoptosis, fibrosis, and hypertrophy. PDE5Is might also benefit patients with treatment-resistant hypertension, preeclampsia, or peripheral arterial disease. This review presents the pathophysiology and trial data with regard to the use of PDE5Is for cardiac diseases.

Topics: Animals; Coronary Circulation; Cross-Over Studies; Disease Models, Animal; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Prognosis; Purines; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Sulfones; Survival Analysis; Treatment Outcome

The perinatal transition from fetal to extrauterine life requires a dramatic change in the circulatory pattern as the organ of gas exchange switches from the placenta to the lungs. Pulmonary hypertension can occur during early newborn life, and present as early respiratory failure or as a complication of more chronic diseases, such as bronchopulmonary dysplasia. The most effective pharmacotherapeutic strategies for infants with persistent pulmonary hypertension of the newborn are directed at selective reduction of pulmonary vascular resistance. This article discusses currently available therapies for pulmonary hypertension, their biologic rationales, and evidence for their clinical effectiveness.

Topics: Administration, Inhalation; Endothelium-Dependent Relaxing Factors; Humans; Hypertension, Pulmonary; Infant, Newborn; Intensive Care Units, Neonatal; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

In the article, an analysis of the modern approaches to pharmacological correction of hypoxic pulmonary hypertension in conjunction with its development mechanisms has been performed. Promising research trends for the creation of new drugs in this field have also been reviewed.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels; Humans; Hypertension, Pulmonary; Hypoxia; Liposomes; Phosphatidylcholines; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventricular Dysfunction, Right; Verapamil

Despite recent advances, Persistent Pulmonary Hypertension of the Newborn (PPHN) still represents an important challenge for neonatologists. The care of newborns with PPHN requires meticulous therapeutic and ventilation strategies including, besides the stabilization of the newborn, the use of selective pulmonary vasodilators as inhaled Nitric Oxide (iNO). However, not all the neonates with PPHN are responsive to this clinical approach. Recent studies have proposed the use of alternative therapies to iNO, when it is not available, or there is no or only a transitory response. Sildenafil, a phosphodiesterase 5 inhibitor, appears as a frequent used therapy in refractory forms of PPHN. The aim of this review is to analyze the current therapeutic strategies in PPHN with special emphasis on iNO.

Topics: Extracorporeal Membrane Oxygenation; Humans; Hypertension, Pulmonary; Infant, Newborn; Nitric Oxide; Piperazines; Purines; Respiration, Artificial; Risk Factors; Severity of Illness Index; Sildenafil Citrate; Sulfones

The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of the β globin gene resulting in the substitution of glutamic acid by valine at position 6 of the β globin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes.

Topics: Anemia, Sickle Cell; Blood Transfusion; Clinical Trials as Topic; Disease Management; Gastrointestinal Diseases; Humans; Hydroxyurea; Hypertension, Pulmonary; Muscular Diseases; Nervous System Diseases; Pain; Phenotype; Piperazines; Purines; Retinal Diseases; Sildenafil Citrate; Sulfones; Treatment Outcome

The long-term prognosis for patients with pulmonary arterial hypertension (PAH) remains poor, despite advances in treatment options that have been made in the past few decades. Recent evidence suggests that World Health Organization functional class I or II patients have significantly better long-term survival rates than patients in higher functional classes, thus providing a rationale for earlier diagnosis and treatment of PAH. However, early diagnosis is challenging and there is frequently a delay between symptom onset and diagnosis. Screening programmes play an important role in PAH detection and expert opinion favours echocardiographic screening of asymptomatic patients who may be predisposed to the development of PAH (i.e. those with systemic sclerosis or sickle cell disease), although current guidelines only recommend annual echocardiographic screening in symptomatic patients. This article reviews the currently available screening programmes, including their limitations, and describes alternative screening approaches that may identify more effectively those patients who require right heart catheterisation for a definitive PAH diagnosis.

Topics: Anemia, Sickle Cell; Antihypertensive Agents; Bosentan; Early Diagnosis; Echocardiography, Doppler; Exercise Test; Humans; Hypertension, Pulmonary; Mass Screening; Natriuretic Peptide, Brain; Peptide Fragments; Piperazines; Practice Guidelines as Topic; Purines; Respiratory Function Tests; Risk Factors; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD), with most cases occurring in patients with congenital cardiac shunts. In patients with an uncorrected left-to-right shunt, increased pulmonary pressure leads to vascular remodelling and dysfunction, resulting in a progressive rise in pulmonary vascular resistance and increased pressures in the right heart. Eventually, reversal of the shunt may arise, with the development of Eisenmenger's syndrome, the most advanced form of PAH-CHD. The prevalence of PAH-CHD has fallen in developed countries over recent years and the number of patients surviving into adulthood has increased markedly. Today, the majority of PAH-CHD patients seen in clinical practice are adults, and many of these individuals have complex disease or received a late diagnosis of their defect. While there have been advances in the management and therapy in recent years, PAH-CHD is a heterogeneous condition and some subgroups, such as those with Down's syndrome, present particular challenges. This article gives an overview of the demographics, pathophysiology and treatment of PAH-CHD and focuses on individuals with Down's syndrome as an important and challenging patient group.

Topics: Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Comorbidity; Down Syndrome; Eisenmenger Complex; Endothelium, Vascular; Epoprostenol; Health Behavior; Heart Defects, Congenital; Heart Transplantation; Humans; Hypertension, Pulmonary; Lung Transplantation; Oxygen Inhalation Therapy; Phosphodiesterase 5 Inhibitors; Piperazines; Practice Guidelines as Topic; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thrombosis

Pulmonary arterial hypertension (PAH) is an enigmatic, often fatal disease of the lung. Excess vasoconstriction and progressive obliteration of the precapillary arterioles combine to reduce the cross-sectional area for blood flow and thus cause chronic elevation in the pulmonary arterial pressures with progressive right heart dysfunction, heart failure and death. In 1995, the FDA approved the first therapy for PAH: epoprostenol, a highly efficacious drug but one that was difficult to use for patients and clinicians alike. Since then, there have been eight additional drugs approved, each offering advantages in terms of convenience over previously available drugs. In 2009, tadalafil (Adcirca®) was approved for PAH. The 405 patients enrolled in the single pivotal trial give this drug the largest initial placebo-controlled dataset of any of the oral PAH therapies; its once-daily dosing and excellent safety profile make it the most convenient of the therapies by a significant margin. After introducing the PAH disease state with references for more interested readers, this paper discusses the nitric oxide pathway as it relates to the pulmonary circulation, provides an overview of clinically available phosphodiesterase inhibitors and discusses tadalafil in relationship to sildenafil (Revatio®), the first phosphodiesterase inhibitor approved for PAH.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Carbolines; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Kidney; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Tadalafil; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a complex disorder in which pulmonary arterial obstruction leads to elevated pulmonary arterial resistance and right ventricular failure. Normal physiologic changes that occur during pregnancy and immediately postpartum may produce fatal consequence in PAH patients. Pregnancy in patients with PAH has a high maternal mortality, estimated at 30-56%. Contemporary estimates of mortality are better but still prohibitively high. Current guidelines recommend that pregnancy be avoided or terminated early in women with PAH. Some patients, despite counselling by their physician, choose to continue with their pregnancy. In addition, some women first present with PAH during pregnancy leading to complex management issues in a high-risk patient. PAH-specific therapies may allow patients to better tolerate pregnancy. These patients should be treated by experienced physicians at tertiary care centres. This review article will focus on the management of the pregnant PAH patient and the preventative options available for this high-risk cohort.

Topics: Abortion, Therapeutic; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Gestational Age; Humans; Hypertension, Pulmonary; Piperazines; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pregnancy, High-Risk; Purines; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Sulfones; Survival Rate

Persistent pulmonary hypertension in neonates (PPHN) is associated with high mortality. Currently, the therapeutic mainstay for PPHN is assisted ventilation and administration of inhaled nitric oxide (iNO). However, nitric oxide is costly and may not be appropriate in resource-poor settings. Approximately 30% of patients fail to respond to iNO. High concentrations of phosphodiesterases in the pulmonary vasculature has led to the use of phosphodiesterase inhibitors such as sildenafil or milrinone.. To assess the efficacy and safety of sildenafil in the treatment of persistent pulmonary hypertension in neonates.. The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL databases were searched from their inception until December 2010; Clinicaltrials.gov web site, the reference lists of identified trials, and abstracts of meetings were searched without any language restriction.. Randomised or quasi-randomised controlled trials of sildenafil compared with placebo or other pulmonary vasodilators, irrespective of dose, route and duration of administration in neonates with PPHN, were included if the trial reported any of the pre-specified outcomes.. The methodological quality of the trials was assessed regarding how bias was minimized at study entry, during study intervention and at outcomes measurement. Data on relevant outcomes were extracted and the effect size was estimated and reported as relative risk (RR), risk difference (RD) and weighted mean difference (MD) as appropriate. The I-squared (I(2)) test of heterogeneity was applied.. Three eligible trials that enrolled 77 infants were identified. The methodological quality of the studies indicated low-moderate risk of bias. All studies were performed in resource-limited settings where iNO and high frequency ventilation were not available at the time of study. There was significant reduction in mortality in the sildenafil group (typical RR 0.20, 95% CI 0.07 to 0.57; typical RD -0.38, 95% CI -0.60 to -0.16; Number needed to treat to benefit 3, 95% CI 2 to 6). Physiological parameters of oxygenation (oxygenation index, PaO(2)) suggested a steady improvement after the first dose of sildenafil. No clinically important side effects were identified.. Sildenafil in the treatment of PPHN has significant potential especially in resource limited settings. However, a large scale randomised trial comparing sildenafil with the currently used vasodilator, inhaled nitric oxide, is needed to assess efficacy and safety.

Topics: Humans; Hypertension, Pulmonary; Infant, Newborn; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension is a rare disease in neonates, infants, and children, and is associated with substantial morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking. Moreover, a minority of research is focused specifically on neonatal and pediatric populations. Although therapeutic options have increased over the past several decades, they remain limited. In advanced pulmonary hypertension, progressive pulmonary vascular functional and structural changes ultimately cause increased pulmonary vascular impedance, right-ventricular failure, and death. Management includes the prevention and/or treatment of active pulmonary vasoconstriction, the support of right-ventricle function, treatment of the underlying disease (if possible), and the promotion of regressive remodeling of structural pulmonary vascular changes. Most currently available therapies augment or inhibit factors, or mediators of their downstream signaling cascades, that originate in the pulmonary vascular endothelium. These pathways include nitric-oxide/cyclic guanosine monophosphate (cGMP), prostacyclin, and endothelin-1. The ability to reverse advanced structural changes remains an as yet unattained goal. This paper reviews the epidemiology, pathophysiology, current treatments, and emerging therapies related to neonatal and pediatric pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Bosentan; Child; Citrulline; Drug Therapy, Combination; Endothelium, Vascular; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Muscle Contraction; Persistent Fetal Circulation Syndrome; Phosphodiesterase 5 Inhibitors; Piperazines; PPAR gamma; Prostaglandins; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance; Vasoconstriction; Ventricular Function, Right

Topics: Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Interferon (IFN) therapy is nowadays widely used in clinical practice. In the literature, there are very few reports of the association between IFN therapy and pulmonary arterial hypertension (PAH), and current guidelines do not mention IFNs as a risk factor for PAH. We describe a patient with multiple sclerosis who developed severe PAH after treatment with IFN-β-1a and the clinical response to sildenafil. Furthermore, we stress the need to further investigate the link between IFNs and PAH.

Topics: Adjuvants, Immunologic; Antihypertensive Agents; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Interferon beta-1a; Interferon-beta; Middle Aged; Multiple Sclerosis; Piperazines; Purines; Sildenafil Citrate; Sulfones

Portopulmonary hypertension (PoPH) is an underrecognized complication of portal hypertension, related to cirrhosis and noncirrhotic portal hypertension. PoPH has been found in 5-6% of patients with decompensated liver disease and may adversely affect outcome after liver transplantation. The prevalence of PoPH is unrelated to the severity of liver disease but associated with female sex and underlying autoimmune liver disease. Diagnosis of PoPH is based on screening with Doppler echocardiography and confirmation by right-heart catheterization. Treatment options with proven efficacy in idiopathic pulmonary hypertension include endothelin receptor antagonists, prostanoids, and sildenafil. In PoPH, such targeted treatment was found to be safe in small uncontrolled studies but randomized trials demonstrating its benefit are lacking.

Topics: Algorithms; Endothelin Receptor Antagonists; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Transplantation; Piperazines; Prostaglandins; Purines; Sex Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

Tadalafil, a long-acting phosphodiesterase-5 inhibitor (PDE-5) is the most recent oral agent to receive FDA approval for the treatment of pulmonary arterial hypertension (PAH).. With several new agents emerging for the treatment of PAH, this article reviews tadalafil, the compound and its properties, clinical evidence supporting its use, and the role of tadalafil in the current treatment approach for patients with PAH.. A broad PubMed literature search was performed to identify the most current data on the use of tadalafil for PAH.. Tadalafil received FDA approval in 2009 following the recently published pivotal trial that demonstrated that the use of tadalafil 40 mg once daily was well tolerated, improved exercise capacity and quality of life measures and reduced time to clinical worsening in PAH patients. As the second PDE-5 inhibitor to gain approval for PAH, clinical properties such as its long half-life leading to once-daily dosing and possibly improved compliance, as well as potential cost benefit, may distinguish tadalafil from sildenafil in the widespread treatment of PAH.

Topics: Carbolines; Erectile Dysfunction; Half-Life; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Vasodilator Agents

Literature about thoracic surgery in patients with pulmonary hypertension is scarce. Perceived high risk has appropriately discouraged any unnecessary operation. However, the medical therapy for pulmonary hypertension has made great advances during the last decade. It is likely that future advances in survival and possibly the need for diagnostic procedures will increase the anesthesiologist's exposure to such patients. Understanding the unique physiology as well as new therapeutic agents will facilitate safe care for these challenging patients.. Since 1998, there have been three World Heath Organization symposiums on pulmonary hypertension. The most recent meeting in 2008 at Dana Point included revisions of the classification scheme and updates on new trials and therapies. New drugs have been utilized in cardiac, lung, or liver transplant operations to treat pulmonary hypertension. It is also recognized that one-lung ventilation presents unique problems for the patient with pulmonary hypertension. Inhalation use of the new pulmonary vasodilator drugs represents a new frontier for intraoperative pharmacology.. Here, the various types of pulmonary hypertension, physiologic changes, and new drug therapies are reviewed. Clinical experience with patients with pulmonary hypertension undergoing both nonthoracic and thoracic procedures is also reviewed. By identifying potential problem areas and application of new pharmacology, an approach to the patient with pulmonary hypertension is synthesized.

Topics: Anesthesia, Inhalation; Antihypertensive Agents; Bosentan; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thoracic Surgical Procedures; Vasodilator Agents

Pulmonary arterial hypertension (PAH) has witnessed dramatic treatment advances over the past decade. However, with the exception of epoprostenol, data from short-term randomized controlled trials (RCTs) have not shown a benefit of these drugs on survival. There remains a need to differentiate between available therapies and current endpoint responses which in turn, could be used to guide treatment selection and provide long-term prognostic information for patients.. We performed a systematic literature search of MEDLINE and EMBASE databases for RCTs of PAH-specific therapy published between January 1980 and May 2009. Articles were selected if they contained a placebo comparator and described hemodynamic changes from baseline. We applied the weighted mean change in hemodynamic variables to the equation developed by the National Institutes of Health (NIH) Registry to estimate long-term survival with each therapy.. Ten RCTs involving 1,635 patients met the inclusion criteria. Suitable hemodynamic data were identified for bosentan, sitaxentan, sildenafil, epoprostenol, beraprost and treprostinil. 77.6% of patients were female and the mean (SD) age was 46.5 +/- 4.9 years. 55.5% of patients had idiopathic PAH (iPAH), 23.9% PAH related to connective tissue disease, and 18.2% PAH related to congenital heart disease. Based on the effects observed in short-term trials and, relative to placebo, all analyzed therapies improved survival. The estimated 1-year survival was 78.4%, 77.8%, 76.1%, 75.8%, 75.2%, and 74.1% for epoprostenol, bosentan, treprostinil, sitaxentan, sildenafil, and beraprost, respectively. These estimates are considerably lower than the 1-year observed survival reported in several open-label and registry studies with PAH-specific therapies: 88% - 97%.. When applied to the NIH Registry equation, hemodynamic changes from baseline appear to underestimate the survival benefits observed with long-term PAH therapy.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Cohort Studies; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Isoxazoles; Male; Middle Aged; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Time Factors; Treatment Outcome

A joint Task Force of the ESC and of the ERS has developed guidelines on the diagnosis and treatment of pulmonary hypertension (PH) to provide updated information on the management of patients with this condition.. The term pulmonary hypertension (PH) describes a group of devastating and life-limiting diseases, defined by mean pulmonary artery pressure >25 mmHg at rest. The diagnosis of PH requires a series of investigations intended to confirm the diagnosis, clarify the clinical group and the specific aetiology and an algorithm for this is proposed. Several drugs are currently approved to try to correct endothelial dysfunction. They lead to a significant improvement in the prognosis of patients who are in NYHA functional class II, III or IV. The evaluation of the severity of PH has a pivotal role in the choice of initial treatment and evaluation of the response to therapy in individual patients.. These guidelines should be widely disseminated and implemented in order to improve the management of patients with PH.. These guidelines summarise recent advances in the understanding and management of PH.

Topics: Algorithms; Antihypertensive Agents; Bosentan; Carbolines; Drug Therapy, Combination; Endothelin Receptor Antagonists; Europe; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Piperazines; Practice Guidelines as Topic; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Tadalafil; Vasodilator Agents

Pharmacologic strategies to reduce pulmonary vascular tone and to treat pulmonary hypertension originally aimed to enrich vascular smooth muscle cyclic adenosine monophosphate levels. Alternatively, increasing cyclic guanosine monophosphate (cGMP) also reduces pulmonary vascular tone. Inhaled nitric oxide is extremely efficacious in increasing cGMP and selectively reducing mean pulmonary arterial pressure in pediatric cardiac patients. It is considered standard treatment in most centers. However, not all patients respond to inhaled nitric oxide and withdrawal is sometimes problematic. This has prompted investigation of alternative methods to increase intracellular vascular smooth muscle cGMP. Phosphodiesterase type 5 is particularly abundant in the lung vasculature of patients with severe pulmonary hypertension. Its inhibition with the sildenafil class of drugs is now commonplace. Drugs that affect cGMP metabolism in children with acute pulmonary hypertension are the subject of this review and consensus statement. Oral sildenafil is recommended in postoperative pulmonary hypertension after failed withdrawal of inhaled NO (class I, level of evidence B). The effectiveness of prolonged treatment with sildenafil in documented postoperative pulmonary hypertension is not well established (class IIb, level of evidence C). Sildenafil is indicated in idiopathic pulmonary hypertension, although data have been extrapolated mainly from adult trial (class I, level of evidence A, extrapolated). Recently, completed pediatric trials have seemed to support this recommendation. Longer-acting and intravenous forms of phosphodiesterase type 5 inhibitors, brain natriuretic peptides, and direct soluble guanylate cyclise activators all have appeal, but there is insufficient experience in children with acute pulmonary hypertensive disorders for recommendations on treatment.

Topics: Acute Disease; Administration, Inhalation; Administration, Oral; Child; Child, Preschool; Clinical Trials as Topic; Cyclic GMP; Endothelium-Dependent Relaxing Factors; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Early right ventricular dysfunction after heart transplantation (HTx) is a major complication especially in patients with pre-transplant pulmonary arterial hypertension (PH). The possibility to reverse secondary PH using sodium nitroprusside (NPS) or inhaled nitric oxide has been already established and there is a well-known stratification of the incidence of early death after HTx related to the reversibility of PH. Despite this, in a group of patients with irreversible disorders of the pulmonary vascular bed, conventional therapy may not be useful. However, the decision to disqualify non-responsive HTx candidates may be inappropriate, considering that PH unresponsiveness to NPS does not exclude the possibility to decrease pulmonary pressures with other medications. In case of non-responsive patients, the debate regarding the role of new selective pulmonary vasodilators is still open and oral sildenafil use in cardiac transplant candidates and recipients is growing. Despite this, there are many reports of the use of phosphodiesterase 5 inhibitors in patients with chronic heart failure and several studies describe the positive effects of sildenafil in reducing pulmonary vascular resistance and pulmonary arterial pressure and in increasing cardiac output. Oral sildenafil use in cardiac transplant candidates or recipients is still limited.

Topics: Administration, Oral; Heart Transplantation; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Severe pulmonary hypertension is a debilitating disease with short life expectancy that often affects young people. It is usually idiopathic pulmonary artery hypertension and is characterized by progressive elevation of pulmonary artery pressure and vascular resistance, right ventricular failure and death with a limited median survival time. There is an imbalance in vasoconstrictive and vasodilatory substances. The phosphodiesterase-5 inhibitor sildenafil, a pulmonary and penile vasodilator initially approved for erectile dysfunction, is found to be efficacious in severe pulmonary artery hypertension. There are limited treatment options for the management of pulmonary artery hypertension in developing countries and sildenafil is a reasonable treatment option. This article reviews the relevant clinical data in pulmonary hypertension and the role of sildenafil in its management.

Topics: Administration, Oral; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The Fontan procedure is the final common pathway in the surgical palliation of many single ventricle heart defects. Mortality has improved but morbidity remains significant. Pleural effusions continue to present challenges after this operation and account for increased length of stay and increased time with draining tube thoracostomies. This review examines recent publications addressing this problem.. Four papers in 2008-2009 addressed effusions after the Fontan procedure. Off-pump Fontan procedures did not decrease time until chest tube removal. Pulmonary vascular compliance, derived from an electrical circuit model, predicted chest tube indwelling time. A retrospective study identified mean pulmonary artery pressure as a risk factor for effusions lasting more than 14 days after the Fontan procedure. One prospective, randomized trial evaluated the effects of lisinopril on pleural effusions after the Fontan procedure. There was no difference in the length of pleural drainage between the two groups.. Pleural effusions after the Fontan procedure continue to be a challenge. The cause is likely multifactorial and could explain why the literature has no clear message. One randomized, prospective trial suggests that fenestration reduces effusions. Many other reviews report no benefit to fenestration. Sildenafil after the Fontan procedure should be studied in a randomized, prospective fashion.

Topics: Antihypertensive Agents; Chest Tubes; Drainage; Fontan Procedure; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Lisinopril; Piperazines; Pleural Effusion; Postoperative Complications; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The aim of the present meta-analysis was to evaluate the efficacy and safety of treating pulmonary arterial hypertension (PAH) with inhaled iloprost, oral bosentan and sildenafil.. The randomized controlled trials on the 3 drugs and placebo were retrieved from the databases MEDLINE, EMBASE, BIOSIS Previews and CNKI up to August 2009. In total 11 studies and 1,391 patients were selected. Compared with placebo, iloprost, bosentan and sildenafil reduced clinical worsening significantly (odds ratio [OR] =0.33, 95% confidence interval [CI] =0.22-0.49, P<0.00001), improved New York Heart Association/World Health Organization functional class (OR =2.81, 95%CI =1.95-4.03, P<0.00001), increased the 6-min walk test by 33.19 m, reduced systolic pulmonary arterial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance, increased the cardiac index by 0.40 L x min(-1) x m(-2) and increased the cardiac output by 0.53 L/min. The incidence of serious adverse events was similar in the medication groups and the placebo group (OR =1.09, 95%CI =0.69-1.71, P=0.72). In terms of the clinical worsening and functional class amelioration, insignificant differences were found among iloprost, bosentan and sildenafil, but iloprost had the highest incidence of serious adverse events among the 3 drugs.. Inhaled iloprost and oral bosentan and sildenafil are effective and safe in treating PAH.

Topics: Antihypertensive Agents; Bosentan; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Sildenafil is an orally administered phosphodiesterase type 5 inhibitor that is approved for the treatment of pulmonary arterial hypertension (PAH). The hemodynamic effects of sildenafil are mitigated primarily via potentiating the effects of endogenous nitric oxide, leading to smooth muscle cell relaxation and reductions in pulmonary arterial pressures and pulmonary vascular resistance. When added to standard background therapy in patients with idiopathic or associated PAH from congenital heart disease, anorexigen use, or connective tissue disease, sildenafil treatment results in improved exercise capacity as measured by 6 minute walk distance, improved hemodynamics, and favorable changes in quality of life. Sildenafil use is contraindicated with concomitant nitrate administration, and caution should be exercised when used in combination with antihypertensive agents due to risks of precipitating hypotension. Side effects are generally mild, and include flushing, headaches, and epistaxis. The combination of sildenafil with intravenous epoprostenol is safe and well tolerated, and further improves exercise capacity. Sildenafil is approved only for treatment of PAH, and although emerging data suggest a potential role in treating other types of pulmonary hypertension, larger trials are required to confirm these findings.

Topics: Clinical Trials as Topic; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Child; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Antihypertensive Agents; Contraindications; Coronary Disease; Drug Interactions; Drug Therapy, Combination; Erectile Dysfunction; Female; Humans; Hypertension, Pulmonary; Hypotension; Imidazoles; Male; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

The pathology of pulmonary arterial hypertension (PAH) is characterized by vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. Experimental studies have shown the beneficial effect of phosphodiesterase type 5 (PDE-5) inhibitors on pulmonary vascular remodeling and vasodilatation. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil which significantly improve clinical status, exercise capacity and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in management of PAH. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia.

Topics: Carbolines; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

Eisenmenger syndrome (ES), the most advanced form of pulmonary arterial hypertension (PAH) associated with congenital heart disease, is a devastating condition that has a considerable impact on patients' lives. Patients who develop ES typically exhibit 1 or more of a range of cardiac defects, including ventricular septal defects, atrial septal defects, and patent ductus arteriosus. The nature of the congenital defect underlying ES is important because it has prognostic implications. Although ES shares similar morphological findings with idiopathic PAH, clinical differences exist between the 2 etiologies. Adults with ES exhibit increased survival and more favorable hemodynamics than those with idiopathic PAH. Treatment options for patients with ES have historically been limited; however, recent successes have been achieved with the use of therapies targeted against the pathophysiological pathways that underlie PAH. The dual endothelin receptor antagonist bosentan was demonstrated to improve hemodynamics and exercise capacity without compromising oxygen saturation, both in the short and long term. Improvements in hemodynamics also have been observed with the single endothelin receptor antagonist sitaxsentan. The phosphodiesterase type V inhibitor sildenafil may improve functional class, oxygen saturation, and hemodynamics in patients with ES, and beneficial effects of prostacyclin and prostacyclin analogs in patients with ES have been reported. The treatment of patients with PAH with the use of combinations of targeted therapies is becoming increasingly commonplace and may offer an alternative option for treatment of patients with ES. The authors of future studies may seek to investigate whether the pulmonary vascular remodeling in ES can be targeted and reversed.

Topics: Antihypertensive Agents; Bosentan; Eisenmenger Complex; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes

Major advances have been made in the understanding and treatment of pulmonary hypertension in the last few years. Without treatment (medication) for idiopathic pulmonary arterial hypertension, which is a rare and potentially fatal condition, the survival time is only about 3 years after diagnosis. However, if pulmonary hypertension is secondary to other causes such as congenital heart disease, it is possible to survive for 30 years or more without treatment. The condition can affect children at any age, from fetal life to adulthood. Patients with pulmonary hypertension can present to the respiratory pediatrician with unresponsive asthma, to the neurologist with faints, or to the general pediatrician with failure to thrive. Over the last few years there have been significant developments in the available therapy for managing this complicated disease. There is now a generally recognized ladder of long-term therapy for chronic pulmonary hypertension. Treatment can start with oxygen at home at night or even during the day. Next is the use of oral phosphodiesterase inhibitors, mostly type V, such as sildenafil, which enhance endogenous nitric oxide. More potent are the endothelin receptor antagonists and the most potent are the prostanoids, especially epoprostenol, which is given by constant intravenous infusion. In addition to interventional catheterization with atrial septostomy, these agents have improved the prognostic outlook. This article reviews the current knowledge about the etiology, investigation, and treatment of children with pulmonary hypertension in the clinical setting.

Topics: Administration, Oral; Cardiac Catheterization; Child; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Oxygen; Oxygen Inhalation Therapy; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins; Purines; Sildenafil Citrate; Sulfones

Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of CTDs. In patients with SSc, PAH has a dramatic impact on prognosis and survival and is the single most common cause of disease-related death.Yearly echocardiographic screening for PAH is recommended in patients with SSc. If suspected, confirmation of PAH diagnosis by right heart catheterization is necessary. Treatment goals for patients with PAH associated with SSc (PAH-SSc) aim to slow disease progression and improve quality of life. Some measures used to gauge the effect of treatment in patients with PAH-SSc remain to be fully validated; the 6-min walk distance, for example, is a simple and reproducible means of assessing exercise capacity, but there exists a need to understand what constitutes a clinically relevant change in this specific patient population. Currently, pharmacological intervention in PAH-SSc may target one or more of three pathophysiological pathways in PAH. The prostacyclin analogue epoprostenol has been shown to improve exercise capacity and haemodynamics in PAH-SSc patients and similar data are available from smaller studies on trepostinil and iloprost. The dual endothelin receptor antagonist bosentan has been shown to improve exercise capacity and haemodynamics in PAH-SSc, and similar data have been obtained in small numbers of patients treated with the endothelin receptor A antagonists sitaxsentan and ambrisentan. Impaired production of nitric oxide may be addressed by inhibiting phosphodiesterase type-5 with sildenafil or possibly tadalafil. Combinations of multiple targeted therapies may be beneficial to this patient population.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Echocardiography; Epoprostenol; Exercise Tolerance; Humans; Hypertension, Pulmonary; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones

Sildenafil is a phosphodiesterase 5 inhibitor widely used for the treatment of pulmonary hypertension in children. Despite limited available safety and efficacy evidence, use of sildenafil continues to increase. To date, sildenafil use for pediatric pulmonary hypertension has been characterized for 193 children through 16 studies and 28 case series and reports. The primary efficacy data suggest that sildenafil is beneficial for facilitating the weaning of inhaled nitric oxide in children after cardiac surgery. Compiled safety data suggest that sildenafil is well tolerated among children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease. This review summarizes the available data describing the use, safety, and efficacy of sildenafil for children with pulmonary hypertension.

Topics: Child; Clinical Trials as Topic; Drug Interactions; Drug Therapy, Combination; Economics, Pharmaceutical; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Pulmonary hypertension (PH) is a relatively common hemodynamic finding in patients with left-sided heart disease and is usually associated with increased morbidity and mortality. However, so far no study has demonstrated long-term benefit from drugs specifically designed to improve pulmonary hemodynamics. There are currently no consensus recommendations on the management of PH in patients with chronic left heart failure. Most importantly, the underlying cause of left heart disease should be treated first. While previous studies with endothelin receptor antagonists or epoprostenol have been disappointing, initial promising results have been published for the phosphodiesterase-5 inhibitor sildenafil. Following acute administration and with chronic therapy for up to 6 months sildenafil improved hemodynamic parameters and exercise capacity in patients with PH and chronic left heart failure. Until the results from larger randomized controlled trials become available, the treatment of chronic left heart failure should follow the current guidelines.

Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Pulmonary arterial hypertension (PAH) is a rare disease characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary arterial resistance, right heart failure, and death. The pathogenesis of PAH is multifactorial, with endothelial cell dysfunction playing an integral role. This endothelial dysfunction is characterized by an overproduction of vasoconstrictors and proliferative factors, such as endothelin-1, and a reduction of vasodilators and antiproliferative factors, such prostacyclin and nitric oxide. Phosphodiesterase type 5 (PDE-5) is implicated in this process by inactivating cyclic guanosine monophosphate, the nitric oxide pathway second messenger. PDE-5 is abundantly expressed in lung tissue, and appears to be upregulated in PAH. Three oral PDE-5 inhibitors are available (sildenafil, tadalafil, and vardenafil) and are the recommended first-line treatment for erectile dysfunction. Experimental studies have shown the beneficial effects of PDE-5 inhibitors on pulmonary vascular remodeling and vasodilatation, justifying their investigation in PAH. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil, which are therefore currently the approved PDE-5 inhibitors in PAH treatment. Sildenafil and tadalafil significantly improve clinical status, exercise capacity, and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in the management of PAH although further studies are needed in this area. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia. Mild and moderate renal or hepatic failure does not significantly affect the metabolism of PDE-5 inhibitors, whereas coadministration of bosentan decreases sildenafil and tadalafil plasma levels. Due to their clinical effectiveness, tolerance profile, and their oral administration, sildenafil and tadalafil are two of the recommended first-line therapies for PAH patients in World Health Organization functional classes II or III.

Topics: Algorithms; Carbolines; Humans; Hypertension, Pulmonary; Imidazoles; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications.. Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies.. The systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out.. In total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12-18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6-110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20-99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13-1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07-1.18), 0.21 (95% CI 0.03-1.76), 0.18 (95% CI 0.02-1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were 277,000 pounds/quality-adjusted life-year (QALY) for FCIII and 343,000 pounds/QALY for FCIV patients for epoprostenol, 101,000 pounds/QALY for iloprost, 27,000 pounds/QALY for bosentan and 25,000 pounds/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing. All five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.

Topics: Antihypertensive Agents; Bosentan; Cost-Benefit Analysis; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; United States; Vasodilator Agents

Topics: Anticoagulants; Diuretics; Drug Therapy, Combination; Dyspnea; Female; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Practice Guidelines as Topic; Purines; Sildenafil Citrate; Sulfones; Warfarin

At least two thirds of patients with chronic severe left heart disease have associated pulmonary hypertension, and mortality associated with biventricular failure is >two-fold higher compared with isolated left ventricular failure. This review considers and discusses emerging concepts and strategies from recent studies of specific treatments in populations with pulmonary hypertension complicating overt left ventricular dysfunction. While the results reported in the studies considered are encouraging, to date there are no large randomised studies of specific treatments in populations with pulmonary hypertension complicating overt left ventricular dysfunction.

Topics: Aged; Antihypertensive Agents; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Heart Disease; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary artery pressure that can lead to right ventricular failure and death. Conventional treatment is based on non-specific drugs (warfarin, oxygen, diuretics). Pure vasodilators like calcium channel antagonists have little or no effect on the vast majority of patients. Although there is no cure for PAH, newer medical therapies have been shown to improve a variety of clinically relevant end-points including survival, functional class, exercise tolerance, haemodynamics, echocardiographic parameters and quality of life measures. Intravenous prostacyclin, was the first introduced drug for treatment of PAH and remains the first-line treatment for the most severe patients. Since then the list of approved drugs for PAH has expanded to include prostacyclin analogues with differing routes of administration, a dual endothelin receptor antagonist, and a phosphodiesterase-5 inhibitor. Novel drugs have also shown promise in experimental trials and are likely to be added to the list of options. This article reviews the current treatments strategies for PAH.

Topics: Bosentan; Diuretics; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones

Treatment of heart failure (HF) is a challenging task. An impaired nitric oxide pathway contributes to several abnormal cardiac and vascular phenotypes typical of the failing cardiovascular system. Inhibition of phosphodiesterase-5 (PDE5) is a new therapeutic strategy for overexpressing nitric oxide signaling by increasing the availability of cyclic guanosine monophosphate (cGMP). A number of background studies support the use of PDE5 inhibitors in HF. Treatment of pulmonary hypertension secondary to left ventricular dysfunction appears to be a primary target by virtue of the high PDE5 selectivity for the pulmonary circulation. Basic studies suggest that increased cGMP activity by PDE5 inhibition has potentially favorable direct myocardial effects that may block adrenergic, hypertrophic, and proapoptotic signaling. Furthermore, studies in humans have underscored the benefits of acute PDE5 inhibition on lung diffusion capacity, systemic endothelial function, muscle perfusion, and exercise performance. Despite promising initial data, larger controlled trials are necessary to define the safety, tolerability, and potential impact of PDE5 inhibitors on morbidity and mortality across the wide spectrum of patients with HF.

Topics: Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium, Vascular; Exercise Tolerance; Female; Heart Failure; Heart Function Tests; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Prognosis; Purines; Respiratory Function Tests; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Sildenafil Citrate; Sulfones; Survival Analysis; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Remodeling

For some years drugs of several different classes have been available in Germany for the treatment of pulmonary arterial hypertension (PHT): prostanoids, endothelin-receptor antagonists and phosphodiesterase inhibitors. To-date all relevant studies have consistently shown improvement in the 6-minute walking test (Iloprost, Treprostinil, Bosentan, Sitaxentan, Ambrisentan, Sildenafil). Results have not been consistent when the end-point has been an improvement in New York Heart Association (NYHA) class III or in the time to clinical worsening. Despite the good safety data for all drugs approved in Germany in the treatment of PHT, there are some clinically relevant interactions and significant contraindications. The availability of several options demands a detailed knowledge of studies to optimize safety and success in the treatment of PHT. Placebo-control mortality studies are not available for ethical reasons for those drugs that have been approved in Germany. But cohort analyses using historical survival rates have demonstrated a impressive improvement in survival of patients with PHT. Although there has been great progress in the treatment of PHT, a cure of this grave disease is not yet possible.

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; Thiophenes; Vasodilator Agents

Despite recent remarkable efforts in the medical treatment options of patients with pulmonary arterial hypertension (PAH) a considerable number of patients need escalations to improve disease related symptoms and pulmonary hemodynamics. Most of the pulmonary vascular vasodilators have been approved in its potency as an initial and sole medical option. However, there is increasing scientific evidence on the reliability, safety and effectiveness of possible combinations. This paper reviews the current scientific literature about medical escalations and combination therapy in patients with PAH.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Drug Therapy, Combination; Exercise Test; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Prostaglandins; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Pulmonary hypertension (PH) is a common complication of connective tissue disease. While there are no reliable epidemiological data, the prevalence of systemic sclerosis (SSc) has been estimated as being 8-12%. Mixed connective tissue disease (MCTD) and systemic lupus erythematodes (SLE) are thought to have a lower prevalence. PH associated with SSc has a poor prognosis, a two-year survival rate of approximately 50%, if untreated. Systematic literature search for studies of PH and CTD between 02/2007 and 02/2008 found 38 articles, a selection of which is reviewed here. One epidemiological study showed that nowadays PH is together with interstitial pulmonary fibrosis the most common cause of death in patients with SSc. Before the introduction of angiotensin- converting enzyme inhibitors the most frequent cause of death was acute renal crisis. Investigations of the pathogenesis of PH in CTD revealed that in patients with a severe, treatment-resistant course there is frequent histological evidence of pulmonary veno-occlusive disease. A prospective study on diagnosis revealed that transthoracic echocardiography (TTE) is better than magnetic resonance imaging or pulmonary function tests especially in screening for PH in patients with SSc, because of its high specificity and good predictive value at higher pulmonary pressures. But because of the low sensitivity of TTE right heart catheterization is the gold standard for verifying PH also in patients with SSc. A therapeutic uncontrolled trial indicated that treatment with bosentan combined with sildenafil results in clinical stabilization, but patients with idiopathic PHT responded better.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Connective Tissue Diseases; Drug Therapy, Combination; Echocardiography; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Piperazines; Prevalence; Prognosis; Purines; Respiratory Function Tests; Sensitivity and Specificity; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; Vasodilator Agents

The present meta-analysis was conducted with the aim of comparing the usefulness of sildenafil for the management of pulmonary hypertension (PH).. A systematic electronic and manual search was conducted to retrieve all published and unpublished randomized clinical trials of sildenafil in PH. Pertinent data related to various outcomes were extracted. Sildenafil was planned for comparison with placebo, prostacyclin analogs and endothelin receptor antagonists. For continuous data weighted mean difference was used while fixed or random effects models were used for dichotomous data. Revman (Version 4.2) was used for all calculations.. Five studies with a total of 190 patients were included in the final analysis. As compared to placebo sildenafil showed a significant improvement in 6-min walk test (68.90 (95% CI 31.14 - 106.65), p = 0.0003), mean pulmonary artery pressure (-13.04 (95% CI - 25.94 to -0.15), p = 0.05), mean cardiac index (0.39 (95% CI 0.24 - 0.54), p < 0.00001), mean Borg dyspnea score (-1.23 (95% CI -1.36 to -1.10), p < 0.00001), mean pulmonary vascular resistance (-171 (95% CI -300 to -30.90), p = 0.02), improvement in functional class (6.48 (95% CI 2.74 - 15.33), p < 0.001) and a nonsignificant change in mean right atrial pressure and clinical worsening. No study satisfied inclusion criteria for comparison with prostacyclin analogs. In comparison with bosentan, sildenafil did not show a significant difference for any of the clinical outcomes of concern.. In conclusion, sildenafil was shown to produce a significant improvement in functional and clinical outcomes as compared to placebo. There was no significant difference between sildenafil and bosentan for the study outcomes. There is a definite need for conducting adequately powered randomized controlled trials of sildenafil comparing it to placebo and also to other treatments approved for use in PH.

Topics: Atrial Function, Right; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Male; Piperazines; Pulmonary Artery; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

The therapeutic effects of phosphodiesterase type 5 inhibitors in patients with pulmonary arterial hypertension (PAH) were reviewed. A double-blind, placebo-controlled study named SUPER-1 showed that sildenafil improved exercise capacity, WHO functional class, hemodynamics, and quality of life. Two randomized, double-blind, crossover studies, showed that sildenafil improved exercise tolerance and quality of life, and reduced estimated pulmonary artery systolic pressure. The dose independent effects of sildenafil on PAH are controversial. There are few case-reports that show vardenafil and tadalafil have benefits in PAH patients. A double-blind study of tadalafil in PAH patients is ongoing.

Topics: Carbolines; Humans; Hypertension, Pulmonary; Imidazoles; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

Modern health care has greatly increased longevity for patients with congenital hemolytic anemias (such as sickle cell disease and thalassemia) and human immunodeficiency virus (HIV) infection. It is estimated that 10% of patients with hemoglobinopathies and 0.5% of patients with HIV infection develop moderate to severe pulmonary hypertension. Pulmonary hypertension is a relentlessly progressive disease leading to right heart failure and death. Worldwide, there are an estimated 30 million patients with sickle cell disease or thalassemia and 40 million patients with HIV disease. Considering the prevalence of pulmonary vascular disease in these populations, sickle cell disease and HIV disease may be the most common causes of pulmonary hypertension worldwide. In this review, the available data on epidemiology, hemodynamics, mechanisms, and therapeutic strategies for these diseases are summarized. Because therapy is likely to reduce morbidity and prolong survival, efforts to screen, diagnose, and treat these patients represent a global health opportunity.

Topics: Anemia, Hemolytic, Congenital; Anemia, Sickle Cell; Antiretroviral Therapy, Highly Active; Blood Transfusion; Echocardiography, Doppler, Color; Heart Failure; HIV Infections; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil citrate (Revatio), an inhibitor of phosphodiesterase type 5 (PDE5), is approved for use in the US, Europe and other countries for the treatment of pulmonary arterial hypertension (PAH). Oral sildenafil 20 mg three times daily added to conventional background therapy was significantly more effective than placebo at increasing exercise capacity in patients with idiopathic PAH or PAH associated with connective tissue diseases or repaired congenital systemic-to-pulmonary shunts. Sildenafil was also associated with improvements in WHO functional class and haemodynamic parameters, and was generally well tolerated. Sildenafil provides benefits in terms of exercise capacity when added to epoprostenol; however, these findings come from a trial that did not use the approved dosage of sildenafil. In conclusion, sildenafil is an effective oral treatment option for patients with PAH.

Topics: Drug Interactions; Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a progressive disease marked by vasoconstriction and vascular remodeling within pulmonary arteries leading to right heart failure and death. Significant advances in understanding the pathobiology of the disease have identified three key pathways involved in progression of this disease, which are the endothelin pathway, the prostacyclin pathway, and the nitric oxide/cyclic guanosine monophosphate pathway. Echocardiogram is the best screening tool to obtain an estimation of the pulmonary artery systolic pressure but right heart catheterization remains the standard by which the diagnosis is made. There are currently six FDA approved therapies for PAH. The mechanistic rationale, evidence behind their use and side effect considerations in utilizing these therapies in PAH patients will be the focus of this review.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Disease Progression; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelium, Vascular; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Prognosis; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Vasoconstriction

Pulmonary arterial hypertension is a group of diseases which forms a small subset of those with elevated pulmonary artery pressure (pulmonary hypertension). The recent development of selective pulmonary vasodilator has lead to a substantial resurgence of interest in what have been previously regarded as rare and incurable diseases. This review aims to describe the spectrum of pulmonary vascular diseases, the evolving understanding as to pathogenesis, the evolving evidence of efficacy for drug therapies, trying to put this into a contemporary Australian context. Several key pathogenic pathways may be involved: prostacycline, Nitric Oxide-cGMP-phosphodiesterase 5 and endothelin- all of which are exploited for therapeutic benefit by newly available drug therapies. A recently modified classification system reasserts the importance of precise diagnosis. The cardinal symptom of exertional dyspnea warrants careful evaluation in an attempt to prevent (frequently occurring) substantial delay in diagnosis. Echocardiogram is the cornerstone of screening for pulmonary arterial hypertension; however, a detailed evaluation including a carefully performed right heart catheterisation with sufficient data to allow calculation of pulmonary vascular resistance is key to accurate diagnosis. These new approaches to therapy are already substantially improving quality of life and prognosis.

Topics: Adolescent; Adult; Aged; Arterioles; Australia; Bosentan; Cardiac Catheterization; Diagnostic Imaging; Disease Progression; Dyspnea; Endothelin A Receptor Antagonists; Epoprostenol; Exercise Test; Female; Forecasting; Heart-Lung Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Male; Middle Aged; Nitric Oxide; Piperazines; Prognosis; Pulmonary Artery; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Right

Pulmonary hypertension is characterised by a progressive increase in pulmonary vascular resistance and a poor prognosis. The exact underlying mechanisms are still poorly understood; however, it is hypothesised that pulmonary medial hypertrophy and endothelial dysfunction lead to impaired production of vasodilators such as nitric oxide (NO) and prostacyclin, and increased expression of vasoconstrictors such as endothelin-1. The current treatment modalities for pulmonary hypertension include conventional supportive therapies and more specific pharmacological therapies that are targeted at abnormalities of endothelial function. NO and phosphodiesterase type 5 (PDE5) inhibitors induce pulmonary vasodilation by increasing intracellular cyclic guanosine monophosphate (cGMP) concentrations. Sildenafil citrate is a highly selective inhibitor of PDE5. Investigations in animal models and recent clinical case reports with some studies in the paediatric population suggest that sildenafil may be a promising agent in treating pulmonary hypertension. The effect of sildenafil on pulmonary vasculature appears to be independent of the underlying cause, thereby providing a role in idiopathic pulmonary arterial hypertension (PAH), PAH associated with congenital heart disease, pulmonary hypertension secondary to lung disease or persistent pulmonary hypertension of the newborn. It may also be beneficial in postoperative pulmonary hypertension and in neonates who are difficult to wean from inhaled NO. It is easily administered and effective, and has minimal systemic adverse effects. Although the reported results in children with pulmonary hypertension are promising, it is an experimental drug and large-scale randomised controlled studies are required to validate the safety, efficacy and dosage in the paediatric population.

Topics: Animals; Child; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

This article briefly reviews the background of endothelium-dependent vasorelaxation, describes the nitric oxide/cGMP/protein kinase pathway and its role in modulating pulmonary vascular tone and remodeling, and describes three approaches that target the nitric oxide/cGMP pathway in the treatment of patients with pulmonary arterial hypertension.

Topics: Animals; Cell Proliferation; Cyclic GMP; Endothelial Cells; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

This review assesses the available evidence supporting the use of drug combinations for the management of the various forms of pulmonary arterial hypertension (PAH). Ongoing and forthcoming randomized trials evaluating this strategy are also highlighted. Furthermore, new types of agents to treat PAH in the future are explored.

Topics: Adrenomedullin; Angiopoietin-1; Antihypertensive Agents; Benzamides; Bosentan; Drug Therapy, Combination; Eicosanoids; Epoprostenol; Genetic Therapy; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Intracellular Signaling Peptides and Proteins; Piperazines; Platelet Aggregation Inhibitors; Prostaglandins; Protein Serine-Threonine Kinases; Purines; Pyrimidines; rho-Associated Kinases; Serotonin; Serotonin Plasma Membrane Transport Proteins; Sildenafil Citrate; Sulfonamides; Sulfones; Vasoactive Intestinal Peptide; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a rare but frequently fatal condition marked by vasoconstriction and vascular remodeling within small pulmonary arteries. The pathobiology of PAH involves imbalances in a multitude of endogenous mediators, which promote aberrant cellular growth, vasoconstriction and hemostasis within the pulmonary vascular tree. The mechanisms promoting these pathologic effects are complex. This complexity is highlighted by the many overlapping secondary messenger systems through which these mediators work. In light of this natural redundancy, it is not surprising that many of the drugs used to treat PAH, which have shown short-term efficacy, fall "short of the mark" in reversing or halting the progression of this disease in the long run. This very redundancy in pathways makes the case for the use of combination of drugs with differing mechanisms of action to treat PAH. Similar to what is now accepted as the standard of care for the treatment of cancer and left ventricular dysfunction, combination therapy has the greatest promise for inducing the most complete vascular remodeling of the pulmonary vasculature by "shutting down" as many of these pathologic pathways as possible. Combination therapies involving existing therapies or new agents with improved pharmacokinetic and/or pharmacodynamic properties represent an emerging clinical paradigm for patients with sub-optimally managed disease. As emerging data in this field of therapy comes to fruition, further reductions in the morbidity and mortality associated with PAH will manifest. The goal of this report is to review the philosophy of combination therapy and present the available data in this area of study.

Topics: Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Endothelin-1; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Piperazines; Pulmonary Artery; Purines; Randomized Controlled Trials as Topic; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Analysis

Type 5 phosphodiesterase inhibitors (5-PDEI), which have been applied as the basic medication for erectile dysfunction, are now being studied in various areas of clinical medicine (pulmonology, cardiology, gastroenterology, gynecology etc.) This systematic literature review is dedicated to 5-PDEI, the state of the problem, the prospects of clinical application of sildenafil, and is based upon 450 literature sources from MEDLINE database (from 1954 to June 2006) and the Cochrane Collaboration database (from 1977 to March 2005) found by key words sildenafil, phosphodiesterase, and 5-PDEI. The issues of physiology and pathophysiology of 5-PDEI, the historical background of their creation, the appropriateness and efficacy of sildenafil in pulmonary arterial hypertension are considered in Part I of the review.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Analgesics, Opioid; Cyclic Nucleotide Phosphodiesterases, Type 5; Dopamine; Endothelium, Vascular; Erectile Dysfunction; Humans; Hypertension, Pulmonary; Male; Organ Specificity; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation; Pulmonary Circulation; Purines; Serotonin; Sildenafil Citrate; Sulfones

Pulmonary hypertension (PH) is a devastating disease that - if untreated - is characterized by a poor prognosis. According to the current classification (Venice, 2003), pulmonary arterial hypertension (PAH) is distinguished from other forms of PH. Recent advances in drug therapy have led to a dramatic improvement of medical care particularly in patients with PAH. Hence, early establishment of the diagnosis appears increasingly important. This review article gives an overview on the definition, classification, pathophysiology, and clinical presentation of various forms of PH. Furthermore, it summarizes the recommended diagnostic work-up and the current treatment options particularly in PAH, with special emphasis on prostanoids, endothelin receptor antagonists (ERAs), and phosphopdiesterase type 5 (PDE5) inhibitors such as sildenafil. Finally, novel developments are being discussed which currently represent an exciting field of research.

Topics: Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Prognosis; Prostaglandins; Purines; Sildenafil Citrate; Sulfones

Type Sphosphodiesterase inhibitors (FDEI-5) used to be applied as the main drugs for treatment of erectile dysfunction. At present, this pharmacological group is being studied intensively in various fields of clinical medicine, such as pulmonology, cardiology, gastroenterology, gynecology etc. Part II of this system literature review is dedicated to analysis of the results of such application. In many randomized and non-randomized controlled studies sildenafil decreased pulmonary arterial pressure (independently of etiology) and pulmonary vascular resistance; it could be successfully combined with nitric oxide, illoprost, or epoprostenolol. Clinical studies have also demonstrated an increase in physical load tolerance, optimization of PAH studies according to NYHA functional classes, and good tolerance to the drug. In the recent years, antiischaemic effects of FDEI-5 and their ability to inhibit apoptosis have been proved It is possible to draw the conclusion that nature created a universal phosphodiesterase mechanism for the interconnection of biochemical processes that provide the vital activity of the cell and organism. The fact that more than 15 controlled studies of clinical application of sildenafil not for treatment of erectile dysfunction have been planned and commenced confirms the importance of further studies of this mechanism. Further analysis of the results will show how universal this mechanism is.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Bronchodilator Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Therapy; Drug Therapy, Combination; Forecasting; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Myocardial Infarction; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Persistent pulmonary hypertension in neonates (PPHN) is associated with high mortality. Currently, the therapeutic mainstay for PPHN is assisted ventilation and administration of inhaled nitric oxide (iNO). However, nitric oxide is costly and may not be appropriate in resource-poor settings. Approximately 30% of patients fail to respond to iNO. High concentrations of phosphodiesterases in the pulmonary vasculature has led to the use of phosphodiesterase inhibitors such as sildenafil or milrinone.. To assess the efficacy and safety of Sildenafil in the treatment of persistent pulmonary hypertension in neonates.. MEDLINE, EMBASE, CINAHL databases were searched from their inception until March 2007; the Cochrane Central Register of Controlled Trials, the Cochrane Library, the reference lists of identified trials, and abstracts of meetings were searched without any language restriction.. Randomized or quasi-randomized controlled trials of Sildenafil compared with placebo or other pulmonary vasodilators, irrespective of dose, route and duration of administration in neonates with PPHN, were included if the trial reported any of the pre-specified outcomes.. The methodological quality of the trials was assessed regarding how bias at study entry, study intervention and outcomes measurement was minimized. Data on relevant outcomes were extracted and the effect size was estimated and reported as relative risk (RR), risk difference (RD) and weighted mean difference (MD) as appropriate. The I-squared (I(2)) test of heterogeneity was applied.. Two small eligible trials (one full article and one abstract) were identified. The methodological quality of the trial presented in the full article was good. Information provided in the abstract was limited. The total number of enrolled patients in the two studies was 37. Both studies were performed in resource-limited settings where iNO and high frequency ventilation are not available. Both studies reported statistically significant improvement in oxygenation (reduction in oxygenation index) in the Sildenafil group. One study reported what would be, if replicated, a strongly protective effect on mortality (RR 0.17, 95% CI 0.03, 1.09) favoring the Sildenafil group. However, this result needs to be replicated in larger studies. No clinically important side effects were reported.. The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials. Further randomized controlled trials of adequate power comparing Sildenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN.

Topics: Humans; Hypertension, Pulmonary; Infant, Newborn; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Vasodilator Agents

To evaluate the short-term efficacy and safety of sildenafil in treatment of pulmonary artery hypertension (PAH).. Literatures in regard to sildenafil treatment of PAH were searched in PubMed (from 01/01/1968 to 01/05/2006), Embase (from 1980 to 2006) and China National Knowledge Infrastructure (CNKI) (from 1994 to 2006). Randomized-controlled trials (RCTs) of sildenafil versus placebo in the treatment of PAH were conducted. The quality of the included trials was evaluated by two reviewers independently. Meta-analysis was done by using the Cochrane Collaboration's RevMan 4.2.8.. Ten literatures were retrieved. Four RCTs, including 328 patients, were included and were graded in terms of the quality of randomization, allocation, concealment and blinding. One study was graded as level A and the other three were graded as level B. The meta-analysis showed that compared with placebo treatment, sildenafil therapy can (1) improve the exercise capacity of the PAH patients measured as distance covered in a 6 minute walk test with an increase of 55.76 meters on average in 6 minutes' walk (95% confidence interval, 41.26 to 70.25; P < 0.01), (2) increase the exercise time of the PAH patients by 221.13s on average (95% confidence interval, 146.13 to 296.14; P < 0.01), (3) decrease the pulmonary artery systolic pressure by 11.51 mmHg on average (95% confidence interval, 1.41 to 21.60, P = 0.03), and (4) alleviate the exacerbation of clinical conditions with a total odds ratio (OR) of 0.36 (95% confidence interval, 0.16 to 0.78, P = 0.01); however, it failed to alleviate the headache and hypotension in comparison with the placebo group. No sexual disturbance was seen in the patients treated with sildenafil.. Sildenafil therapy improves the clinical symptoms and exercise capacity, and decreases the pulmonary artery systolic pressure of the PAH patients; and causes no serious side effects.

Topics: Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Artery; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

The therapy of systemic sclerosis (SSc) remains a challenge for dermatology, rheumatology, internal medicine, and other disciplines. Organ involvement, above all kidney and lungs, is a key therapeutic issue. The current developments in organ-specific therapy are the main topic of the article. Finally, possibilities of disease-modifying drugs and value of HSCT are discussed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Fibrosis; Fingers; Gastrointestinal Agents; Hematopoietic Stem Cell Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Kidney Transplantation; Piperazines; Purines; PUVA Therapy; Raynaud Disease; Recurrence; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfones; Ultraviolet Therapy; Vasodilator Agents

The treatment of pediatric pulmonary arterial hypertension (PAH) is challenging due to the serious nature of the disease, its rapid progression, and the limited treatment options available. While oral calcium channel antagonists and continuous intravenous epoprostenol have been used successfully for over a decade, novel treatment options - including prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors - may change the course of this disease for many children in the future.Prostacyclin analogs offer the benefit over continuous intravenous epoprostenol of an alternative delivery system. However, the efficacy of these medications compared with intravenous epoprostenol and the risk/benefits of each analog need to be weighed in future trials, which need to include larger numbers of pediatric patients to optimize therapy and outcome for individual children with PAH.For patients who do not have an acute response to vasodilator testing or have failed treatment with oral calcium channel antagonists, endothelin receptor antagonists may offer a viable treatment option. Furthermore, in the future, the addition of endothelin receptor antagonists to long-term therapy with calcium channel antagonists or to epoprostenol or a prostacyclin analog may increase the overall efficacy of treatment of PAH. Large multi-institutional randomized trials to determine whether sildenafil is effective and safe for the long-term treatment of PAH in children are in progress.A comprehensive review of these newer agents with an emphasis on the pathobiology/pathophysiology of PAH provides insight into the future management of pediatric PAH patients.

Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Pulmonary arterial hypertension (PAH) is a devastating disease that leads to right heart failure and premature death. Historically, we are restricted by limited options for drug treatment. Over the past decade, with advances in our understanding of pathophysiological and molecular mechanisms, many new therapeutic strategies (synthetic prostacyclin and prostacyclin analogues, endothelin receptor antagonists and sildenafil) have been developed for the treatment of PAH, and the clinical efficacy has been tested in many randomized-controlled trials (RCTs). In this overview, we review the evidence for the use of historical and new treatments that arises from the Cochrane Collaboration of Systematic Reviews and from recent RCTs.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Piperazines; Platelet Aggregation Inhibitors; Purines; Randomized Controlled Trials as Topic; Receptors, Endothelin; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones

Pulmonary hypertension is a devastating disorder, characterized by vascular proliferation, intimal hypertrophy and vasoconstriction. In this disorder, alterations in the nitric oxide pathway have borne out to be important in not only vascular proliferation, but also in the maintenance of vascular tone. After synthesis by soluble guanylate cyclase, cGMP effects vasodilation via protein kinase G and other mediators, and is hydrolyzed by phosphodiesterases (PDEs). PDE5 is abundantly expressed in the mammalian lung and its inhibition by sildenafil has been demonstrated to improve pulmonary vascular physiology in vitro and in vivo animal models of pulmonary hypertension. Recent human data has confirmed the efficacy of sildenafil in therapy for humans with pulmonary arterial hypertension. The following review will discuss the underlying basic science supporting the use of sildenafil, as well as human evidence supporting the critical role of this drug in therapy of patients with pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antihypertensive Agents; Bosentan; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins, Synthetic; Purines; Sildenafil Citrate; Sulfonamides; Sulfones

Evidence-based therapies and guidelines for pulmonary arterial hypertension are critiqued.. Morbidity and mortality in pulmonary arterial hypertension reflects failure of right ventricular compensation for increased afterload caused by obstructive pulmonary arterial remodeling. This predominantly reflects excessive proliferation/impaired apoptosis of smooth muscle and endothelial cells, rather than vasoconstriction. To exclude confounding effects of cardiac output and left ventricular end-diastolic pressure, the diagnosis of pulmonary arterial hypertension should require a pulmonary vascular resistance >3 Wood-units, not simply a mean pulmonary arterial pressure >25 mmHg. A 'positive' response (20% fall in pulmonary arterial pressure/pulmonary vascular resistance PAP/PVR) to acute, selective, pulmonary vasodilators (e.g. inhaled nitric oxide), occurs in 20% of patients, portends a favorable prognosis and justifies a trial of calcium channel blockers. Randomized controlled trials support treatment of NYHA class III pulmonary arterial hypertension with oral endothelin antagonists or phosphodiesterase-5 inhibitors. Prostacyclin analogues (inhaled/subcutaneous) are useful adjunctive therapies. Intravenous epoprostenol remains the therapeutic mainstay for class IV PAH. Emerging antiproliferative-proapoptotic therapies that merit investigator-initiated clinical trials include: statins, Imatinib, NONO-ates, anti-survivin, potassium channel modulation, and dichloroacetate.. The diagnostic criteria for pulmonary arterial hypertension should be revised to include PVR. Sildenafil's efficacy and price recommend it as a first-line oral therapy. New pulmonary arterial hypertension-regression therapies and therapeutic combinations offer the potential for cure of pulmonary arterial hypertension.

Topics: Antihypertensive Agents; Benzamides; Bosentan; Calcium Channel Blockers; Comorbidity; Dichloroacetic Acid; Drug Therapy, Combination; Epoprostenol; Evidence-Based Medicine; Fluoxetine; Humans; Hypertension, Pulmonary; Iloprost; Imatinib Mesylate; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins, Synthetic; Pulmonary Artery; Purines; Pyrimidines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Simvastatin; Sulfonamides; Sulfones; Thiophenes; Vasodilator Agents

In less than 20 years, the first selective type 5 phosphodiesterase inhibitor, sildenafil, has evolved from a potential anti-angina drug to an on-demand oral treatment for erectile dysfunction (Viagra), and more recently to a new orally active treatment for pulmonary hypertension (Revatio). Here we describe the key milestones in the development of sildenafil for these diverse medical conditions, discuss the advances in science and clinical medicine that have accompanied this journey and consider possible future indications for this versatile drug.

Topics: Angina Pectoris; Cerebrovascular Circulation; Erectile Dysfunction; Heart Failure; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Pulmonary arterial hypertension is a life-threatening, rare disease characterised by vasoconstriction and vascular remodelling of pulmonary artery vessels. Pulmonary arterial hypertension can occur without an obvious cause or can be secondary. Until several years ago, therapeutic approaches were represented mainly by 'conventional therapy' (anticoagulants, calcium channel blockers, diuretics and digoxin, and oxygen therapy). But recently 'specific therapies' (i.e., therapies targeting specific pathogenic pathways) have become available; these are therapies represented by prostacyclin and its derivatives, endothelin receptor antagonists or phosphodiesterase-5 inhibitors. Sildenafil citrate is a phosphodiesterase-5 inhibitor and is the second oral pharmacological agent recently approved for the treatment of pulmonary arterial hypertension. Sildenafil has demonstrated short- and long-term clinical efficacy in the treatment of various forms of pulmonary arterial hypertension, either alone or in combination with other agents, but its safety profile needs further assessment.

Topics: Animals; Color; Cyclic GMP; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

In the past decade, three classes of medications have been approved for the treatment of pulmonary arterial hypertension. A review of the clinical trial data for the prostanoids, endothelin antagonists, and phosphodiesterase-5 inhibitors has shown that all agents have similar efficacy on the 6-min walk distance over 12 to 16 weeks, which was the primary end point in the randomized clinical trials. However, little is known about their long-term efficacy or about how these drugs affect the underlying disease, if at all. Successful therapy is currently defined as an improvement in exercise tolerance over a 4-month period. Future trials need to better characterize how therapies affect the pulmonary vasculature pathologically, biologically, and hemodynamically, and whether survival is actually improved.

Topics: Bosentan; Endothelins; Epoprostenol; Exercise Test; Humans; Hypertension, Pulmonary; Long-Term Care; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Pulmonary arterial hypertension (PAH) has been a disease with limited treatment options and poor prognosis. This article reviews the recent advances that took place in the medical management of PAH.. Sildenafil is a type 5 cGMP-specific phosphodiesterase inhibitor originally developed to treat erectile dysfunction. Multiple uncontrolled and randomized controlled trials have proven that it is useful in the treatment of PAH and it was approved by the US Food and Drug Administration. The switch from continuous intravenous infusion of epoprostenol to subcutaneous infusion of treprostinil has been proven feasible and safe. Bosentan has been shown effective as a monotherapy and it also improves survival in patients with functional classes III and IV. In smaller clinical trials bosentan has improved symptoms in different forms of PAH. Combinations of drugs of different classes such as prostanoids, endothelin receptor blockers and sildenafil are tested, and such a strategy improves both symptoms and survival. Animal models and anecdotal clinical experience suggest the possibility of using imatinib mesylate in PAH.. With the approval of sildenafil, treatment options for this difficult disease have improved significantly. Combinations of drugs of different groups are promising and need further exploration.

Topics: Antihypertensive Agents; Bosentan; Disease Progression; Drug Therapy, Combination; Endothelin-1; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Prognosis; Prostaglandins; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Recent advances in our understanding of the pathophysiological and molecular mechanisms involved in pulmonary arterial hypertension have led to the development of novel and rational pharmacological therapies. In addition to conventional therapy (i.e., supplemental oxygen and calcium channel blockers), prostacyclin or endothelin receptor antagonists have been recommended as a first-line therapy for pulmonary arterial hypertension. However, these treatments have potential limitations with regard to their long-term efficacy and improvement in survival. Furthermore, intravenous prostacyclin (epoprostenol) therapy, which is recommended by most experts for patients with New York Heart Association (NYHA) functional class IV, is complicated, uncomfortable for patients, and expensive because of the cumbersome administration system. Considering these circumstances, it is necessary to develop additional novel therapeutic approaches that target the various components of this multifactorial disease.. In this short review, we present an overview of the current treatment options for pulmonary arterial hypertension and describe a case report with primary pulmonary hypertension. A male patient with NYHA functional class IV and showing no response to calcium channel blockers and prostacyclin exhibited significantly improved exercise tolerance and hemodynamics and long-term survival for more than 2.5 years after receiving an oral combination therapy of a phosphodiesterase type 5 inhibitor (sildenafil), phosphodiesterase type 3 inhibitor (pimobendan), and nicorandil.. We also discuss the background and plausible potential mechanisms involved in this case, as well as future perspectives in the treatment of pulmonary arterial hypertension.

Topics: Anticoagulants; Antihypertensive Agents; Calcium Channel Blockers; Diuretics; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nicorandil; Nitric Oxide Donors; Oxygen Inhalation Therapy; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary Arterial Hypertension includes a heterogeneous group of disorders with a common genetic, pathological and hemodinamyc origin. It is characterized by a high pulmonary artery pressure due to a primary vascular disease, as a consequence of genetic and environmental factors. The common pathway is a vascular imbalance towards vasoconstriction and proliferation inside the small vessels. According to the World Health Organization, 2003, Pulmonary Arterial Hypertension is classified as idiopathic, familiar or associated to connective tissue diseases, HIV, drugs, porto-pulmonary hypertension, congenital intracardiac shunts and others. The diagnosis is based in hemodynamics. Echocardiogram is a non invasive and right ventricular catheterization is an invasive diagnostic tool. Follow up is based on a clinical and functional assessment through functional class classification, dyspnea scores and 6-minute walking test. The prognosis is historically devastating but new therapies are changing the natural history of the disease. New treatments have demonstrated improvement in symptoms, hemodynamic profiles and survival. Intravenous, subcutaneous or inhaled prostanoids such as Epoprostenol, Treprostinil or Iloprost respectively have been approved for Pulmonary Arterial Hypertension treatment as well as oral endothelial receptor blockers. They are all considered first line treatments for arterial pulmonary hypertensive patients with even better benefits than lung transplantation. Phosphodiesterase inhibitors (Sildenafil), have been recently approved for the treatment of pulmonary arterial hypertension.

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Prognosis; Purines; Sildenafil Citrate; Sulfones

To perform a review of the diagnostic and therapeutic management of pulmonary hypertension in the pediatric population, with emphasis on pharmacological factors.. Electronic search of publications on the MEDLINE/PubMed, LILACS and Cochrane Collaboration databases. The search strategy adopted gave priority to the identification of clinical trials (controlled or uncontrolled), systematic reviews and directives published during the last 10 years.. Many advances have been incorporated into our understanding of pulmonary hypertension during recent years. Issues related to differences in the pathophysiological mechanism of the disease between different age groups have altered both the treatment and prognosis of patients. The combined effect of more selective vasodilatory properties and antiproliferative action and the employment of new drugs are the basic principles of new treatment proposals. In order to be able to gauge the benefits associated with the use of these new therapies, it is of fundamental importance that all patients have their disease correctly diagnosed, the degree of functional compromise classified and their vascular reactivity capacity established, which is more difficult with pediatric patients.. To date there is no treatment that can be considered ideal for the management of pulmonary hypertension. With reference to the possibility of employing new drugs, the majority of studies that have been published were undertaken with adult populations. Few data are available on children, and the majority of studies are uncontrolled trials or case series. Taking into account differences that have already been established between different age groups in terms of disease mechanisms and prognostic aspects, it is difficult to claim that these drugs can be incorporated into the treatment of childhood pulmonary hypertension with the same indications and results.

Topics: Antihypertensive Agents; Bosentan; Child; Endothelin Receptor Antagonists; Endothelium-Dependent Relaxing Factors; Epoprostenol; Humans; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Prognosis; Purines; Receptors, Endothelin; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones

Phosphodiesterase-5 inhibitors (PDE5I) are an important new class of drugs in the treatment of pulmonary artery hypertension (PHT). Sildenafil, a selective PDE5I, through its action on the NO/cGMP signal pathway, causes a selective reduction of pulmonary vascular resistance and improves symptoms and exercise capacity of patients with PHT. The phase III trial (SUPER-1) has clearly shown the efficacy and safety of sildenafil in PHT so that its use for this indication has recently been approved. Current guidelines of several large specialist societies have included sildenafil for the treatment of PHT, supported by a high degree of evidence. Sildenafil can also be combined with other drugs and has the potential of being efficacious also in other forms of pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Hypertension, Pulmonary; Imidazoles; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

Chronic thromboembolic pulmonary hypertension is one of the most common forms of pulmonary hypertension (PHT), but frequently remains undiagnosed and untreated. Pulmonary thrombendarterectomy is the treatment of choice, but only about 50 % of such patients are operable. About 15 % of patients are not improved by surgery, usually because of residual PHT with advanced vascular changes. Drug treatment has favorable effects in inoperable forms and in postoperative recurrence of PHT.

Topics: Antihypertensive Agents; Bosentan; Endarterectomy; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Pulmonary Embolism; Purines; Recurrence; Sildenafil Citrate; Splenectomy; Sulfonamides; Sulfones; Vasodilator Agents

The clinical condition of patients with chronic pulmonary arterial hypertension (PHT) often deteriorates progressively, despite monotherapy with presently available groups of drugs: prostanoids, endothelin-receptor antagonists and phosphodiesterase-5-inhibitors. In such situations there is in principle the opportunity of giving a combination of drugs, especially as one can expect synergistic effects. Trials with a small number of patients have indicated that the combination of inhaled iloprost and bosentan, inhaled iloprost and sildenafil or bosentan and sildenafil are more efficacious than any one of these drugs taken as monotherapy. The decision when to use a combination treatment should be made on the basis of defined targets that are of significant prognostic value. It should be considered for patients in NYHA class III or IV, if monotherapy has not achieved the desired efficacy. Combination treatment with two or three of the mentioned drugs are being tested as part of controlled studies of their efficacy and safety: they currently constitute the most important therapeutic advances. Analogously to the management of heart failure, combination therapy is likely to be the standard treatment of PHT in future, with the aim of providing optimal results for exertional capacity and lasting functional stability.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Bosentan; Drug Synergism; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc) and a leading cause of death in patients with it. Recent publications suggest that a prevalence of 10-15% is likely. The prognosis remains poor compared to that of idiopathic PAH. WHO recommends annual echocardiography for PAH screening of patients with SSc. Right heart catheterization is necessary to confirm the diagnosis. Nevertheless, more than half of all SSc patients have symptoms classified as WHO functional class III or IV at diagnosis. Prostacyclin therapy, delivered via continuous intravenous infusion (epoprostenol), has been demonstrated to be effective in patients with severe PAH (both idiopathic and scleroderma-related). Prostacyclin analogs (such as treprostinil and iloprost) are other options. Bosentan is the first endothelin receptor antagonist approved in the EU for the treatment of PAH, both idiopathic and related to connective tissue diseases such as scleroderma, in patients in WHO functional class III. Sildenafil by its selective inhibition of phosphodiesterase type 5 is also effective against both types of PAH. It too is now approved in the EU for this purpose in patients in WHO functional class III, but we do not yet have any information about its long-term effects in scleroderma.

Topics: Algorithms; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Cohort Studies; Echocardiography, Doppler; Epoprostenol; European Union; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Prevalence; Prognosis; Purines; Randomized Controlled Trials as Topic; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Time Factors; Vasodilator Agents; World Health Organization

Porto-pulmonary hypertension (PoPH) is the association of pulmonary artery hypertension and portal hypertension. The diagnosis of PoPH is based on pulmonary haemodynamic criteria, obtained via right heart catheterisation, including an increase in mean pulmonary arterial pressure (> 25 mmHg) and in pulmonary vascular resistance (> 240 dyn.s.cm-5).. The exact pathophysiological mechanisms of PoPH are unknown. However, since PoPH has been reported in patients with non-hepatic portal hypertension, the factor that determines the development must be portal hypertension rather than liver disease per se. Moreover, no simple relationship has been identified between the degree of hepatic impairment and the severity of PoPH. The clinical presentation is non-specific with haemodynamic failure occurring at the end stage. As a consequence, screening by annual transthoracic echocardiography is highly recommended in potential liver transplant candidates. Therapy with prostacyclin analogues may partially relieve pulmonary arterial hypertension (PAH). Liver transplantation has an uncertain effect in PoPH and because PoPH is associated with a high perioperative mortality, moderate to severe PoPH remains a contraindication for liver transplantation.. Recent advances in the management of PoPH have improved the prognosis. The safety and efficacy of oral endothelin receptor antagonists and oral phosphodiesterase inhibitors is currently under evaluation. A therapeutic approach utilising combinations of drugs should provide better long-term results.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Drug Therapy, Combination; Echocardiography; Epoprostenol; Humans; Hypertension, Portal; Hypertension, Pulmonary; Oxygen Inhalation Therapy; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension is a progressive disease that has a high rate of mortality. For these reasons, early treatment is essential. Treatment choices for pulmonary arterial hypertension are limited by drug tolerability, drug cost and inconvenience associated with administration techniques and dosing schedules. Therefore, a therapy that provides oral dosing with limited side effects would prove useful in managing many patients. Sildenafil citrate, the first and highly publicized oral medication to receive approval from the U.S. Food and Drug Administration for erectile dysfunction, has recently been approved for treatment of pulmonary arterial hypertension. This review summarizes the normal physiology of the pulmonary vasculature, and the pathophysiology involved in pulmonary arterial hypertension and the role of sildenafil in its treatment.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Pediatrics; Piperazines; Prostaglandins I; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Vasodilator Agents

The therapy of pulmonary hypertension has evolved rapidly in the last 10 years from the use of non-selective vasodilators to drugs that specifically target pulmonary vasodilation, endothelial function, and vascular remodeling. Sildenafil is a phosphodiesterase type 5 inhibitor that has an expanding role in the treatment of pulmonary hypertension. Case series and small studies, as well as the first large randomized controlled trial, have demonstrated the safety and efficacy of sildenafil in improving mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and exercise tolerance in pulmonary arterial hypertension. It may be useful in adults, children, and neonates after cardiac surgery, with left heart failure, in fibrotic pulmonary disease, high altitude exposure, and thromboembolic disease, and in combination with other therapies for pulmonary hypertension, such as inhaled iloprost. The oral formulation and favorable adverse effect profile make sildenafil an attractive alternative in the treatment of selected patients with pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Antihypertensive Agents; Blood Pressure; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Treatment of postoperative pulmonary hypertension with intravenous (IV) pulmonary vasodilators is hampered by the lack of selectivity. Inhaled nitric oxide produces selective pulmonary vasodilation; however, it requires a special device, and weaning can cause rebound. Oral sildenafil is a phosphodiesterase type V inhibitor. Sildenafil can produce sustained pulmonary vasodilatation in patients with hypoxic or primary pulmonary hypertension; however, experience with postoperative pulmonary hypertension is limited. We report our initial experience with eight patients who received oral sildenafil as adjunctive therapy for postoperative pulmonary hypertension. We reviewed the charts of eight adult patients with postoperative pulmonary hypertension who received oral sildenafil (25 to 50 mg) to facilitate weaning of IV (milrinone, nitroglycerine, and sodium nitroprusside) and inhaled (nitric oxide) pulmonary vasodilators. Hemodynamic data were recorded before and 30 and 60 minutes after the initial dose of sildenafil.. After the initial dose of sildenafil, mean pulmonary artery pressure was reduced by 20% and 22% at 30 and 60 minutes, respectively (p < 0.05). Pulmonary vascular resistance index decreased by 49% and 44% at 30 and 60 minutes, respectively (p < 0.05). Sildenafil had no clinically significant effects on cardiac index, mean arterial pressure, or systemic vascular resistance. Subsequent doses of sildenafil were administered at regular intervals, allowing successful weaning of concomitant pulmonary vasodilators.. Oral sildenafil is an effective agent for treatment of postoperative pulmonary hypertension and can be used to facilitate weaning of inhaled and IV pulmonary vasodilators.

Topics: Adult; Aged; Cardiac Surgical Procedures; Drug Evaluation; Drug Resistance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Milrinone; Nitric Oxide; Nitroglycerin; Nitroprusside; Phosphodiesterase Inhibitors; Piperazines; Postoperative Complications; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

To evaluate the efficacy of sildenafil for treatment of pulmonary hypertension.. Literature retrieval was accessed through MEDLINE (1977-March 2005), Cochrane Library, and International Pharmaceutical Abstracts (1977-March 2005) using the terms sildenafil and pulmonary hypertension. In addition, reference citations from publications identified were reviewed.. All articles in English identified from the data sources were evaluated. Studies including >5 patients with primarily adult populations were included in the review.. The treatment of pulmonary hypertension is challenging. Sildenafil has recently been studied as monotherapy and in combination with other vasodilators in the management of pulmonary hypertension. Eight hemodynamic studies and 12 clinical trials were reviewed (1 retrospective, 3 double-blind, 8 open-label). Sildenafil reduced pulmonary arterial hypertension and pulmonary vascular resistance/peripheral vascular resistance index and tended to increase cardiac output/cardiac index compared with baseline. Sildenafil was comparable to nitric oxide and at least as effective as iloprost or epoprostenol in terms of its pulmonary vasoreactivity. Combination therapy with iloprost, nitric oxide, or epoprostenol resulted in enhanced and prolonged pulmonary vascular effects. Clinical trials suggest that sildenafil improves exercise tolerance and New York Heart Association functional class, but large, randomized controlled trials are needed to confirm these findings. Overall, sildenafil was well tolerated.. Overall, sildenafil is a promising and well-tolerated agent for management of pulmonary hypertension. Further well-designed trials are warranted to establish its place in the treatment of pulmonary hypertension.

Topics: Adult; Double-Blind Method; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Vasodilator Agents

Phosphodiesterase-5 (PDE5) inhibitors and other agents that modulate intracellular cGMP are now emerging as promising, safe, and easy to administer therapies for pulmonary hypertension, with relatively few side effects. Recent studies have shown that PDE5 inhibitors are potent acute pulmonary vasodilators in experimental models that partially reverse established pulmonary arterial hypertension and blunt chronic pulmonary hypertension. In addition, studies on animals reveal that PDE5 inhibitors work in concert with nitric oxide and/or natriuretic peptide levels by enhancing intracellular cGMP and cGMP-mediated vasodilator effects. Further, the combination of PDE5 inhibitors and agents that increase cGMP or cAMP also yields additive beneficial effects on pulmonary hemodynamics in patients with pulmonary arterial hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Inhalation; Adult; Animals; Bronchodilator Agents; Clinical Trials as Topic; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones

Pulmonary arterial hypertension (PAH) affects vascular proliferation and remodeling in small pulmonary arteries and results in right ventricular failure and death due to a progressive increase in pulmonary vascular resistance. Recent advances in understanding of the molecular mechanisms involved in PAH suggest that endothelial dysfunction plays a major role. Impaired production of vasoactive mediators, such as prostacyclin and nitric oxide, accompanied with prolonged overexpression of vasoconstrictors such as endothelin-1, affects vascular tone and reinforces vascular remodeling. As the latter substances represent logical pharmacological targets, new drugs affecting these mechanisms have evolved during the past 2 decades and led to umpteen placebo-controlled trials in bygone years. Prognosis and quality of life of patients suffering from PAH seem to improve due to these new treatment strategies resulting in a reduction of mortality and morbidity, but there is still a substantial need for further long-term and head-to-head trials.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Practice Patterns, Physicians'; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Besides all progress in the therapy of pulmonary arterial hypertension over the past years, there is still no cure for this devastating disease. By introducing effective and nonparenteral medications (e. g., oral endothelin receptor antagonists [ERAs], inhaled prostanoids), quality of life, exercise tolerance and prognosis of patients have substantially improved. However, applicability of these therapies can be hampered by serious side effects and/or the necessity for elaborate application techniques. Whether selective ERAs--due to their specificity for the A-type receptor--have potential benefits over the nonselective ERA bosentan remains to be answered by the analysis of pivotal trials recently carried out with ambrisentan and sitaxsentan. Inhaled treprostinil can potentially have benefits over the already approved inhaled iloprost, related to its higher pulmonary selectivity as well as to the longer biological half-life. However, this has yet to be proven in long-term randomized controlled trials. In comparison to the previously mentioned substances, the selective phosphodiesterase-5 (PDE5) inhibitor sildenafil approached approval closest as new therapy for pulmonary arterial hypertension. Oral sildenafil has proven its efficacy as a selective pulmonary vasodilator in various forms of pulmonary hypertension. The results of the pivotal phase III trial have confirmed the strong efficacy and excellent tolerability of this substance. Combination therapies, despite all progress seen for single agents, can be regarded as the most promising therapeutic approach for the future. However, controlled randomized trials that are currently under consideration have to confirm this notion.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Practice Patterns, Physicians'; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). The increase in pulmonary artery pressures is often mild to moderate. However, 5-10% of patients with advanced COPD may suffer from severe pulmonary hypertension and present with a progressively downhill clinical course because of right heart failure added to ventilatory handicap. The prevalence of clinically significant severe pulmonary hypertension in COPD is roughly estimated to be of 1-2/1,000. The cause of pulmonary hypertension in COPD is generally assumed to be hypoxic pulmonary vasoconstriction leading to permanent medial hypertrophy. However, recent pathologic studies point rather at extensive remodeling of all layers of the pulmonary arterial walls. These aspects account for minimal reversibility with supplemental oxygen. There may be a case for pharmacologic treatment of pulmonary hypertension in selected patients with advanced COPD and right heart failure. However, it will be a challenge for randomized controlled trials to overcome the difficulties of the diagnosis of right ventricular failure and the definition of a relevant primary endpoint in pulmonary hypertensive patients with COPD.

Topics: Antihypertensive Agents; Bosentan; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents; Ventricular Dysfunction, Right

Topics: Endothelium, Vascular; Humans; Hypertension, Pulmonary; Pedigree; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The pathobiology of pulmonary arterial hypertension (PAH) reflects a multifactorial process and complex evolution that involves dysfunction of underlying cellular pathways and mediators. Among these, the endothelin system has been shown to be important in the pathogenesis of PAH. Endothelin-1 (ET-1), which is found in high levels in PAH, is a known potent vasoconstrictor with proliferative vascular remodeling properties. Left unchecked, endothelin excess, along with other derangements, may contribute to the development and perpetuation of PAH. There is now substantial evidence from clinical trials and long-term data that monotherapy with an endothelin receptor antagonist (ERA) is a beneficial, therapeutic approach in PAH. Combination therapy of an ERA with a prostanoid or phosphodiesterase-5 inhibitor, two drug classes that have different mechanisms of action, is conceptually appealing, but the evidence for its efficacy and safety are still being investigated. This review provides an overview of endothelin biology and the clinical use of ERAs for the treatment of PAH. The use of ERAs for other forms of pulmonary hypertension will not be reviewed here.

Topics: Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Epoprostenol; Humans; Hypertension, Pulmonary; Isoxazoles; Piperazines; Pulmonary Artery; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes

Pulmonary arterial hypertension (PAH) is a progressive arteriopathy of the pulmonary circulation that can affect a wide group of patients. Presentation and natural history of PAH are intimately linked to progressive right ventricular failure. Historically, survival in PAH has been poor, especially for patients with PAH associated with progressive systemic sclerosis and human immunodeficiency virus. Oral, subcutaneous, and intravenous therapies that have emerged during the last decade can improve symptoms and hemodynamics. This review explores the impact of these therapies on prognosis in PAH, which ultimately rests on the ability to reverse the pulmonary arteriopathy and preserve right ventricular function.

Topics: Anticoagulants; Antihypertensive Agents; Bosentan; Calcium Channel Blockers; Clinical Trials as Topic; Epoprostenol; Humans; Hypertension, Pulmonary; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Analysis; Warfarin

Exaggerated vasospasm, platelet activation, and early graft occlusion are significant barriers to successful coronary artery bypass grafting (CABG). Interestingly, vascular smooth muscle and platelets are predominant sources of type-5 phosphodiesterase (PDE5) in the body, and this enzyme is specifically inhibited by PDE5 inhibitors (eg, sildenafil citrate). Together with endogenous nitric oxide, sildenafil can induce pulmonary and coronary vasodilation, precondition the myocardium, reduce platelet activation, and potentially reduce early graft occlusion. Currently, there are no published clinical trials investigating sildenafil in coronary surgery. Recent studies on the potential use of sildenafil strongly support its beneficial effects in a wide range of patients with cardiovascular diseases. Therefore, we sought to review the literature, explore the current hypothesis that the use of sildenafil in coronary surgery patients can be beneficial, and attempt to define its potential place in the setting of CABG.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Coronary Artery Bypass; Coronary Vasospasm; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Hypertension, Pulmonary; Ischemic Preconditioning, Myocardial; Muscle, Smooth, Vascular; Phosphodiesterase Inhibitors; Piperazines; Platelet Activation; Purines; Sildenafil Citrate; Sulfones

Topics: Anticoagulants; Antihypertensive Agents; Bosentan; Calcium Channel Blockers; Cardiotonic Agents; Diuretics; Drug Monitoring; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prostaglandins; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

New approaches to the treatment of pulmonary arterial hypertension (PH) have increased symptomatic relief and prolonged survival. PH is a common sequela of the hemoglobinopathies, but the use of standard oral treatment options is limited because of toxicity and poor effectiveness. Sildenafil citrate is a selective and potent inhibitor of cGMP-specific phosphodiesterase-5 (PDE5), which promotes selective smooth muscle relaxation in lung vasculature and has been used successfully in the treatment of PH. Hemoglobinopathic patients suffering from severe PH who were treated with sildenafil citrate (50 mg b.i.d.) for periods ranging from 4 to 48 months showed a significant decrease in pulmonary pressure and improvement in exercise capacity and functional class. No significant adverse events were reported. These data, described in a small group of patients, indicate that sildenafil citrate is effective in the treatment of PH in hemoglobinopathies and is well tolerated long-term at a daily dose of 100 mg.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Evaluation; Exercise Tolerance; Hemoglobinopathies; Humans; Hypertension, Pulmonary; Hypoxia; Muscle, Smooth, Vascular; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Phosphodiesterase type-5 (PDE-5) inhibitors including sildenafil, vardenafil and tadalafil are a new class of vasoactive drugs that have been developed for treatment of erectile dysfunction in patients. A growing number of studies in recent years suggest that sildenafil may be used clinically for treatment of pulmonary hypertension and endothelial dysfunction. In addition, recent studies primarily from our laboratory suggested that sildenafil has preconditioning-like powerful cardioprotective effect in the animal models of ischemia-reperfusion injury. Sildenafil has been found to exert cardioprotection through nitric oxide generated from endothelial and/or inducible nitric oxide synthases and opening of mitochondrial ATP-sensitive potassium channels. Future demonstration of the cardioprotective effect in patients with the relatively safe and effective FDA-approved PDE-5 inhibitors, such as sildenafil, could have an enormous impact on bringing the long-studied phenomena of ischemic and pharmacologic preconditioning to the clinical forefront.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cardiotonic Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones

Pulmonary hypertension is an uncommon, yet devastating, syndrome with a complex underlying pathobiology. Hypoxia, inflammation, and increased shear stress appear to be the primary pathogenic events; however, mechanisms by which these processes lead to pulmonary hypertension remain incompletely understood. The ultimate increase in pulmonary vascular resistance is attributed to remodelling of the walls of resistance vessels, which can lead to encroachment on and reduction of the vascular lumen. The number of blood vessels per unit of cross-sectional area in the hypertensive lung is also reduced, which can contribute to increased vascular resistance. Regardless of its etiology, endothelial dysfunction underlies pulmonary hypertension, one manifestation of which is the attenuated production of bioactive nitric oxide. Nitric oxide administration can exert beneficial effects at various stages of the disease. Here we review the known pathobiology of pulmonary hypertension, with a principal focus on endothelial nitric oxide, and also summarize the data on nitric oxide replacement therapy and other novel therapies that relate to nitric oxide as one approach to treatment.

Topics: Administration, Inhalation; Cell Hypoxia; Free Radical Scavengers; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Topics: Calcium Channel Blockers; Drug Therapy, Combination; Endothelins; Epoprostenol; Humans; Hypertension, Pulmonary; Patient Selection; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension (PH) is a disease of various origins. Nitric oxide-a potent vasodilator-is a key player of pulmonary vasoregulation. Nitric oxide signaling is mainly mediated by the guanylate cyclase/cyclic guanylate monophosphate pathway. The effects of this second messenger system are limited by enzymatic degradation through phosphodiesterases (PDEs). Recently, beneficial effects of the oral PDE-5 inhibitor sildenafil (originally approved for the treatment of erectile dysfunction) were reported for the treatment of PH. We provide a brief overview of the experimental and clinical application of PDE inhibitors in the field of PH. In particular, studies reporting the clinical effectiveness of sildenafil are highlighted. This agent, despite oral application, displays characteristics of a pulmonary selective vasodilator. In addition, evidence shows that sildenafil is operative mainly in the vasculature of well-ventilated areas of the lung. However, to date, controlled randomized trials proving the efficacy of this approach for the treatment of pulmonary arterial hypertension are lacking. The results of such studies have to confirm the current encouraging findings before recommendations regarding the use of PDE-5 inhibitors as a new treatment for PH can be made.

Topics: Animals; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Treatment strategies for pulmonary hypertension in children have dramatically evolved. Traditional therapy with calcium channel blockers and pulmonary transplantation is only indicated in selected patients and does not reduce mortality very significantly. New pulmonary vasodilators are emerging from recent trials in the adult population. Their indications are based on the patient's NYHA classification. The epoprostenol (prostacyclin, Flolan) has shown reduction in mortality and improvement in functional symptoms in pediatric patients. The frequent side effects and continuous intravenous infusion limit the indication of prostacyclin in NYHA class IV children. The endothelin receptor blocker bosentan (Tracleer) is an orally given agent. It improves functional symptoms in adults and hemodynamic measures in children. It can be started in children with moderate functional symptoms (NYHA class II and III). The type V phosphodiesterase inhibitor sildenafil (Viagra) is being evaluated and may represent a promising therapy in the future. Invasive strategies like catheter-based atrial septostomy may be useful in particular cases. Randomized-controlled studies are urgently needed to evaluate the safety and efficacy of these new therapies.

Topics: Antihypertensive Agents; Bosentan; Calcium Channel Blockers; Catheter Ablation; Child; Epoprostenol; Heart Atria; Humans; Hypertension, Pulmonary; Lung Transplantation; Patient Selection; Pediatrics; Piperazines; Purines; Randomized Controlled Trials as Topic; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Administration, Inhalation; Antihypertensive Agents; Calcium Channel Blockers; Diuretics; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The discovery in 1989 of sildenafil, a highly selective inhibitor of phosphodiesterase-5 (PDE-5), was the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Initial clinical studies on sildenafil in the early 1990s were not promising with respect to its antianginal potential. However, the incidental discovery of its antiimpotence effect led to its approval of for the treatment of erectile dysfunction. Thereafter, several reports of adverse cardiac events in patients on sildenafil raised concerns about its safety in cardiovascular disorders. Novel therapeutic indications are emerging for sildenafil with the recent discovery that PDE-5 is expressed in various other tissues such as the arterial vasculature, including pulmonary and coronary arteries, venous vasculature, skeletal muscles, platelets, and visceral and tracheobronchial muscles. In this review we briefly summarize the pharmacology of sildenafil and the current available evidence on its potential therapeutic applications in cardiovascular disorders.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Blood Platelets; Cardiovascular Diseases; Child; Coronary Circulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelium, Vascular; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Myocardial Contraction; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Stress, Physiological; Sulfones; Sympathetic Nervous System; Vasodilator Agents

Pulmonary Hypertension (PH) can be either of unknown aetiology (primary pulmonary hypertension (PPH)) or due to a known underlying cause (secondary pulmonary hypertension (SPH). Pulmonary arteriolar vasoconstriction is considered to be an important characteristic of PH. Therapies which aim to vasodilate are used to treat pulmonary hypertension.. To determine the clinical efficacy of sildenafil, a vasodilator which works through inhibition of the enzyme phosphodiesterase type V (PDE5I), administered via any route to people with pulmonary hypertension in primary or secondary forms.. Electronic databases were searched with pre-defined search terms. Searches were current as of November 2003.. Randomised controlled trials were considered for inclusion in the review. We included studies which assessed the effects of sildenafil in participants with PPH and SPH.. Two reviewers independently assessed and extracted data from clinical trials. Data were entered in RevMan Analyses 1.0.2. Continuous data were pooled with an estimate on either WMD (weighted mean difference) or SMD (standardised mean difference) scales. Dichotomous data were pooled and a RR (relative risk) was calculated.. Four studies recruiting 77 participants met the inclusion criteria of the review. Two studies assessed the acute effects of sildenafil. Two small crossover study assessed the effects of long term administration. The 'acute effect' studies indicated that sildenafil has a pulmonary vasodilatory effect. The two crossover studies showed improvement in symptoms. One study showed improvement in fatigue domains from a validated health status questionnaire. Both crossover studies reported that the drug was well tolerated.. The validity of the observed effects is undermined by small participant numbers and inadequate exploration of the different disease etiologies. The effects on long term outcome such as NYHA functional class, symptoms, mortality and exercise capacity require further validation. More studies of adequate size are required before the long term effects of sildenafil on clinically important outcomes can be established.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Humans; Hypertension, Pulmonary; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Vasodilator Agents

The availability of selective inhibitors of the cyclic guanosine monophosphate (cGMP)-specific type 5 phosphodiesterase (PDE5) has created increasing interest in unlocking the therapeutic potential of PDE5 inhibition in cardiovascular diseases that are marked by dysfunction of nitric oxide (NO)-cGMP signaling. Pulmonary arterial hypertension (PAH) and heart failure (HF) are characterized by pulmonary arterial vasoconstriction that is thought to be caused by relative deficiencies of vasodilators such as NO and exaggerated production of vasoconstrictors such as endothelin. PDE5 is abundant in the pulmonary vasculature where it catabolizes cGMP, the second messenger of NO. Inhibition of PDE5 has been shown to lower pulmonary vascular resistance in PAH and HF by augmenting local cGMP. This review outlines the therapeutic potential of PDE5 inhibition for the treatment of PAH and HF.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Failure; Humans; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones

Pulmonary hypertension (PH) occurs frequently in parenchymal lung disease and is usually correlated with increased mortality. Thus, the treatment of PH in patients with lung disease has been an active area of interest. Secondary pulmonary hypertension (SPH), whether from parenchymal lung disease or other etiologies, is more common than primary pulmonary hypertension (PPH). In 2002, two new medications, oral bosentan and subcutaneous treprostinil, were released for the treatment of pulmonary arterial hypertension (PAH). These new agents are not restricted to use in PPH, as they are approved for use in PAH in general. It is reasonable to consider the use of these medications in select patients with SPH caused by parenchymal lung disease, although these groups have not yet been studied in clinical trials. The initial hemodynamic evaluation of SPH patients, the potential use of these new medications in the context of standard care, and the assessment of response to therapy are discussed in this update. A relevant case report is used to illustrate use of these new agents in SPH, and ongoing clinical trials are reviewed. The available treatment options for patients with SPH are rapidly improving.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Clinical Trials as Topic; Echocardiography; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Middle Aged; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

The field of cardiac intensive care is rapidly evolving with nearly simultaneous advances in surgical techniques and adjunctive therapies, respiratory care, intensive care technology and monitoring, pharmacologic research and development, and computing and electronics. The focus of care has now shifted toward reducing morbidity and improving "quality of life" while the survival of infants and children with congenital heart defects, including those with univentricular hearts has dramatically improved during the last three decades. Despite these advances, there remains a predictable fall in cardiac output after cardiopulmonary bypass. This article focuses on early identification and aggressive treatment of the low cardiac output syndrome peculiar to these patients. The authors also briefly review the recent advances in the treatment of pulmonary hypertension, mechanical support, and neurologic surveillance after cardiac surgery.

Topics: Cardiac Output, Low; Cardiac Surgical Procedures; Cardiotonic Agents; Child; Critical Care; Dye Dilution Technique; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Iloprost; Intraoperative Care; Milrinone; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Antihypertensive Agents; Electrocardiography; Epoprostenol; HIV Infections; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The prognosis of patients with pulmonary arterial hypertension (PAH) is poor. Available therapies (Ca(++)-channel blockers, epoprostenol, bosentan) have limited efficacy or are expensive and associated with significant complications. PAH is characterized by vasoconstriction, thrombosis in-situ and vascular remodeling. Endothelial-derived nitric oxide (NO) activity is decreased, promoting vasoconstriction and thrombosis. Voltage-gated K+ channels (Kv) are downregulated, causing depolarization, Ca(++)-overload and PA smooth muscle cell (PASMC) contraction and proliferation. Augmenting the NO and Kv pathways should cause pulmonary vasodilatation and regression of PA remodeling. Several inexpensive oral treatments may be able to enhance the NO axis and/or K+ channel expression/function and selectively decrease pulmonary vascular resistance (PVR). Oral L-Arginine, NOS' substrate, improves NO synthesis and functional capacity in humans with PAH. Most of NO's effects are mediated by cyclic guanosine-monophosphate (c-GMP). cGMP causes vasodilatation by activating K+ channels and lowering cytosolic Ca++. Sildenafil elevates c-GMP levels by inhibiting type-5 phosphodiesterase, thereby opening BK(Ca). channels and relaxing PAs. In PAH, sildenafil (50 mg-po) is as effective and selective a pulmonary vasodilator as inhaled NO. These benefits persist after months of therapy leading to improved functional capacity. 3) Oral Dichloroacetate (DCA), a metabolic modulator, increases expression/function of Kv2.1 channels and decreases remodeling and PVR in rats with chronic-hypoxic pulmonary hypertension, partially via a tyrosine-kinase-dependent mechanism. These drugs appear safe in humans and may be useful PAH therapies, alone or in combination.

Topics: Administration, Inhalation; Administration, Oral; Animals; Arginine; Dichloroacetic Acid; Disease Models, Animal; Humans; Hypertension, Pulmonary; Models, Biological; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Potassium Channels; Pulmonary Circulation; Purines; Rats; Sildenafil Citrate; Sulfones

Sildenafil is an inhibitor of phosphodiesterase 5, which has important vasodilatory properties. Though sildenafil provokes a decrease in systemic arterial pressure, its safety has been confirmed in large series of patients on several kinds of anti-hypertensive therapy. Likewise, post-marketing surveys, in the US or United Kingdom, have recorded a number of cardio-vascular deaths following sildenafil administration which was lower than expected, provided the contra-indication with the concomitant use of nitrates is observed. In patients with known or suspected coronary artery disease, sildenafil does not modify the tolerance or results of echocardiographic exercise testing. However, sildenafil does increase coronary flow reserve, both in narrowed or normal coronary arteries, with no sign of a "steal" phenomenon. Because of its capacity to retard the degradation of cGMP, by the inhibition of phosphodiesterase 5, the effect of sildenafil in primary pulmonary hypertension has been evaluated in several studies: acutely, sildenafil decreases pulmonary artery pressure, either alone or in combination with inhaled iloprost or NO. On the same line, sildenafil decreases hypoxia-induced pulmonary hypertension in normal volunteers. These findings, together with reports of long-term improvement in symptoms and levels of pulmonary artery pressure in patients with primary pulmonary hypertension, will warrant further trials to document its potential role in this otherwise severe disease.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Computer Graphics; Contraindications; Coronary Artery Disease; Coronary Circulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Interactions; Humans; Hypertension; Hypertension, Pulmonary; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

There have been remarkable advances in our understanding of the pathobiology of pulmonary hypertension. A region on chromosome 2 encoding bone morphogenetic receptor type 2 has been identified to underlie familial and many cases of sporadic primary pulmonary arterial hypertension. The vasoactive mediators, discovered and defined by vascular biologists, have been translated into promising treatments of human disease. Prostacyclin, endothelin receptor blockers, sildenafil, and nitric oxide have been applied therapeutically to limit, and occasionally reverse, the inexorable damage to the pulmonary circulation initiated by recently identified genetic and environmental triggers of pulmonary arterial hypertension.

Topics: Antihypertensive Agents; Bone Morphogenetic Protein Receptors, Type II; Bronchodilator Agents; Child; Chromosomes, Human, Pair 2; Eisenmenger Complex; Epoprostenol; Humans; Hypertension, Pulmonary; Mutation; Nitric Oxide; Piperazines; Protein Serine-Threonine Kinases; Pulmonary Artery; Purines; Receptors, Endothelin; Sildenafil Citrate; Sulfones; Transforming Growth Factor beta; Vasodilator Agents

For many years, the management of pulmonary hypertension has been frustrated by an inadequate understanding of its pathology and limited therapeutic options, but this is changing rapidly. Recently, novel insight into the pathogenesis of primary pulmonary hypertension (PPH) has been provided by the demonstration of mutations in BMPR2 and ALK-1 genes in a significant number of patients with the condition. These genes encode members of the TGF-b receptor superfamily and their integrity is important in the maintenance of normal pulmonary vascular structure and function. At the same time, there has been a major advance in the treatment of the condition due to development of 2 orally active pharmacological agents, bosentan and sildenafil, which demonstrate some selectivity for the pulmonary vasculature. This review examines how the management of PPH and severe pulmonary hypertension in associated diseases has changed and looks at exciting future developments.

Topics: Antihypertensive Agents; Bosentan; Endothelins; Forecasting; Genetic Therapy; Genotype; Humans; Hypertension, Pulmonary; Mutation; Phosphodiesterase Inhibitors; Piperazines; Polymorphism, Genetic; Purines; Receptors, Transforming Growth Factor beta; Serotonin; Sildenafil Citrate; Sulfonamides; Sulfones; Transcription, Genetic; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is common in severe coronavirus disease 2019 (COVID-19) and worsens the prognosis. Sildenafil, a phosphodiesterase-5 inhibitor, is approved for PAH treatment but little is known about its efficacy in cases of severe COVID-19 with PAH. This study aimed to investigate the clinical efficacy of sildenafil in patients with severe COVID-19 and PAH. Intensive care unit (ICU) patients were randomly assigned to receive sildenafil or a placebo, with 75 participants in each group. Sildenafil was administered orally at 0.25 mg/kg t.i.d. for one week in a placebo-controlled, double-blind manner as an add-on therapy alongside the patient's routine treatment. The primary endpoint was one-week mortality, and the secondary endpoints were the one-week intubation rate and duration of ICU stay. The mortality rate was 4% vs. 13.3% (

Topics: COVID-19; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Sildenafil Citrate; Treatment Outcome

Long-term benefits of pulmonary artery denervation (PADN) for patients with combined precapillary and postcapillary pulmonary hypertension (CpcPH) secondary to left heart failure are unknown.. The authors sought to report the 3-year clinical results of PADN for patients with CpcPH.. A total of 98 patients with CpcPH, defined as having mean pulmonary arterial pressure of ≥25 mm Hg, pulmonary capillary wedge pressure of >15 mm Hg, and pulmonary vascular resistance of >3.0 WU, were randomly assigned to receive the sham + sildenafil or PADN. The primary endpoint was the occurrence of clinical worsening defined as cardiopulmonary death, rehospitalization or heart/lung transplantation at 3-year follow-up. Changes in the 6-minute walk distance and N-terminal pro-B-type natriuretic peptide served as secondary points.. At the 3-year follow-up, clinical worsening was reported in 49 (50.0%) patients, with 31 (62.0%) in the sham + sildenafil group and 18 (37.5%) in the PADN group (HR: 2.13 [95% CI: 1.19-3.81]; P = 0.011), largely driven by a higher rate of rehospitalization in the sham + sildenafil group (56.2% vs 35.4%; HR: 1.96 [95% CI: 1.07-3.58]; P = 0.029) by Cox proportional hazards regression. At the end of the study, cardiopulmonary-related deaths occurred in 16 (32.0%) patients in the sham and 9 (18.8%) (P = 0.167) patients in the PADN group. PADN also resulted in a more profound increase in the 6-minute walk distance and reduction in N-terminal pro-B-type natriuretic peptide.. PADN is associated with significant improvements in exercise capacity, cardiac function, and clinical outcomes. Further study without approved drugs for pulmonary arterial hypertension is required to confirm the benefits of PADN for patients with CpcPH. (Pulmonary Arterial Denervation in Patients With Pulmonary Hypertension Associated With the Left Heart Failure [PADN-5]; NCT02220335).

Topics: Heart Failure; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Pulmonary Artery; Sildenafil Citrate

The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02).. Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a "rebound" vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action.. • In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo.. • The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension. • The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed.

Topics: Birth Weight; Female; Fetal Growth Retardation; Gestational Age; Humans; Hypertension, Pulmonary; Infant, Newborn; Pregnancy; Sildenafil Citrate

Pulmonary hypertension is a significant complication in thalassemia patients. Recent studies showed that inhaled nebulized nitrite could rapidly decrease pulmonary artery pressure. We conducted a multicenter, randomized, double-blind, placebo-controlled trial in thalassemia patients with symptomatic pulmonary hypertension diagnosed by right heart catheterization. Eleven patients were recruited; five were assigned to the nitrite group and six to the placebo group. Patients were treated with the optimal doses of sildenafil for pulmonary hypertension and randomly assigned into the placebo or nitrite groups. Patients in the nitrite group were given inhaled nebulized 30 mg sodium nitrite twice a day for 12 weeks. The clinical outcomes measured at week 12 were the changes in 6-min walk distance (6MWD), mean pulmonary artery pressure (MPAP), and N-terminal pro B-type natriuretic peptide. The MPAP estimated by echocardiography was significantly reduced from 33.6 ± 7.5 mmHg to 25.8 ± 6.0 mmHg (mean difference = 7.76 ± 3.69 mmHg, p = 0.009 by paired t-test). Furthermore, 6MWD was slightly increased from 382.0 ± 54.0 m to 432 ± 53.9 m (mean difference = 50.0 ± 42.8 m, p = 0.059 by paired t-test) in the nitrite group. At week 12, the nitrite group had lower MPAP than the placebo group (25.8 ± 6.0 vs. 45.7 ± 18.5 mmHg, p = 0.048 by unpaired t-test). No significant difference in 6MWD and N-terminal pro B-type natriuretic peptide between the two groups was observed at week 12. There was no hypotension or other significant adverse effects in the nitrite group.

Topics: Administration, Inhalation; Adult; Blood Pressure; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Sildenafil Citrate; Sodium Nitrite; Thalassemia; Young Adult

Topics: Humans; Hypertension, Pulmonary; Infant, Newborn; Persistent Fetal Circulation Syndrome; Sildenafil Citrate; Vasodilator Agents

Pulmonary hypertension (PHT) may complicate heart failure with reduced ejection fraction (HFrEF) and is associated with a substantial symptom burden and poor prognosis. Sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, might have beneficial effects on pulmonary haemodynamics, cardiac function and exercise capacity in HFrEF and PHT. The aim of this study was to determine the safety, tolerability, and efficacy of sildenafil in patients with HFrEF and indirect evidence of PHT.. The Sildenafil in Heart Failure (SilHF) trial was an investigator-led, randomized, multinational trial in which patients with HFrEF and a pulmonary artery systolic pressure (PASP) ≥40 mmHg by echocardiography were randomly assigned in a 2:1 ratio to receive sildenafil (up to 40 mg three times/day) or placebo. The co-primary endpoints were improvement in patient global assessment by visual analogue scale and in the 6-min walk test at 24 weeks. The planned sample size was 210 participants but, due to problems with supplying sildenafil/placebo and recruitment, only 69 patients (11 women, median age 68 (interquartile range [IQR] 62-74) years, median left ventricular ejection fraction 29% (IQR 24-35), median PASP 45 (IQR 42-55) mmHg) were included. Compared to placebo, sildenafil did not improve symptoms, quality of life, PASP or walk test distance. Sildenafil was generally well tolerated, but those assigned to sildenafil had numerically more serious adverse events (33% vs. 21%).. Compared to placebo, sildenafil did not improve symptoms, quality of life or exercise capacity in patients with HFrEF and PHT.

Topics: Aged; Double-Blind Method; Exercise Tolerance; Female; Heart Failure; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase 5 Inhibitors; Quality of Life; Sildenafil Citrate; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Sildenafil is the drug of choice for neonatal pulmonary hypertension in developing countries where inhaled nitric oxide is not available. Available as oral and intravenous preparation - no study has been done in the past to compare the two forms. Each has its own benefits - but requires comparison in terms of efficacy and safety. This study was done to compare the efficacy of oral versus intravenous (IV) sildenafil in infants with mild to moderate pulmonary hypertension.. An open labelled randomized trial was conducted in a neonatal intensive care unit of urban tertiary hospital in western India between February 2019 to December 2020. Infants born after 34 weeks of gestation with Pulmonary arterial pressure (PAP) > 25 mm Hg measured by echocardiography, within 72 h of birth, were enrolled for the study. Participants were randomly assigned to receive sildenafil either orally or by intravenous route. Primary outcome was the time taken for PAP to decrease below 25 mm Hg. Secondary outcomes were time taken for oxygenation index to decrease by 25%, duration of invasive and non-invasive mechanical ventilation, nasal oxygen, hospital stay, time to achieve full feeds, mortality, and side effects.. Forty patients were enrolled. The baseline characteristics of neonates in both groups were similar except for APGAR scores at 1 min and 5 min, with oral group having lower score [MEDIAN (IQR) 5.00 (4.00- 7.00) and 7.00 (6.00- 8.00)] compared to IV group [MEDIAN (IQR) 7.00 (6.00-8.00) and 9.00 (8.00-9.00)] respectively. Time taken for PAP to decrease below 25 mm was not statistically different between the oral and intravenous groups. Systemic hypotension occurred in 4 neonates of the intravenous group but none in the oral group.. Oral and intravenous sildenafil had equal efficacy at reducing PAP in neonatal pulmonary hypertension, albeit intravenous sildenafil use was associated with a greater complication rate.. Trial was registered in the clinical trials registry of India [ CTRI/2019/04/018781 ][25/04/2019].

Topics: Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Double-Blind Method; Exercise Tolerance; Heart Failure; Humans; Hypertension, Pulmonary; Sildenafil Citrate; Stroke Volume; Ventricular Dysfunction, Left

Persistent pulmonary hypertension of the newborn (PPHN) is a condition caused by failure of pulmonary vascular adaptation at birth, resulting in severe hypoxia. Several therapeutic modalities are being tried in developing countries where established therapies (inhaled nitric oxide and extracorporeal membrane oxygenation) are widely unavailable. This study aimed to assess the efficacy of milrinone versus sildenafil as available alternative therapeutics in treating PPHN. Forty neonates (>34 weeks) admitted to neonatal intensive care units with evidence of PPHN were randomly allocated to receive either oral sildenafil (0.5-2 mg/kg/6 hours) or intravenous milrinone (0.25-0.75 mic/kg/min). Primary outcomes included improvements in systolic pulmonary artery pressure and oxygen saturation index (OSI) at 24 and 48 hours after treatment. Secondary outcomes included the duration of hospitalization and mechanical ventilation. The ClinicalTrials identifier is NCT04391478. Both groups showed significant improvement in the post-treatment hemodynamic variables compared with pretreatment levels ( P < 0.05 for all parameters). Systolic pulmonary artery pressure and OSI values significantly improved in both study groups compared with baseline ( P < 0.001). The 24-hour and 48-hour post-treatment OSI values were much lower in the milrinone group than those in the sildenafil group ( P < 0.05). The length of hospital stay was significantly shorter in the milrinone group than that in the sildenafil group ( P < 0.05). There were no significant differences in the duration of mechanical ventilation, incidence of intracranial hemorrhage and pulmonary hemorrhage, or mortality between the 2 groups ( P > 0.05). In conclusion, milrinone and sildenafil are effective and well-tolerated in neonates with PPHN, particularly when inhaled nitric oxide and extracorporeal membrane oxygenation are not available. Milrinone is superior to sildenafil in improving oxygenation without lowering blood pressure parameters.

Topics: Humans; Hypertension, Pulmonary; Infant, Newborn; Milrinone; Nitric Oxide; Persistent Fetal Circulation Syndrome; Sildenafil Citrate; Vasodilator Agents

The benefit of sildenafil in patients with advanced idiopathic pulmonary fibrosis (IPF) at risk of poor outcomes from pulmonary hypertension, whether already present or likely to develop, is uncertain. We aimed to assess the efficacy and safety of sildenafil added to pirfenidone versus placebo added to pirfenidone for 52 weeks in patients with advanced IPF and at risk of group 3 pulmonary hypertension.. We did a multicentre, international, double-blind, randomised, placebo-controlled, phase 2b study at 56 university clinics, research hospitals, and tertiary sites in Canada, Europe (Belgium, Czech Republic, Germany, Greece, Hungary, Italy, the Netherlands, Spain, and Turkey), Israel, and Africa (Egypt and South Africa). Eligible patients (aged 40-80 years) had advanced IPF (carbon monoxide diffusing capacity ≤40% predicted at screening), and were at risk of group 3 pulmonary hypertension (mean pulmonary artery pressure of ≥20 mm Hg with pulmonary artery wedge pressure of ≤15 mm Hg on previous right-heart catheterisation, or intermediate or high probability of group 3 pulmonary hypertension on echocardiography as defined by the 2015 European Society of Cardiology and European Respiratory Society guidelines). Patients were randomly assigned 1:1 to oral sildenafil tablets (20 mg three times daily) or placebo, both in addition to oral pirfenidone capsules (801 mg three times daily), using a validated interactive voice-based or web-based response system with permuted block randomisation, stratified by previous right-heart catheterisation (yes or no) and forced expiratory volume in 1 s to forced vital capacity ratio (<0·8 or ≥0·8). The composite primary endpoint was disease progression, defined as either a relevant decline in 6-min walk distance, respiratory-related admission to hospital, or all-cause mortality, after 52 weeks and was assessed in the intention-to-treat population; safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02951429, and is no longer recruiting. The 11-month safety follow-up is ongoing.. Between Jan 13, 2017, and Aug 30, 2018, 247 patients were screened for eligibility, 177 of whom were randomly assigned to a treatment group (n=88 sildenafil; n=89 placebo) and were assessed for the primary outcome. There was no difference in the proportion of patients with disease progression over 52 weeks between the sildenafil (64 [73%] of 88 patients) and placebo groups (62 [70%] of 89 patients; between-group difference 3·06% [95% CI -11·30 to 17·97]; p=0·65). Serious treatment-emergent adverse events were reported in 54 (61%) patients in the sildenafil group and 55 (62%) patients in the placebo group. Treatment-emergent adverse events leading to mortality occurred in 22 (25%) patients in the sildenafil group and 26 (29%) in the placebo group.. Addition of sildenafil to pirfenidone did not provide a treatment benefit versus pirfenidone plus placebo up to 52 weeks in patients with advanced IPF and risk of pulmonary hypertension. No new safety signals were identified with either treatment. Although the absence of a beneficial treatment effect suggests that sildenafil is not an appropriate treatment in the overall population, further research is required to establish if specific subgroups of patients with IPF might benefit from sildenafil.. F Hoffmann-La Roche.

Topics: Aged; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Male; Pyridones; Sildenafil Citrate

Background The determinants and consequences of pulmonary hypertension after successfully corrected valvular heart disease remain poorly understood. We aim to clarify the hemodynamic bases and risk factors for mortality in patients with this condition. Methods and Results We analyzed long-term follow-up data of 222 patients with pulmonary hypertension and valvular heart disease successfully corrected at least 1 year before enrollment who had undergone comprehensive hemodynamic and imaging characterization as per the SIOVAC (Sildenafil for Improving Outcomes After Valvular Correction) clinical trial. Median (interquartile range) mean pulmonary pressure was 37 mm Hg (32-44 mm Hg) and pulmonary artery wedge pressure was 23 mm Hg (18-26 mm Hg). Most patients were classified either as having combined precapillary and postcapillary or isolated postcapillary pulmonary hypertension. After a median follow-up of 4.5 years, 91 deaths accounted for 4.21 higher-than-expected mortality in the age-matched population. Risk factors for mortality were male sex, older age, diabetes mellitus, World Health Organization functional class III and higher pulmonary vascular resistance-either measured by catheterization or approximated from ultrasound data. Higher pulmonary vascular resistance was related to diabetes mellitus and smaller residual aortic and mitral valve areas. In turn, the latter correlated with prosthetic nominal size. Six-month changes in the composite clinical score and in the 6-minute walk test distance were related to survival. Conclusions Persistent valvular heart disease-pulmonary hypertension is an ominous disease that is almost universally associated with elevated pulmonary artery wedge pressure. Pulmonary vascular resistance is a major determinant of mortality in this condition and is related to diabetes mellitus and the residual effective area of the corrected valve. These findings have important implications for individualizing valve correction procedures. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00862043.

Topics: Diabetes Mellitus; Double-Blind Method; Female; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Heart Valves; Humans; Hypertension, Pulmonary; Long Term Adverse Effects; Male; Middle Aged; Organ Size; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Pulmonary Wedge Pressure; Risk Factors; Sildenafil Citrate; Vascular Resistance

Pulmonary hypertension (PH) can develop secondary to many common cardiopulmonary diseases, and the use of sildenafil has improved care of affected dogs.. To evaluate response to sildenafil in dogs with respiratory-associated PH.. Twenty-five dogs with PH.. Prospective clinical trial. Doppler echocardiography identified dogs with moderate to severe PH, and additional tests were performed to detect underlying diseases. A 17-point quality of life (QOL) questionnaire was completed, and sildenafil was prescribed, along with other medications deemed necessary for the management of clinically diagnosed respiratory diseases. After 30 days, dogs returned to the hospital for repeat echocardiogram and QOL survey.. The median age was 12.4 years, and most dogs were small breed dogs (median weight, 6.5 kg). Syncope (64%), cough (56%), and respiratory difficulty (32%) were the most common presenting complaints. Respiratory diseases associated with PH included tracheobronchomalacia, pulmonary fibrosis, inflammatory airway disease, and brachycephalic syndrome, with multiple diseases in some dogs. Eight of 25 dogs (32%) died or were euthanized within 1 month. In the remaining dogs, tricuspid regurgitation pressure gradient (83.0 ± 17.4 mm Hg before, 55.4 ± 17.4 mm Hg after) and QOL scores were significantly improved after 1 month of sildenafil. Fifty percent mortality was reached 6 months after study entry, with 4 dogs alive 5 years after diagnosis.. Sildenafil responsiveness is variable in dogs with respiratory-associated PH, but improved QOL was demonstrated in dogs surviving >1 month, and long-term survival was noted in some cases.

Topics: Animals; Dog Diseases; Dogs; Female; Hypertension, Pulmonary; Lung Diseases; Male; Quality of Life; Sildenafil Citrate; Survival Analysis; Treatment Outcome; Vasodilator Agents

Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes.. To determine whether sildenafil reduces perinatal mortality or major morbidity.. This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants.. Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo.. The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge.. Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008).. These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension.. ClinicalTrials.gov Identifier: NCT02277132.

Topics: Adult; Birth Weight; Double-Blind Method; Early Termination of Clinical Trials; Female; Fetal Growth Retardation; Gestational Age; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Newborn, Diseases; Intention to Treat Analysis; Male; Middle Cerebral Artery; Perinatal Mortality; Phosphodiesterase 5 Inhibitors; Placenta Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Pulsatile Flow; Sildenafil Citrate; Umbilical Arteries

The management of severe persistent pulmonary hypertension (PPHN) can be very challenging in many resource-limited centers without access to inhaled nitric oxide or extracorporeal membrane oxygenation.. The current study aimed to investigate the efficacy of oral sildenafil and intravenous milrinone infusion and compare the effects of these drugs in combination versus as monotherapy in neonates with PPHN.. A double-blind randomized controlled trial was conducted in which neonates with PPHN were divided into three groups of 20 patients each: group 1 received oral sildenafil starting at 0.5 mg/kg every 6 h to a target maintenance dose of 2 mg/kg every 6 h; group 2 received intravenous milrinone 0.5 μg/kg/min as a continuous infusion; and group 3 received both oral sildenafil and intravenous milrinone.. Post-treatment pulmonary artery systolic pressure was significantly lower in group 3 than in groups 1 and 2, which both received monotherapy (p = 0.031). The oxygenation index also decreased significantly in the dual-therapy group (p = 0.002) compared with the monotherapy groups. Combined use of both drugs demonstrated a beneficial synergistic effect with better outcomes and reduced mortality.. Dual therapy using sildenafil and milrinone was superior to monotherapy with either drug in neonates with severe PPHN and is recommended for use in resource-constrained settings.. Pan African Clinical Trial Registry identifier number PACTR201902691230243.

Topics: Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Milrinone; Sildenafil Citrate; Vasodilator Agents

Canine pulmonary hypertension (PH) is associated with high morbidity and mortality. Tadalafil, a phosphodiesterase-5 inhibitor used commonly in humans with PH, has not been evaluated in a clinical trial in dogs with naturally occurring PH. Our objectives were to compare the efficacy of tadalafil and sildenafil on PH assessed by peak tricuspid regurgitant flow velocity, estimated systolic pulmonary arterial pressure gradient, voluntary activity, quality of life, and safety profiles in dogs with moderate to severe PH.. Twenty-three dogs with echocardiographic evidence of moderate to severe PH were enrolled.. A prospective short-term, randomized, double-blinded pilot study was carried out. Dogs with PH were randomly allocated to receive sildenafil or tadalafil for 2 weeks and assessed via echocardiography, activity monitors, and owner-reported outcomes.. Collectively, phosphodiesterase-5 inhibition significantly decreased (improved) quality of life scores (p = 0.003) and visual analog score (p = 0.024) without significant between-treatment difference of these variables. Phosphodiesterase-5 inhibition did not significantly affect peak tricuspid regurgitant flow velocity (p = 0.056) or voluntary activity (p = 0.27). A total of 33% (7/21) of dogs experienced at least one adverse event during the study (tadalafil, n = 5; sildenafil, n = 2) with no significant difference between treatment type and incidence of adverse events (p = 0.36).. In this pilot study, phosphodiesterase-5 inhibition led to apparent improvement in quality of life scores without documenting superiority of tadalafil over sildenafil.. Tadalafil at a dose of 2 mg/kg once daily appears to be a viable alternative to sildenafil in dogs with moderate to severe PH.

Topics: Animals; Dog Diseases; Dogs; Double-Blind Method; Electrocardiography; Female; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Pilot Projects; Prospective Studies; Random Allocation; Severity of Illness Index; Sildenafil Citrate; Surveys and Questionnaires; Tadalafil; Treatment Outcome

To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants.. We performed a multicentre, open-label trial to characterize the PK of sildenafil in infants ≤28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose-exposure simulations using the software NONMEM®.. We enrolled 34 infants (cohort 1 n = 25; cohort 2 n = 9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (n = 4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro.. We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study.

Topics: Administration, Oral; Cohort Studies; Cytochrome P-450 CYP3A; Fluconazole; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Intravenous; Models, Biological; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on 'trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking.. In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses.. Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained.. NTR6982; Pre-results.

Topics: Administration, Inhalation; Administration, Intravenous; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Nitric Oxide; Randomized Controlled Trials as Topic; Sildenafil Citrate; Vasodilator Agents

Ideally, vasodilator therapies for pulmonary arterial hypertension (PAH) should have a favorable impact on markers of vascular dysfunction, in addition to their known effects on hemodynamics, cardiac function, and patient's physical capacity.. We analyzed circulating (plasma) markers of endothelial and platelet activation/dysfunction (enzyme-linked immunoassays) in the specific setting of advanced PAH associated with congenital heart disease, during the course of sildenafil and tadalafil therapies. Thirty-one patients were enrolled (age 10-54 years), most of them with chronic hypoxemia and elevated hematocrit. Drugs were administered orally for 6 months (sildenafil [n = 16], 20 mg t.i.d.; tadalafil [n = 15], single daily dose of 40 mg). Measurements were performed at baseline, and 90 and 180 days.. Compared to controls, patients had elevated baseline β-thromboglobulin (β-TG, P = .002), P-selectin (P = .027), tissue-type plasminogen activator (t-PA, P = .009), and von Willebrand factor antigen (VWF:Ag, P = .010). Thrombomodulin was importantly reduced (TM, P < .001), while soluble CD40 Ligand was not changed (P = .320). Tadalafil administration was associated with improvement of β-TG (P = .004), t-PA (P = .003) and TM (P = .046) levels, while P-selectin was improved by sildenafil treatment only (P = .034). VWF:Ag improved transiently in the sildenafil group (P = .019). Both therapies were associated with improvement of the physical capacity (functional class and distance walked during the 6-minute test, P < .05), hematocrit and hemoglobin level (P < .05), and health-related quality of life (physical and mental components, P < .05).. In PAH associated with congenital heart disease, phosphodiesterase 5 inhibitors seem to have beneficial actions at microcirculatory level, beyond the proposed effects as vasodilators.

Topics: Adolescent; Adult; Cardiac Catheterization; Child; Dose-Response Relationship, Drug; Echocardiography; Female; Follow-Up Studies; Heart Defects, Congenital; Heart Ventricles; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging, Cine; Male; Microcirculation; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Circulation; Pulmonary Wedge Pressure; Retrospective Studies; Sildenafil Citrate; Tadalafil; Treatment Outcome; Young Adult

We aimed to determine whether treatment with sildenafil improves outcomes of patients with persistent pulmonary hypertension (PH) after correction of valvular heart disease (VHD).. The sildenafil for improving outcomes after valvular correction (SIOVAC) study was a multricentric, randomized, parallel, and placebo-controlled trial that enrolled stable adults with mean pulmonary artery pressure ≥ 30 mmHg who had undergone a successful valve replacement or repair procedure at least 1 year before inclusion. We assigned 200 patients to receive sildenafil (40 mg three times daily, n = 104) or placebo (n = 96) for 6 months. The primary endpoint was the composite clinical score combining death, hospital admission for heart failure (HF), change in functional class, and patient global self-assessment. Only 27 patients receiving sildenafil improved their composite clinical score, as compared with 44 patients receiving placebo; in contrast 33 patients in the sildenafil group worsened their composite score, as compared with 14 in the placebo group [odds ratio 0.39; 95% confidence interval (CI) 0.22-0.67; P < 0.001]. The Kaplan-Meier estimates for survival without admission due to HF were 0.76 and 0.86 in the sildenafil and placebo groups, respectively (hazard ratio 2.0, 95% CI = 1.0-4.0; log-rank P = 0.044). Changes in 6-min walk test distance, natriuretic peptides, and Doppler-derived systolic pulmonary pressure were similar in both groups.. Treatment with sildenafil in patients with persistent PH after successfully corrected VHD is associated to worse clinical outcomes than placebo. Off-label usage of sildenafil for treating this source of left heart disease PH should be avoided. The trial is registered with ClinicalTrials.gov, number NCT00862043.

Topics: Aged; Double-Blind Method; Female; Heart Failure; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Male; Placebos; Pulmonary Wedge Pressure; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension (PH) is commonly observed in patients with advanced idiopathic pulmonary fibrosis (IPF). Despite the availability of therapies for both IPF and PH, none are approved for PH treatment in the context of significant pulmonary disease. This study will investigate the use of sildenafil added to pirfenidone in patients with advanced IPF and risk of PH, who represent a group with a high unmet medical need.. This Phase IIb, randomised, double-blind, placebo-controlled trial is actively enrolling patients and will study the efficacy, safety and tolerability of sildenafil or placebo in patients with advanced IPF and intermediate or high probability of Group 3 PH who are receiving a stable dose of pirfenidone. Patients with advanced IPF (diffusing capacity for carbon monoxide ≤40% predicted) and risk of Group 3 PH (defined as mean pulmonary arterial pressure ≥20 mm Hg with pulmonary arterial wedge pressure ≤15 mm Hg on a previous right-heart catheterisation [RHC], or intermediate/high probability of Group 3 PH as defined by the 2015 European Society of Cardiology/European Respiratory Society guidelines) are eligible. In the absence of a previous RHC, patients with an echocardiogram showing a peak tricuspid valve regurgitation velocity ≥2.9 m/s can enrol if all other criteria are met. The primary efficacy endpoint is the proportion of patients with disease progression over a 52-week treatment period. Safety will be evaluated descriptively.. Combination treatment with sildenafil and pirfenidone may warrant investigation of the treatment of patients with advanced IPF and pulmonary vascular involvement leading to PH.

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials, Phase II as Topic; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Male; Middle Aged; Multicenter Studies as Topic; Pyridones; Randomized Controlled Trials as Topic; Research Design; Sildenafil Citrate; Vasodilator Agents

Congenital diaphragmatic hernia is an orphan disease with high neonatal mortality and significant morbidity. An important cause for this is pulmonary hypertension, for which no effective postnatal therapy is available to date. An innovative strategy aiming at treating or preventing pulmonary hypertension more effectively is urgently needed. Prenatal sildenafil administration to expectant mothers prevented fetal and neonatal vascular changes leading to pulmonary hypertension in several animal models, and is, therefore, a promising approach. Before transferring this antenatal medical approach to the clinic, more information is needed on transplacental transfer and safety of sildenafil in humans.. This is a randomized, investigator-blinded, double-armed, parallel-group, phase I/IIb study with as a primary objective to measure the in-vivo transplacental transfer of sildenafil in women in the second and early third trimester of pregnancy (sub-study 1; weeks: 20.0-32.6) and at term (sub-study 2; weeks: 36.6-40). Participants will be randomized to two different sildenafil doses: 25 or 75 mg. In sub-study 1, a single dose of the investigational product will be administered to women undergoing termination of pregnancy, and maternal and fetal blood samples will be collected for determination of sildenafil concentrations. In sub-study 2, sildenafil will be administered three times daily from 3 days before planned delivery until actual delivery, following which maternal and umbilical cord samples will be collected. Proxies of maternal and fetal tolerance as well as markers of fetal pulmonary vasodilation will also be measured.. This is the first study evaluating in-vivo transplacental passage of sildenafil in humans.. EU Clinical Trials Register 2016-002619-17, validated on 12 August 2016. Trial sponsor: UZ Leuven, Herestraat 49, 3000 Leuven.

Topics: Adult; Antihypertensive Agents; Belgium; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Female; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Maternal-Fetal Exchange; Placental Circulation; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Prenatal Care; Randomized Controlled Trials as Topic; Sildenafil Citrate; Young Adult

Despite the increased risk for pulmonary hypertension in children with Down syndrome, the response to treatment with targeted therapies for pulmonary hypertension in these patients is not well characterized. The Sildenafil in Treatment-naive children, Aged 1-17 years, with pulmonary arterial hypertension (STARTS-1) trial was a dose-ranging study of the short-term efficacy and safety of oral sildenafil in children with pulmonary arterial hypertension. We assessed the safety and efficacy of oral sildenafil in children with Down syndrome and pulmonary arterial hypertension.. This was a post-hoc analysis of children with Down syndrome and pulmonary arterial hypertension enrolled in the STARTS-1 trial. Mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance index (PVRI), and cardiac index (CI) were assessed at baseline and following 16 weeks of treatment with sildenafil.. Of 234 patients randomized and treated in the STARTS-1 trial, 48 (20.5%) had Down syndrome. Although sildenafil produced dose-related reductions in PVRI and mPAP, compared with placebo, in non-Down syndrome patients and children developmentally able to exercise, this was not satisfactorily marked in patients with Down syndrome. The dose-related reductions in PVRI, compared with placebo, occurred in all subgroups, with the exception of the Down syndrome subgroup. Sildenafil appeared to be well tolerated in the Down syndrome subpopulation and the most frequently reported AEs were similar to those reported for the entire STARTS-1 population.. Sildenafil treatment for 16 weeks had no effect on PVRI or mPAP in children with Down syndrome and pulmonary arterial hypertension. The results suggest that children with Down syndrome may be less responsive to sildenafil for pulmonary arterial hypertension, but the incomplete work-up for the etiology of pulmonary arterial hypertension may have introduced a potential bias.. Study received, September 8, 2005 (retrospectively registered); Study start, August 2003; ClinicalTrials.gov identifier, NCT00159913 .

Topics: Administration, Oral; Adolescent; Antihypertensive Agents; Arterial Pressure; Child; Child, Preschool; China; Down Syndrome; Female; Humans; Hypertension, Pulmonary; Infant; Male; Pulmonary Artery; Sildenafil Citrate; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Few controlled clinical trials exist to support oral combination therapy in pulmonary arterial hypertension (PAH).. Patients with PAH (idiopathic [IPAH] or associated with connective tissue disease [APAH-CTD]) taking bosentan (62.5 or 125 mg twice daily at a stable dose for ≥3 months) were randomized (1:1) to sildenafil (20 mg, 3 times daily; n = 50) or placebo (n = 53). The primary endpoint was change from baseline in 6-min walk distance (6MWD) at week 12, assessed using analysis of covariance. Patients could continue in a 52-week extension study. An analysis of covariance main-effects model was used, which included categorical terms for treatment, baseline 6MWD (<325 m; ≥325 m), and baseline aetiology; sensitivity analyses were subsequently performed.. In sildenafil versus placebo arms, week-12 6MWD increases were similar (least squares mean difference [sildenafil-placebo], -2.4 m [90% CI: -21.8 to 17.1 m]; P = 0.6); mean ± SD changes from baseline were 26.4 ± 45.7 versus 11.8 ± 57.4 m, respectively, in IPAH (65% of population) and -18.3 ± 82.0 versus 17.5 ± 59.1 m in APAH-CTD (35% of population). One-year survival was 96%; patients maintained modest 6MWD improvements. Changes in WHO functional class and Borg dyspnoea score and incidence of clinical worsening did not differ. Headache, diarrhoea, and flushing were more common with sildenafil.. Sildenafil, in addition to stable (≥3 months) bosentan therapy, had no benefit over placebo for 12-week change from baseline in 6MWD. The influence of PAH aetiology warrants future study.. ClinicalTrials.gov NCT00323297 (registration date: May 5, 2006).

Topics: Adult; Aged; Antihypertensive Agents; Arterial Pressure; Bosentan; Double-Blind Method; Drug Therapy, Combination; Endothelin Receptor Antagonists; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Least-Squares Analysis; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Recovery of Function; Sildenafil Citrate; Sulfonamides; Time Factors; Treatment Outcome; Vasodilator Agents; Walk Test

Young children with CHD and large systemic-to-pulmonary shunts eventually develop pulmonary hypertension. At present, phosphodiesterase type-5 inhibitors such as sildenafil have been used to control pulmonary pressure before and after cardiac surgery. Recently, tadalafil has been utilised in older children with similar efficacy, but it has been used to a lesser extent in young infants. From April, 2015 to June, 2016, 42 patients aged 3-24 months with a large septal defect and pulmonary arterial hypertension were randomly divided into two equal groups: one group received oral sildenafil (1-3 mg/kg/day every 8 hours), whereas the other group received oral tadalafil (1 mg/kg once a day) from 7-10 days before surgery to 3-4 weeks after surgery. During the first 48 hours after surgery, pulmonary artery-to-aortic pressure ratio and recorded systolic pulmonary artery pressures were not significantly different between the two groups (p>0.05); moreover, there were no differences in paediatric ICU length of stay, mechanical ventilation time, clinical findings of low cardiac output state, and echocardiographic data between the two groups (p>0.05). Most of the patients had no side effects, and only five patients had a minor with no significant difference in both groups (p=0.371). Tadalafil can be considered as an effective oral therapy for preoperative and postoperative pulmonary hypertension in young infants. It can be administered at a once-daily dose with an appropriate efficacy and safety profile as sildenafil, and therefore it can be considered as an alternative to sildenafil in young children.

Topics: Cardiac Surgical Procedures; Child, Preschool; Echocardiography; Female; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Infant; Iran; Length of Stay; Male; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Sildenafil Citrate; Tadalafil; Treatment Outcome

Pulmonary hypertension (PH) is a well-known independent prognostic factor in chronic obstructive pulmonary disease (COPD) and a sufficient criterion for lung transplant candidacy. Limited data are currently available on the hemodynamic and clinical effect of phosphodiesterase 5 inhibitors in patients with severe PH associated with COPD. This study assessed the effect of sildenafil on pulmonary hemodynamics and gas exchange in severe PH associated with COPD.. After screening, this multicenter, randomized, placebo-controlled double-blind trial randomized patients to receive 20 mg sildenafil or placebo 3 times a day (ratio 2:1) for 16 weeks. The primary end point was the reduction in pulmonary vascular resistance. Secondary end points included BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, 6-minute walk test, and quality of life questionnaire. Changes in the partial pressure of arterial oxygen were evaluated as a safety parameter.. The final population included 28 patients, 18 in the sildenafil group and 10 in the placebo group. At 16 week, patients treated with sildenafil had a decrease in pulmonary vascular resistance (mean difference with placebo -1.4 WU; 95% confidence interval, ≤ -0.05; p = 0.04). Sildenafil also improved the BODE index, diffusion capacity of the lung for carbon monoxide percentage, and quality of life. Change from baseline in the partial pressure of arterial oxygen was not significantly different between the sildenafil and placebo groups.. This pilot study found that treatment with sildenafil reduced pulmonary vascular resistance and improved the BODE index and quality of life, without a significant effect on gas exchange.

Topics: Adult; Aged; Aged, 80 and over; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Patient Selection; Pilot Projects; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Reference Values; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Treatment Outcome; Vascular Resistance

We recently showed that sildenafil did not improve pulmonary pressures and exercise capacity in a cohort of patients with heart failure and preserved ejection fraction (HFpEF) and predominantly postcapillary pulmonary hypertension. Here, we present the effects of sildenafil on cardiac structure and function, cardiopulmonary exercise testing, laboratory parameters and health-related quality of life measures.. Fifty-two HFpEF patients with pulmonary hypertension (mean pulmonary artery pressure >25 mmHg; pulmonary artery wedge pressure >15 mmHg) were randomized to sildenafil 60 mg three times a day or placebo and treated for 12 weeks. Sildenafil neither changed cardiac structure nor function on echocardiography compared with placebo. Considering all patients irrespective of maximal effort, sildenafil reduced peak heart rate by 8 b.p.m. [95% confidence interval (CI) -14.97 to -1.03] and peak blood pressure by 13.8 mmHg (95% CI -22.04 to -5.47)/7.3 mmHg (95% CI -13.60 to -1.07) (both P < 0.05 vs. placebo). The minute ventilation/carbon dioxide production (VE/VCO. Treatment with sildenafil for 12 weeks in patients with HFpEF and predominantly isolated postcapillary pulmonary hypertension did not affect cardiac structure and function, integrative exercise responses, laboratory parameters, and/or quality of life. Clinicaltrials.gov number NCT01726049.

Topics: Aged; Aged, 80 and over; Blood Pressure; Cardiac Catheterization; Echocardiography; Exercise Test; Female; Glycated Hemoglobin; Health Status; Heart Failure; Heart Rate; Hemoglobins; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Pulmonary Wedge Pressure; Quality of Life; Sildenafil Citrate; Stroke Volume; Treatment Outcome

Patients with pulmonary arterial hypertension (PAH) who do not have an adequate response to therapy with phosphodiesterase-5 inhibitors (PDE-5i) may have insufficient synthesis of cyclic guanosine monophosphate (cGMP). These patients may respond to a direct soluble guanylate cyclase (sGC) stimulator such as riociguat. RESPITE (NCT02007629) was an open-label, multicenter, uncontrolled, single-arm phase 3b study of riociguat in patients with PAH who demonstrated an insufficient response to treatment with PDE-5i. Insufficient response was defined as World Health Organization functional class (WHO FC) III despite PDE-5i therapy for at least 90 days; 6-min walk distance (6MWD) of 165-440 m, and right-heart catheterization showing mean pulmonary artery pressure >30 mmHg, cardiac index <3.0 L/min/m

Topics: Adolescent; Adult; Aged; Endothelin Receptor Antagonists; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Nitric Oxide; Outcome Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyrimidines; Quality of Life; Sildenafil Citrate; Soluble Guanylyl Cyclase; Young Adult

In a previous study, 6-minute walk distance (6MWD) improvement with sildenafil was not dose dependent at the 3 doses tested (20, 40, and 80 mg 3 times daily [TID]). This study assessed whether lower doses were less effective than the approved 20-mg TID dosage.. Treatment-naive patients with pulmonary arterial hypertension were randomized to 12 weeks of double-blind sildenafil 1, 5, or 20 mg TID; 12 weeks of open-label sildenafil 20 mg TID followed. Changes from baseline in 6-minute walk distance (6MWD) for sildenafil 1 or 5 mg versus 20 mg TID were compared using a Williams test. Hemodynamics, functional class, and biomarkers were assessed.. The study was prematurely terminated for non-safety reasons, with 129 of 219 planned patients treated. At week 12, 6MWD change from baseline was significantly greater for sildenafil 20 versus 1 mg (P = 0.011) but not versus 5 mg. At week 24, 6MWD increases from baseline were larger in those initially randomized to 20 versus 5 or 1 mg (74 vs 50 and 47 m, respectively). At week 12, changes in hemodynamic parameters were generally small and variable between treatment groups; odds ratios for improvement in functional class were not statistically significantly different. Improvements in B-type natriuretic peptide levels were significantly greater with sildenafil 20 versus 1 but not 5 mg.. Sildenafil 20 mg TID appeared to be more effective than 1 mg TID for improving 6MWD; sildenafil 5 mg TID appeared to have similar clinical and hemodynamic effects as 20 mg TID.. ClinicalTrials.gov NCT00430716 (Registration date: January 31, 2007).

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Echocardiography; Female; Hemodynamics; Humans; Hypertension, Pulmonary; International Cooperation; Male; Middle Aged; Natriuretic Peptide, Brain; Severity of Illness Index; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents; Walk Test; Young Adult

To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4-5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration-time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime.

Topics: Adult; Bosentan; Drug Therapy, Combination; Exercise; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Pyridazines; Sildenafil Citrate; Sulfonamides

Exposure to high altitudes especially with rapid ascent may induce hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension (PH) possibly leading to life-threatening high-altitude pulmonary edema (HAPE). The aim of the study was to evaluate the incidence of PH on a 1-day rapid ascent up Mount Fuji (3775 m) in recreational climbers and also to determine the effectiveness of sildenafil for this rapid ascent-induced PH as measured by echocardiography.. Twenty-five subjects who climbed Mount Fuji showed significantly increased pulmonary artery systolic pressure (PASP) from 22.3 ± 5.3 mmHg at sea level to 29.4 ± 8.7 mmHg at 3775 m. Five subjects showed PASP >35 mmHg (35.6-46.2 mmHg, average 42.0 ± 3.9 mmHg) and took oral sildenafil 50 mg after which PASP decreased significantly to 24.5 ± 4.6 mmHg (18.7-31.0 mmHg) after 30 minutes.. One-day rapid ascent of Mount Fuji may induce mild-to-moderate PH and intervention with sildenafil can reduce this PH, suggesting that the therapeutic use of sildenafil would be more reasonable for the relatively infrequent occurrence of altitude-induced PH than its prophylactic use.

Topics: Adult; Aged; Altitude; Altitude Sickness; Antihypertensive Agents; Echocardiography; Female; Humans; Hypertension, Pulmonary; Incidence; Japan; Male; Middle Aged; Mountaineering; Risk Factors; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Pulmonary vascular (PV) distensibility, defined as the percent increase in pulmonary vessel diameter per mm Hg increase in pressure, permits the pulmonary vessels to increase in size to accommodate increased blood flow. We hypothesized that PV distensibility is abnormally low in patients with heart failure (HF) and serves as an important determinant of right ventricular performance and exercise capacity.. Patients with HF with preserved ejection fraction (n=48), HF with reduced ejection fraction (n=55), pulmonary arterial hypertension without left heart failure (n=18), and control subjects (n=30) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and first-pass radionuclide ventriculography. PV distensibility was derived from 1257 matched measurements (mean±SD, 8.3±2.8 per subject) of pulmonary arterial pressure, pulmonary arterial wedge pressure and cardiac output. PV distensibility was lowest in the pulmonary arterial hypertension group (0.40±0.24% per mm Hg) and intermediate in the HF with preserved ejection fraction and HF with reduced ejection fraction groups (0.92±0.39 and 0.84±0.33% per mm Hg, respectively) compared to the control group (1.39±0.32% per mm Hg, P<0.0001 for all three). PV distensibility was associated with change in right ventricular ejection fraction (RVEF, ρ=0.39, P<0.0001) with exercise and was an independent predictor of peak VO2. PV distensibility also predicted cardiovascular mortality independent of peak VO2 in HF patients (n=103; Cox hazard ratio, 0.30; 95% confidence interval, 0.10-0.93; P=0.036). In a subset of patients with HF with reduced ejection fraction (n=26), 12 weeks of treatment with the pulmonary vasodilator sildenafil or placebo led to a 24.6% increase in PV distensibility (P=0.015) in the sildenafil group only.. PV distensibility is reduced in patients with HF and pulmonary arterial hypertension and is closely related to RV systolic function during exercise, maximal exercise capacity, and survival. Furthermore, PV distensibility is modifiable with selective pulmonary vasodilator therapy and may represent an important target for therapy in selected HF patients with pulmonary hypertension.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00309790.

Topics: Adult; Aged; Antihypertensive Agents; Arterial Pressure; Case-Control Studies; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Heart Failure; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Models, Cardiovascular; Multivariate Analysis; Phosphodiesterase 5 Inhibitors; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Pulmonary Artery; Risk Assessment; Risk Factors; Severity of Illness Index; Sildenafil Citrate; Stroke Volume; Time Factors; Treatment Outcome; Vascular Stiffness; Vasodilator Agents; Ventricular Function, Right

High pulmonary vascular resistance (PVR) may be a risk factor for early and late mortality in both Glen shunt and Fontan operation patients. Furthermore, PVR may increase long after the Fontan operation. Whether pulmonary vasodilators such as phosphodiesterase 5 inhibitors can decrease PVR in patients with single ventricular physiology remains undetermined.. This was a prospective, multicenter study. Patients with single ventricular physiology who have a PVR index higher than 2.5 Wood units·㎡ (WU) were enrolled. Cardiac catheterization was performed before and after administration of sildenafil in all patients. After the Fontan operation, a six minute walk test (6MWT) was also performed. A total of 42 patients were enrolled. PVR was significantly decreased in each stage of single ventricular physiology after sildenafil administration: from 4.3±1.5WU to 2.1±0.6WU (p<0.01) in patients before a Glenn shunt, from 3.2±0.5WU to 1.6±0.6WU (p<0.001) in patients after a Glenn shunt, and from 3.9±1.7WU to 2.3±0.8WU (p<0.001) in patients after Fontan. In patients after Fontan, the 6MWT increased from 416±74m to 485±72m (p<0.01), and NYHA functional class improved significantly (p<0.05) after sildenafil administration. No major side effects were observed in any patients.. Sildenafil reduced PVR in patients with single ventricle physiology. Sildenafil increased exercise capacity and improved NYHA functional class in patients after a Fontan operation. This implies that pulmonary vasodilation is a potential therapeutic target in selected patients with elevated PVR with single ventricle physiology. Long-term clinical significance warrants further study.

Topics: Adolescent; Child, Preschool; Female; Fontan Procedure; Heart Defects, Congenital; Heart Ventricles; Hemodynamics; Humans; Hypertension, Pulmonary; Infant, Newborn; Japan; Male; Outcome and Process Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Sildenafil Citrate; Vascular Resistance; Vasodilator Agents

A treatment strategy for patients with pulmonary hypertension (PH) and atrial septal defect (ASD) remains unclear. This study was designed to evaluate the effects of initial repair of ASD followed by treatment with PH-specific drugs in patients with PH and ASD. Eligible patients receive transcatheter ASD closure followed by treatment with bosentan and sildenafil. Right heart catheterization is performed at baseline and at 12, 24 and 48 weeks. The primary endpoint is change in pulmonary artery pressure and pulmonary vascular resistance from baseline to follow-up. This study should provide valuable information to establish a therapeutic strategy for PH and ASD.

Topics: Antihypertensive Agents; Bosentan; Clinical Protocols; Drug Administration Schedule; Feasibility Studies; Heart Septal Defects, Atrial; Humans; Hypertension, Pulmonary; Prospective Studies; Sildenafil Citrate; Sulfonamides

The efficacy of nebulized sodium nitrite (AIR001) has been demonstrated in animal models of pulmonary arterial hypertension (PAH), but it was not known if inhaled nitrite would be well tolerated in human subjects at exposure levels associated with efficacy in these models.. Inhaled nebulized sodium nitrite was assessed in three independent studies in a total of 82 healthy male and female subjects. Study objectives included determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) under normal and mildly hypoxic conditions, and following co-administration with steady-state sildenafil, assessment of nitrite pharmacokinetics, and evaluation of the fraction exhaled nitric oxide (FENO) and concentrations of iron-nitrosyl hemoglobin (Hb(Fe)-NO) and S-nitrosothiols (R-SNO) as biomarkers of local and systemic NO exposure, respectively.. Nebulized sodium nitrite was well tolerated following 6 days of every 8 h administration up to 90 mg, producing significant increases in circulating Hb(Fe)-NO, R-SNO, and FENO. Pulmonary absorption of nitrite was rapid and complete, and plasma exposure dose was proportional through the MTD dosage level of 90 mg, without accumulation following repeated inhalation. At higher dosage levels, DLTs were orthostasis (observed at 120 mg) and hypotension with tachycardia (at 176 mg), but venous methemoglobin did not exceed 3.0 % at any time in any subject. Neither the tolerability nor pharmacokinetics of nitrite was impacted by conditions of mild hypoxia, or co-administration with sildenafil, supporting the safe use of inhaled nitrite in the clinical setting of PAH.. On the basis of these results, nebulized sodium nitrite (AIR001) has been advanced into randomized trials in PAH patients.

Topics: Administration, Inhalation; Adolescent; Adult; Biomarkers; Cohort Studies; Drug Interactions; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sodium Nitrite; Sulfonamides; Young Adult

This study characterized the population pharmacokinetics (PK) of imatinib in patients with severe pulmonary arterial hypertension (PAH), investigated drug-drug interactions (DDI) among imatinib, sildenafil and bosentan, and evaluated their clinical implications.. Plasma concentrations of imatinib, bosentan and sildenafil were collected in a phase III study and were used to characterize the PK of imatinib in this population. DDIs among the three drugs were quantified using a linear mixed model and log-transformed drug concentrations.. The population mean estimates of apparent clearance (CL/F) and volume (V/F) were 10.8 l h(-1) (95% CI 9.2, 12.4 l h(-1) ) and 267 l (95% CI 208, 326 l), respectively. It was estimated that sildenafil concentrations increased, on average, by 64% (95% CI 32%, 103%) and bosentan concentrations by 51% (95% CI 12%, 104%), in the presence of imatinib. Despite increased concentrations of co-medications, treatment differences between imatinib and placebo for change in 6 min walk distance and pulmonary vascular resistance were relatively constant across the entire concentration range for sildenafil and bosentan. Overall, higher concentrations of imatinib and bosentan were not associated with increasing liver enzymes (serum glutamic oxaloacetic transaminases [SGOT]/serum glutamic-pyruvic transaminase [SGPT]).. Population PKs of imatinib in patients with severe PAH were found comparable with those of patients with chronic myeloid leukemia. Imatinib was found effective regardless of the co-medications and showed intrinsic efficacy beyond merely elevating the concentrations of the co-medications due to DDIs. There was no evidence of increased risk of liver toxicity upon co-administration with bosentan.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Bosentan; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Male; Sildenafil Citrate; Sulfonamides; Vascular Resistance; Young Adult

PATENT PLUS evaluated the safety and efficacy of riociguat in combination with sildenafil in pulmonary arterial hypertension patients. Patients receiving sildenafil (20 mg three times daily) were randomised to placebo or riociguat (up to 2.5 mg three times daily) for 12 weeks. The primary outcome was maximum change in supine systolic blood pressure (SBP) from baseline within 4 h of dosing. Secondary objectives comprised additional blood pressure, heart rate and exploratory efficacy variables, and safety. Patients could enter a long-term extension (LTE), where all patients received riociguat plus sildenafil. There was no difference in maximum change in supine SBP from baseline within 4 h between the riociguat (n=12) (mean±sd baseline: -20.2±15.3 mmHg; week 12: -20.7±18.0 mmHg) and placebo groups (n=6) (-7.6±3.9 and -20.2±12.9 mmHg, respectively). Changes in standing SBP and supine or standing diastolic blood pressure were also not different. Combination therapy showed no favourable effects on exploratory clinical parameters, including haemodynamics and exercise capacity. In the LTE, there were high rates of discontinuation due to hypotension and three (18%) deaths (not considered study drug-related by the investigator). There were potentially unfavourable safety signals with sildenafil plus riociguat and no evidence of a positive benefit/risk ratio. Concomitant use of riociguat with phosphodiesterase-5 inhibitors is therefore contraindicated.

Topics: Aged; Antihypertensive Agents; Diastole; Double-Blind Method; Europe; Exercise; Female; Follow-Up Studies; Guanylate Cyclase; Heart Rate; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Patient Safety; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyrimidines; Sildenafil Citrate; Systole

Elevated serum creatinine (sCr) and low estimated glomerular filtration rate (eGFR) are associated with poor outcomes in patients with pulmonary arterial hypertension (PAH) whereas sildenafil treatment improves PAH outcomes. This post hoc analysis assessed the effect of sildenafil on kidney function and links with clinical outcomes including 6-min walk distance, functional class, time to clinical worsening and survival.. Patients with PAH received placebo or sildenafil 20, 40 or 80 mg three times daily in the SUPER-1 study and open-label sildenafil titrated to 80 mg three times daily (as tolerated) in the extension study.. Baseline characteristics were similar among groups (n = 277). PAH was mostly idiopathic (63%) and functional class II (39%) or III (58%). From baseline to week 12, kidney function improved (increased eGFR, decreased sCr) with sildenafil and worsened with placebo. In univariate logistic regression, improved kidney function was associated with significantly improved exercise and functional class (odds ratios 1.17 [95% CI 1.01, 1.36] and 1.21 [95% CI 1.03, 1.41], respectively, for sCr and 0.97 [95% CI 0.94, 0.99] and 0.97 [95% CI 0.94, 0.99] for eGFR, all P < 0.05). In patients who maintained or improved kidney function, time to worsening was significantly delayed (P < 0.02 for both kidney parameters). Observed trends towards improved survival were not significant. Patients with eGFR <60 (vs. ≥60) ml min(-1) 1.73 m(-2) appeared to have worse survival.. Sildenafil treatment was associated with improved kidney function in patients with PAH, which was in turn associated with improved exercise capacity and functional class, a reduced risk of clinical worsening, and a trend towards reduced mortality.

Topics: Creatinine; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Kidney; Logistic Models; Male; Middle Aged; Mortality; Prognosis; Sildenafil Citrate; Urological Agents

Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafil's acute cardiovascular effects.. In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (-1 ± 2%; P = 0.043), systemic vascular resistance (-87 ± 156 dyn·s·cm; P = 0.034), and RVTG (-2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil.. Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation-perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension.

Topics: Chronic Disease; Cross-Over Studies; Double-Blind Method; Echocardiography, Doppler; Exercise; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Male; Middle Aged; Oxygen Consumption; Pulmonary Circulation; Sildenafil Citrate; Vasodilator Agents; Ventricular Function, Left; Ventricular Function, Right

The safety and efficacy of adding bosentan to sildenafil in pulmonary arterial hypertension (PAH) patients was investigated.In this prospective, double-blind, event-driven trial, symptomatic PAH patients receiving stable sildenafil (≥20 mg three times daily) for ≥3 months were randomised (1:1) to placebo or bosentan (125 mg twice daily). The composite primary end-point was the time to the first morbidity/mortality event, defined as all-cause death, hospitalisation for PAH worsening or intravenous prostanoid initiation, atrial septostomy, lung transplant, or PAH worsening. Secondary/exploratory end-points included change in 6-min walk distance and World Health Organization functional class at 16 weeks, change in N-terminal pro-brain natriuretic peptide (NT-proBNP) over time, and all-cause death.Overall, 334 PAH patients were randomised to placebo (n=175) or bosentan (n=159). A primary end-point event occurred in 51.4% of patients randomised to placebo and 42.8% to bosentan (hazard ratio 0.83, 97.31% CI 0.58-1.19; p=0.2508). The mean between-treatment difference in 6-min walk distance at 16 weeks was +21.8 m (95% CI +5.9-37.8 m; p=0.0106). Except for NT-proBNP, no difference was observed for any other end-point. The safety profile of bosentan added to sildenafil was consistent with the known bosentan safety profile.In COMPASS-2, adding bosentan to stable sildenafil therapy was not superior to sildenafil monotherapy in delaying the time to the first morbidity/mortality event.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies; Sildenafil Citrate; Sulfonamides; Switzerland; Treatment Outcome; Vasodilator Agents

Heart failure with preserved ejection fraction (HFpEF), with associated pulmonary hypertension is an increasingly large medical problem. Phosphodiesterase (PDE)-5 inhibition may be of value in this population, but data are scarce and inconclusive.. In this single centre, randomized double-blind, placebo-controlled trial, we included 52 patients with pulmonary hypertension [mean pulmonary artery pressure (PAP) >25 mmHg; pulmonary artery wedge pressure (PAWP) >15 mmHg] due to HFpEF [left ventricular ejection fraction (LVEF) ≥45%]. Patients were randomized to the PDE-5 inhibitor sildenafil, titrated to 60 mg three times a day, or placebo for 12 weeks. The primary endpoint was change in mean PAP after 12 weeks. Secondary endpoints were change in mean PAWP, cardiac output, and peak oxygen consumption (peak VO2). Mean age was 74 ± 10 years, 71% was female, LVEF was 58%, median NT-proBNP level was 1087 (535-1945) ng/L. After 12 weeks, change in mean PAP was -2.4 (95% CI -4.5 to -0.3) mmHg in patients who received sildenafil, vs. -4.7 (95% CI -7.1 to -2.3) mmHg in placebo patients (P = 0.14). Sildenafil did not have a favourable effect on PAWP, cardiac output, and peak VO2. Adverse events were overall comparable between groups.. Treatment with sildenafil did not reduce pulmonary artery pressures and did not improve other invasive haemodynamic or clinical parameters in our study population, characterized by HFpEF patients with predominantly isolated post-capillary pulmonary hypertension. (ClinicalTrials.gov, number NCT01726049).

Topics: Aged; Double-Blind Method; Drug Administration Schedule; Exercise Tolerance; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Stroke Volume

Sildenafil (Viagra, Pfizer) is being used to treat pulmonary hypertension (PH). However, there are limited data on the effects of sildenafil on patients with PH after left-sided valvular surgery. The purpose of this study was to determine the optimal dosage and the effects of sildenafil on prognosis of patients with PH after left-sided valvular surgery.. This randomised controlled trial, double-blind study enrolled patients with PH undergoing left-sided valvular surgery in our hospital from January to December, 2010. Ninety patients were enrolled. And 0.5 mg/kg sildenafil citrate or placebo was administered through nasogastric tubes, the haemodynamics changes in the 0.5/1/2/4 hours were assessed. The sildenafil citrate/placebo was continued to the discharges and the early prognoses of these patients were compared.. Compared with placebo, a 0.5 mg/kg dose of sildenafil significantly reduced the time of mechanical ventilation, stay-in-ICU and hospitalisation duration.. Sildenafil might be beneficial to the early prognosis of patients with PH after left-sided valvular surgery.

Topics: Aged; Cardiac Surgical Procedures; Female; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Length of Stay; Male; Middle Aged; Piperazines; Postoperative Period; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The double-blind, placebo-controlled Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study assessed sildenafil in pediatric patients with pulmonary arterial hypertension; improved hemodynamics and exercise capacity occurred in medium- and high-dose groups. STARTS-2 was the extension study.. In STARTS-1, 234 children ≥8 kg were randomly assigned to low-, medium-, or high-dose sildenafil or placebo orally thrice daily; within-group dose depended on weight. In STARTS-2, sildenafil-treated patients continued STARTS-1 dosing; placebo-treated patients were randomized to 1 of the 3 sildenafil dose groups. Patients requiring additional pulmonary arterial hypertension-specific therapy discontinued study treatment; survival follow-up was attempted. As of August 2011, all children received ≥3 years of treatment (unless discontinued) from STARTS-1 baseline; 37 deaths were reported (26 on study treatment), 1 of which occurred within the first year of treatment. Most patients who died (28/37) had idiopathic/heritable pulmonary arterial hypertension (76% versus 33% overall) and baseline functional class III/IV disease (38% versus 15% overall); patients who died had worse baseline hemodynamics. Kaplan-Meier estimated 3-year survival rates from start of sildenafil were 94%, 93%, and 88% for patients randomized to low-, medium-, and high-dose sildenafil, respectively; 87%, 89%, and 80% were known to be alive at 3 years. Hazard ratios for mortality were 3.95 (95% confidence interval, 1.46-10.65) for high versus low and 1.92 (95% confidence interval, 0.65-5.65) for medium versus low dose; however, multiple analyses raised uncertainty about the survival/dose relationship.. Although children randomized to higher compared with lower sildenafil doses had an unexplained increased mortality, all sildenafil dose groups displayed favorable survival for children with pulmonary arterial hypertension.. http://clinicaltrials.gov/ct2/show/NCT00159874 (extension study of NCT00149913). Unique identifier: NCT00159874.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Kaplan-Meier Estimate; Male; Piperazines; Purines; Regression Analysis; Sildenafil Citrate; Sulfones; Survival Rate; Time Factors; Treatment Outcome; Vasodilator Agents

In pulmonary arterial hypertension (PAH), adding oral sildenafil to intravenous epoprostenol improved 6-minute walk distance (6MWD) and hemodynamics and delayed time to clinical worsening in a 16-week randomized, placebo-controlled trial (Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil [PACES-1]).. Patients completing PACES-1 could receive sildenafil (titrated to 80 mg, three times daily, as tolerated) in an open-label extension study (PACES-2) for ≥ 3 years; additional therapy was added according to investigator judgment. Survival and changes from PACES-1 baseline in World Health Organization Functional Class and 6MWD were captured.. In an open-label setting, 6MWD, an effort-dependent outcome measure, was known to have improved or to have been maintained in 59%, 44%, and 33% of patients at 1, 2, and 3 years, respectively; functional class was known to have improved or to have been maintained in 73%, 59%, and 46%. At 3 years, 66% of patients were known to be alive, 24% were known to have died, and 10% were lost to follow-up. Patients with PACES-1 baseline 6MWD < 325 meters without 6MWD improvement during the first 20 weeks of sildenafil treatment subsequently had poorer survival.. Although reliable assessments of safety and efficacy require a long-term randomized trial, the addition of sildenafil to background intravenous epoprostenol therapy appeared generally to be well tolerated in PAH patients.

Topics: Administration, Intravenous; Adult; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epoprostenol; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Longitudinal Studies; Male; Middle Aged; Outcome Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Survival Rate; Time Factors; Treatment Outcome; Walking

Sildenafil, a phosphodiesterase-5 inhibitor, has been shown to decrease pulmonary vascular resistance (PVR) in patients with heart failure. The purpose of the study was to evaluate the effect of sildenafil on clinical status and pulmonary vascular reactivity in patients with congestive heart failure.. We enrolled 20 patients (18 men and 2 women, mean age 51 ± 12 years, diagnosed with congestive heart failure and pulmonary hypertension. This was a prospective, single-center study. Patients were treated with sildenafil 25 mg TDS for 12 months. Protocol included NYHA evaluation and repeated echocardiography, cardiac pulmonary stress tests, and right- sided catheterization.. Initially, there were 16 (80%) patients in III NYHA status and 4 (20%) patients in II NYHA. After 12 months, 8 patients were in NYHA III (40%) status and 12 patients in NYHA II (60%). Peak oxygen consumption increased from 12 ± 3 ml/kg/min to 19 ± 4 ml/kg/min after 1-year therapy (p<0.001). The cardiac index increased from 3.1 ± 0.6 L/min/m2 to 3.6 ± 0.4 L/min/m2 (p<0.05). Pulmonary vasculature resistance decreased after 1-year therapy (4.7 ± 1 vs. 1.6 ± 0.5 Woods units (p<0.005) comparing to initials. Mean pulmonary artery pressure decreased to 23 ± 6 mmHg from 42 ± 5 mmHg (p<0.001) after 1-year therapy.. One-year sildenafil therapy effectively improved clinical status and pulmonary vascular resistance in patients diagnosed with congestive heart failure.

Topics: Adult; Cardiac Catheterization; Exercise Test; Female; Follow-Up Studies; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Prognosis; Prospective Studies; Pulmonary Wedge Pressure; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

To observe the clinical efficacy and safety of sildenafil in the treatment of high altitude heart disease associated with severe pulmonary arterial hypertension (PAH) in children.. Fifty children (aged 2 months to 2 years) with high altitude heart disease associated with severe PAH, who were continuously transferred to the Intensive Care Unit between January 2011 and October 2013, were randomly assigned to observation and control groups. The control group was given conventional treatment, while the observation group received oral sildenafil [1 mg/(kg . d)] three times daily for 7-10 days in addition to the conventional treatment. Before and after treatment, hemodynamics, blood gas, routine blood parameters, and blood biochemical parameters were recorded.. After treatment, the observation group had a significantly higher decrease in mean pulmonary artery pressure and significantly higher increases in arterial partial pressure of oxygen, cardiac output, cardiac index, and oxygenation index compared with the control group (P<0.05). In the observation group, there were no significant changes in mean arterial pressure, routine blood parameters and blood biochemical parameters (P>0.05), and no obvious adverse reactions were found.. For children with high altitude heart disease associated with severe PAH, sildenafil can effectively reduce pulmonary artery pressure and improve cardiac function and does not cause adverse reactions. This therapy has good safety according to the preliminary evaluation.

Topics: Altitude; Familial Primary Pulmonary Hypertension; Female; Heart Diseases; Humans; Hypertension, Pulmonary; Infant; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

To explored the effect of sildenafil in treatment of pregnant women with pulmonary arterial hypertension.. From January 2012 to November 2013, 64 pregnant women with pulmonary arterial hypertension (PAH) were randomly divided into group and control group.. 16 cases with mild and 16 cases with moderate PAH. To treatment with low-flow oxygen, low-salt diet therapy, cardiac, etc.sildenafil group: 15 cases were mild pulmonary hypertension, and 17 cases moderate PAH. Treatment sildenafil 25 mg, tid in this study. Then the variation of the blood oxygen saturation, pulmonary artery systolic pressure, hemodynamic parameters and pregnancy outcome, including delivery modes, neonatal weight, morbidity of mother and fetus were compared.. (1) Cardiac function and pulmonary hypertension: control group: the proportion of cardiac functional class I-II reduced from 81% (26/32) to 56% (18/32) significantly after treatment (P < 0.05).Sildenafil group:the proportion of cardiac functional class I-II increased from 75% (24/32) to 84% (27/32) significantly after treatment (P < 0.05). Between two groups, the proportion of mild and moderate turning to server PAH patients were significant difference (P < 0.05).(2) The pregnancy outcome of two group: the premature birth rate, low birth weight rate and cesarean section rate of 9% (3/32) , 9% (3/32) and 69% (22/32) in sildenafil group were significantly lower than 16% (5/32), 19% (6/32) and 81% (26/32) in control group (P < 0.05) . The rate of vaginal delivery, term pregnancy and neonatal weight of 31% (10/32) , 91% (29/32) and (3 214 ± 306) g in sildenafil group were different with 19% (6/32) , 84% (27/32) and (3 004 ± 458) g in control group (P < 0.05). (3) Hemodynamic parameters:in control group, arterial partial pressure of oxygen, oxygen saturation and left ventricular ejection fraction, pulmonary systolic pression were (80 ± 5)% to (72 ± 8)%, (87 ± 8) to (83 ± 9) mmHg (1 mmHg = 0.133 kPa), 0.77 ± 0.24 to 0.70 ± 0.38 and (63 ± 9) to (69 ± 12) mmHg before and after treatment, which showed remarkable decreased trends (P < 0.05). The other parameter were not significantly different (P > 0.05).In sildenafil group, arterial partial pressure of oxygen, oxygen saturation and left ventricular ejection fraction, pulmonary systolic pression showed increased trend before and after treatment, which were (80 ± 9)% to (88 ± 9)%, (84 ± 3) to (89 ± 7) mmHg, 0.70 ± 0.32 to 0.79 ± 0.27 (P < 0.05), in the mean time, pulmonary systolic pression showed decreased trend from (65 ± 18) to (60 ± 13) mmHg (P < 0.05) . The other parameter did not show significant different (P > 0.05).. Sildenafil treatment can significantly improve the clinical symptoms, cardiac function and hemodynamic parameters.It also could significantly improve pregnancy outcomes, reduce premature delivery, the incidence of low birth weight children, and cesarean section rate.

Topics: Arterial Pressure; Blood Pressure; Cesarean Section; Child; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Piperazines; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Purines; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension is a serious complication of chronic obstructive pulmonary disease (COPD) that currently has no established pharmacological treatment. This study aimed to assess whether concomitant treatment with sildenafil would enhance the results of pulmonary rehabilitation in patients with COPD and increased pulmonary arterial pressure (PAP). In this double-blind, randomised controlled trial patients received 20 mg sildenafil or placebo three times daily and underwent pulmonary rehabilitation for 3 months. The primary end-point was the gain in the cycle endurance time at a constant work-rate. Secondary end-points included performance in the incremental exercise test, 6-min walk distance and quality of life. 63 patients with severe COPD and moderately increased PAP were randomised. Cycle endurance time increased by 149 s (95% CI 26-518 s) in the sildenafil group and by 169 s (95% CI 0-768 s) in the placebo group (median change difference -7 s, 95% CI -540-244 s; p=0.77). Gains in the incremental exercise test, 6-min walk distance and quality of life at the end of the study did not differ between groups. Measurements of arterial oxygenation and adverse events were similar in both groups. In patients with severe COPD and moderately increased PAP, concomitant treatment with sildenafil does not improve the results of pulmonary rehabilitation in exercise tolerance.

Topics: Aged; Arterial Pressure; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Placebos; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We, therefore, designed a 12-week, open-label, phase 1/2, pilot-scale, proof-of-principle trial of sildenafil therapy in 10 patients with β-thalassemia and at increased risk of pulmonary hypertension based on an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables compared at baseline and after 12 weeks of sildenafil treatment included Doppler-echocardiographic parameters, 6-minute walked distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function, and laboratory parameters. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0±0.7 versus 2.6±0.5 m/s, P=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in 6-minute walked distance was noted. Sildenafil was well tolerated, although minor expected adverse events were commonly reported. The total dose of sildenafil (mg) was strongly correlated with percent change in nitric oxide metabolite concentration in the plasma (ρ=0.80, P=0.01). There were also significant increases in plasma and erythrocyte arginine concentrations. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk of pulmonary hypertension; however, it was not demonstrated to improve the distance walked in 6 minutes. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in patients with β-thalassemia. (clinicaltrials.gov identifier: NCT00872170).

Topics: Adult; Echocardiography, Doppler; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Thalassemia; Vasodilator Agents

Pulmonary hypertension in paediatric patients with ventricular septal defect remains one of the most important determinants of perioperative morbidity and mortality. Sildenafil is an oral, well-tolerated pulmonary vasodilator with few drug interactions. We studied the effect of oral sildenafil, when given before and after surgical closure compared with starting it postoperatively, on the pulmonary artery pressure and patients' outcome.. We enrolled 101 infants with large ventricular septal defects who had moderate-to-severe pulmonary hypertension scheduled for surgical closure. They were randomly assigned to the sildenafil group (n = 51, mean age 10 months and mean weight 6.5 kg), in which oral sildenafil was started 2 weeks before surgery to be continued postoperatively, and to the control group (n = 50, mean age 11 months and mean weight 7.3 kg), in which sildenafil was started only postoperatively. It was started at 0.5 mg/kg and increased gradually to a maximum dose of 2 mg/kg in both groups.. Overall hospital mortality was 4.9%. Mean pulmonary artery pressure decreased significantly at all time points of recording in both groups (P < 0.0001). In the sildenafil group, it decreased preoperatively after sildenafil administration from 75.4 to 59.4 mmHg and postoperatively from 50.4 mmHg immediate post-cardiopulmonary bypass to reach 44.2 mmHg before discharge. In the control group, it decreased from 74.6 mmHg to 51 mmHg immediate post-cardiopulmonary bypass to reach 42.7 mmHg before discharge. No adverse effects have been recorded. Although there was no difference in the duration of mechanical ventilation and hospital stay between the two groups, intensive care unit stay was significantly shorter in the sildenafil group. Dobutamine doses were significantly higher in the sildenafil group; however, milrinone and epinephrine have been used more significantly in the control group.. The low cost, the oral availability and the good tolerability of sildenafil make it a suitable and simple alternative therapy for secondary pulmonary hypertension including persistent postoperative pulmonary hypertension associated with ventricular septal defect in resource limited places. However, starting sildenafil early before surgery does not add a great benefit in terms of improving postoperative pulmonary hypertension or patients' outcome.

Topics: Administration, Oral; Antihypertensive Agents; Arterial Pressure; Cardiac Surgical Procedures; Drug Administration Schedule; Egypt; Female; Heart Septal Defects, Ventricular; Hospital Mortality; Humans; Hypertension, Pulmonary; Infant; Length of Stay; Male; Perioperative Care; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Pulmonary Artery; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents

Sildenafil decreases pulmonary vascular resistance index (PVRI), in patients with pulmonary hypertension (PH). We investigated sildenafil's effects on central hemodynamics of mechanically ventilated patients with WHO group-III PH and RV failure necessitating dobutamine administration.. Prospective non-controlled study involving 12 (9 males, 59 ± 4 years old), patients with the above characteristics. All patients in phase-1 (days 1-2) received dobutamine (5 μg/kg/min IV). During phase-2 (days 3-6), sildenafil was started via nasogastric tube (80 mg/day) and dobutamine discontinuation was attempted. Patients were designated responders or non-responders based on whether dobutamine could be stopped or not. Phase-3 lasted from day 7 to day of weaning from mechanical ventilation; or if weaning failed, until day 20 following admission (end-of-study). Invasive and echocardiographic parameters were repeatedly recorded throughout the study.. Significantly changed parameters (P<0.025) from baseline to phase-1, -2 and -3 (%change of mean ratios), in responders (n=7) included among others PVRI (-40%, -51%, -42%), RV stroke work index (RVSWI: 43%, 79%, 41%) and cardiac index (49%, 54%, 48%), which also differed significantly from non-responders (N=5). In phases-1 and -3 non-responders had not significant changes, in phase-2 PVRI (27%) and RVSWI (-22%) changed significantly. In contrast to non-responders, all responders were weaned from mechanical ventilation until the end-of-study (P<0.025).. Sildenafil may improve central hemodynamics and RV function indices in ventilated patients with WHO group-III PH and RV failure requiring dobutamine infusion, when they respond favorably to the latter. Accordingly, an adequate RV systolic reserve may be mandatory for sildenafil to exert its actions.

Topics: Adrenergic beta-1 Receptor Agonists; Dobutamine; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Purines; Respiration, Artificial; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Ventricular Dysfunction, Right

Pulmonary artery hypertension (PAH) remains the leading cause of morbidity and mortality in systemic sclerosis, while Raynaud's phenomenon and digital ulcers significantly add to the morbidity in systemic sclerosis (SSc). This study was undertaken to evaluate the role of sildenafil in PAH, Raynaud's phenomenon, and digital ulcers in systemic sclerosis patients. A prospective, open-label, uncontrolled pilot study was done at a tertiary care centre in India to study the safety and efficacy of oral sildenafil in PAH, Raynaud's phenomenon, digital infarcts, and ulcers in SSc. Seventeen patients fulfilling ACR classification criteria for scleroderma and having PAH were recruited. Six-minute walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and 2D ECHO were performed in all the study subjects at baseline and at 3 months post-treatment. All patients were treated with oral sildenafil 25 mg three times a day for a period of 3 months. The pre- and post-treatment values of mean pulmonary artery pressure (PAP), 6-min walk test, WHO class of dyspnoea, and severity of Raynaud's phenomenon were compared to look for any significant change. Sixteen patients who completed 3-month follow-up had shown statistically significant improvement in 6-min walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and mPAP. Also, there was no occurrence of new digital infarcts or ulcers, and existing ulcers showed signs of healing. Sildenafil is highly efficacious cheaper and safe alternative to other available therapies for SSc-associated PAH, Raynaud's phenomenon, and digital infarcts/ulcers.

Topics: Adult; Arterial Pressure; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Prospective Studies; Pulmonary Artery; Purines; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Skin; Skin Ulcer; Sulfones; Treatment Outcome; Vasodilator Agents

We followed patients with pulmonary arterial hypertension (PAH) receiving specific vasodilator therapy and tested for predictors of clinical outcome.. Thirty-two patients (mean age 39 ± 15 years, 22 women, diagnosed with pulmonary hypertension; PH): 29 with PAH and 3 patients with inoperable chronic thromboembolic PH received therapy with either bosentan, sildenafil, or both and were evaluated with clinical parameters, biomarkers (B-type natriuretic peptide values), and echocardiography before receiving specific medication and every 3 months thereafter. A right heart catheterization was performed at baseline. A composite endpoint of death, worsening of functional class, or the need of a second vasodilator agent was used to define the clinical nonresponders.. Patients were followed for 14 months (7.5-21). The endpoint was reached by 15 patients: four patients died (two idiopathic PAH and two PAH in context of Eisenmenger syndrome), seven patients showed 1 functional class worsening, and four patients needed to be switched to combination therapy. Patients who remained clinically stable or improved had at baseline a better cardiac output with a less remodeled right ventricle (RV) and better functioning RV (all P < 0.05). A RV fractional area change (RVFAC) lower than 25.7% and a RV global strain value higher than -13.4% predict with 87% sensitivity and 83% specificity (AUC 87.3%, P = 0.001) and 73% sensitivity and 91% specificity (AUC 84.2%, P = 0.003), respectively, patients who will deteriorate clinically under specific vasodilator therapy. A multivariate model showed RVFAC to be the only independent predictor of the endpoint with a HR of 0.87 (0.8-0.96), P = 0.007.. Over an average period of 1 year, almost half of patients showed signs of clinical deterioration despite specific vasodilator therapy. Parameters of right ventricular morphology and function had prognostic value in these patients.

Topics: Adult; Bosentan; Echocardiography; Female; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Reproducibility of Results; Sensitivity and Specificity; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Right; Ventricular Function, Right

Exercise tolerance in pulmonary arterial hypertension (PAH) is most commonly assessed by the 6-min walk test (6MWT). Whether endurance exercise tests are more responsive than the 6MWT remains unknown. 20 stable PAH patients (mean±sd age 53±15 years and mean pulmonary arterial pressure 44±16 mmHg) already on PAH monotherapy completed the 6MWT, the endurance shuttle walk test (ESWT) and the cycle endurance test (CET) before and after the addition of sildenafil citrate 20 mg three times daily or placebo for 28 days in a randomised double-blind crossover setting. Pre- or post-placebo tests were used to assess repeatability of each exercise test, whereas pre- or post-sildenafil citrate tests were used to assess their responsiveness. Sildenafil citrate led to placebo-corrected changes in exercise capacity of 18±25 m (p = 0.02), 58±235 s (p = 0.58) and 29±77 s (p = 0.09) for the 6MWT, the ESWT and the CET, respectively. The 6MWT was associated with a lower coefficient of variation between repeated measures (3% versus 18% versus 13%), resulting in a higher standardised response mean compared with endurance tests (0.72, 0.25 and 0.38 for the 6MWT, the ESWT and the CET, respectively). The 6MWT had the best ability to capture changes in exercise capacity when sildenafil citrate was combined with patients' baseline monotherapy, supporting its use as an outcome measure in PAH.

Topics: Adult; Aged; Cross-Over Studies; Double-Blind Method; Exercise; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Reproducibility of Results; Sildenafil Citrate; Sulfones; Treatment Outcome; Walking

Sildenafilcitrate (SILD) orodispersable sublingual tablets (ODSTs) have been developed using two comparative techniques for improving their oral disintegration, dissolution and bioavailability in order to manage acute attacks of pulmonary arterial hypertension (PAH). The techniques employed were direct compression of SILD-poloxamer 188 solid dispersions (SDs) and freeze drying using various excipients. The physicochemical and solid-state properties, as well as the dissolution behavior of the tablets were evaluated. Moreover, SILD bioavailability in human volunteers from the prepared ODSTs was compared to that of the conventional oral tablet. Incorporation of SD of poloxamer188 in sublingual tablets together with Pharmaburst using the direct compression technique enhanced the extent and dissolution rate of SILD with 100% of drug being dissolved after 7 minutes. However, the lyophilization process was superior in enhancing dissolution and 100% of SILD was dissolved after only one minute. Moreover, the in vivo study showed that the AUC₀₋₁₂ of lyophilized tablets was significantly higher than that of directly compressed tablets, with bioavailability values of 159.81 and 140.85%, respectively, compared to the commercial oral product.

Topics: Absorption; Administration, Sublingual; Adult; Antihypertensive Agents; Biological Availability; Chemical Phenomena; Cross-Over Studies; Excipients; Familial Primary Pulmonary Hypertension; Half-Life; Humans; Hypertension, Pulmonary; Mouth Mucosa; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Saliva; Sildenafil Citrate; Solubility; Sulfones; Tablets; Vasodilator Agents; Water; Young Adult

The aim of the present study was to evaluate the safety, tolerability, clinical and haemodynamic impact of add-on sildenafil in patients with congenital heart disease (CHD)-related pulmonary arterial hypertension (PAH) and Eisenmenger physiology after failure of oral bosentan therapy.. Thirty-two patients with CHD-related PAH (14 male, mean age 37.1 ± 13.7 years) treated with oral bosentan underwent right heart catheterization (RHC) for clinical worsening. After RHC, all patients received oral sildenafil 20mg thrice daily in addition to bosentan. Clinical status, resting transcutaneous oxygen saturation (SpO(2)), 6-minute walk test (6MWT), serology and RHC were assessed at baseline (before add-on sildenafil) and after 6 months of combination therapy.. Twelve patients had ventricular septal defect, 8 atrio-ventricular canal, 6 single ventricle, and 6 atrial septal defect. Twenty-eight/32 had Eisenmenger physiology and 4 (all with atrial septal defect) did not. All patients well tolerated combination therapy. After 6 months of therapy, an improvement in clinical status (WHO functional class 2.1 ± 0.4 vs 2.9 ± 0.3; P=0.042), 6-minute walk distance (360 ± 51 vs 293 ± 68 m; P=0.005), SpO(2) at the end of the 6MWT (72 ± 10 vs 63 ± 15%; P=0.047), Borg score (2.9 ± 1.5 vs 4.4 ± 2.3; P=0.036), serology (pro-brain natriuretic peptide 303 ± 366 vs 760 ± 943 pg/ml; P=0.008) and haemodynamics (pulmonary blood flow 3.4 ± 1.0 vs 3.1 ± 1.2l/min/m(2), P=0.002; pulmonary vascular resistances index 19 ± 9 vs 24 ± 16 WU/m(2), P=0.003) was observed.. Addition of sildenafil in adult patients with CHD-related PAH and Eisenmenger syndrome after oral bosentan therapy failure is safe and well tolerated at 6-month follow-up, resulting in a significant improvement in clinical status, effort SpO(2), exercise tolerance and haemodynamics.

Topics: Administration, Oral; Adult; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eisenmenger Complex; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Piperazines; Prospective Studies; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Time Factors; Treatment Outcome; Vascular Resistance

The impact of sildenafil on pulmonary arterial hypertension (PAH) in Chinese patients has been less investigated. A prospective, open-label, uncontrolled and multicenter study, therefore, was carried out to address this issue. Ninety patients with multicause-induced PAH received oral sildenafil (75 mg/day) for 12 weeks. The 6-minute walk test (SMWT) and cardiac catheterization were performed at the beginning and the end of the 12 weeks. The primary endpoint was the changes in exercise capacity assessed by the SMWT; the secondary endpoint included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening. Drug safety and tolerability were also examined. The results showed that there was a significant improvement in SMWT distances (342 ± 93 m vs 403 ± 88 m, P < .0001), Borg dyspnea score (2.9 ± 2.6 vs 2.4 ± 2.0, P = .0046), World Health Organization functional class, and cardiopulmonary hemodynamics (mean pulmonary artery pressure, P < .0001; cardiac index, P < .0001; pulmonary vascular resistance, P < .0001) after 12 weeks of oral sidenafil therapy. Almost all enrolled patients did not experience significant clinical worsening. This study confirms and extends the findings of previous studies relating to effects of sildenafil on PAH, suggesting that oral sildenafil is safe and effective for the treatment of adult patients with PAH in the Chinese population.

Topics: Administration, Oral; Adult; China; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Young Adult

Sildenafil and epoprostenol are effective therapies in pulmonary arterial hypertension (PAH). Both drugs increase cardiac output, which has been in part attributed to improved right ventricular (RV) contractility. We therefore used tissue Doppler imaging (TDI) to test whether sildenafil and epoprostenol might differently affect RV function in normal subjects before and after induction of acute hypoxic pulmonary hypertension. Ten healthy volunteers underwent this randomized, double-blind, placebo-controlled cross-over study. Echocardiographic measurements were obtained 60 min after the intake of a placebo or 50 mg sildenafil or under 8 ng/kg/min iv epoprostenol, in normoxia or after 60 min of hypoxic breathing (FIO(2) of 0.12). Right ventricular systolic function was assessed by systolic strain (ε), strain rate (SR), isovolumic contraction acceleration (IVA) and tricuspid annulus plane systolic excursion (TAPSE), and diastolic function by tricuspid annulus E/A ratio and isovolumic relaxation time related to RR interval (IRT/RR). Pulmonary artery pressure was calculated from the acceleration time of pulmonary flow and cardiac output from the left ventricular outflow tract flow-velocity. Hypoxia increased pulmonary vascular resistance (PVR) by 78%, did not affect indices of RV systolic function, decreased E/A and increased IRT/RR. Epoprostenol more than sildenafil increased cardiac output, apical ε and TAPSE, the latter in proportion to decreased PVR. In addition, apical SR was increased only by epoprostenol. None of the drugs affected IVA, basal SR, E/A and IRT/RR. These results are not suggestive of intrinsic positive inotropic effects of either sildenafil or epoprostenol at maximal doses tolerated by normal subjects.

Topics: Adult; Analysis of Variance; Antihypertensive Agents; Belgium; Blood Pressure; Cardiac Output; Cross-Over Studies; Double-Blind Method; Echocardiography, Doppler; Epoprostenol; Female; Heart Rate; Humans; Hypertension, Pulmonary; Hypoxia; Least-Squares Analysis; Linear Models; Male; Piperazines; Placebos; Predictive Value of Tests; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Ventricular Function, Right; Young Adult

It has been reported that short-term sildenafil therapy is safe and effective for patients with pulmonary arterial hypertension. However, data regarding the impact of sildenafil on the survival of patients with idiopathic pulmonary arterial hypertension remain limited. The study was conducted on 77 patients with newly diagnosed idiopathic pulmonary arterial hypertension at Fu Wai Hospital between September 2005 and September 2009. Patients were divided into 2 groups: the sildenafil group and the conventional group. Nine patients treated with sildenafil were re-evaluated by right heart catheterization after 3 months. Our data demonstrated that the 6-minute walk distance, World Health Organization functional class, mixed venous oxygen saturation, and hemodynamics significantly improved after 3 months of sildenafil therapy (P < .05). The baseline characteristics of the sildenafil group were similar to those of the conventional group. The 1-, 2-, and 3-year survival rates in the sildenafil group were 88%, 72%, and 68% compared with 61%, 36%, and 27% in the conventional group (P < .001). The absence of sildenafil therapy, lower body mass index, and lower mixed venous oxygen saturation were found to be independent predictors of mortality. In conclusion, sildenafil therapy was found to be associated with improved survival in patients with idiopathic pulmonary arterial hypertension.

Topics: Adult; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Phosphodiesterase 5 Inhibitors; Physical Endurance; Piperazines; Purines; Sildenafil Citrate; Sulfones; Survival Rate; Vasodilator Agents; Young Adult

Exercise oscillatory breathing (EOB) is a ventilatory abnormality that occurs in ∼20% of heart failure (HF) patients and carries a very unfavourable prognosis. Pulmonary vasoconstriction has been suggested to be involved in this disorder. We hypothesized that modulation of pulmonary vascular hypertone by oversignalling of the nitric oxide pathway with phosphodiesterase 5 (PDE5) inhibition might be beneficial. Accordingly, we performed a 1-year pilot trial with sildenafil in patients with HF and EOB.. Among 122 HF cases, 32 presented with EOB during cardiopulmonary exercise testing (CPX) and were randomized to receive placebo (n = 16) or sildenafil (n = 16) at the dose of 50 mg three times a day, in addition to their current antifailure treatment. CPX-derived variables and pulmonary haemodynamics were assessed at 6 and 12 months. Sildenafil reversed EOB in 87% of patients at 6 months and 93% at 1 year, respectively (P < 0.01). This effect was accompanied by an improvement in functional performance (peak VO(2); from 9.6 to 12.4 and 13.2 mL/min/kg; P < 0.01) and exercise ventilation efficiency (ventilation to CO(2) production slope; from 41.1 to 32.7 and 31.5; P < 0.01). Chronic treatment with PDE5 inhibition significantly decreased pulmonary capillary wedge pressure (from 21 to 14 and 14 mmHg), mean pulmonary artery pressure (PAP; from 34.8 to 23 and 24 mmHg), and pulmonary vascular resistance (PVR; from 360 to 270 and 266 dyne/s/cm(5)) compared with placebo (P < 0.01 for each comparison). On exploratory analysis, there was a correlation between PAP and PVR and the decrease in EOB in the treatment group. Placebo did not alter any of the aforementioned variables.. PDE5 inhibition in HF patients with EOB offers the dual advantage of improving functional capacity and modulating the EOB pattern. PAP and PVR reduction seem to underlie the correction of the breathing disorder. Whether reversal of this unfavourable prognostic signal can affect survival remains unconfirmed at the moment.

Topics: Aged; Double-Blind Method; Exercise Test; Exercise Tolerance; Female; Heart Failure; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Outcome Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Circulation; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Time; Treatment Outcome; Vascular Resistance; Vasoconstriction; Ventilation-Perfusion Ratio

Topics: Aged; Heart Failure; Humans; Hypertension, Pulmonary; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Safe, effective therapy is needed for pediatric pulmonary arterial hypertension.. Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV(O(2))) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PV(O(2)) for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). PV(O(2)), functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses.. Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV(O(2)) for the 3 sildenafil doses combined was only marginally significant; however, PV(O(2)), functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight.. http://www.clinicaltrials.gov. Unique identifier: NCT00159913.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Test; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Oxygen Consumption; Piperazines; Purines; Sildenafil Citrate; Sulfones

Distal-type chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease for which a new therapeutic strategy needs to be developed. We examined the effects of percutaneous transluminal pulmonary angioplasty (PTPA).. We prospectively enrolled 12 patients with distal-type CTEPH. After stabilizing their condition with pulmonary vasodilators, we then performed PTPA, which markedly improved pulmonary hemodynamics and pulmonary artery structure, as confirmed by angiography and optical coherence tomography, and also significantly improved their long-term prognosis compared with 39 historical controls.. PTPA is a promising therapeutic option for distal-type CTEPH.

Topics: Aged; Angioplasty; Antihypertensive Agents; Bosentan; Chronic Disease; Combined Modality Therapy; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Prognosis; Prospective Studies; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Sildenafil has been demonstrated as effective for the treatment of pulmonary arterial hypertension (PAH). The purpose of this study was to investigate the occurrence of clinical events after sildenafil monotreatment as a first-line therapy in patients with PAH over a long-term observation period.. Sildenafil was administered as a first-line drug to 46 patients with PAH (including 24 patients with idiopathic PAH) during 2003-2010. We investigated subsequent clinical events such as the addition of epoprostenol, hospitalization for right-side heart failure, and death. All the hemodynamic parameters and the 6-min walk distance improved significantly in the enrolled patients as a whole receiving sildenafil treatment; 15 (33%) of the 46 patients required the addition of epoprostenol during follow-up. Kaplan-Meier analysis demonstrated that more than 60% of the patients receiving first-line sildenafil treatment did not require the addition of epoprostenol for a 5-year period. Furthermore, the 5-year survival rate after first-line sildenafil treatment was 81%. Finally, more than 75% of the enrolled patients did not reach the composite endpoint of hospitalization for right-side heart failure and death for a 5-year period.. This study describes the long-term outcome of patients with PAH receiving sildenafil monotreatment as a first-line therapy and suggests that it is a promising therapeutic strategy.

Topics: Adult; Antihypertensive Agents; Disease-Free Survival; Epoprostenol; Female; Follow-Up Studies; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Survival Rate

To assess the ocular effects and safety profile of chronic sildenafil oral dosing in patients with pulmonary arterial hypertension.. 12 week, double masked, randomised, placebo controlled, phase III trial with open label extension.. 53 institutions worldwide.. 277 adults with idiopathic pulmonary arterial hypertension or pulmonary arterial hypertension associated with connective tissue disease or after congenital heart disease repair (mean pulmonary artery pressure ≥25 mm Hg; pulmonary capillary wedge pressure ≤15 mm Hg at rest).. During the double masked study, oral sildenafil 20 mg, 40 mg, or 80 mg or placebo (1:1:1:1) three times daily for 12 weeks was added to baseline drug treatment. In the extension study, the placebo, 20 mg and 40 mg groups received 40 mg three times daily titrated to 80 mg three times daily at week 6. After unmasking, the dose was titrated according to clinical need.. Ocular safety (ocular examinations, visual function tests, participants' reports of adverse events, and visual disturbance questionnaire completed by investigators) by treatment group at 12 weeks, 24 weeks, 18 months, and yearly.. Findings of the objective assessments-that is, intraocular pressure and visual function tests (visual acuity, colour vision, and visual field)-were similar across groups (20 mg, n=69; 40 mg, n=67; 80 mg, n=71; placebo, n=70). No clinically significant changes occurred between baseline and 12 weeks, except for an efficacy signal in contrast sensitivity for the sildenafil 40 mg three times daily group. In right eyes, changes in intraocular pressure from baseline to week 12 ranged from a mean of -0.5 (95% confidence interval -1.3 to 0.2) mm Hg with placebo, -0.2 (-0.9 to 0.5) mm Hg with sildenafil 40 mg, and -0.1 (-0.7 to 0.5) mm Hg with 80 mg to 0.3 (-0.4 to 0.9) mm Hg with sildenafil 20 mg (the approved dose for pulmonary arterial hypertension). Mean changes from baseline to week 12 in contrast sensitivity in right eyes were -0.02 (SD 0.12) in the sildenafil 20 mg three times daily group compared with -0.05 (0.18) in the placebo group (P=0.044). Percentages of participants with deterioration in visual acuity (Snellen) from baseline to week 12 ranged from 10% (n=7) in the placebo group to 3% (n=2) in the sildenafil 20 mg three times daily group; the same percentages had visual field changes from normal to abnormal during the period in these two groups. The investigators did not deem any findings on colour vision assessment to be clinically significant. Findings of the objective assessments in the 40 mg and 80 mg three times daily sildenafil treatment groups and in left eyes were not substantially different, nor were any measures different throughout the open label extension compared with week 12. However, objective data were limited after month 18, as most participants had missing data or visual parameters were no longer collected by investigators. Incidence of ocular adverse events reported on the case report forms and assessed by the investigator was low with all doses, but a modest, dose related incidence of chromatopsia, cyanopsia, photophobia, and visual disturbance was reported with 80 mg three times daily consistent with the indicated dosing for erectile dysfunction. Retinal haemorrhages, captured on funduscopy, occurred in 2% (4/207) of sildenafil treated participants and none in the placebo group during the double masked study and in 4% (10/259) during the open label extension.. Sildenafil dosing up to 80 mg three times daily is safe and well tolerated from an ocular perspective in patients with pulmonary arterial hypertension. Daily chronic dosing in this patient population was not associated with visual change and had no detrimental effect on best corrected visual acuity, contrast sensitivity, colour vision, or visual field, or on slit lamp examinations, funduscopy, or intraocular pressure during the duration of this study.. Clinical trials NCT00644605 and NCT00159887.

Topics: Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Eye; Eye Diseases; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Incidence; Intraocular Pressure; Male; Middle Aged; Piperazines; Pulmonary Wedge Pressure; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Surveys and Questionnaires; Time Factors; Treatment Outcome; Vasodilator Agents; Visual Acuity

Pulmonary hypertension with exercise is common in chronic obstructive pulmonary disease (COPD) and may contribute to exercise limitation in this disease. We aimed to determine the effects of treatment with sildenafil on exercise capacity in patients with COPD and emphysema.. We performed a randomized, double-blind, placebo-controlled 2-period crossover trial of sildenafil thrice daily in ten adults with COPD and emphysema on CT scan without pulmonary hypertension. We randomized study participants to 4 weeks of sildenafil (or placebo) followed by a 1-week washout and then 4 weeks of placebo (or sildenafil). The 2 primary outcomes were the 6-minute walk distance and oxygen consumption at peak exercise.. Sildenafil had no effect on 6-minute walk distance (placebo-corrected difference = -7.8 m, 95% confidence interval, -23.2 to 7.5 m, p = 0.35) or oxygen consumption at peak exercise (placebo-corrected difference = -0.1 ml/kg/min, 95% confidence interval -2.1 to 1.8 ml/kg/min, p = 0.89). Sildenafil increased the alveolar-arterial oxygen gradient (p = 0.02), worsened symptoms (p = 0.04), and decreased quality-of-life (p = 0.03). Adverse events were more frequent while receiving sildenafil (p = 0.005).. Routine sildenafil administration did not have a beneficial effect on exercise capacity in patients with COPD and emphysema without pulmonary hypertension. Sildenafil significantly worsened gas exchange at rest and quality of life. (clinicaltrials.gov NCT00104637).

Topics: Aged; Cross-Over Studies; Double-Blind Method; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Consumption; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

The objective of this study was to investigate mechanisms of exercise-induced pulmonary hypertension in patients with congenital cardiac septal defects. This was a randomized, placebo controlled, crossover drug trial in a single national pediatric cardiology centre that performs congenital cardiac defect surgery. There were 14 patients with cardiac septal defects and known exercise-induced pulmonary hypertension. The intervention consisted of 50 mg oral sildenafil versus placebo. Measurements included supine bicycle exercise echocardiography and oxygen uptake. The outcome measure was right-ventricular systolic pressure as estimated by Doppler tracings of tricuspid regurgitant jet as well as systolic and diastolic longitudinal myocardial velocities by color tissue Doppler echocardiography. Sildenafil did not change exercise right-ventricular systolic pressure during exercise; however, decreased systemic systolic pressure was seen. Enhanced biventricular longitudinal function with sildenafil compared with placebo was indicated by greater tissue Doppler velocities and displacement measurements during exercise. Finally, a less steep increase of right-ventricular pressure during exercise was associated with greater left-ventricular diastolic myocardial tissue Doppler velocity. Exercise-induced pulmonary hypertension in cardiac septal defects does not seem to have a pulmonary vasoconstrictive component, but it may be related to left-ventricular filling pressure. Furthermore, sildenafil improved biventricular systolic performance in this patient group, possibly related to decreased systemic afterload.

Topics: Adolescent; Adult; Cross-Over Studies; Diastole; Echocardiography, Doppler; Echocardiography, Stress; Exercise Test; Female; Heart Septal Defects; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Placebos; Purines; Regression Analysis; Sildenafil Citrate; Sulfones; Treatment Outcome

Unresponsive pulmonary hypertension (PH) may contraindicate heart transplant since it implies poor early outcomes. The present study reports the effectiveness of oral perioperative sildenafil in allowing heart transplant candidacy and surgery in a selected group of patients initially deemed ineligible because of PH.. Between May 2005 and December 2009, 31 consecutive patients (5 females, 9 with a history of idiopatic cardiomyopathy and 16 with a history of coronary artery disease, 10 with previous sternotomies, 71.42 ± 27.69 ml/min/m(2) mean preoperative epidermal growth factor receptor) were qualified for oral sildenafil because of unresponsive PH at baseline right heart catheterization (RHC). After a 12-week trial, RHC disclosed PH reversibility (mean pulmonary vascular resistance index: 9.57 ± 4.07 WU, mean transpulmonary gradient 14.47 ± 5.66 mmHg and mean systolic pulmonary artery pressure: 68.96 ± 15.15 mmHg), allowing listing despite a higher risk for early post-transplant RV failure. Transplant protocol included donor/recipient size matching ≥ 0.8 and inhaled nitric oxide in the early postoperative period followed by reinstitution of oral sildenafil.. All patients underwent heart transplantation. Mean overall graft ischaemic time was 179 ± 47 min; mean donor recipient weight ratio was 1.04 ± 0.17. Right ventricular failure developed in three patients (9.6%) and hospital mortality was 3.2%. Protocol RHC disclosed pulmonary haemodynamic profile normalization within the third postoperative month allowing weaning from sildenafil in the 30 hospital survivors. One-year RHC confirmed PH reversal (n = 29 patients, all who survived up to 1 year).. This pilot prospective uncontrolled trial suggests that oral sildenafil is effective in allowing candidacy, safe transplantation and postoperative pulmonary profile normalization in potential recipients initially disqualified because of PH.

Topics: Administration, Oral; Adult; Cardiac Catheterization; Contraindications; Drug Administration Schedule; Female; Heart Failure; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pilot Projects; Piperazines; Prospective Studies; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome

Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor.. A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score.. Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m).. The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies.. ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Walking; Young Adult

Topics: Child; Double-Blind Method; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension is associated with a worse prognosis after cardiac transplantation. The pulmonary hypertension reversibility test with sodium nitroprusside (SNP) is associated with a high rate of systemic arterial hypotension, ventricular dysfunction of the transplanted graft and high rates of disqualification from transplantation.. This study was aimed at comparing the effects of sildenafil (SIL) and SNP on hemodynamic, neurohormonal and echocardiographic variables during the pulmonary reversibility test.. The patients underwent simultaneously right cardiac catheterization, echocardiography, BNP measurement, and venous blood gas analysis before and after receiving either SNP (1 - 2 µg/kg/min) or SIL (100 mg, single dose).. Both drugs reduced pulmonary hypertension, but SNP caused a significant systemic hypotension (mean blood pressure - MBP: 85.2 vs. 69.8 mm Hg; p < 0.001). Both drugs reduced cardiac dimensions and improved left cardiac function (SNP: 23.5 vs. 24.8%, p = 0.02; SIL: 23.8 vs. 26%, p < 0.001) and right cardiac function (SIL: 6.57 ± 2.08 vs. 8.11 ± 1.81 cm/s, p = 0.002; SNP: 6.64 ± 1.51 vs. 7.72 ± 1.44 cm/s, p = 0.003), measured through left ventricular ejection fraction and tissue Doppler, respectively. Sildenafil, contrary to SNP, improved venous oxygen saturation, measured on venous blood gas analysis.. Sildenafil and SNP are vasodilators that significantly reduce pulmonary hypertension and cardiac geometry, in addition to improving biventricular function. Sodium nitroprusside, contrary to SIL, was associated with systemic arterial hypotension and worsening of venous oxygen saturation.

Topics: Blood Pressure; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Hypotension; Male; Middle Aged; Nitroprusside; Piperazines; Preoperative Care; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Function

The 6-minute walk test evaluates the effect of pharmacologic intervention in adults with pulmonary arterial hypertension (PAH) but, for reasons of compliance or reliability, may not be appropriate for children at all ages. Thus, peak oxygen consumption (VO2, maximal exercise test) was used instead in a pediatric PAH trial (STARTS-1) to evaluate pharmacologic intervention with sildenafil. This was the first large placebo-controlled trial to use the peak VO2 endpoint in this population. Our working hypothesis was that, as with other populations, percentage changes in peak VO2 in pediatric patients with PAH are reliable and are associated with changes in other clinical endpoints.. Using data from the subpopulation of 106 patients who were developmentally and physically able to perform exercise testing, all of whom were World Health Organization Functional Class (WHO FC) I, II, or III, reliability was assessed using the intraclass correlation coefficient and Bland-Altman plot on screening and baseline data. Relationships between percentage change in peak VO2 from baseline to end of treatment and other endpoints were evaluated using correlation coefficients and regression analyses.. The intraclass correlation was 0.79 between screening and baseline peak VO2, an agreement that was supported by the Bland-Altman plot. Percentage change in peak VO2 correlated well (r ≥0.40) and showed responsiveness to a physician global assessment of change and with change in WHO FC (for baseline classes I and III). Percentage change in peak VO2 did not correlate with change in the Family Cohesion of the Child Health Questionnaire (r = 0.04) or with a subject global assessment of change (r = 0.12). The latter may have been influenced by child and parental-proxy response and instrument administration.. In pediatric PAH patients who are developmentally and physically able to perform exercise testing, peak VO2 measurements exhibited good reliability and improvements that were associated with improvements in certain other clinical endpoints, such as the WHO FC and a physician global assessment.. ClinicalTrials.gov identifier NCT00159913.

Topics: Adolescent; Child; Child, Preschool; Double-Blind Method; Endpoint Determination; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Oxygen Consumption; Piperazines; Purines; Reproducibility of Results; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents; Walking

There is a high incidence of pulmonary hypertension during the lung transplant peri-operative period, and could lead to a haemodynamic deterioration that may require the need of extracorporeal circulation. Our aim was to study the haemodynamic effects on the pulmonary and systemic circulation of the combination of inhaled nitric oxide and iloprost and oral sildenafil in patients with severe pulmonary hypertension during lung transplant surgery.. Seventeen patients received 10μg of nebulised iloprost during the peri-operative period of the lung transplant when their mean pulmonary pressure exceeded 50mmHg. AU the patients received 50mg of oral sildenafil 30min before anaesthetic induction, 20ppm of inhaled nitric oxide after tracheal intubation. The haemodynamic and respiratory variables were recorded at baseline (after anaesthetic induction), prior to the administering of iloprost, and at 5 and 30min after it was given.. The administering of iloprost significantly reduced the pulmonary arterial pressure and significantly increases the cardiac Índex and the right ventrícular ejection fractíon. There were no signíficant changes occurred in the systemic arterial pressure.. The triple combination significantly reduces the pulmonary pressures in the lung transplant peri-operative and should be considered when there is severe pulmonary hypertension during the surgery or during the immediate post-operative period of lung transplantation.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Cystic Fibrosis; Dobutamine; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Intraoperative Complications; Lung Transplantation; Male; Middle Aged; Nebulizers and Vaporizers; Nitric Oxide; Norepinephrine; Piperazines; Preoperative Care; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

The aim of this prospective, randomized and controlled study was to compare the clinical efficacy of intravenous magnesium sulfate (MgSO₄) and oral sildenafil therapies with persistent pulmonary hypertension of the newborn. A total of 34 infants in the MgSO₄ group and 31 infants in the sildenafil group completed the study. The time to reach the adequate clinical response [defined as oxygen index (OI) level of <15, a pulmonary artery pressure of < 20 mmHg) was significantly shorter in the sildenafil group (p = 0.002). Duration of mechanical ventilation was longer and the number of the patients requiring inotropic support was higher in the MgSO₄ group (p = 0.001 and p = 0.002, respectively). Although among two groups the difference in OI > 5 as speculated in our hypothesis could only be found at 36 h of the treatment, sildenafil was more effective than MgSO₄ in the treatment of persistent pulmonary hypertension of the newborns with regard to time to adequate clinical response, duration of mechanical ventilation and support requirement with inotropic agents.

Topics: Administration, Oral; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Injections, Intravenous; Intensive Care Units; Magnesium Sulfate; Male; Oxygen; Persistent Fetal Circulation Syndrome; Piperazines; Prospective Studies; Purines; Respiration, Artificial; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

To evaluate the efficacy and safety of intravenous sildenafil for immediate postoperative pulmonary hypertension (PH) in pediatric patients undergoing congenital heart surgery.. A double-blind, multicenter, placebo-controlled, dose-ranging, parallel-group trial was conducted. Patients were randomized to one of three doses of intravenous sildenafil, or placebo, for a minimum of 24 h.. The study was heavily underpowered. Whereas enrollment of 228 patients (57 per treatment arm) was required to achieve the sample size estimate to detect difference between arms, the sponsor terminated the study after 15 months owing to slow patient accrual. Seventeen patients (median age 5 months) experiencing postoperative PH were randomized and treated, five with placebo and four each with low-, medium-, and high-dose sildenafil. In the first 24 h, 40% of placebo and 17% of sildenafil patients required additional therapy (p = 0.330). Median time to extubation (3 versus 8 days, p = 0.023) and intensive care unit stay (6 versus 15 days, p = 0.008) were shorter for sildenafil patients. Mean ± standard deviation systolic pulmonary artery pressure was reduced with sildenafil (46 ± 11 to 35 ± 6 mmHg, p = 0.027 versus placebo). No adverse events or systemic hypotension were attributed to sildenafil.. Intravenous sildenafil reduced pulmonary artery pressure and shortened time to extubation and intensive care unit stay in children with postoperative PH.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Infusions, Intravenous; Male; Piperazines; Postoperative Complications; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

The authors investigated the safety of oral tetrahydrobiopterin (BH4), a cofactor for nitric oxide synthesis, as a novel treatment for pulmonary hypertension (PH). Eighteen patients with pulmonary arterial hypertension or inoperable chronic thromboembolic PH received sapropterin dihydrochloride (6R-BH4), the optically active form of BH4, in addition to treatment with sildenafil and/or endothelin receptor antagonists in an open-label, dose-escalation study. 6R-BH4 was administered starting at a dose of 2.5 mg/kg and increasing to 20 mg/kg over 8 weeks. Changes in markers of nitric oxide synthesis, inflammation and oxidant stress, as well as exercise capacity and cardiac function were measured. 6R-BH4 was well tolerated at all doses without systemic hypotension, even when given in combination with sildenafil. There was a small but significant reduction in plasma monocyte chemoattractant protein (MCP)-1 levels on 5 mg/kg. No significant changes in measures of nitric oxide synthesis or oxidant stress were observed. There was improvement in 6-minute walk distance, most significant at a dose of 5 mg/kg, from 379 ± 61 to 413 ± 57 m 414 ± 57 m (P = .002). Oral 6R-BH4 can be administered safely in doses up to 20 mg/kg daily to patients with PH. Further studies are needed to explore its therapeutic potential.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Biomarkers; Biopterins; Chemokine CCL2; Drug Therapy, Combination; Endothelin Receptor Antagonists; Exercise Test; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; London; Male; Middle Aged; Natriuretic Peptide, Brain; Nitric Oxide; Oxidative Stress; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Recovery of Function; Sildenafil Citrate; Sulfones; Tennessee; Time Factors; Treatment Outcome; Walking

In some patients, heart failure (HF) is associated with increased pulmonary vascular resistance (PVR). The magnitude and the reversibility of PVR elevation affect the HF management. Sildenafil has been recently recognized as potent PVR-lowering drug in HF. The aim of the study was to compare hemodynamic effects and pulmonary selectivity of sildenafil to prostaglandin E(1) (PGE(1)). Right-heart catheterization was performed in 13 euvolemic advanced HF patients with elevated PVR (6.3+/-2 Wood's units). Hemodynamic parameters were measured at the baseline, during i.v. infusion of PGE1 (alprostadil 200 ng · kg(-1) · min(-1)) and after 40 mg oral dose of sildenafil. Both drugs similarly reduced systemic vascular resistance (SVR), but sildenafil had higher effect on PVR (-28 % vs. -49 %, p = 0.05) and transpulmonary pressure gradient than PGE(1). The PVR/SVR ratio--an index of pulmonary selectivity, did not change after PGE(1) (p = 0.7) but it decreased by -32 % (p = 0.004) after sildenafil. Both drugs similarly reduced pulmonary artery mean and wedge pressures and increased cardiac index (+27 % and +28 %). Sildenafil led more often to transplant-acceptable PVR while causing smaller drop of mean systemic pressure than PGE(1). In conclusion, vasodilatatory effects of sildenafil in patients with heart failure are more pronounced in pulmonary than in systemic circulation.

Topics: Adult; Alprostadil; Cardiac Catheterization; Cardiac Output; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Artery; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

We hypothesised that sildenafil would improve hemodynamics in children with pulmonary hypertension and attenuate rebound pulmonary hypertension after inhaled nitric oxide withdrawal.. We undertook an open-label, single-drug study of sildenafil in patients under 5 years of age with either symptomatic or rebound pulmonary hypertension following inhaled nitric oxide withdrawal.. We recruited 25 patients (median age 180 days, 10-1790) to receive sildenafil. The median right ventricular to systemic systolic blood pressure ratio before sildenafil therapy was 1.0 (0.5-1.4) and decreased to 0.5 (with a range from 0.3 to 1.3; p = 0.0002). In five patients the baseline pulmonary vascular resistance index was 10 (7.1-13.6) Wood units metre square and decreased to 5.8 (2.7-15.6) Wood units metre square (p = 0.04) at 6 months. Ten patients were treated with sildenafil for a median of 34 days (9-499) until resolution of pulmonary artery hypertension and continue to do well. Six patients continued sildenafil therapy for a median of 1002 days (384-1574) with improvement but without resolution of pulmonary hypertension. There was no change in serum creatinine, urea, liver function tests, or platelet count. In 15 patients sildenafil abolished rebound pulmonary artery hypertension following withdrawal of inhaled nitric oxide. Median right ventricular pressure to systemic systolic pressure ratio decreased from 1.0 (0.8-1.4) during nitric oxide withdrawal to 0.4 (0.3-0.8) p = 0.006 after pre-treatment with sildenafil.. In children under 5 years of age with severe pulmonary hypertension, sildenafil therapy resulted in prolonged hemodynamic improvements without adverse effects. Sildenafil attenuated rebound pulmonary hypertension after withdrawal of inhaled nitric oxide.

Topics: Administration, Oral; Cardiac Catheterization; Child, Preschool; Dose-Response Relationship, Drug; Echocardiography; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Treatment Outcome; Ventricular Function, Right; Ventricular Pressure

To assess pharmacokinetics and pharmacodynamics of a 10 mg intravenous sildenafil bolus in pulmonary arterial hypertension (PAH) patients stabilized on 20 mg sildenafil orally three times daily.. Pharmacokinetic parameters were calculated using noncompartmental analysis.. After an acute increase, plasma concentrations stabilized within the range reported previously for a 20 mg oral tablet. At 0.5 h, mean ± SD changes from baseline were -8.4 ± 11.7 mmHg (systolic pressure), -2.6 ± 7.3 mmHg (diastolic pressure) and -3.5 ± 10.4 beats min(-1) (heart rate). There was no symptomatic hypotension.. Although further research is warranted, a 10 mg sildenafil intravenous bolus appears to provide similar exposure, tolerability and safety to the 20 mg tablet.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Drug Administration Schedule; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Young Adult

There is evidence that phosphodiesterase type-5 is effective for the treatment of pulmonary arterial hypertension (PAH).. A phase III, multicenter, open-label clinical trial of sildenafil 20mg t.i.d. was conducted in 21 Japanese patients with PAH to examine its efficacy, safety, and pharmacokinetics. The present trial consisted of a screening period and 12-week treatment. Patients who were enrolled in the present trial increased their 6-min walking distance of administration increased at week 12 by 84.2m from baseline. Hemodynamic parameters (eg, mean pulmonary artery pressure and pulmonary vascular resistance), Borg dyspnea scores, and plasma brain natriuretic peptide concentrations also improved compared to baseline. Most patients improved or sustained WHO functional class. Seven subjects, who were examined for the pharmacokinetics of sildefanil, showed relatively large interindividual variations in the C(max), AUC(0-8), C(ss,av), and C(trough) of the drug. Any serious adverse events, severe adverse events, and deaths were not observed. Most of events of undeniable causality were mild or moderate in severity. Sildefanil was well tolerated by the subjects.. Sildenafil 20mg t.i.d. was effective and safe for Japanese patients with PAH.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Blood Pressure; Female; Humans; Hypertension, Pulmonary; Japan; Male; Middle Aged; Natriuretic Peptide, Brain; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Walking; Young Adult

Sildenafil has been shown to be effective in pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH has been under-investigated in China. The aim of the present study was to evaluate the efficacy and safety of oral sildenafil in PAH patients in China.. In this prospective, open-label and multi-center study, 90 patients were recruited from 14 centers to receive oral sildenafil (75 mg/d) for 12 weeks. They underwent a six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of 12 weeks. The primary endpoint was the changes in exercise capacity as assessed by SMWT. And the secondary endpoints included assessment of functional class, evaluation of cardiopulmonary hemodynamics and clinical deterioration (defined as death, transplantation and re-hospitalization for PAH). Drug safety and tolerability were also examined.. There were 19 males and 71 females with an average age of 32.5 ± 12.1 years old (range: 18 - 61). Their etiologies were idiopathic (n = 15), related with congenital heart disease (n = 60), or related with connective tissue disease (n = 9) and chronic thromboembolic pulmonary hypertension (n = 6). Oral sildenafil significantly increased the SMWT distances [(342 ± 93) m vs. (403 ± 88) m, P < 0.001]. There was also remarkable improvement in Borg dyspnea score (2.9 ± 2.6 vs. 2.4 ± 2.0, P = 0.005). Furthermore, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also found (mean pulmonary artery pressure, P < 0.001; cardiac index, P < 0.001; pulmonary vascular resistance, P < 0.001). Side effects were mild and consistent with other reports.. This study confirms and extends previous studies. Oral sildenafil is both safe and effective for the treatment of adult PAH patients in China.

Topics: Adolescent; Adult; Antihypertensive Agents; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Young Adult

In a randomised trial, we compared the effects of oral sildenafil (0.5 mg.kg(-1) ) and placebo, administered the day before cardiac surgery, in 24 children. In sildenafil vs placebo patients, pre-cardiopulmonary bypass median (IQR [range]) cyclic-guanosine-monophosphate was not significantly different (29.9 (2.1-208.1 [0.5-391.5]) vs 5.2 (0.3-54.6 [0-628.9]) pmol.ml(-1) , respectively). Post-cardiopulmonary bypass, nitrate/nitrite levels were also not significantly different (0.7 (0-8.0 [0-142.8]) vs 0 (0-2.7 [0-52.7]) μM, respectively). Postoperatively, mean (SD) pulmonary vascular resistance (2.64 (2.28) vs 1.90 (1.12) WU.m(-2) , respectively and oxygenation index (5.29 (4.60) vs 3.38 (2.54), respectively) remained unchanged, whilst oxygen delivery (57.18 (21.24) vs 74.13 (35.46) ml.min(-1) .m(-2) , respectively) and bi-ventricular systolic function (left ventricle 3.78 (0.94) vs 4.55 (1.08) cm.s(-1) , respectively; p=0.002; right ventricle 6.93 (1.47) vs 8.09 (2.25) cm.s(-1) , respectively; p<0.001) were significantly reduced in the sildenafil group. In this trial, pre-operative sildenafil did not affect postoperative pulmonary vascular resistance. There was, however, a negative impact on ventricular function and oxygenation.

Topics: Administration, Oral; Cardiopulmonary Bypass; Child, Preschool; Endothelium, Vascular; Female; Heart Septal Defects; Humans; Hypertension, Pulmonary; Infant; Male; Oxygen Inhalation Therapy; Piperazines; Postoperative Care; Preoperative Care; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Function, Left; Ventricular Function, Right

The long-term safety and tolerability of sildenafil treatment of pulmonary arterial hypertension (PAH) were assessed.. Two hundred fifty-nine of 277 randomized and treated patients completed a 12-week, double-blind, placebo-controlled trial (SUPER-1 [Sildenafil Use in Pulmonary Arterial Hypertension]) of oral sildenafil in treatment-naive patients with PAH (96% functional class II/III) and entered an open-label uncontrolled extension study (SUPER-2) that continued until the last patient completed 3 years of sildenafil treatment. Patients titrated to sildenafil 80 mg tid; one dose reduction for tolerability was allowed during the titration phase.. The median duration of sildenafil treatment across SUPER-1 and SUPER-2 was 1,242 days (range, 1-1,523 days); 170 patients (61%) completed both studies, and 89 patients discontinued from SUPER-2. After 3 years, 87% of 183 patients on treatment were receiving sildenafil 80 mg tid. Of patients remaining under follow-up, 3%, 10%, and 18% were receiving a second approved PAH therapy at 1, 2, and 3 years, respectively. At 3 years post-SUPER-1 baseline, 127 patients had an increased 6-min walk distance (6MWD); 81 improved and 86 maintained functional class. Most adverse events were of mild or moderate severity. At 3 years, 53 patients had died (censored, n = 37). Three-year estimated survival rate was 79%; if all censored patients were assumed to have died, 3-year survival rate was 68%. No deaths were considered to be treatment related.. Long-term treatment of PAH initiated as sildenafil monotherapy was generally well tolerated. After 3 years, the majority of patients (60%) who entered the SUPER-1 trial improved or maintained their functional status, and 46% maintained or improved 6MWD.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Placebos; Proportional Hazards Models; Purines; Sildenafil Citrate; Sulfones; Survival Rate; Treatment Outcome; Vasodilator Agents

The difference in underlying pathophysiology in different congenital heart disease (CHD) may have an influence on clinical outcome. It remains unclear whether the effect of sildenafil on pulmonary arterial hypertension (PAH) varies in different types of CHD.. The potential effect of sildenafil on pulmonary arterial hypertension related to CHD may be associated with shunt location.. In this 12-week, prospective, open label, multicenter trial, 55 patients with CHD were divided into the 3 groups: atrial septal defects group (ASD, n = 15), ventricular septal defects group (VSD, n = 24), and patent ductus arteriosus group (PDA, n = 16). Exercise capacity, hemodynamic parameters, and arterial oxygen saturation were assessed at baseline and after sildenafil therapy (25 mg, 3 times daily).. Six-minute walk distance significantly increased from 377.2 ± 68.7 m to 436.0 ± 70.4 m in patients with ASD, from 371.2 ± 66.0 m to 413.7 ± 83.1 m in VSD, and from 384.3 ± 90.2 m to 440.9 ± 71.8 m in PDA (P<0.01, respectively). Moreover, sildenafil also improved the pulmonary vascular resistance and pulmonary blood flow index in the 3 groups, whereas no significant changes in systemic vascular resistance and systemic arterial pressure were observed. However, arterial oxygen saturation was significantly improved in the ASD group only. The incidence of adverse events was similar among the 3 groups.. Sildenafil therapy seems to be effective and safe for PAH secondary to ASD, VSD, and PDA, although some clinical and hemodynamic parameters were changed in a different manner among the 3 groups.

Topics: Adolescent; Adult; Antihypertensive Agents; Chi-Square Distribution; China; Ductus Arteriosus, Patent; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Oxygen; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents; Young Adult

The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil.. Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction ≥50%, and pulmonary artery systolic pressure >40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (-42.0±13.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (+69.0±19.0%) and ejection rate (+17.0±8.3%), and reduced right atrial pressure (-54.0±7.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, +15.8±4.5%), the pulmonary vasculature (arteriolar resistance, -71.0±8.2%), and left-sided cardiac function (wedge pulmonary pressure, -15.7±3.1%; cardiac index, +6.0±0.9%; deceleration time, -13.0±1.9%; isovolumic relaxation time, -14.0±1.7%; septal mitral annulus velocity, -76.4±9.2%). Results were similar at 12 months.. The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy.. URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01156636.

Topics: Aged; Aged, 80 and over; Double-Blind Method; Female; Heart Failure; Humans; Hypertension, Pulmonary; Longitudinal Studies; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prevalence; Purines; Respiratory Function Tests; Sildenafil Citrate; Stroke Volume; Sulfones

To explore the safety and efficacy of oral sildenafil therapy for pulmonary arterial hypertension (PAH), and to provide evidence for sildenafil treatment for Chinese patients with PAH.. In this 12-week, prospective, open-label, uncontrolled study, 56 patients with PAH were given oral sildenafil (25 mg, tid). The primary end point was change from baseline to 12 weeks in exercise capacity assessed by 6 min walk (6MW) test. Secondary end points included changes in WHO class and cardiopulmonary hemodynamics. Clinical worsening was defined as death, transplantation, hospitalization for PAH, or initiation of additional therapies for PAH, such as intravenous epoprostenol or oral bosentan.. After 12 weeks, the compliance was good in 56 patients. Significant improvement was seen in NYHA heart function class and WHO class as compared to baseline (P < 0.01): from class IV to class III in 2, from class III to class II in 8 and to class I in 2 cases, and from class II to class I in 5 cases. No NYHA heart function class and WHO PAH function class deterioration were observed. Oral sildenafil increased 6MW distance, from (352 ± 80) m to (396 ± 78) m, with a change of (44 ± 70) m (P < 0.01). Significant improvement was seen in hemodynamics (mean pulmonary artery pressure, P < 0.01; cardiac index, P < 0.01; pulmonary vascular resistance, P < 0.01) at week 12 as compared with baseline. Mean right atrial pressure decreased (3 ± 11) mm Hg (1 mm Hg = 0.133 kPa), mean pulmonary arterial pressure decreased (6 ± 14) mm Hg, cardiac output increased (1.1 ± 2.0) L/min, cardiac index increased (0.7 ± 1.1) L×min(-1)×m(-2), and total pulmonary resistance decreased (490 ± 831) Dys×s×cm(-5). Side effects were mild and consistent with those reported with sildenafil treatment. No statistically significant clinical worsening was observed with sildenafil therapy for PAH patients.. Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with pulmonary arterial hypertension.

Topics: Adolescent; Adult; Aged; Drug Tolerance; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Young Adult

The chronic use of bosentan has been reported to reduce the plasma concentration of sildenafil. However, it remains unclear how sildenafil exerts the effect at reduced concentrations in pulmonary arterial hypertension (PAH) patients chronically treated with bosentan.We examined the hemodynamic effects of sildenafil (50 mg) in 8 Japanese patients with PAH, and simultaneously measured the plasma concentration of sildenafil ([Sil]) and its major metabolite, desmethylsildenafil ([Des]).The overall effects of sildenafil were 12.4% decrease in mean pulmonary arterial pressure, 19.9% increase in cardiac index (CI), and 25% reduction in derived pulmonary vascular resistance (PVR). When the patients were divided into two groups, a group with bosentan pretreatment [BOS (+), n = 4] and a group without bosentan pretreatment [BOS (-), n = 4], both [Sil] and [Des] were lower at the peak concentration (C(max)) and the area under the plasma concentration versus time curve (AUC(0-6h)), and the time to reach C(max) was longer in BOS (+), although only the difference in AUC(0-6h) of [Des] reached statistical significance (P = 0.02). In spite of lower concentration, the effect of sildenafil on CI was maintained in the BOS (+) group, while the decrease in PVR was less marked.Sildenafil acutely dilated the pulmonary artery and increased CI in the PAH patients. These effects were still observed or maintained in the PAH patients chronically treated with bosentan, even when [Sil] was reduced.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Pulmonary Artery; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vascular Resistance; Young Adult

Exaggerated hypoxic pulmonary vasoconstriction is a key factor in the development of high altitude pulmonary edema (HAPE). Due to its effectiveness as a pulmonary vasodilator, sildenafil has been proposed as a prophylactic agent against HAPE. By conducting a parallel-group double blind, randomized, placebo-controlled trial, we investigated the effect of chronic sildenafil administration on pulmonary artery systolic pressure (PASP) and symptoms of acute mountain sickness (AMS) during acclimatization to high altitude. Sixty-two healthy lowland volunteers (36 male; median age 21 years, range 18 to 31) on the Apex 2 research expedition were flown to La Paz, Bolivia (3650 m), and after 4-5 days acclimatization ascended over 90 min to 5200 m. The treatment group (n=20) received 50 mg sildenafil citrate three times daily. PASP was recorded by echocardiography at sea level and within 6 h, 3 days, and 1 week at 5200 m. AMS was assessed daily using the Lake Louise Consensus symptom score. On intention-to-treat analysis, there was no significant difference in PASP at 5200 m between sildenafil and placebo groups. Median AMS score on Day 2 at 5200 m was significantly higher in the sildenafil group (placebo 4.0, sildenafil 6.5; p=0.004) but there was no difference in prevalence of AMS between groups. Sildenafil administration did not affect PASP in healthy lowland subjects at 5200 m but AMS was significantly more severe on Day 2 at 5200 m with sildenafil. Our data do not support routine prophylactic use of sildenafil to reduce PASP at high altitude in healthy subjects with no history of HAPE. TRIALS REGISTRATION NUMBER: NCT00627965.

Topics: Adolescent; Adult; Altitude; Altitude Sickness; Blood Pressure; Double-Blind Method; Echocardiography; Female; Humans; Hypertension, Pulmonary; Hypoxia; Intention to Treat Analysis; Male; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Systole; Vasodilator Agents; Young Adult

Inhaled treprostinil improved functional capacity as add-on therapy in the short-term management of patients with pulmonary arterial hypertension (PAH). This study investigated the long-term effects of inhaled treprostinil in patients concurrently receiving oral background therapy.. A total of 206 patients (81% women) completing the 12-week double-blind phase of the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study transitioned into an open-label extension. Patients were assessed every 3 months for changes in 6-minute walk distance (6MWD), Borg dyspnea score, New York Heart Association (NYHA) functional class, quality of life (QOL) scores, and signs and symptoms of PAH.. Patients were primarily NYHA class III (86%), with a mean baseline 6MWD of 349 ± 81 meters. A median change in 6MWD of 28, 31, 32, and 18 meters in patients continuing therapy was observed at 6, 12, 18, and 24 months, respectively. This effect was more prominent in those patients originally allocated to active therapy in the double-blind phase. Survival rates for patients remaining on therapy were 97%, 94%, and 91% at 12, 18, and 24 months, respectively. In addition, 82%, 74%, and 69% of patients maintained treatment benefit as evidenced by lack of clinical worsening at 12, 18, and 24 months. The most common adverse events were known effects of prostanoid therapy (headache [34%], nausea [21%], and vomiting [10%]) or were due to the route of administration (cough [53%], pharyngolaryngeal pain [13%], and chest pain [13%]).. Long-term therapy with inhaled treprostinil demonstrated persistent benefit for PAH patients who remained on therapy for up to 24 months.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Antihypertensive Agents; Blood Pressure; Bosentan; Double-Blind Method; Drug Therapy, Combination; Epoprostenol; Female; Headache; Humans; Hypertension, Pulmonary; Incidence; Longitudinal Studies; Male; Middle Aged; Nausea; Physical Endurance; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Young Adult

Sildenafil, a phosphodiesterase-5 inhibitor, could be useful for treating pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD). However, vasodilators may inhibit hypoxic pulmonary vasoconstriction and impair gas exchange in this condition.. To assess the acute hemodynamic and gas exchange effects of sildenafil in patients with COPD-associated PH.. We conducted a randomized, dose comparison trial in 20 patients with COPD-associated PH. Eleven patients were assigned to 20 mg, and 9 patients to 40 mg, of sildenafil. Pulmonary hemodynamics and gas exchange, including ventilation-perfusion (V(A)/Q) relationships, were assessed at rest and during constant-work rate exercise, before and 1 hour after sildenafil administration.. Both sildenafil doses reduced the mean pulmonary arterial pressure (PAP) at rest and during exercise, without differences between them. Overall, PAP decreased -6 mm Hg (95% confidence interval [95% CI], -7 to -4) at rest and -11 mm Hg (95% CI, -14 to -8) during exercise. After sildenafil, Pa(O(2)) decreased -6 mm Hg (95% CI, -8 to -4) at rest because of increased perfusion in units with low V(A)/Q ratio, without differences between doses. No change in Pa(O(2)) (95% CI, -3 to 0.2 mm Hg) or V(A)/Q relationships occurred during exercise after sildenafil. Changes induced by sildenafil in Pa(O(2)) and V(A)/Q distributions at rest correlated with their respective values at baseline.. In patients with COPD-associated PH, sildenafil improves pulmonary hemodynamics at rest and during exercise. This effect is accompanied by the inhibition of hypoxic vasoconstriction, which impairs arterial oxygenation at rest. The use of sildenafil in COPD should be done cautiously and under close monitoring of blood gases. Clinical trial registered with www.clinicaltrials.gov (NCT00491803).

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Dose-Response Relationship, Drug; Exercise; Exercise Test; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Purines; Rest; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Data on long-term efficacy of bosentan, an oral dual ET receptor antagonist, in SSc-associated pulmonary arterial hypertension (SSc-PAH) are lacking. We aimed to describe the long-term outcome of SSc-PAH treated with first-line monotherapy bosentan followed or not by the addition of prostanoids or sildenafil.. A prospective analysis of 49 consecutive SSc-PAH patients treated with first-line bosentan was performed. New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD) and haemodynamics were assessed at baseline and after 4 and 12 months.. At 4 months, significant improvements in NYHA functional class and haemodynamics were observed with stabilization at 1 year. There was no significant improvement in 6MWD. Overall survival estimates were 80, 56 and 51% at 1, 2 and 3 years, respectively, and were significantly worse than those in a cohort of patients with idiopathic PAH (92, 89 and 79% at 1, 2 and 3 years, respectively; P < 0.0001). Twenty-three patients (47%) died after a mean follow-up of 23 (18) months. In multivariate analysis, baseline and 4-month NYHA functional class and 4-month cardiac index were independent factors associated with overall survival.. In our cohort of consecutive SSc-PAH patients treated with first-line bosentan, improvement in NYHA functional class and haemodynamics was significant after 4 months of treatment and stabilized afterwards. One-year overall survival rate was higher than previously reported in historical series. However, long-term prognosis remains poor. Our study underlines the importance of haemodynamic evaluation 4 months after the start of treatment to provide strong parameters associated with survival-like cardiac index.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Drug Administration Schedule; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Epidemiologic Methods; Epoprostenol; Exercise Test; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Pulmonary hypertension is a characteristic feature of acute respiratory distress syndrome (ARDS) and contributes to mortality. Administration of sildenafil in ambulatory patients with pulmonary hypertension improves oxygenation and ameliorates pulmonary hypertension. Our aim was to determine whether sildenafil is beneficial for patients with ARDS.. Prospective, open-label, multicenter, interventional cohort study.. Medical-surgical ICU of two university hospitals.. Ten consecutive patients meeting the NAECC criteria for ARDS.. A single dose of 50 mg sildenafil citrate administered via a nasogastric tube.. Administration of sildenafil in patients with ARDS decreased mean pulmonary arterial pressure from 25 to 22 mmHg (P = 0.022) and pulmonary artery occlusion pressure from 16 to 13 mmHg (P = 0.049). Systemic mean arterial pressures were markedly decreased from 81 to 75 mmHg (P = 0.005). Sildenafil did not improve pulmonary arterial oxygen tension, but resulted in a further increase in the shunt fraction.. Although sildenafil reduced pulmonary arterial pressures during ARDS, the increased shunt fraction and decreased arterial oxygenation render it unsuitable for the treatment of patients with ARDS.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Aged; Cohort Studies; Female; Humans; Hypertension, Pulmonary; Intensive Care Units; Male; Middle Aged; Oxygen; Oxygen Consumption; Piperazines; Prospective Studies; Pulmonary Artery; Purines; Respiratory Distress Syndrome; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil is a strong pulmonary vasodilator that increases the intracellular cyclic guanosine monophosphate concentration through inhibition of phosphodiesterase-5. We assessed the benefit of oral sildenafil for persistent pulmonary hypertension early after congenital cardiac surgery in paediatric patients.. Sildenafil was administered at a starting dose of 0.5 mg kg(-1) following admission to the intensive care unit. With careful monitoring of haemodynamics, the dose was increased stepwise by 0.5 mg kg(-1) every 4-6 h up to a maximum of 2 mg kg(-1). After successful weaning from a ventilator and from other vasodilators, sildenafil was gradually discontinued over the next 5-7 days.. A retrospective review of medical records showed an age distribution of <1 month (n=26), > or = 1-<6 months (n=36), > or = 6-<12 months (n=19), 1-3 years (n=8), 4-9 years (n=9) and >10 years (n=2) at the time of surgery. The surgeries were performed for ventricular septal defect closure (n=17), arterial switch (n=30), truncus arteriosus repair (n=10), complete atrioventricular septal defect repair (n=12), total anomalous venous drainage repair (n=9), and other open-heart surgery (n=22). The aforementioned concomitant inhaled nitrous oxide treatment was performed in 66 patients. Pulmonary arterial pressure decreased in 28, was unchanged in five and elevated in one patient out of the total of 34 cases for which data from continuous pressure monitoring were available. Bosentan was added in three cases with persistent symptoms due to pulmonary hypertension despite sildenafil treatment. After sildenafil administration, modest oxygen desaturation occurred in seven cases, but no 'rebound' pulmonary hypertension occurred. There were no significant adverse events during sildenafil treatment.. Our results suggest that oral sildenafil is a safe and effective alternate for persistent pulmonary hypertension following congenital heart surgery in children.

Topics: Administration, Oral; Age Distribution; Child; Child, Preschool; Drug Administration Schedule; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Piperazines; Postoperative Care; Postoperative Complications; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Relative area change (RAC) of the proximal pulmonary artery is a measurement of pulmonary artery distensibility and has been shown to correlate with vasoreactivity studies in patients with idiopathic pulmonary arterial hypertension. We have previously noted a relationship between invasive hemodynamic vasoreactivity testing and long-term response to sildenafil in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). We therefore set out to determine whether RAC can provide useful correlatory non-invasive data.. Patients recruited to a randomized, controlled trial (RCT) of sildenafil at 40 mg 3 times daily underwent additional magnetic resonance imaging (MRI) at the baseline of the trial. Eighteen patients had an MRI that led to a diagnosis of inoperable distal CTEPH or significant residual CTEPH post-operatively. The primary end-point was improvement in 6-minute walk test (6MWT) with secondary end-points of right heart catheterization-based hemodynamics, N-terminal pro-brain natriuretic peptide (NT pro-BNP) and functional class. RAC assessed by MRI was correlated with trial end-points.. Fourteen subjects with baseline MRI completed the protocol. RAC was the only baseline variable that correlated at 1 year to the primary end-point of improvement in 6MWT (r = 0.7, p = 0.006), and also to a change in NT pro-BNP (r = 0.59, p = 0.03). Using a cut-off of RAC over 20% there was an 87.5% sensitivity (95% confidence interval [CI]: 45% to 100%) and a 66.7% specificity (95% CI: 22% to 96%) for an improvement in 6MWT of >40 meters.. RAC correlates with functional response to sildenafil, as measured by the 6MWT, and improved heart function, as measured by NT pro-BNP. RAC shows potential in understanding and possibly predicting treatment response.

Topics: Adult; Aged; Cardiac Catheterization; Chronic Disease; Female; Heart; Hemodynamics; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Piperazines; Pulmonary Artery; Purines; Recovery of Function; Sensitivity and Specificity; Sildenafil Citrate; Single-Blind Method; Sulfones; Thromboembolism; Time Factors; Treatment Outcome; Vasodilator Agents; Walking

The purpose of our study was to characterize the hemodynamic and corresponding pharmacokinetic responses to a single dose of oral sildenafil by children with pulmonary arterial hypertension (PAH) undergoing invasive testing.. Although used frequently for the treatment of children with PAH, data regarding the acute responses to sildenafil are limited.. Thirty-six patients (mean age 7.5+/-5.9 years; 24 females) were studied during cardiac catheterization with general anesthesia. Eight of 36 (22%) had idiopathic PAH; the remainder had associated congenital heart disease. Hemodynamics and serum cyclic-guanosine monophosphate levels (cGMP) were evaluated at baseline and after inhaled nitric oxide (NO) (40 ppm). In addition, cGMP and sildenafil levels were measured 30 min after administration of sildenafil (0.5 mg/kg, suspended in 5 ml sterile water) through a nasogastric tube.. For the 36 patients, the pulmonary vasodilating capability of oral sildenafil was lower than that of inhaled NO (2.8% vs. 11.6% reduction in pulmonary vascular resistance indexed to body surface area [PVRI], respectively; p=0.01). However, only 21 of 36 (58%) patients had a detectable sildenafil level. In those with detectable sildenafil levels, the fall in PVRI was greater (-11.6% vs. -19.1%, p=NS). Mean cGMP levels at baseline and after NO were 41.8+/-20.0 pmol/ml and 83.8+/-35.5 pmol/ml, respectively (p<0.0001). Surprisingly, there was no significant increase in cGMP in patients with either undetectable (37.5+/-29.8 pmol/ml) or detectable (44.4+/-31.7 pmol/ml) sildenafil levels (p=NS compared with baseline) with sildenafil.. Our study demonstrates suboptimal absorption of sildenafil in almost half the children undergoing acute hemodynamic testing. When detectable, there was no statistically significant difference between the fall in PVRI associated with sildenafil and NO despite lower circulating cGMP levels in the sildenafil group. These data should be taken into account when designing acute testing protocols, and assessing the acute response to sildenafil in patients with PAH.

Topics: Adolescent; Child; Child, Preschool; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Administration, Oral; Antihypertensive Agents; Blood Pressure; Bosentan; Contraindications; Heart Failure; Heart Transplantation; Humans; Hypertension, Pulmonary; Piperazines; Prospective Studies; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance; Vasodilator Agents

This study assessed the efficacy and safety of inhaled treprostinil in pulmonary arterial hypertension (PAH) patients receiving therapy with either bosentan or sildenafil.. There is no cure for PAH, despite effective treatments, and outcomes remain suboptimal. The addition of inhaled treprostinil, a long-acting prostacyclin analog, might be a safe and effective treatment addition to other PAH-specific oral therapies.. Two hundred thirty-five PAH patients with New York Heart Association (NYHA) functional class III (98%) or IV symptoms and a 6-min walk distance (6MWD) of 200 to 450 m while treated with bosentan (70%) or sildenafil were randomized to inhaled treprostinil (up to 54 mug) or inhaled placebo 4 times daily. The primary end point was peak 6MWD at 12 weeks. Secondary end points included time to clinical worsening, Borg Dyspnea Score, NYHA functional class, 12-week trough 6MWD, 6-week peak 6MWD, quality of life, and PAH signs and symptoms. The biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed.. Twenty-three patients withdrew from the study prematurely (13 treprostinil, 10 placebo). The Hodges-Lehmann between-treatment median difference in change from baseline in peak 6MWD was 19 m at week 6 (p = 0.0001) and 20 m at week 12 (p = 0.0004). Hodges-Lehmann between-treatment median difference in change from baseline in trough 6MWD at week 12 was 14 m (p = 0.0066). Quality of life measures and NT-proBNP improved on active therapy. There were no improvements in other secondary end points, including time to clinical worsening, Borg Dyspnea Score, NYHA functional class, and PAH signs and symptoms. Inhaled treprostinil was safe and well-tolerated.. This trial demonstrates that, among PAH patients who remain symptomatic on bosentan or sildenafil, inhaled treprostinil improves exercise capacity and quality of life and is safe and well-tolerated. (TRIUMPH I: Double Blind Placebo Controlled Clinical Investigation Into the Efficacy and Tolerability of Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension; NCT00147199).

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents; Young Adult

Sildenafil and beraprost, as orally available pulmonary vasodilators, are used increasingly to treat pulmonary hypertension (PH). An evaluation was made, in patients with PH undergoing valvular heart surgery, as to whether preoperative combined oral sildenafil and beraprost treatment could induce synergistic and prolonged pulmonary vasodilation, or result in a loss of pulmonary selectivity.. Fifty patients scheduled for valvular heart surgery with a mean pulmonary arterial pressure (PAP) > 30 mmHg were randomly assigned to receive either 50 mg oral sildenafil + 40 microg beraprost, or a placebo, 15 min before the induction of anesthesia. Hemodynamic variables were measured intraoperatively.. The treatment group had a significantly lower systemic vascular resistance index at 60 min after medication. No other significant intergroup differences in hemodynamic variables were observed. In addition, significantly more patients in the treatment group required vasopressor therapy. In both groups, the PAP was significantly reduced by general anesthesia, and almost normalized after valvular heart surgery.. Preoperative oral sildenafil and beraprost treatment resulted in a loss of pulmonary selectivity, and did not provide any additional pulmonary vasodilation or favorable perioperative hemodynamics in patients with PH undergoing valvular heart surgery.

Topics: Adult; Aged; Anesthesia, General; Blood Pressure; Comorbidity; Drug Therapy, Combination; Epoprostenol; Female; Heart Valve Diseases; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Preoperative Care; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

It has been demonstrated that sildenafil is effective in patients with pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH in adults with congenital heart disease (CHD) has been less investigated.. In this prospective, open-label, uncontrolled and multicenter study, 60 patients with PAH related to CHD received oral sildenafil (75 mg/day) for 12 weeks. The enrolled patients underwent six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of the 12 weeks. The primary end point was the changes in exercise capacity assessed by SMWT; the secondary end point included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening (defined as death, transplantation, and rehospitalization for PAH). Drug safety and tolerability were also examined.. Oral sidenafil significantly increased SMWT distances (422.94 ± 76.95 m vs. 371.99 ± 78.73 m, P < 0.0001). There was also remarkable improvement in Borg dyspnea score (2.1 ± 1.32 vs. 2.57 ± 1.42, P = 0.0307). Moreover, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also discovered (mean pulmonary artery pressure, P = 0.0002; cardiac index, P < 0.0001; pulmonary vascular resistance, P < 0.0001). Side effects in this study were mild and consistent with reported studies. None of the enrolled patients experienced significant clinical worsening.. This study confirmed and extended previous studies. It suggested that oral sildenafil was safe and effective for the treatment of adult patients with CHD-related PAH.

Topics: Administration, Oral; Adolescent; Adult; Antihypertensive Agents; Blood Pressure; Cardiac Catheterization; China; Drug Administration Schedule; Dyspnea; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Young Adult

We aimed to assess the acute cardiopulmonary effects of a 100-mg oral single dose of sildenafil in patients with idiopathic pulmonary hypertension (IPAH) using a well-validated but less-used noninvasive echocardiographic method for the measurement of both systolic and diastolic pulmonary artery pressure (PAP), by tricuspid regurgitation (TR) velocity curve analysis. We studied 12 consecutive patients with IPAH (10 patients with New York Heart Association functional class III, and 2 patients with functional class II). A 100-mg oral single dose of sildenafil was added to previous medications of all patients and its immediate effects were evaluated 1, 5, and 12 h after treatment. Using paired analysis, administration of a 100-mg oral single dose of sildenafil led to a significant reduction in mean PAP and a remarkable increase in pulmonary acceleration time (PAT) 1 h after treatment (P = 0.000; 95% confidence interval [CI] 18.99-26.00 and P = 0.005; 95% CI -12.89 to -2.95, respectively). In addition, although the right heart dimensions (right atrium and right ventricle) showed a trend toward improvement, the differences were not statistically significant (P = 0.13 and P = 0.08, respectively). Our results demonstrated that Doppler examination of TR alone can be easily used for the estimate of systolic and diastolic PAP in patients with IPAH. This study also shows that sildenafil is the only drug given orally that can evaluate the vasodilatory capacity of the pulmonary vascular bed in patients with IPAH, with promising effects on mPAP and PAT in these patients.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Blood Flow Velocity; Blood Pressure; Echocardiography, Doppler; Female; Humans; Hypertension, Pulmonary; Iran; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Predictive Value of Tests; Prospective Studies; Pulmonary Artery; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Tricuspid Valve Insufficiency; Vasodilator Agents; Young Adult

No guidelines exist to help physicians determine whether functional and health-related quality of life (HRQoL) changes observed following treatment of patients with pulmonary arterial hypertension (PAH) represent important benefits. These analyses were undertaken to help define a minimally important difference (MID) in exercise capacity, measured by the 6-min walk distance (6MWD), and HRQoL, measured by the Short Form-36 (SF-36) questionnaire in patients with PAH.. Data from a 12-week sildenafil study in patients with PAH were used to calculate MIDs for 6MWD and the SF-36 physical functioning, role-physical, social functioning, and vitality scales using effect size, SEM, and SE of the difference approaches. Data from all patients enrolled into the treatment groups in the study were included.. A range of plausible MID estimates, including a score change for SF-36 scales and a change in distance walked in meters for 6MWD, were generated for each end point. Mean values were calculated for each outcome and recommended as MIDs for each parameter. Based on these computations, the mean MIDs for the SF-36 physical functioning, role-physical, social functioning, and vitality scales and for 6MWD were 13, 25, 21, and 15 points, and 41 m, respectively.. This is the first clinical investigation to estimate MIDs for key SF-36 domains and 6MWD in patients with PAH and provides a much needed metric for interpreting the level of change in patients with PAH against which other treatments and trials can be measured.

Topics: Double-Blind Method; Exercise Tolerance; Female; Health Status; Humans; Hypertension, Pulmonary; Male; Outcome Assessment, Health Care; Piperazines; Purines; Quality of Life; Reproducibility of Results; Sildenafil Citrate; Sulfones; Vasodilator Agents

The reversibility of elevated pulmonary vascular resistance in heart failure bears an important relation to outcome after cardiac transplantation. The phosphodiesterase 3 (PDE3) and PDE5 inhibitors both increase levels of cyclic nucleotides in the vascular smooth muscle, causing vasodilatation. PDE3 inhibitors also have direct inotropic effects. We contrasted the acute hemodynamic responses to intravenous PDE3 and PDE5 inhibitors in patients with congestive cardiac failure to assess their relative suitability for reversibility testing in this setting.. Thirty patients undergoing assessment for cardiac transplantation underwent right heart catheterization. Patients were randomized to receive an intravenous bolus of milrinone (0.05 mg/kg) or sildenafil citrate at a high (0.43 mg/kg) or low dose (0.05 mg/kg).. Differences between low- and high-dose sildenafil were not significant. Both agents caused similar reductions in systemic and pulmonary vascular resistance. Milrinone caused significantly greater reductions in pulmonary artery wedge and mean pulmonary artery pressure, and increases in heart rate. In all study groups, greater increases in cardiac index (>25%) were seen in patients with a higher pulmonary artery wedge pressure at baseline (29 +/- 1 vs 20 +/- 2 mm Hg; p < 0.001).. In end-stage congestive cardiac failure, intravenous milrinone and sildenafil both cause similar reductions in systemic and pulmonary vascular resistance; however, milrinone has more cardiac selective effects on left ventricular filling and heart rate. Both agents appear to have a suitable hemodynamic profile for testing of reversibility of secondary pulmonary hypertension in congestive cardiac failure. Larger studies are needed to confirm these results.

Topics: Adult; Blood Pressure; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Heart Failure; Heart Rate; Heart Transplantation; Humans; Hypertension, Pulmonary; Injections, Intravenous; Male; Middle Aged; Milrinone; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance

Sildenafil has been suggested to be a cost-effective treatment for pulmonary arterial hypertension (PAH). On account of the lack of data confirming its benefit in PAH patients, sildenafil has not been adopted in China for the treatment of PAH. The purpose of this study was to evaluate the efficacy, safety and 1-year survival of Chinese patients with PAH treated with sildenafil. Sixty Chinese patients with PAH were enrolled in this preliminary study. Their 6-min walk distance, WHO functional class and hemodynamic parameters (such as right atrial pressure, pulmonary arterial pressure, cardiac index and pulmonary vascular resistance) at both baseline and 16 weeks after initiation of sildenafil treatment were recorded. In addition, 1-year overall survival was assessed in this cohort. The 6-min walk distance improved from 392.13+/-91.35 to 467.22+/-80.38 m during the course of treatment (P<0.001). There was a significant decrease in the mean pulmonary vascular resistance (15.28+/-8.12-14.99+/-7.88 Woods units; P=0.02) and a significant increase in the mean cardiac index (2.39+/-0.90-2.75+/-0.92 l/min/m(2), P=0.006) of the included patients at 16 weeks. The mean systemic oxygen saturation improved significantly at 16 weeks (91.44+/-7.54%-94.11+/-4.28%; P=0.002). No serious adverse reactions were reported. The Kaplan-Meier analysis showed that the 1-year survival rate improved significantly in the sildenafil-treated cohort compared with predicted survival (94.7% compared with 63.3%, P=0.03). In conclusion, sildenafil may be a safe and effective treatment for Chinese PAH patients. Sildenafil, when added to conventional therapy, was associated with improvements in exercise capacity, hemodynamic parameters and overall survival in a cohort of Chinese patients with PAH.

Topics: Adult; Biomarkers; Cardiac Catheterization; Exercise; Exercise Test; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Survival; Vasodilator Agents

This study investigated the acute pharmacodynamic effects of sildenafil in patients with pulmonary arterial hypertension (PAH) and concomitant bosentan treatment, in view of a mutual pharmacokinetic interaction between the 2 drugs. This prospective, open-label, noncomparative, multicenter, phase II study enrolled 45 patients (>or=18 years) with stable PAH (idiopathic, familial, or related to corrected congenital systemic-to-pulmonary shunts, drugs, or toxins) and on bosentan treatment for at least 3 months. Patients underwent right heart catheterization to evaluate the acute hemodynamic effects of (a) inhaled nitric oxide (iNO) and (b) a single oral dose of sildenafil (25 mg). Mean pulmonary vascular resistance (PVR) decreased from baseline following iNO (-15%; 95% confidence limits: -21%, -8%; P = .0001). A statistically significant decrease from baseline in mean PVR was also observed 60 minutes following sildenafil administration (-15%; 95% confidence limits: -21%, -10%; P < .0001). The reduction in PVR following sildenafil was comparable to that resulting from iNO. There were no unexpected safety findings. The pharmacodynamic effect suggests that addition of sildenafil to bosentan treatment can elicit additional hemodynamic benefits. These data represent a rationale for long-term combination studies with the 2 compounds.

Topics: Antihypertensive Agents; Bosentan; Drug Interactions; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Models, Cardiovascular; Nitric Oxide; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension.. Inhaled nitric oxide (20ppm; n=50), sildenafil (50mg; n=50) and inhaled treprostinil (15microg; n=25 or 30microg; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5).. Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3+/-5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7+/-3.5% and increased cardiac output (CO) to 102.4+/-2.9%. Sildenafil reduced PVR to 80.1+/-5.0%, mPAP to 86.5+/-2.9% and increased CO to 103.8+/-3.2%. Treprostinil, inhaled 1h after sildenafil, reduced PVR to 66.3+/-3.8%, mPAP to 77.8+/-3.3%, and increased CO to 107.1+/-3.3% (mean+/-95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed.. The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Area Under Curve; Blood Pressure; Cough; Drug Synergism; Drug Therapy, Combination; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Fibrosis; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance

Oral sildenafil and intravenous epoprostenol have independently been shown to be effective in patients with pulmonary arterial hypertension.. To investigate the effect of adding oral sildenafil to long-term intravenous epoprostenol in patients with pulmonary arterial hypertension.. A 16-week, double-blind, placebo-controlled, parallel-group study.. Multinational study at 41 centers in 11 countries from 3 July 2003 to 27 January 2006.. 267 patients with pulmonary arterial hypertension (idiopathic, associated anorexigen use or connective tissue disease, or corrected congenital heart disease) who were receiving long-term intravenous epoprostenol therapy.. Patients were randomly assigned to receive placebo or sildenafil, 20 mg three times daily, titrated to 40 mg and 80 mg three times daily, as tolerated, at 4-week intervals. Of 265 patients who received treatment, 256 (97%) patients (123 in the placebo group and 133 in the sildenafil group) completed the study.. Change from baseline in exercise capacity measured by 6-minute walk distance (primary end point) and hemodynamic measurements, time to clinical worsening, and Borg dyspnea score (secondary end points).. A placebo-adjusted increase of 28.8 meters (95% CI, 13.9 to 43.8 meters) in the 6-minute walk distance occurred in patients in the sildenafil group; these improvements were most prominent among patients with baseline distances of 325 meters or more. Relative to epoprostenol monotherapy, addition of sildenafil resulted in a greater change in mean pulmonary arterial pressure by -3.8 mm Hg (CI, -5.6 to -2.1 mm Hg); cardiac output by 0.9 L/min (CI, 0.5 to 1.2 L/min); and longer time to clinical worsening, with a smaller proportion of patients experiencing a worsening event in the sildenafil group (0.062) than in the placebo group (0.195) by week 16 (P = 0.002). Health-related quality of life also improved in patients who received combined therapy compared with those who received epoprostenol monotherapy. There was no effect on the Borg dyspnea score. Of the side effects generally associated with sildenafil treatment, the most commonly reported in the placebo and sildenafil groups, respectively, were headache (34% and 57%; difference, 23 percentage points [CI, 12 to 35 percentage points]), dyspepsia (2% and 16%; difference, 13 percentage points [CI, 7 to 20 percentage points]), pain in extremity (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]), and nausea (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]).. The study excluded patients with pulmonary arterial hypertension associated with other causes. There was an imbalance in missing data between groups, with 8 placebo recipients having no postbaseline walk assessment compared with 1 sildenafil recipient. These patients were excluded from the analysis.. In some patients with pulmonary arterial hypertension, the addition of sildenafil to long-term intravenous epoprostenol therapy improves exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life, but not Borg dyspnea score. Increased rates of headache and dyspepsia occurred with the addition of sildenafil.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Double-Blind Method; Drug Therapy, Combination; Dyspepsia; Epoprostenol; Female; Headache; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Intravenous; Male; Middle Aged; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents; Walking

Ventilatory efficiency, right ventricular (RV) function, and secondary pulmonary hypertension are each prognostic indicators in patients with heart failure due to left ventricular systolic dysfunction, but the relationships among these variables have not been comprehensively investigated. In this study, we hypothesized that inefficient ventilation during exercise, as defined by an abnormally steep relationship between ventilation and carbon dioxide output (Ve/Vco(2) slope), may be a marker of secondary pulmonary hypertension and RV dysfunction in heart failure.. A cohort of patients with systolic heart failure (mean+/-SD age, 58+/-13 years; left ventricular ejection fraction, 0.27+/-0.05; peak oxygen uptake, 11.2+/-3.2 mL kg(-1) min(-1)) underwent incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring and first-pass radionuclide ventriculography before and after 12 weeks of treatment with sildenafil, a selective pulmonary vasodilator, or placebo. Ve/Vco(2) slope was positively related to rest and exercise pulmonary vascular resistance (R=0.39 and R=0.60, respectively) and rest pulmonary capillary wedge pressure (R=0.49, P<0.005 for all) and weakly indirectly related to peak exercise RV ejection fraction (R=-0.29, P=0.03). Over the 12-week study period, Ve/Vco(2) slope fell 8+/-3% (P=0.02) with sildenafil and was unchanged with placebo. Changes in Ve/Vco(2) slope correlated with changes in exercise pulmonary vascular resistance (R=0.69, P<0.001) and rest and exercise RV ejection fraction (R=-0.58 and -0.40, respectively, both P<0.05).. In patients with systolic heart failure and secondary pulmonary hypertension, ventilatory efficiency is closely related to RV function and pulmonary vascular tone during exercise.

Topics: Aged; Carbon Dioxide; Cohort Studies; Double-Blind Method; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Muscle Tonus; Muscle, Smooth, Vascular; Piperazines; Pulmonary Circulation; Purines; Respiration; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Function, Right; Ventriculography, First-Pass

The aim of this study was to systematically investigate the mutual pharmacokinetic interactions in healthy volunteers between sildenafil, a phosphodiesterase-5 inhibitor, and bosentan, a dual endothelin receptor antagonist, both approved for treating pulmonary arterial hypertension (PAH).. A randomised, double-blind, placebo-controlled, parallel-group study with three treatment arms (sildenafil plus placebo, bosentan plus placebo and sildenafil plus bosentan) was conducted in 55 healthy male volunteers (51 completers). Study duration was 18 days per treatment group. Sildenafil was administered three times daily on Days 1-6 and 11-16 (20 mg initially, increased to 80 mg after 3 days), and bosentan (125 mg) was administered twice daily on Days 7-17.. On Day 16, bosentan decreased the maximum plasma concentration of sildenafil (c)(max)) by 55.4% [90% confidence interval (CI) 40.3-66.6%] and the area under the plasma concentration versus time curve over a dosing interval (AUC(tau)) by 62.6% (90% CI 56.8-67.7%). Sildenafil increased bosentan C(max) by 42.0% (90% CI 15.4-74.8%) and (AUC(tau)) by 49.8% (90% CI 28.7-74.5%). Bosentan and sildenafil in combination were well tolerated, with no serious adverse events reported. All adverse events were of mild or moderate intensity.. In healthy volunteers, there is a mutual pharmacokinetic interaction between bosentan and sildenafil that may influence the dosage of each drug in a combination treatment. The clinical implications of combination therapy with bosentan and sildenafil are as yet unknown, and further trials in patients with PAH are needed.

Topics: Adolescent; Adult; Antihypertensive Agents; Area Under Curve; Bosentan; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones

It is shown that phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil can modulate pulmonary arterial hypertension (PAH) via increasing the level of guanosine-3,5-cyclic monophosphate (cGMP) and decreases pulmonary artery pressure (PAP). In this study we determined the effectiveness of sildenafil and compared its efficacy with inhaled nasal oxygen (O2) during cardiac catheterization in patients with congenital heart diseases (CHD) and PAH, as a test of feasibility for surgical repair of the patients. We studied 15 patients, 9 male and 6 female, with a mean age of 8.3 years. Hemodynamic measurements were made at baseline, after O2 administration for 20 min (5 L/min by mask), and then 45 min after administration of a single dose of sildenafil (0.5 mg/kg orally or via nasogastric tube). Mean PAP at baseline was 72.2 +/- 12.54 mm Hg and was reduced by sildenafil to 52.5 +/- 9.6 and by O2 to 61.3 +/- 10.39. Both sildenafil and O2 decreased PAP effectively (p = 0.08 and p = 0.04, respectively). Pulmonary vascular resistance (PVR) was calculated for 12 patients, with a baseline level of 9.08 +/- 1.09 mm Hg . L(-1) . min, which was significantly decreased by O2, to 3.74 +/- 0.43, and by sildenafil, to 5.93 +/- 0.75 (p = 0.005 and p = 0.05, respectively). Sildenafil, as a single oral dose, can effectively reduce PAP and PVR. This novel PDE5 inhibitor can be used for assessment of feasibility of operation for patients with CHD and PAH when inhaled NO is not available.

Topics: Administration, Oral; Adolescent; Cardiac Catheterization; Child; Child, Preschool; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Male; Oxygen Inhalation Therapy; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones

In chronic obstructive pulmonary disease (COPD) patients, stroke volume response to exercise is impaired. The aim of the present study was to investigate whether 3 months of sildenafil treatment improves stroke volume and, if so, whether this improvement is related to the pulmonary artery pressure and translated into an improved exercise capacity. A total of 15 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage II-IV) underwent right heart catheterisation at rest and during exercise. Stroke volume was assessed by magnetic resonance imaging (MRI) at rest and during submaximal exercise in the supine position and compared with eight age-matched controls. Additionally, a cardiopulmonary exercise test and a 6-min walking distance test were performed. Exercise tests and MRI were repeated after 12 weeks of oral therapy with 50 mg sildenafil three times daily. Stroke volume in COPD patients was significantly lower than in healthy controls (62+/-12 versus 81+/-22 mL at rest and 70+/-15 versus 101+/-28 mL during exercise). Pulmonary hypertension (PH) was diagnosed in nine patients and was absent in six. Treatment with sildenafil had no effect on stroke volume or exercise capacity. Although the stroke volume was lower in COPD patients with associated PH in comparison with non-PH patients, there was no difference in treatment response between both groups. In the present group of 15 chronic obstructive pulmonary disease patients, a reduced stroke volume was found at rest and during exercise. Neither stroke volume nor exercise capacity were improved by 3 months of sildenafil therapy.

Topics: Aged; Case-Control Studies; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Vasodilator Agents

Sildenafil inhibits phosphodiesterase-5, enhancing cyclic guanosine monophosphate- mediated relaxation of pulmonary vasculature and is effective in treating patients with pulmonary arterial hypertension (PAH).. Patients with PAH (n = 278) received oral sildenafil (20, 40, or 80 mg three times daily) in a 12-week, double-blind, placebo-controlled study and an open-label extension. Health-related quality of life (HRQoL) was recorded by patients using the Medical Outcomes Study 36-item short form (SF-36) and EuroQol 5D (EQ-5D) questionnaires at baseline and after 12 and 24 weeks of therapy. Data are presented for patients who received sildenafil for up to 24 weeks.. Sildenafil-treated patients, compared with placebo-treated patients, exhibited significant improvement in exercise capacity at week 12 (p < 0.001). Increases from baseline to week 12 were observed in all SF-36 domains for sildenafil-treated patients, with statistically significant improvements, compared with placebo-treated control subjects, in physical functioning (p < 0.001), general health (p < 0.001), and vitality (p < 0.05). Statistically significant improvements were also observed for the EQ-5D current health status (p < 0.01) and utility index (p < 0.01). These benefits were maintained for 24 weeks. Treatment groups were pooled for analyses as the results for the 6-min walk distance, SF-36, and EQ-5D were not dose dependent.. Sildenafil improves HRQoL of PAH patients. These improvements appear to be maintained for at least 24 weeks. The effects are strongest in domains addressing the physical impact of health on daily activities and patients' overall perception of health.

Topics: Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfones

There are currently no licensed medical therapies for inoperable chronic thromboembolic pulmonary hypertension (CTEPH).. In this double-blind, placebo-controlled pilot study, 19 subjects with inoperable CTEPH were randomly assigned to sildenafil or placebo for 12 weeks. The primary end point was change in 6-min walking distance (6MWD). Secondary end points included changes in World Health Organization (WHO) class, cardiopulmonary hemodynamics, quality of life (QOL) scores, and N-terminal pro brain natriuretic peptide (NT-proBNP). All subjects were transferred to open-label sildenafil at the end of the study and offered repeat assessment at 12 months.. There were no significant differences between the two groups with respect to change in exercise capacity. However significant improvements were seen in WHO class and pulmonary vascular resistance (PVR). Seventeen subjects were eligible for reassessment at 12 months and demonstrated significant improvements in 6MWD, activity and symptom components of QOL, cardiac index, PVR, and NT-proBNP.. Although this pilot study was insufficiently powered to test the primary end point, it did suggest beneficial effects in favor of sildenafil in several secondary end points at both 3 months and 12 months. Further larger-scale trials of sildenafil in inoperable CTEPH are required to confirm these findings and potentially increase the treatment options available for this devastating disease.. The study protocol was registered with the UK National Research Register database (publication ID N0542136603).

Topics: Adult; Aged; Double-Blind Method; Drug Administration Schedule; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Pulmonary Embolism; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

We investigated in chronic obstructive pulmonary disease (COPD) patients whether a single dose of sildenafil can attenuate the exercise-induced increase in pulmonary artery pressure, thereby allowing augmentation of stroke volume (SV), and improving maximal exercise capacity.. Eighteen COPD patients (GOLD II-IV) underwent right heart catheterization at rest and submaximal exercise. Mean pulmonary artery pressure (mPpa) and cardiac output (CO) were assessed. Resting and exercise measurements were repeated 60 min after oral intake of 50mg sildenafil. Also, on different days, patients performed two maximal exercise tests (CPET) randomly, 1h after placebo and after 50mg sildenafil.. Five COPD patients had pulmonary hypertension (PH) at rest (mPpa >25 mmHg) and six developed PH during exercise (mPpa >30 mmHg). In all patients, mPpa increased from rest to submaximal exercise (23+/-10-35+/-14 mmHg). After sildenafil mPpa at rest was 20+/-10 mmHg, in exercise mPpa was increased less to 30+/-14 mmHg (p<0.01). The reduced augmentation in mPpa was not accompanied by an increased SV and CO. In COPD patients with PH the percentage increase in mPpa to submaximal exercise was 68% before, and 51% after oral intake of sildenafil (p=0.07). In COPD without PH, these values were 46% and 41% (ns), respectively. Maximal exercise capacity and CPET characteristics were unchanged after sildenafil.. Regardless of mPpa at rest, sildenafil attenuates the increase in mPpa during submaximal exercise in COPD. This attenuated increase is neither accompanied by enhanced SV and CO, nor by improved maximal exercise capacity.

Topics: Aged; Anaerobic Threshold; Cardiac Catheterization; Cardiac Output; Exercise Test; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen; Piperazines; Pulmonary Circulation; Pulmonary Disease, Chronic Obstructive; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Vasodilator Agents; Ventricular Function, Right

To test the hypothesis that chronic sildenafil treatment has similar functional and hemodynamic effects in patients with severe pulmonary arterial hypertension due to Eisenmenger syndrome as those due to idiopathic pulmonary arterial hypertension without intracardiac shunts.. A prospective open-label study was carried out to compare the effects of sildenafil on the pulmonary hemodynamics between two groups of patients with severe pulmonary hypertension and similar baseline functional capacity--Eisenmenger syndrome (ES group) (n=7) versus idiopathic pulmonary arterial hypertension (IPAH group) (n=6).. After 6 months of sildenafil, there was a significant improvement in the functional capacity, the arterial saturation and the pulmonary hemodynamics in the ES group, as shown by significant reduction in the systolic and mean pulmonary artery pressures and the pulmonary vascular resistance.. Sildenafil increases pulmonary blood flow and improves cyanosis in patients with Eisenmenger syndrome. Efficacy of sildenafil as treatment for idiopathic pulmonary arterial hypertension may be extended to patients with Eisenmenger syndrome.

Topics: Adult; Eisenmenger Complex; Exercise Test; Female; Humans; Hypertension, Pulmonary; Lung; Male; Oxygen; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Purines; Regional Blood Flow; Sildenafil Citrate; Sulfones; Systole; Vascular Resistance

Pulmonary hypertension is a common finding in patients with idiopathic pulmonary fibrosis (IPF), and is associated with increased morbidity and mortality. Therapy with sildenafil has been shown to decrease pulmonary vascular resistance in patients with pulmonary fibrosis and may improve functional status. Patients with IPF and documented pulmonary hypertension were followed up in an open-label study of sildenafil. The 6-min walk test distance (6MWD) was obtained before and after 3 months of sildenafil therapy. Fourteen patients were followed up in the study; 11 patients completed both 6-min walk tests. The mean improvement in walk distance was 49.0 m (90% confidence interval, 17.5 to 84.0 m). When all 14 patients were dichotomized into groups of "responders" (ie, >/= 20% improvement in 6MWD) or "nonresponders" (ie, < 20% change or unable to complete), 57% were classified as responders. Sildenafil is a promising and well-tolerated therapeutic agent for use in patients with IPF and pulmonary hypertension, and should be studied in a large, well-controlled trial.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Aged, 80 and over; Cyclic Nucleotide Phosphodiesterases, Type 5; Exercise Test; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Fibrosis; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents; Walking

Although surgery is the treatment of choice for CTEPH, it is not appropriate for patients with surgically inaccessible distal disease. These patients are traditionally managed supportively, but may benefit from newer, more specific vasoactive therapies. This study examines the acute haemodynamic responses to inhaled nitric oxide (iNO) and intravenous sildenafil in this patient population.. Nine patients with de novo distal CTEPH and nine with persistent pulmonary hypertension post-pulmonary endarterectomy (PEA) were enrolled. At right heart catheterisation, following baseline haemodynamic measurements, iNO was administered at 20 ppm for 10 min. Following repeat measurements, iNO was discontinued with a subsequent washout period of 10 min. Sildenafil was then administered intravenously at two doses, to achieve plasma levels equivalent to 25 mg and 50 mg orally, with further measurements obtained at the end of each infusion.. Significant reductions in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) were demonstrated following both iNO (-4.3 mm Hg or -10.3% p=0.001 and -101 dyn/s/cm(5) or -15.6% p<0.001) and sildenafil (-7.4 mm Hg or -16.9% p<0.001 and -188.8 dyn/s/cm(5) or -25.1% p<0.001). Individual mPAP and cardiac output (CO) responses to iNO and sildenafil correlated well, but haemodynamic changes following sildenafil were consistently more marked. There was, however, no difference in effect between the two doses of sildenafil. Although sildenafil caused significant reductions in systemic vascular resistance, the net haemodynamic effect of sildenafil remained pulmonary selective. Subgroup analysis suggested that post-PEA patients were more responsive to both iNO and sildenafil than de novo patients.. Although all but one patient failed to fulfil the formal haemodynamic response criteria typically used in idiopathic pulmonary arterial hypertension (IPAH), subjects displayed significant acute responses to both iNO and sildenafil suggesting that increased vascular tone forms an important component of distal CTEPH. It is possible that these acute haemodynamic responses may translate to improved clinical outcomes, and thus further long term trials of sildenafil in distal CTEPH are warranted.

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Blood Pressure; Cardiac Output; Chronic Disease; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Injections, Intravenous; Male; Middle Aged; Nitric Oxide; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Thromboembolism; Treatment Outcome; Vascular Resistance; Vasodilation; Vasodilator Agents

This study investigates the role of oral sildenafil in decreasing pulmonary pressure after congenital heart surgery. Between September 2002 and September 2004, among a group of postoperative children with large septal defects, moderate to severe pulmonary hypertension [pulmonary artery (PA) to aortic (Ao) pressure ratio of 0.76 +/- 0.17] and systemic desaturation (Ao Sat = 0.89 +/- 0.11), oral sildenafil (0.3 mg x kg(-1), every 3 hours) was administered for a period of 24-48 hours (sildenafil group). These patients were compared to a group of 22 children with similar pathologies who did not receive sildenafil (control group). Postoperative PA pressure (28.61 +/- 7.80 vs 39.40 +/- 10.80 mm Hg) and PA/Ao pressure (0.28 +/- 0.08 vs 0.41 +/- 0.11) were significantly lower in the sildenafil group ( p = 0.001 and 0.001 respectively). Pulmonary hypertensive crisis was detected in 4 patients in the control group, but none in the sildenafil group ( p = 0.02). There was no significant rise in PA pressure following discontinuation of the drug (26.30 +/- 6.66 vs 28.49 +/- 10.93 mm Hg, p = 0.366). No significant complications were noticed regarding sildenafil use. Low doses of oral sildenafil appear to be effective and safe to control postoperative PA pressure in children. Absence of rebound pulmonary hypertension, availability, and low cost of the drug are considered as its major advantages.

Topics: Administration, Oral; Adolescent; Antihypertensive Agents; Cardiac Surgical Procedures; Child; Child, Preschool; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

This study investigated whether right ventricular (RV) diastolic function is impaired in pulmonary hypertension (PH) patients, and whether it is related to RV mass and afterload. In addition, the effects of an acute reduction of RV afterload by the oral intake of sildenafil were studied. Finally, we assessed whether diastolic function is related to cardiac parameters of disease severity.. Twenty-five PH patients and 11 control subjects were studied. Right-heart catheterization and N-terminal pro-brain natriuretic peptide (NT-proBNP) sampling were performed in patients. MRI measured RV ejection fraction, mass, and diastolic function. Isovolumic relaxation time (IVRT), normalized early peak filling rate (E), atrium-induced peak filling rate (A), and E/A ratio described diastolic function. Compared to control subjects, patients had prolonged mean (+/- SD) IVRT (133.5 +/- 53.2 vs 29.3 +/- 20.8 ms, respectively; p < 0.001), decreased E (3.0 +/- 1.6 vs 6.4 +/- 2.5 s(-1), respectively; p < 0.001) and E/A ratio (1.1 +/- 0.7 vs 5.3 +/- 4.9, respectively; p < 0.001), and increased A (3.0 +/- 1.4 vs 1.5 +/- 0.9 s(-1), respectively; p = 0.001). IVRT was related to RV mass (r(25) = 0.56; p = 0.005) and pulmonary vascular resistance (r(25) = 0.74; p < 0.0001). Sildenafil therapy reduced RV afterload and improved RV diastolic and systolic function. IVRT was correlated with NT-proBNP level (r = 0.70; p < 0.001), and was inversely related to cardiac index (r = -0.70; p < 0.001) and RV ejection fraction (r = -0.69; p < 0.001).. In PH patients, RV diastolic dysfunction is related to RV mass and afterload. RV diastolic function improves by reducing afterload. The correlations between diastolic function and prognostic parameters showed that diastolic function is most impaired in patients with severe disease.

Topics: Adult; Antihypertensive Agents; Blood Circulation; Blood Pressure; Bosentan; Epoprostenol; Female; Heart Ventricles; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Male; Middle Aged; Nitric Oxide; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Stroke Volume; Sulfonamides; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Right

For chronic thromboembolic pulmonary hypertension not amenable to pulmonary endarterectomy, effective medical therapy is desired. In an open-label uncontrolled clinical trial, 104 patients (mean +/- sem age 62 +/- 11 yrs) with inoperable chronic thromboembolic pulmonary hypertension were treated with 50 mg sildenafil t.i.d. At baseline, patients had severe pulmonary hypertension (pulmonary vascular resistance 863 +/- 38 dyn.s.cm(-5)) and a 6-min walking distance of 310 +/- 11 m. Eight patients were in World Health Organization functional class II, 76 in class III and 20 in class IV. After 3 months' treatment, there was significant haemodynamic improvement, with reduction of pulmonary vascular resistance to 759 +/- 62 dyn.s.cm(-5). The 6-min walking distance increased significantly to 361 +/- 15 m after 3 months' treatment, and to 366 +/- 18 m after 12 months' treatment. A subset of 67 patients received a single dose of 50 mg sildenafil during initial right heart catheterisation. The acute haemodynamic effect of this was not predictive of long-term outcome. In this large series of patients with inoperable chronic thromboembolic pulmonary hypertension, open-label treatment with sildenafil led to significant long-term functional improvement. The acute effect of sildenafil may not predict the long-term outcome of therapy.

Topics: Adult; Aged; Aged, 80 and over; Cardiac Catheterization; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Statistics, Nonparametric; Sulfones; Thromboembolism; Treatment Outcome; Vascular Resistance; Vasodilator Agents

The pulmonary vasculopathy in pulmonary arterial hypertension (PAH) results in increased resistance to pulmonary blood flow, limiting the cardiac output required for the increased O(2) demands of exercise.. We sought to determine the physiologic basis for clinical improvement in PAH patients receiving sildenafil, hypothesizing that the key mechanisms of improvement are improved blood flow and ventilatory efficiency, leading to improved exercise capacity and O(2) pulse over time.. We studied 28 PAH patients with (n=14) and without (n=14) sildenafil treatment. All received warfarin and diuretic therapy, and 13/14 sildenafil-treated patients were already receiving specific PAH drugs. Cardiopulmonary exercise testing was performed before and after sildenafil.. Peak VO2 , peak O(2) pulse, V E/CO2 and PETCO2, were 0.84+/-0.1 L/min, 6.1+/-0.7 mL beat(- 1), 49+/-2 and 26+/-1.5 mm Hg, and improved after adding sildenafil to 0.91+/-0.1 L/min, 6.8+/-0.8 mL beat(- 1), 43+/-2, and 30+/-1.9, respectively, whereas control patients worsened (p=0.012, 0.008, 0.008 and 0.0002, treated vs. controls, respectively).. Sildenafil improves PETCO2, V E/V CO(2), peak O2 pulse and peak VO2 during exercise compared to controls. A prospective, placebo-controlled study is needed to validate these findings.

Topics: Adult; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Ventilation; Purines; Respiratory Function Tests; Sildenafil Citrate; Sulfones; Vasodilator Agents

Patients with systolic heart failure (HF) who develop secondary pulmonary hypertension (PH) have reduced exercise capacity and increased mortality compared with HF patients without PH. We tested the hypothesis that sildenafil, an effective therapy for pulmonary arterial hypertension, would lower pulmonary vascular resistance and improve exercise capacity in patients with HF complicated by PH.. Thirty-four patients with symptomatic HF and PH were randomized to 12 weeks of treatment with sildenafil (25 to 75 mg orally 3 times daily) or placebo. Patients underwent cardiopulmonary exercise testing before and after treatment. The change in peak VO2 from baseline, the primary end point, was greater in the sildenafil group (1.8+/-0.7 mL x kg(-1) x min(-1)) than in the placebo group (-0.27 mL x kg(-1) x min(-1); P=0.02). Sildenafil reduced pulmonary vascular resistance and increased cardiac output with exercise (P<0.05 versus placebo for both) without altering pulmonary capillary wedge or mean arterial pressure, heart rate, or systemic vascular resistance. The ability of sildenafil treatment to augment peak VO2 correlated directly with baseline resting pulmonary vascular resistance (r=0.74, P=0.002) and indirectly with baseline resting right ventricular ejection fraction (r=-0.64, P=0.01). Sildenafil treatment also was associated with improvement in 6-minute walk distance (29 m versus placebo; P=0.047) and Minnesota Living With Heart Failure score (-14 versus placebo; P=0.01). Subjects in the sildenafil group experienced fewer hospitalizations for HF and a higher incidence of headache than those in the placebo group without incurring excess serious adverse events.. Phosphodiesterase 5 inhibition with sildenafil improves exercise capacity and quality of life in patients with systolic HF with secondary PH.

Topics: Aged; Blood Pressure; Exercise; Female; Follow-Up Studies; Heart Failure; Heart Rate; Humans; Hypertension, Pulmonary; Male; Middle Aged; Motor Activity; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Systole; Treatment Outcome; Vascular Resistance

Topics: Aged; Aged, 80 and over; Diuretics; Female; Furosemide; Humans; Hypertension, Pulmonary; Male; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD) is difficult to manage, and has a poor prognosis. The phosphodiesterase-5 inhibitor sildenafil citrate enhances vasodilatation, has antiproliferative effects, and is effective in the treatment of PAH. We examined the efficacy and safety of oral sildenafil in patients with PAH-CTD.. In a 12-week, double-blind study (SUPER-1), 278 patients with PAH were randomized to oral placebo, sildenafil 20 mg, sildenafil 40 mg, or sildenafil 80 mg 3 times daily (tid). In a post-hoc subgroup analysis of 84 patients with PAH-CTD, exercise capacity, hemodynamic measures, World Health Organization functional class, and tolerability were assessed.. Forty-five percent of the patients had scleroderma, 23% had systemic lupus erythematosus, and the rest (32%) were categorized as other. Patients were predominantly functional class II (38%) or III (61%) at baseline. Sildenafil-treated patients exhibited mean increases in 6-minute walk distance at Week 12 of 42 m (95% CI 20, 64) for 20 mg, 36 m (95% CI 14, 58) for 40 mg, and 15 m (95% CI -24, 54) for 80 mg, while placebo-treated patients exhibited a mean decrease of 13 m (95% CI -36, 10). Improvement of at least 1 functional class occurred in 29%-42% of sildenafil-treated patients, compared to 5% for placebo. Significant improvements in mean pulmonary arterial pressure and pulmonary vascular resistance were observed with sildenafil 20 mg, and sildenafil was generally well tolerated.. In patients with PAH-CTD, sildenafil improves exercise capacity, hemodynamic measures (at the 20 mg dose), and functional class after 12 weeks of treatment.

Topics: Adult; Aged; Connective Tissue Diseases; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

We performed a short-term outcome analysis of orthotopic heart transplantation (OHT) in patients with pulmonary hypertension (PH) treated perioperatively with oral sildenafil.. PH (pulmonary vascular resistance > 2.5 Wood units, and/or transpulmonary gradient > 12 mmHg) was diagnosed in 6 of 25 (group A) heart transplant recipients operated in 2006. This group of patients underwent a modified medication protocol including perioperative administration of oral sildenafil: 50 mg before followed by 50 or 25 mg TID after heart transplantation. Sildenafil treatment was discontinued 10 to 14 days post OHT, after stepwise dose reduction. During the ICU stay all patients underwent circulatory monitoring of pulmonary and systemic pressures and resistance as well as transthoracic echocardiogram (TTE) evaluation.. Perioperative oral sildenafil administration in PH patients undergoing OHT was associated with good short-term outcomes in the majority of transplanted patients (4/6). Sildenafil treatment reduced pulmonary resistance and pressures with a low rate of hemodynamic instability among OHT patients.. Pharmacologic perioperative reduction of PH improves the short-term prognosis for successful OHT. One may speculate whether sildenafil treatment transplant recipients with PH would be associated with long-term improvement of pulmonary vascular status, therefore leading to extended life-expectancy and improved outcomes.

Topics: Adult; Cardiac Output; Drug Administration Schedule; Echocardiography, Transesophageal; Female; Heart Failure; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Pulmonary hypertension (PH) is a predictor of early death risk owing to right heart insufficiency after orthotopic heart transplantation (OHT). The aim of this study was to evaluate the effectiveness and safety of sildenafil therapy to decrease pulmonary vascular resistance (PVR) in patients with heart failure requiring transplantation, who may otherwise have been excluded because of PH.. We analyzed the hemodynamic results of six men (aged 47 to 61) with well-grounded OHT indications and PH diagnosed by a transpulmonary gradient (TPG) > 12 mmHg and/or PVR > 2.5 Wood units. Patients underwent a PH reversibility test with sodium nitroprusside (NPS) to achieve normal TPG and PVR results without a drop in systolic arterial pressure <85 mmHg. Unresponsiveness to NPS was shown in all subjects, who were subsequently qualified for sildenafil therapy (50 mg bid).. After 1 month of sildenafil, three subjects achieved normal TPG and PVR, and acceptable responsiveness of PH to NPS in two other patients, all of whom qualified for OHT. Therapy was unsuccessful in one patient, which was confirmed also by right heart catheterization after 3 months of sildenafil use. Therapy was well tolerated in all patients, namely, no significant drop in arterial pressure on angiotensin-converting enzyme inhibitors.. Sildenafil may be effectively used for treatment of secondary, irreversible PH in potential heart transplant recipients.

Topics: Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Pulmonary Circulation; Purines; Safety; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5), and has been shown to improve 6-minute walk distance (SMWD) and World Health Organization (WHO) functional class in patients with idiopathic pulmonary arterial hypertension (iPAH) and PAH associated with connective tissue disease or with repaired congenital systemic-to-pulmonary shunts. Despite the efficacy of sildenafil in patients on conventional therapy with diuretics and anti-coagulants, little is known of the safety and efficacy of transitioning patients already established on parenteral prostanoid therapy to sildenafil.. We studied 14 patients on long-term subcutaneous treprostinil for PAH (from a cohort of 51 patients [27%]), who wished to discontinue treatment because of injection-site pain. The etiology of their PAH included iPAH (7 of 14), PAH secondary to scleroderma (2 of 14), thromboembolic disease (3 of 14) and PAH post-surgical correction of ventricular septal defect (2 of 14). Treprostinil was gradually weaned and all patients were started open-label with 50 mg sildenafil four times per day for 3 months. New York Heart Association (NYHA) functional class, SMWD, echocardiogram and quality-of-life (QOL) measures were determined at baseline and after 3 months of therapy with sildenafil.. Of 14 patients, 4 discontinued the transition because of deterioration during treprostinil withdrawal, despite the introduction of sildenafil. Replacement of chronic subcutaneous treprostinil with sildenafil was possible in 10 of 14 patients (71%), who demonstrated stable NYHA class (mean +/- SD: 3.1 +/- 0.3 at baseline to 2.6 +/- 0.8 at 3 months, p = 0.138), stable SMWD (434 +/- 83 m at baseline, 451 +/- 72 at 3 months, p = 0.23) and significantly improved QOL measures at 3 months.. The transition from subcutaneous treprostinil to sildenafil was safely achieved in most (71%), but not all, patients with pulmonary arterial hypertension of varied etiology. These patients had an improvement in both NYHA functional class and QOL, and maintained stable walk distances over a 3-month period on sildenafil therapy.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Drug-Related Side Effects and Adverse Reactions; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Middle Aged; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Vasodilator Agents

Prostaglandins and nitric oxide play a pivotal role in the regulation of macro- and microcirculatory blood flow distribution. Interference with both mediator systems have been implicated in cerebrovascular dysfunction. Inhaled iloprost (long-acting prostacyclin analogue) and the phosphodiesterase-5 inhibitor sildenafil have recently shown efficacy in the treatment of chronic pulmonary hypertension. We investigated the impact of these agents on cerebral microcirculatory regulation in patients suffering from this disease.. In 11 patients suffering from severe pulmonary hypertension, a functional transcranial Doppler test utilizing a visual stimulation paradigm was undertaken to measure the evoked flow velocity in the posterior cerebral artery. Measurements were performed in parallel to right heart catheterization and pharmacological testing of the pulmonary vasoreactivity. After assessment of baseline measurements, inhaled iloprost and oral sildenafil were given consecutively for testing of cerebral and pulmonary vascular function. The data gained from the Doppler measurements were compared to data from 22 healthy volunteers.. Both substances provoked a significant reduction of pulmonary arterial pressure and vascular resistance, accompanied by minor changes in systemic vascular resistance. In contrast to these superimposable hemodynamic profiles opposite effects were observed regarding cerebral vascular tone: cerebral microvascular reactivity, as assessed by attenuation and time rate parameters, was significantly improved by sildenafil, but slightly worsened by iloprost.. Sildenafil has beneficial effects on cerebral vascular reactivity indicative of an improvement in neurovascular coupling in patients with pulmonary hypertension. These results warrant further investigations of the influence of sildenafil on dynamic vascular function in the brain independent of the underlying disease.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Blood Flow Velocity; Blood Pressure; Brain; Case-Control Studies; Cerebrovascular Circulation; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Piperazines; Posterior Cerebral Artery; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Ultrasonography, Doppler, Transcranial; Vascular Resistance; Vasodilator Agents

Sildenafil causes pulmonary vasodilation, thus potentially reducing impairments of hypoxia-induced pulmonary hypertension on exercise performance at altitude. The purpose of this study was to determine the effects of sildenafil during normoxic and hypoxic exercise. We hypothesized that 1) sildenafil would have no significant effects on normoxic exercise, and 2) sildenafil would improve cardiac output, arterial oxygen saturation (SaO2), and performance during hypoxic exercise. Ten trained men performed one practice and three experimental trials at sea level (SL) and simulated high altitude (HA) of 3,874 m. Each cycling test consisted of a set-work-rate portion (55% work capacity: 1 h SL, 30 min HA) followed immediately by a time trial (10 km SL, 6 km HA). Double-blinded capsules (placebo, 50, or 100 mg) were taken 1 h before exercise in a randomly counterbalanced order. For HA, subjects also began breathing hypoxic gas (12.8% oxygen) 1 h before exercise. At SL, sildenafil had no effects on any cardiovascular or performance measures. At HA, sildenafil increased stroke volume (measured by impedance cardiography), cardiac output, and SaO2 during set-work-rate exercise. Sildenafil lowered 6-km time-trial time by 15% (P<0.05). SaO2 was also higher during the time trial (P<0.05) in response to sildenafil, despite higher work rates. Post hoc analyses revealed two subject groups, sildenafil responders and nonresponders, who improved time-trial performance by 39% (P<0.05) and 1.0%, respectively. No dose-response effects were observed. During cycling exercise in acute hypoxia, sildenafil can greatly improve cardiovascular function, SaO2, and performance for certain individuals.

Topics: Adolescent; Adult; Altitude; Cardiac Output; Double-Blind Method; Exercise; Exercise Test; Humans; Hypertension, Pulmonary; Hypoxia; Male; Oxygen Consumption; Physical Endurance; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Time Factors; Vasodilation; Vasodilator Agents

Severe pulmonary artery hypertension (PAH) is a disorder with limited treatment options. Recently, several newer drugs have recently been introduced to treat PAH. Sildenafil is one which has shown promise in several uncontrolled studies, but controlled trials have been few. In this randomized placebo-controlled study, we evaluated the efficacy of oral sildenafil in idiopathic PAH and PAH caused by Eisenmenger syndrome.. This was a randomized, double-blind, placebo-controlled crossover study. Twenty patients, 10 of each of idiopathic PAH and Eisenmenger syndrome, were randomized to receive placebo or sildenafil in a double-blind manner for 6 weeks and, after a washout period of 2 weeks, were crossed over. The primary end point of efficacy was the improvement in distance covered in 6-minute walk test. Secondary end points were reduction in pulmonary artery pressure as measured by Doppler echocardiography after 6 weeks of treatment, improvement in clinical condition, New York Heart Association (NYHA) class, and exercise duration and metabolic equivalents (Mets) achieved on modified Bruce exercise protocol.. There was significant improvement in primary and secondary end points. The primary end point of distance covered in 6-minute walk test improved from 262 +/- 99 to 358.9 +/- 96.5 m (P < .0001) after treatment with sildenafil. Pulmonary artery pressure, the secondary end point, improved from the baseline of 98.8 +/- 20.5 to 78.3 +/- 15.3 mm Hg (P < .0001), NYHA class improved from 2.65 +/- 0.59 to 1.55 +/- 0.51 (P < .0001), exercise duration from 6.4 +/- 3.1 to 10.2 +/- 2.05 minutes (P < .0001), and Mets achieved from 3.32 +/- 1.57 to 6.04 +/- 1.87 (P < .0001) after treatment with sildenafil. There was no significant fall in blood pressure with placebo and sildenafil, and no serious side effects of drug were observed in the study.. Sildenafil significantly improved the symptomatic status, exercise capacity, NYHA class, and hemodynamic parameters of patients with severe PAH and can be safely used as a primary or adjunctive treatment of the same.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adolescent; Adult; Child; Child, Preschool; Cross-Over Studies; Double-Blind Method; Eisenmenger Complex; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil offers potential to treat patients with pulmonary hypertension by selectively inhibiting phosphodiesterase type five pathways in the lung. It is recommended for selected patients with pulmonary arterial hypertension, but its role in the management of pulmonary hypertension associated with parenchymal lung disease is unclear.. Seven patients (68-86 years) with end stage chronic obstructive pulmonary disease (COPD, 4) and idiopathic pulmonary fibrosis (IPF, 3) were referred to our unit. All patients had a long-term history of chronic lung disease and were on maximal appropriate therapy prescribed by their referring pulmonologist. Thromboembolic disease was excluded by pulmonary angiography and all patients had had high resolution thoracic CT scan. At assessment right heart catheterisation, 2D echocardiography and 6-min walk test were performed prior to commencement of sildenafil 50mg tds. Their medication was otherwise unchanged. After 8 weeks treatment, right heart catheterisation, 2D echocardiography and 6-min walk test were repeated.. The pulmonary vascular resistance was reduced in six patients (from 13, 3, 3, 6.5, 3.5 and 10.5 wood units to 9.7, 2.5, 2.8, 4.4, 2.5 and 5.4 wood units, respectively). Six-minute walk test increased in six patients (from 110 m, 210 m, 80 m, 30 m, 210 m and 80 m to 130 m, 312 m, 120 m, 82 m, 244 m and 100 m, respectively). One patient with COPD did not demonstrate a favourable response although their cardiac output increased on sildenafil therapy. 2D echocardiography showed a reduction in estimated PA pressure in six patients with an improvement in right ventricular systolic function in two COPD patients.. Our results suggest that sildenafil may have a role for selected patients with COPD and IPF who have pulmonary hypertension.

Topics: Aged; Aged, 80 and over; Cardiac Catheterization; Echocardiography; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Walking

Portopulmonary hypertension (POPH) is regarded as a subtype of pulmonary arterial hypertension (PAH); however, established PAH therapies have not been evaluated for this condition. The current authors treated 14 patients (four male, 10 female; mean (range) age 55 (39-75) yrs) with moderate (n = 1) or severe (n = 13) POPH caused by alcoholic liver disease (n = 7), chronic viral hepatitis (n = 3), autoimmune hepatitis (n = 3), and hepatic manifestation of hereditary haemorrhagic teleangiectasia (n = 1) with oral sildenafil. Eight patients were newly started on pulmonary vasoactive treatment, while six patients were already on treatment with inhaled prostanoids (iloprost, n = 5; treprostinil, n = 1). During treatment with sildenafil, mean +/- sd 6-min walk distance increased from 312 +/- 111 m to 397 +/- 99 m after 3 months, and 407 +/- 97 m after 12 months. Mean +/- sd pro-brain natriuretic peptide levels decreased from 582 +/- 315 ng x mL(-1) to 230 +/- 278 ng x mL(-1), and to 189 +/- 274 ng x mL(-1) after 3 and 12 months, respectively. Two patients died after 1 and 2 months from liver failure and cardiac failure, respectively. There was a similar response to sildenafil treatment after 3 and 12 months in patients on monotherapy and those on combination therapy. In conclusion, sildenafil might be effective in monotherapy and in combination therapy with inhaled prostanoids in portopulmonary hypertension, leading to significant improvement by 3 months and sustained response over 12 months.

Topics: Administration, Oral; Adult; Aged; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Rebound pulmonary hypertension (PHT) can complicate the weaning of nitric oxide (NO), and is in part related to transient depletion of intrinsic cyclic guanosine monophosphate. Rebound is characterized by increased pulmonary arterial (PA) pressure, cardiopulmonary instability, and in some cases, the need to continue NO beyond the intended period of use. There is anecdotal evidence that sildenafil, a phosphodiesterase-5 inhibitor, may prevent recurrence of rebound.. We investigated the role of sildenafil in preventing rebound (an increase in PA pressure of 20% or greater, or failure to discontinue NO) in patients in whom previous attempts had not been made to wean from NO.. Thirty ventilated infants and children, receiving 10 ppm or greater inhaled NO, were randomized to receive 0.4 mg/kg of sildenafil, or placebo, 1 h before discontinuing NO. Twenty-nine patients completed the study.. PA pressures and blood gases were measured before the study drug, and 1 and 4 h after stopping NO.. Rebound occurred in 10 of 14 placebo patients, and 0 of 15 sildenafil patients (p < 0.001). PA pressure increased by 25% (14-67) in placebo patients, and by 1%(-9-5) in sildenafil patients (p < 0.001). Four placebo patients could not be weaned from NO due to severe cardiovascular instability, whereas all sildenafil patients were weaned (p = 0.042). Duration of ventilation after study was 98.0 (47.0-223.5) h for placebo patients and 28.2 (15.7-54.6) h for sildenafil patients (p = 0.024).. A single dose of sildenafil prevented rebound after withdrawal of NO, and reduced the duration of mechanical ventilation. Prophylaxis with sildenafil should be considered when weaning patients from inhaled NO.

Topics: Administration, Inhalation; Blood Pressure; Double-Blind Method; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Pulmonary Artery; Purines; Respiration, Artificial; Sildenafil Citrate; Sulfones; Time Factors

Both prostanoids and sildenafil are effective treatments for severe pulmonary arterial hypertension (PAH). The combined use of these drugs to maximize the clinical benefit is an emerging treatment option. This study describes a 2-year experience with adjunct sildenafil as a rescue therapy for patients with severe PAH treated long term with prostanoids and who showed clinical deterioration or onset of heart failure.. Twenty patients (11 men, 9 women; mean age 42 +/- 11 years) with severe PAH, who showed clinical or functional worsening despite ongoing treatment with prostanoids (8 subcutaneous, 7 intravenous, 5 inhaled), were started on adjunct oral sildenafil. New York Heart Association (NYHA) functional class, 6-minute walking test, signs of right ventricular failure and echocardiography were assessed before and after 1 and 2 years of combined therapy.. There was a significant improvement of NYHA functional class and signs of right heart failure after 1- and 2-year follow-up. Patients showed a mean increase in 6-minute walking distance of 79 m and 105 m after 1 and 2 years of adjunct sildenafil, respectively. Two patients died during follow-up. The echocardiographic parameters showed a significant reduction of right ventricular end-diastolic diameter and left ventricular diastolic eccentricity index. No serious side effects related to sildenafil were observed.. Adjunct sildenafil to long-term prostacyclin therapy in patients with severe PAH provided sustained clinical stabilization and an improved clinical situation, exercise capacity and echocardiographic parameters of right ventricular function. The beneficial effects were strong and lasted >24 months.

Topics: Adult; Blood Pressure; Drug Administration Schedule; Drug Therapy, Combination; Echocardiography; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Longitudinal Studies; Male; Middle Aged; New York; Piperazines; Prostaglandins; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Vasodilator Agents; Ventricular Dysfunction, Right

Pulmonary hypertension remains a major problem during the perioperative period for surgical correction of long-standing valvular heart disease. Sildenafil citrate (INN sildenafil) is a selective phosphodiesterase type 5 inhibitor that is being increasingly recognized as a treatment modality for pulmonary hypertension. There is lack of evidence, however, regarding its pulmonary vasodilatory effect in anesthetized cardiac surgical patients. We therefore evaluated the effects of sildenafil on hemodynamics in patients with concomitant pulmonary hypertension undergoing valvular heart surgery in a controlled, prospective, randomized, double-blind trial.. Fifty-three patients scheduled for valvular heart surgery with mean pulmonary arterial pressure greater than 30 mm Hg were randomly treated with either 50 mg oral sildenafil (n = 26) or placebo (n = 27) 10 minutes before induction of anesthesia. Hemodynamic variables were measured 5 minutes after induction of anesthesia (baseline) and at 30 and 60 minutes after medication.. Patient characteristics and baseline hemodynamics were similar between groups. Systolic and mean pulmonary arterial pressures and pulmonary vascular resistance were significantly lower in the sildenafil group at 30 minutes after medication, without any changes in mean systemic arterial pressure and systemic vascular resistance.. Sildenafil produced significant pulmonary vasodilatory effect relative to placebo in anesthetized cardiac surgical patients with pulmonary hypertension. With respect to the predominant selectivity of sildenafil to pulmonary vasculature shown in this study and other potentially beneficial effects such as myocardial protection, use of sildenafil in the intraoperative period in cardiac surgical patients with pulmonary hypertension should be considered.

Topics: Administration, Oral; Double-Blind Method; Female; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Intraoperative Period; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones

Exposure to high altitude induces pulmonary hypertension that may lead to life-threatening conditions. In a randomized, double-blind, placebo-controlled study, the effects of oral sildenafil on altitude-induced pulmonary hypertension and gas exchange in normal subjects were examined. Twelve subjects (sildenafil [SIL] n = 6; placebo [PLA] n = 6) were exposed for 6 days at 4,350 m. Treatment (3 x 40 mg/day) was started 6 to 8 hours after arrival from sea level to high altitude and maintained for 6 days. Systolic pulmonary artery pressure (echocardiography) increased at high altitude before treatment (+29% versus sea level, p < 0.01), then normalized in SIL (-6% versus sea level, NS) and remained elevated in PLA (+21% versus sea level, p < 0.05). Pulmonary acceleration time decreased by 27% in PLA versus 6% in SIL (p < 0.01). Cardiac output and systemic blood pressures increased at high altitude then decreased similarly in both groups. Pa(O(2)) was higher and alveolar-arterial difference in O(2) lower in SIL than in PLA at rest and exercise (p < 0.05). The altitude-induced decrease in maximal O(2) consumption was smaller in SIL than in PLA (p < 0.05). Sildenafil protects against the development of altitude-induced pulmonary hypertension and improves gas exchange, limiting the altitude-induced hypoxemia and decrease in exercise performance.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Altitude Sickness; Blood Pressure; Cardiac Output; Double-Blind Method; Echocardiography; Exercise Tolerance; Humans; Hypertension, Pulmonary; Hypoxia; Lung; Male; Oxygen Consumption; Phosphodiesterase Inhibitors; Piperazines; Placebos; Pulmonary Diffusing Capacity; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones

We aimed to assess the effects of sildenafil and evaluate optimal dosing in primary pulmonary hypertension (PPH). Sildenafil selectively inhibits phosphodiesterase 5 (PDE5), which is abundant in pulmonary and penile tissue. This results in increasing nitric oxide (NO) at tissue level leading to pulmonary vasodilatation.. Our study was a prospective study of sildenafil in 15 consecutive patients with severe symptomatic PPH of NYHA class III-IV. All patients were stabilized for a minimum period of 5 days with antifailure medications. Sildenafil was started at 50 mg twice daily for 4 weeks and increased to 100 mg bid for 4 more weeks in a step-up protocol. Primary end-points were change in Borg dyspnea index, NYHA class and 6-min walk distance, estimated at baseline 1, 2, 4 and 8 weeks.. NYHA class (baseline 3.8 +/- 0.4 vs. 4 weeks 2.4 +/- 0.5, p = 0.002), Borg dyspnea index (8.1 +/- 1.7 vs. 4.4 +/- 1.9, p = 0.0007), 6-min walk distance (234 +/- 44 vs. 377 +/- 128 m, p = 0.001) and Pulmonary artery pressure (125 +/- 15 vs. 113 +/- 18 mm Hg p = 0.05) are significantly improved with sildenafil 50 mg bid at 4 weeks. Increasing the dose to 100 mg bid did not produce further benefit. Echocardiography parameters of right heart dimensions and functions did not change markedly in the study period.. Sildenafil is well tolerated with no adverse effects in severe pulmonary hypertension. It reduces symptoms, improves effort tolerance and controls refractory heart failure significantly by 2 weeks in 70% of patients at 50 mg twice daily. Three patients (20%) failed to respond with sildenafil.

Topics: Adult; Female; Humans; Hypertension, Pulmonary; Male; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Phosphodiesterase type 5 (PDE5) inhibition has been proposed for the treatment for pulmonary arterial hypertension (PAH).. This study compared adding sildenafil, a PDE5 inhibitor, to conventional treatment with the current practice of adding bosentan, an endothelin receptor antagonist.. Twenty-six patients with PAH, idiopathic or associated with connective tissue disease, World Health Organization (WHO) functional class III, were randomized in a double-blind fashion to receive sildenafil (50 mg twice daily for 4 weeks, then 50 mg three times daily) or bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily) over 16 weeks.. Changes in right ventricular (RV) mass (using cardiovascular magnetic resonance), 6-minute walk distance, cardiac function, brain natriuretic peptide, and Borg dyspnea index.. When analyzed by intention to treat, there were no significant differences between the two treatment groups. One patient on sildenafil died suddenly. Patients on sildenafil who completed the protocol showed significant changes from baseline, namely, reductions in RV mass (-8.8 g; 95% confidence interval [CI], -2, -16; n = 13, p = 0.015) and plasma brain natriuretic peptide levels (-19.4 fmol x ml(-1); 95% CI, -5, -34; p = 0.014) and improvements in 6-minute walk distance (114 m; 95% CI, 67, 160; p = 0.0002), cardiac index (0.3 L x min(-1) x m(-2); 95% CI, 0.1, 0.4; p = 0.008), and systolic left ventricular eccentricity index (-0.2; 95% CI, -0.02, -0.37; p = 0.031). Bosentan improved 6-minute walk distance (59 m; 95% CI, 29, 89; n = 12, p = 0.001) and cardiac index (0.3; 95% CI, 0.1, 0.4; p = 0.008).. Sildenafil added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH, WHO functional class III. Safety monitoring is important until more experience is obtained.

Topics: Adult; Antihypertensive Agents; Bosentan; Double-Blind Method; Endothelin Receptor Antagonists; Exercise Tolerance; Female; Heart Ventricles; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Organ Size; Phosphodiesterase Inhibitors; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Epoprostenol (prostaglandin I(2)) has become recognized as a therapeutic breakthrough that can improve hemodynamics and survival in patients with primary pulmonary hypertension (PPH). However, a significant number of patients have PPH that is refractory to epoprostenol, and lung transplantation has been the only remaining treatment option.. The study subjects included 20 consecutive patients with PPH (mean pulmonary arterial pressure: 65+/-15 mmHg) who had received epoprostenol for more than 12 months. The patients were divided into 2 groups; responders and non-responders. In the non-responders, New York Heart Association (NYHA) functional class did not improve and mean right atrial pressure (mRA) increased to 8 mmHg or more, and additional sildenafil, a phosphodiesterase-5 inhibitor, was started. Six patients were included in the non-responders, whose mRA was 9+/-5 mmHg before and significantly increased to 13+/-3 mmHg after epoprostenol administration (p < 0.05). One patient died and the other 5 patients received oral sildenafil. The mRA of 12+/-4 mmHg (value before sildenafil) improved to 8+/-5 mmHg after sildenafil administration. Three patients were classified in the NYHA functional class 4 and improved to class 3, and 2 patients were in class 3 and remained in the same class after the addition of sildenafil.. In patients with severe PPH refractory to epoprostenol treatment, additional oral sildenafil can improve pulmonary hemodynamics and symptoms. The combination therapy of epoprostenol and sildenafil is a new medical treatment to attempt before progressing to lung transplantation for patients with PPH refractory to epoprostenol.

Topics: Administration, Oral; Adult; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Salvage Therapy; Sildenafil Citrate; Sulfones; Treatment Outcome

Sildenafil is a selective Phosphodiesterase-5 inhibitor that has been reported to be a potent pulmonary vasodilator. We evaluated the safety, efficacy and pharmacokinetics of oral Sildenafil in a case series of children with pulmonary hypertension.. Three children, 1 with primary pulmonary hypertension (patient 1) and 2 with pulmonary hypertension associated with congenital heart disease (patients 2 and 3) were enrolled. Sildenafil was started at 0.5 mg/kg 4-hourly and the dose increased to 1.0 and then to 2.0 mg/kg/dose. Patients were assessed at baseline and then monthly for a total of 6 visits.. All patients reported increased exercise capacity with improvement in New York Heart Association functional class. The distance walked during the 6-min test increased by 74% (patient 1), 75% (patient 2) and 25% (patient 3) and oxyhaemoglobin saturations increased from 79%, 97% and 80% to 93%, 100% and 93%, respectively. There were no side effects and no fall in systemic blood pressure. Sildenafil plasma levels 1 h after a 0.5, 1.0 and 2 mg/kg dose of Sildenafil were 109+/-87, 150+/-62 and 368+/-200 ng/ml, respectively. They fell to 211+/-106 ng/ml 3 h after the 2.0 mg/kg dose.. Medium term Sildenafil therapy improves oxyhaemoglobin saturations and exercise tolerance in children with pulmonary hypertension without any side effects. Mean plasma levels 1 h after doses of 0.5-2.0 mg/kg are similar to the maximum plasma concentrations reported in adults receiving doses within the therapeutic range. Sildenafil use in children appears to be safe and may be beneficial in the management of pulmonary arterial hypertension.

Topics: Administration, Oral; Adolescent; Child; Chronic Disease; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Safety; Sildenafil Citrate; Sulfones

Sildenafil and inhaled nitric oxide (iNO) relax smooth muscle by inhibiting the degradation and stimulating the production of cyclic guanosine monophosphate, respectively. We compared the acute pulmonary vasodilator effects of sildenafil, iNO, and epoprostenol and asked whether the combination of iNO with sildenafil had additive pulmonary vasodilator effects. We assessed the effects of extended use of sildenafil in a small cohort of patients. Twenty patients with pulmonary arterial hypertension underwent an acute vasodilator trial with sildenafil (all patients), iNO and iNO plus sildenafil (11), and epoprostenol (19). We also provided sildenafil to patients who were ineligible for, or had clinical deterioration on epoprostenol, treprostinil, or bosentan. Mean+/-se pulmonary artery pressure dropped by 13+/-3%, 19+/-4%, 14+/-3%, and 26+/-4% with epoprostenol, iNO, sildenafil, and iNO+sildenafil, respectively. Cardiac index increased with epoprostenol and sildenafil. A correlation was found between the effects of iNO and epoprostenol. Nine out of ten patients who were started on long-term sildenafil treatment alone or in combination with other vasodilators had symptomatic improvement. Three died of right heart failure. In conclusion, sildenafil is a potent acute pulmonary vasodilator, an effect that is potentiated by combination with iNO. Long-term therapy of pulmonary hypertension with sildenafil alone or in combination with other agents appears to be safe and well tolerated.

Topics: Administration, Inhalation; Analysis of Variance; Cardiac Output; Drug Administration Schedule; Drug Therapy, Combination; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Nitric Oxide; Piperazines; Prospective Studies; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sildenafil is a type 5 phosphodiesterase inhibitor and pulmonary vasodilator. Therefore, we hypothesized that sildenafil would improve distance walked in 6 minutes and hemodynamics in children with PAH.. After baseline assessment of hemodynamics by cardiac catheterization and distance walked in 6 minutes, we administered oral sildenafil at 0.25 to 1 mg/kg 4 times daily to 14 children (median age, 9.8 years; range, 5.3 to 18). Diagnoses were primary (n=4) and secondary (n=10) PAH. We repeated the 6-minute walk test at 6 weeks and at 3, 6, and 12 months (n=14) and cardiac catheterization (n=9) after a median follow-up of 10.8 months (range, 6 to 15.3). During sildenafil therapy, the mean distance walked in 6 minutes increased from 278+/-114 to 443+/-107 m over 6 months (P=0.02), and at 12 months, the distance walked was 432+/-156 m (P=0.005). A plateau was reached between 6 and 12 months (P=0.48). Mean pulmonary artery pressure decreased from a median of 60 mm Hg (range, 50 to 105) to 50 mm Hg (range, 38 to 84) mm Hg (P=0.014). Median pulmonary vascular resistance decreased from 15 Wood units m2 (range, 9 to 42) to 12 Wood Units m2 (range, 5 to 29) (P=0.024).. Oral sildenafil has the potential to improve hemodynamics and exercise capacity for up to 12 months in children with PAH. Confirmation of these results in a randomized, controlled trial is essential.

Topics: Adolescent; Blood Pressure; Child; Child, Preschool; Exercise Test; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Pilot Projects; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Walking

Pulmonary hypertension is a frequent complication of sickle cell disease that is associated with haemolysis, impaired nitric oxide bioavailability and high mortality. We sought to evaluate the safety and efficacy of selective pulmonary vasodilators and antiproliferative agents in this at-risk population. After optimising sickle cell disease therapy to stabilise haemoglobin and fetal haemoglobin levels, we evaluated the safety and efficacy of sildenafil in 12 patients with sickle cell disease and pulmonary hypertension. Sildenafil therapy (mean duration 6 +/- 1 months) decreased the estimated pulmonary artery systolic pressure [50 +/- 4 to 41 +/- 3 mmHg; difference 9 mmHg, 95% confidence interval (CI): 0.3-17, P = 0.043] and increased the 6-min walk distance (384 +/- 30 to 462 +/- 28 m; difference 78 m, 95% CI: 40-117, P = 0.0012). Transient headaches occurred in two patients and transient eye-lid oedema in four patients. No episodes of priapism occurred in the three men in the study; two of them were on chronic exchange transfusions and one had erectile dysfunction.. (1) sickle cell disease patients with anaemia and pulmonary hypertension have significant exercise limitation; (2) the 6-min walk distance may be a valid endpoint in this population; (3) therapy with sildenafil appears safe and improves pulmonary hypertension and exercise capacity. Additional phase I studies in males with sickle cell disease followed by phase II/III placebo controlled trials evaluating the safety and efficacy of sildenafil therapy in sickle cell disease patients with pulmonary hypertension are warranted.

Topics: Adult; Anemia, Sickle Cell; Cardiac Catheterization; Echocardiography; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Purines; Reproducibility of Results; Sildenafil Citrate; Statistics, Nonparametric; Sulfones; Systole; Vascular Resistance; Vasodilator Agents

This study explored phosphodiesterase type 5 (PDE5) inhibition as a strategy for treating high altitude pulmonary arterial hypertension (HAPH).. 689 subjects (313 men) of mean (SD) age 44 (0.6) years living above 2500 m were screened for HAPH by medical examination and electrocardiography, and 188 (27%) met the criteria for right ventricular hypertrophy. 44 underwent cardiac catheterisation and 29 (66%) had a resting mean pulmonary artery pressure (PAP) above 25 mmHg. 22 patients with a raised mean PAP were randomised to receive sildenafil (25 or 100 mg) or matching placebo taken 8 hourly for 12 weeks.. At 3 months, patients on sildenafil 25 mg 8 hourly (n = 9) had a significantly (p = 0.018) lower mean PAP (-6.9 mmHg) at the end of the dosing interval than those on placebo (n = 8) (95% CI -12.4 to -1.3). The treatment effect for sildenafil 100 mg 8 hourly (n = 5) compared with placebo was -6.4 mm Hg (95% CI -12.9 to 0.1). Both doses improved 6 minute walk distance, the lower dose by 45.4 m (95% CI 11.5 to 79.4; p = 0.011) and the higher dose by 40.0 m (95% CI 0.2 to 79.8; p = 0.049). Sildenafil was well tolerated. Necroscopic lung specimens from three subjects with HAPH showed abundant PDE5 in the muscular coat of remodelled pulmonary arterioles.. PDE5 is an attractive drug target for the treatment of HAPH and a larger study of the long term effects of PDE5 inhibition in HAPH is warranted.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adolescent; Adult; Aged; Aged, 80 and over; Altitude Sickness; Cyclic Nucleotide Phosphodiesterases, Type 5; Double-Blind Method; Electrocardiography; Female; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Middle Aged; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones

Pulmonary arterial hypertension (PAH) is characterized by abnormalities in endothelial and smooth muscle cell function. Prostacyclin released by endothelial cells is a potent vasodilator by increasing cyclic adenosine monophosphate. Sildenafil, an inhibitor of phosphodiesterase-5, increases cyclic guanosine monophosphate in the lungs, producing vasodilation. To test for a therapeutic benefit of the combination of a prostacyclin analogue, subcutaneous treprostinil, and sildenafil, a proof-of-concept, open-label investigational trial was initiated. Subjects with PAH in World Health Organization (WHO) functional classes II to IV receiving subcutaneous treprostinil for > or =6 months were evaluated with an exercise treadmill test using the Naughton-Balke protocol at baseline and after 12 weeks. Sildenafil 50 mg 3 times daily was added to the treprostinil. Mean treadmill times in seconds were compared before and after 12 weeks of therapy. Nine subjects enrolled in the trial; 7 were women (mean age 35 years). At baseline, 3 subjects were in WHO functional class II and 6 subjects were in WHO functional class III. The mean treadmill time at baseline was 465 +/- 167 seconds and at 12 weeks was 656 +/- 205 seconds (42% improvement, p = 0.049). All patients had symptomatic improvement. In conclusion, this pilot study of subcutaneous treprostinil with sildenafil for PAH suggests additive beneficial effects.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Drug Therapy, Combination; Epoprostenol; Exercise Test; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Pilot Projects; Piperazines; Pulmonary Wedge Pressure; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Combination therapy may improve outcome in patients with severe pulmonary arterial hypertension (PAH). PAH patients were treated according to a goal-oriented therapeutic strategy. Patients who did not reach the treatment goals with monotherapy received combination treatment according to a predefined strategy, including bosentan, sildenafil and inhaled iloprost. Intravenous iloprost and lung transplantation were reserved for treatment failures. End points were overall survival, transplantation-free survival, and survival free from transplantation and intravenous prostanoid treatment. Between January 2002 and December 2004, 123 consecutive patients with PAH were treated according to the novel approach. Survival at 1, 2 and 3 yrs was 93.0, 83.1 and 79.9%, respectively, which was significantly better than the survival of a historical control group, as well as the expected survival. Compared to the historical control group, the use of combination treatment also significantly improved the combined end point of death, lung transplantation and need for intravenous iloprost treatment. In conclusion, a therapeutic approach utilising combinations of bosentan, sildenafil and inhaled iloprost in conjunction with a goal-oriented treatment strategy provides acceptable long-term results in patients with severe pulmonary arterial hypertension, and reduces the need for intravenous prostaglandin treatment and lung transplantation.

Topics: Administration, Inhalation; Algorithms; Antihypertensive Agents; Bosentan; Decision Support Systems, Clinical; Drug Administration Schedule; Drug Therapy, Combination; Female; Germany; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Analysis; Survival Rate; Treatment Outcome

Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung.. In this double-blind, placebo-controlled study, we randomly assigned 278 patients with symptomatic pulmonary arterial hypertension (either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts) to placebo or sildenafil (20, 40, or 80 mg) orally three times daily for 12 weeks. The primary end point was the change from baseline to week 12 in the distance walked in six minutes. The change in mean pulmonary-artery pressure and World Health Organization (WHO) functional class and the incidence of clinical worsening were also assessed, but the study was not powered to assess mortality. Patients completing the 12-week randomized study could enter a long-term extension study.. The distance walked in six minutes increased from baseline in all sildenafil groups; the mean placebo-corrected treatment effects were 45 m (+13.0 percent), 46 m (+13.3 percent), and 50 m (+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively (P<0.001 for all comparisons). All sildenafil doses reduced the mean pulmonary-artery pressure (P=0.04, P=0.01, and P<0.001, respectively), improved the WHO functional class (P=0.003, P<0.001, and P<0.001, respectively), and were associated with side effects such as flushing, dyspepsia, and diarrhea. The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo. Among the 222 patients completing one year of treatment with sildenafil monotherapy, the improvement from baseline at one year in the distance walked in six minutes was 51 m.. Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Double-Blind Method; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Walking

In a randomized, double-blind, crossover design, we compared the efficacy of sildenafil with placebo in patients with primary pulmonary hypertension (PPH). The primary end point was the change in exercise time on treadmill using the Naughton protocol. Secondary end points were change in cardiac index and pulmonary artery systolic pressure as assessed by Doppler echocardiography and quality of life (QOL) as assessed by a questionnaire.. Primary pulmonary hypertension is a disorder with limited treatment options. Uncontrolled studies had shown sildenafil to be beneficial in the treatment of PPH.. After initial clinical evaluation, including Doppler echocardiography and treadmill exercise test, patients were randomized to placebo or sildenafil with dosages ranging from 25 to 100 mg thrice daily on the basis of body weight. The evaluation was repeated after six weeks. Then patients were crossed over to alternate therapy. Final evaluation was performed after another six weeks of treatment.. Twenty-two patients completed the study. Exercise time increased by 44% from 475 +/- 168 s at the end of placebo phase to 686 +/- 224 s at the end of sildenafil phase (p < 0.0001). With sildenafil, cardiac index improved from 2.80 +/- 0.9 l/m2 to 3.45 +/- 1.1 l/m(2) (p < 0.0001), whereas pulmonary artery systolic pressure decreased insignificantly from 105.23 +/- 17.82 mm Hg to 98.50 +/- 24.38 mm Hg. There was significant improvement in the dyspnea and fatigue components of the QOL questionnaire. During the placebo phase, one patient died and another had syncope. There were no serious side effects with sildenafil.. Sildenafil significantly improves exercise tolerance, cardiac index, and QOL in patients with PPH.

Topics: Adolescent; Adult; Aged; Cardiac Volume; Child; Cross-Over Studies; Double-Blind Method; Echocardiography, Doppler; Exercise Test; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Systole; Treatment Outcome; Vasodilator Agents

Alveolar hypoxia causes pulmonary hypertension and enhanced right ventricular afterload, which may impair exercise tolerance. The phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation.. To investigate the effects of sildenafil on exercise capacity under conditions of hypoxic pulmonary hypertension.. Randomized, double-blind, placebo-controlled crossover study.. University Hospital Giessen, Giessen, Germany, and the base camp on Mount Everest.. 14 healthy mountaineers and trekkers.. Systolic pulmonary artery pressure, cardiac output, and peripheral arterial oxygen saturation at rest and during assessment of maximum exercise capacity on cycle ergometry 1) while breathing a hypoxic gas mixture with 10% fraction of inspired oxygen at low altitude (Giessen) and 2) at high altitude (the Mount Everest base camp).. Oral sildenafil, 50 mg, or placebo.. At low altitude, acute hypoxia reduced arterial oxygen saturation to 72.0% (95% CI, 66.5% to 77.5%) at rest and 60.8% (CI, 56.0% to 64.5%) at maximum exercise capacity. Systolic pulmonary artery pressure increased from 30.5 mm Hg (CI, 26.0 to 35.0 mm Hg) at rest to 42.9 mm Hg (CI, 35.6 to 53.5 mm Hg) during exercise in participants taking placebo. Sildenafil, 50 mg, significantly increased arterial oxygen saturation during exercise (P = 0.005) and reduced systolic pulmonary artery pressure at rest (P < 0.001) and during exercise (P = 0.031). Of note, sildenafil increased maximum workload (172.5 W [CI, 147.5 to 200.0 W]) vs. 130.6 W [CI, 108.8 to 150.0 W]); P < 0.001) and maximum cardiac output (P < 0.001) compared with placebo. At high altitude, sildenafil had no effect on arterial oxygen saturation at rest and during exercise compared with placebo. However, sildenafil reduced systolic pulmonary artery pressure at rest (P = 0.003) and during exercise (P = 0.021) and increased maximum workload (P = 0.002) and cardiac output (P = 0.015). At high altitude, sildenafil exacerbated existing headache in 2 participants.. The study did not examine the effects of sildenafil on normoxic exercise tolerance.. Sildenafil reduces hypoxic pulmonary hypertension at rest and during exercise while maintaining gas exchange and systemic blood pressure. To the authors' knowledge, sildenafil is the first drug shown to increase exercise capacity during severe hypoxia both at sea level and at high altitude.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Altitude; Blood Pressure; Cardiac Output; Cross-Over Studies; Double-Blind Method; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Oxygen; Phosphodiesterase Inhibitors; Piperazines; Placebos; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

We sought to compare the short-term impact of three different phosphodiesterase-5 (PDE5) inhibitors on pulmonary and systemic hemodynamics and gas exchange parameters in patients with pulmonary arterial hypertension (PAH).. The PDE5 inhibitor sildenafil has been reported to cause pulmonary vasodilation in patients with PAH. Vardenafil and tadalafil are new PDE5 inhibitors, recently being approved for the treatment of erectile dysfunction.. Sixty consecutive PAH patients (New York Heart Association functional class II to IV) who underwent right heart catheterization received short-term nitric oxide (NO) inhalation and were subsequently assigned to oral intake of 50 mg sildenafil (n = 19), 10 mg (n = 7) or 20 mg (n = 9) vardenafil, or 20 mg (n = 9), 40 mg (n = 8), or 60 mg (n = 8) tadalafil. Hemodynamics and changes in oxygenation were assessed over a subsequent 120-min observation period.. All three PDE5 inhibitors caused significant pulmonary vasorelaxation, with maximum effects being obtained after 40 to 45 min (vardenafil), 60 min (sildenafil), and 75 to 90 min (tadalafil). Sildenafil and tadalafil, but not vardenafil, caused a significant reduction in the pulmonary to systemic vascular resistance ratio. Significant improvement in arterial oxygenation (equally to NO inhalation) was only noted with sildenafil.. In PAH patients, the three PDE5 inhibitors differ markedly in their kinetics of pulmonary vasorelaxation (most rapid effect by vardenafil), their selectivity for the pulmonary circulation (sildenafil and tadalafil, but not vardenafil), and their impact on arterial oxygenation (improvement with sildenafil only). Careful evaluation of each new PDE5 inhibitor, when being considered for PAH treatment, has to be undertaken, despite common classification as PDE5 inhibitors.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Adult; Aged; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Hypertension, Pulmonary; Imidazoles; Male; Middle Aged; Oxygen; Phosphoric Diester Hydrolases; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Treatment Outcome; Triazines; Vardenafil Dihydrochloride; Vascular Resistance; Vasodilator Agents

This study sought to evaluate the utility of sildenafil in assessing pulmonary artery reactivity in left-sided cardiac failure and secondary pulmonary hypertension (PH). Fourteen consecutive patients with heart failure were studied, with oral doses of either sildenafil 25 mg (n = 8) or 50 mg (n = 6) every 8 hours for 20% decreases in pulmonary artery pressures. There was also a 20% reduction of the pulmonary vascular resistance/systemic vascular resistance ratio, indicating relative pulmonary artery selectivity. Compared with sildenafil 25 mg, sildenafil 50 mg demonstrated greater reductions of pulmonary pressures. Oral sildenafil is safe and effective for the evaluation of PH reactivity in heart failure.

Topics: Administration, Oral; Adult; Aged; Dose-Response Relationship, Drug; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Left

We sought to investigate the impact of adjunct sildenafil on exercise capacity and hemodynamic parameters in patients with pulmonary arterial hypertension (PAH) who fulfilled predefined criteria of deterioration despite ongoing treatment with inhaled iloprost.. Inhaled iloprost is an effective therapy in PAH. The phosphodiesterase-5 inhibitor sildenafil exerts pulmonary vasodilation and may amplify prostanoid efficacy.. Of 73 PAH patients receiving long-term inhaled iloprost treatment, 14 fulfilled criteria of deterioration unresponsive to conventional treatment. These patients received adjunct oral sildenafil over a period of nine to 12 months, leaving the inhalative iloprost regimen unchanged.. Before iloprost therapy, the baseline 6-min walking distance was 217 +/- 31 m (mean +/- SEM), with an improvement to 305 +/- 28 m within the first three months of iloprost treatment and a subsequent decline to 256 +/- 30 m after 18 +/- 4 months. Adjunct therapy with sildenafil reversed the deterioration and increased the 6-min walk distance to 346 +/- 26 m (p = 0.002, Wilcoxon test) at three months of combined therapy, with a sustained efficacy up to 12 months (349 +/- 32 m, p = 0.002). The distribution of New York Heart Association functional classes (IV/III/II) improved from September 9, 2000, before sildenafil, to January 8, 2003, after nine to 12 months with sildenafil. All hemodynamic variables changed favorably: pulmonary vascular resistance decreased from 2,494 +/- 256 before sildenafil to 1,950 +/- 128 dynes.s.cm(-5).m(2) after three months of adjunct sildenafil (p = 0.036). Two patients died of severe pneumonia during the period of combined therapy. No further serious adverse events occurred. CONCLUSIONS; In patients with severe PAH deteriorating despite ongoing prostanoid treatment, long-term adjunct oral sildenafil improves exercise capacity and pulmonary hemodynamics. A combination of prostanoids and sildenafil is an appealing concept for future treatment of pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

To investigate the acute effects of intravenous sildenafil on haemodynamics and oxygenation, and its interaction with inhaled nitric oxide (iNO) in infants at risk of pulmonary hypertension early after cardiac surgery.. Prospective, randomised trial.. Paediatric intensive care unit of a children's hospital.. Sixteen ventilated infants early after closure of ventricular or atrioventricular septal defects, were randomly assigned to one of two groups. The study was completed in 15 infants.. Studies were commenced within 7 h of separation from bypass. Seven infants received iNO (20 ppm) first, with the addition of intravenous sildenafil (0.35 mg/kg over 20 min) after 20 min. Eight infants received sildenafil first, iNO was added after 20 min. Vascular pressures, cardiac output and a blood gas were recorded at 0, 20 and 40 min.. In infants receiving iNO first, iNO lowered the pulmonary vascular resistance index (PVRI) from 3.45 to 2.95 units (p=0.01); sildenafil further reduced PVRI to 2.45 units p<0.05). In those receiving sildenafil first, PVRI was reduced from 2.84 to 2.35 units (p<0.05) with sildenafil, and fell to 2.15 units (p=0.01) with the addition of iNO. In both groups, sildenafil reduced the systemic blood pressure and systemic vascular resistance (p<0.01) and worsened arterial oxygenation and the alveolar-arterial gradient (p<0.05).. Intravenous sildenafil augmented the pulmonary vasodilator effects of iNO in infants early after cardiac surgery. However, sildenafil produced systemic hypotension and impaired oxygenation, which was not improved by iNO.

Topics: Administration, Inhalation; Blood Pressure; Bronchodilator Agents; Cardiac Output; Drug Synergism; Drug Therapy, Combination; Female; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infusions, Intravenous; Male; Nitric Oxide; Piperazines; Postoperative Complications; Prospective Studies; Pulmonary Circulation; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

The prognosis and functional capacity of patients with pulmonary arterial hypertension (PAH) is poor, and there is a need for safe, effective, inexpensive oral treatments. A single dose of sildenafil, an oral phosphodiesterase type-5 (PD-5) inhibitor, is an effective and selective pulmonary vasodilator in PAH. However, the long-term effects of PD-5 inhibition and its mechanism of action in human pulmonary arteries (PAs) are unknown.. We hypothesized that 3 months of sildenafil (50 mg orally every 8 hours) added to standard treatment would be safe and improve functional capacity and hemodynamics in PAH patients. We studied 5 consecutive patients (4 with primary pulmonary hypertension, 1 with Eisenmenger's syndrome; New York Heart Association class II to III). Functional class improved by > or =1 class in all patients. Pretreatment versus posttreatment values (mean+/-SEM) were as follows: 6-minute walk, 376+/-30 versus 504+/-27 m, P<0.0001; mean PA pressure, 70+/-3 versus 52+/-3 mm Hg, P<0.007; pulmonary vascular resistance index 1702+/-151 versus 996+/-92 dyne x s x cm(-5) x m(-2), P<0.006. The systemic arterial pressure was unchanged, and no adverse effects occurred. Sildenafil also reduced right ventricular mass measured by MRI. In 7 human PAs (6 cardiac transplant donors and 1 patient with PAH on autopsy), we showed that PD-5 is present in PA smooth muscle cells and that sildenafil causes relaxation by activating large-conductance, calcium-activated potassium channels.. This small pilot study suggests that long-term sildenafil therapy might be a safe and effective treatment for PAH. At a monthly cost of 492 dollars Canadian, sildenafil is more affordable than most approved PAH therapies. A large multicenter trial is indicated to directly compare sildenafil with existing PAH treatments.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Adult; Cell Separation; Creatinine; Cyclic Nucleotide Phosphodiesterases, Type 5; Exercise Test; Female; Heart Ventricles; Hemodynamics; Humans; Hypertension, Pulmonary; In Vitro Techniques; Large-Conductance Calcium-Activated Potassium Channels; Liver; Male; Middle Aged; Muscle, Smooth, Vascular; Patch-Clamp Techniques; Phosphoric Diester Hydrolases; Pilot Projects; Piperazines; Potassium Channels, Calcium-Activated; Pulmonary Artery; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Time; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Lung fibrosis can be complicated by pulmonary hypertension, limiting exercise tolerance and life expectancy. Furthermore, vasodilators might cause deterioration in gas exchange. Our aim was to compare acute effects of sildenafil, nitric oxide, and epoprostenol in individuals with pulmonary hypertension secondary to lung fibrosis.. We did a randomised controlled, open-label trial, in 16 individuals admitted to our hospital with pulmonary hypertension secondary to lung fibrosis. After inhalation of nitric oxide (10-20 ppm), we assigned patients to either maximum tolerated dose of intravenous epoprostenol (mean 8.0 ng/kg per min; n=8) or oral sildenafil (50 mg; n=8). Our primary objective was to assess pulmonary vasodilative potency (decrease in pulmonary vascular resistance index) of sildenafil by comparison with inhaled nitric oxide and infused epoprostenol. Analyses were by intention to treat.. Pulmonary vascular resistance index was reduced by nitric oxide (-21.9%, 95% CI -14.1 to -36.2), epoprostenol (-36.9%, -24.4 to -59.6), and sildenafil (-32.5%, -10.2 to -54.1). However, ratio of pulmonary to systemic vascular resistance decreased only in individuals who received nitric oxide and sildenafil. Baseline measurement of multiple-inert-gas elimination showed right-to-left shunt flow (4.8%, 0.0-28.2) and little perfusion of low ventilation(V)/perfusion(Q) areas (0.1%, 0.0-13.0). Prostacyclin increased V/Q mismatch (shunt 16.8%, 10.8-35.9; low V/Q 3.8%, 0.0-13.0) and decreased arterial oxygenation. By contrast, nitric oxide (4.5%, 0.0-18.0; 0.0%, 0.0-17.3) and sildenafil (3.3%, 0.0-11.3; 0.0%, 0.0-12.4) maintained V/Q matching, with raised arterial partial pressure of oxygen (14.3 mm Hg, -1.7 to 31.3) noted for sildenafil. We recorded no adverse events.. Sildenafil causes preferential pulmonary vasodilation and improves gas exchange in patients with severe lung fibrosis and secondary pulmonary hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Piperazines; Pulmonary Fibrosis; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Inhalation of the stable prostacyclin analogue iloprost is being studied for treatment of pulmonary hypertension. The selective phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation.. To evaluate the safety and effectiveness of oral sildenafil, alone and in combination with inhaled iloprost, for treatment of pulmonary hypertension.. Randomized, controlled, open-label trial.. Intensive care unit.. 30 patients with severe pulmonary arterial hypertension (n = 16), chronic thromboembolic pulmonary hypertension (n = 13), or pulmonary hypertension due to aplasia of the left pulmonary artery (n = 1), all classified as New York Heart Association class III or IV.. All patients received inhaled nitric oxide and aerosolized iloprost (inhaled dose, 2.8 microg). They were then randomly assigned to receive 12.5 mg of oral sildenafil, 50 mg of sildenafil, 12.5 mg of sildenafil plus inhaled iloprost, or 50 mg of sildenafil plus inhaled iloprost.. Systemic and pulmonary arterial pressure, pulmonary arterial occlusion pressure, cardiac output, central venous pressure, peripheral arterial oxygen saturation, and arterial and mixed venous blood gases were measured during right-heart catheterization by using a Swan-Ganz catheter.. In rank order of pulmonary vasodilatory potency (maximum reduction of pulmonary vascular resistance and increase in cardiac index), 50 mg of sildenafil plus iloprost was most effective, followed by 12.5 mg of sildenafil plus iloprost. Iloprost alone and 50 mg of sildenafil were almost equally effective but were less potent than the combination regimens, and the least potent treatments were 12.5 mg of sildenafil and nitric oxide. In patients who received 50 mg of sildenafil plus iloprost, the maximum change in pulmonary vasodilatory potency was -44.2% (95% CI, -49.5% to -38.8%), compared with -14.1% (CI, -19.1% to -9.2%) in response to nitric oxide. With administration of 50 mg of sildenafil plus iloprost, the area under the curve for reduction in pulmonary vasodilatory resistance surpassed that of administration of 50 mg of sildenafil alone and iloprost alone combined, the vasodilatory effect lasted longer than 3 hours, and systemic arterial pressure and arterial oxygenation were maintained. No serious adverse events occurred.. Although limited by the small sample and lack of long-term observations, the study shows that oral sildenafil is a potent pulmonary vasodilator that acts synergistically with inhaled iloprost to cause strong pulmonary vasodilatation in both severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Analysis of Variance; Area Under Curve; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The prognosis of patients with severe pulmonary hypertension (PHT) is poor. To determine prognosis and guide therapy, an acute hemodynamic trial of selective pulmonary vasodilators, usually inhaled nitric oxide (iNO), was performed. We hypothesized that oral sildenafil, a phosphodiesterase-5 inhibitor, is a safe and effective alternative to iNO.. We studied 13 consecutive patients (mean+/-SEM, 44+/-2 years of age; 9 women) referred for consideration of heart-lung transplantation or as a guide to medical therapy. All but one were functional class III or IV. Patients had primary PHT (n=9), pulmonary arterial hypertension (n=2), or secondary PHT (n=2). Hemodynamics and serum cyclic guanosine-monophosphate levels (cGMP) were measured at baseline and at peak effects of iNO (80 ppm), sildenafil (75 mg), and their combination. The decrease in pulmonary vascular resistance was similar with iNO (-19+/-5%) and sildenafil (-27+/-3%), whereas sildenafil+iNO was more effective than iNO alone (-32+/-5%, P<0.003). Sildenafil and sildenafil+iNO increased cardiac index (17+/-5% and 17+/-4%, respectively), whereas iNO did not (-0.2+/-2.0%, P<0.003). iNO increased, whereas sildenafil tended to decrease, pulmonary capillary wedge pressure (+15+/-6 versus -9+/-7%, P<0.0007). Systemic arterial pressure was similar among groups and did not decrease with treatment. cGMP levels increased similarly with iNO and sildenafil, and their combination synergistically elevated cGMP (P<0.0001).. A single oral dose of sildenafil is as effective and selective a pulmonary vasodilator as iNO. Sildenafil may be superior to iNO in that it increases cardiac output and does not increase wedge pressure. Future studies are indicated to establish whether sildenafil could be effective over a longer duration.

Topics: Administration, Oral; Adult; Cyclic GMP; Diuretics; Drug Therapy, Combination; Female; Headache; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Predictive Value of Tests; Pulmonary Artery; Pulmonary Circulation; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Warfarin

This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice.. In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O(2) for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PAP produced by hypoxia during placebo treatment (mean PAP [mean+/-SD mm Hg]: normoxia 16.0+/-2.1 versus hypoxia 25.0+/-4.8) was almost abolished by sildenafil (normoxia 16.0+/-2.1 versus hypoxia 18.0+/-3.6), with no significant effect on systemic blood pressure. In the isolated perfused lung of wild-type and endothelial nitric oxide synthase (eNOS)-deficient mice, sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction. Wild-type mice dosed orally with the drug (25 mg. kg(-1). d(-1)) throughout 3 weeks of exposure to hypoxia (10% O(2)) exhibited a significant reduction in right ventricular systolic pressure (placebo versus sildenafil: 43.3+/-9.9 versus 29.9+/-9.7 mm Hg, P<0.05) coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mutant mice, sildenafil attenuated the increase in right ventricular systolic pressure but without a significant effect on right ventricular hypertrophy or vascular remodeling.. Sildenafil attenuates hypoxia-induced pulmonary hypertension in humans and mice and offers a novel approach to the treatment of this condition. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, but other biochemical sources of cGMP also play a role. Sildenafil has beneficial pulmonary hemodynamic effects even when eNOS activity is impaired.

Topics: Adolescent; Adult; Animals; Cyclic GMP; Double-Blind Method; Genotype; Heart Ventricles; Humans; Hypertension, Pulmonary; Hypertrophy; Hypoxia; In Vitro Techniques; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Ventricular Function, Right

The application of iloprost, a stable prostacyclin analogue, by inhalation has been shown to improve hemodynamic variables in patients with primary pulmonary hypertension. However, repetitive inhalations are required due to its short-term effects. One potential approach to prolong and increase the vasorelaxant effects of aerosolized iloprost might be to combine use with phosphodiesterase inhibitors.. The short-term effects of 8.4 to 10.5 microgram of aerosolized iloprost, the phosphodiesterase type 5 inhibitor sildenafil, and the combination thereof were compared in 5 patients with primary pulmonary hypertension. Aerosolized iloprost resulted in a more pronounced decrease in mean pulmonary arterial pressure (PAP) than sildenafil alone (9.4+/-1.3 versus 6.4+/-1.1 mm Hg; P<0.05). The reduction in mean PAP after sildenafil was maximal after the first dose (25 mg). The combination of sildenafil plus iloprost lowered mean PAP significantly more than iloprost alone (13.8+/-1.4 versus 9.4+/-1.3 mm Hg; P<0.009). No significant changes in heart rate or systemic arterial pressure were observed during any treatment. The treatments were well tolerated, without major adverse effects.. Sildenafil caused a long-lasting reduction in mean PAP and pulmonary vascular resistance, with a further additional improvement after iloprost inhalation. These data suggest that small doses of a phosphodiesterase type 5 inhibitor may be a useful adjunct to inhaled iloprost in the management of pulmonary hypertension.

Topics: Administration, Inhalation; Administration, Oral; Blood Pressure; Cardiac Output; Cough; Drug Therapy, Combination; Female; Headache; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nausea; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) is characterized by pulmonary arterial remodeling mainly because of apoptosis resistance and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Sildenafil is a phosphodiesterase-5 inhibitor. Some reports have shown that sildenafil exerts protective effects against PPHN. However, the function of sildenafil in PPHN and the underlying molecular mechanisms is not clear. Here, we revealed that sildenafil effectively suppressed hypoxia-induced PASMC proliferation and apoptosis inhibition ( P < 0.05). Also, sildenafil obviously reduced ventricular hypertrophy, and inhibited pulmonary vascular remodeling in the PPHN model ( P < 0.05). Moreover, sildenafil treatment significantly attenuated the induction of Notch3 and Hes1 induced by hypoxia treatment ( P < 0.05). Furthermore, overexpression of Notch3 abolished the reduction of PASMC proliferation and promotion of PASMC apoptosis induced by sildenafil under hypoxia ( P < 0.05), whereas knockdown of Notch3 had an opposite effect ( P < 0.05). Together, our study demonstrates that sildenafil shows a potential benefit against the development of PPHN by inhibiting Notch3 signaling, providing a strategy for treating PPHN in the future.

Topics: Animals; Hypertension, Pulmonary; Hypoxia; Pulmonary Artery; Rats; Sildenafil Citrate; Vascular Remodeling

Topics: Carbolines; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Phosphodiesterase 5 Inhibitors; Phosphoric Diester Hydrolases; Purines; Sildenafil Citrate; Tadalafil

Pulmonary hypertension (PH) is a cardiovascular disease affecting patient's life. Sildenafil citrate (SC), the first-line treatment, is present in oral and injectable forms with some drawbacks, primarily poor patient's comfort and low oral bioavailability. To counter these limitations, stratum corneum-penetrating hydrogel-forming microneedles (HFM) was created, making it easier to distribute SC transdermally. HFM was fabricated using polyvinyl alcohol (PVA) and two variations of polyvinyl pyrrolidone's (PVP) concentration as polymers and citric acid (CA) as crosslinking agent. The crosslinking time was also variated. The assessment of swelling, insertion characteristics, and mechanical resistance revealed that it possessed swelling capacities up to 470 % and strong insertion capabilities. This HFM was integrated with a tablet reservoir prepared using several concentrations of sodium starch glycolate (SSG) as super disintegrant. The tablet reservoir's hardness, dissolution rate, XRD, and FTIR profiles were evaluated and the results showed that 4 % of SSG was the option for enhancing SC's solubility. According to ex vivo study, this system released 24.12 ± 0.92 % of SC. For the first time, SC was successfully incorporated into a system of HFM and tablet reservoir and was non-toxic, showing promise in terms of improving PAH therapy's efficacy following comprehensive in vivo studies in the future.

Topics: Drug Delivery Systems; Humans; Hydrogels; Hypertension, Pulmonary; Polymers; Sildenafil Citrate; Solubility; Tablets

Efficacy of therapies that target the downstream nitric oxide (NO) pathway in pulmonary arterial hypertension (PAH) depends on the bioavailability of NO. Reduced NO level in PAH is secondary to "uncoupling" of endothelial nitric oxide synthase (eNOS). Stimulation of β3 adrenergic receptors (β3 ARs) may lead to the recoupling of NOS and therefore be beneficial in PAH. We aimed to examine the efficacy of β3 AR agonism as a novel pathway in experimental PAH. In hypoxia (5 weeks) and Sugen hypoxia (hypoxia for 5 weeks + SU5416 injection) models of PAH, we examined the effects of the selective β3 AR agonist CL316243. We measured echocardiographic indices and invasive right ventricular (RV)-pulmonary arterial (PA) hemodynamics and compared CL316243 with riociguat and sildenafil. We assessed treatment effects on RV-PA remodeling, oxidative stress, and eNOS glutathionylation, an oxidative modification that uncouples eNOS. Compared with normoxic mice, RV systolic pressure was increased in the control hypoxic mice (p < 0.0001) and Sugen hypoxic mice (p < 0.0001). CL316243 reduced RV systolic pressure, to a similar degree to riociguat and sildenafil, in both hypoxia (p < 0.0001) and Sugen hypoxia models (p < 0.03). CL316243 reversed pulmonary vascular remodeling, decreased RV afterload, improved RV-PA coupling efficiency and reduced RV stiffness, hypertrophy, and fibrosis. Although all treatments decreased oxidative stress, CL316243 significantly reduced eNOS glutathionylation. β3 AR stimulation improved RV hemodynamics and led to beneficial RV-PA remodeling in experimental models of PAH. β3 AR agonists may be effective therapies in PAH.

Topics: Adrenergic beta-Agonists; Animals; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Mice; Pulmonary Arterial Hypertension; Pulmonary Artery; Sildenafil Citrate

Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling.

Topics: Animals; Familial Primary Pulmonary Hypertension; Heart Failure; Hypertension, Pulmonary; Hypoxia-Inducible Factor-Proline Dioxygenases; Mice; Pulmonary Arterial Hypertension; Pulmonary Artery; Sildenafil Citrate; Vascular Remodeling; Vasodilator Agents

Despite the growing evidence of efficacy, little is known regarding the efficiency of ambrisentan to decrease cost and improve the functional classes of pediatric patients with pulmonary arterial hypertension. This study aims to determine the cost-utility of ambrisentan regarding sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia.. A decision tree model was used to estimate the cost and quality-adjusted life-years (QALYs) of ambrisentan, or sildenafil in pediatric patients with pulmonary arterial hypertension. Multiple sensitivity analyses were conducted to evaluate the robustness of the model. Cost-effectiveness was evaluated at a willingness-to-pay (WTP) value of US$5180.. The base-case analysis showed that compared with sildenafil, ambrisentan was associated with higher costs and higher QALYs. The expected annual cost per patient with ambrisentan was US$16,105 and with sildenafil was US$1431. The QALYs per person estimated with ambrisentan was 0.40 and for sildenafil was 0.39. The estimated improvement in quality of life and reduced costs results in an estimate of economic dominance for sildenafil over ambrisentan.. Our economic evaluation shows that ambrisentan is not cost-effective regarding sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines.

Topics: Child; Cost-Benefit Analysis; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Quality of Life; Sildenafil Citrate

Sildenafil, a well-known vasodilator known to interfere with purinergic signaling through effects on cGMP, is a mainstay in the treatment of pulmonary hypertension (PH). However, little is known regarding its effects on the metabolic reprogramming of vascular cells, which is a hallmark of PH. Purine metabolism, especially intracellular de novo purine biosynthesis is essential for vascular cell proliferation. Since adventitial fibroblasts are critical contributors to proliferative vascular remodeling in PH, in this study we aimed to investigate if sildenafil, beyond its well-known vasodilator role in smooth muscle cells, impacts intracellular purine metabolism and proliferation of fibroblasts derived from human PH patients.. Integrated omics approaches (plasma and cell metabolomics) and pharmacological inhibitor approaches were employed in plasma samples and cultured pulmonary artery fibroblasts from PH patients.. Plasma metabolome analysis of 27 PH patients before and after treatment with sildenafil, demonstrated a partial, but specific effect of sildenafil on purine metabolites, especially adenosine, adenine, and xanthine. However, circulating markers of cell stress, including lactate, succinate, and hypoxanthine were only decreased in a small subset of sildenafil-treated patients. To better understand potential effects of sildenafil on pathological changes in purine metabolism (especially purine synthesis) in PH, we performed studies on pulmonary fibroblasts from PAH patients (PH-Fibs) and corresponding controls (CO-Fibs), since these cells have previously been shown to demonstrate stable and marked PH associated phenotypic and metabolic changes. We found that PH-Fibs exhibited significantly increased purine synthesis. Treatment of PH-Fibs with sildenafil was insufficient to normalize cellular metabolic phenotype and only modestly attenuated the proliferation. However, we observed that treatments which have been shown to normalize glycolysis and mitochondrial abnormalities including a PKM2 activator (TEPP-46), and the histone deacetylase inhibitors (HDACi), SAHA and Apicidin, had significant inhibitory effects on purine synthesis. Importantly, combined treatment with HDACi and sildenafil exhibited synergistic inhibitory effects on proliferation and metabolic reprogramming in PH-Fibs.. While sildenafil alone partially rescues metabolic alterations associated with PH, treatment with HDACi, in combination with sildenafil, represent a promising and potentially more effective strategy for targeting vasoconstriction, metabolic derangement and pathological vascular remodeling in PH.

Topics: Cell Proliferation; Histone Deacetylase Inhibitors; Humans; Hypertension, Pulmonary; Pulmonary Artery; Purines; Sildenafil Citrate; Vascular Remodeling; Vasodilator Agents

Topics: Administration, Intravenous; Administration, Oral; Humans; Hypertension, Pulmonary; Infant, Newborn; Sildenafil Citrate; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) is a common neonatal condition associated with significant morbidity and mortality. First-line diagnostic and treatment options such as echocardiography and inhaled nitric oxide (iNO) are not routinely available in resource limited settings and alternative treatment modalities need to be utilized. This study was conducted to assess current diagnostic and management strategies used for PPHN in Indian neonatal intensive care units (NICUs).. A questionnaire in multiple choice question format was sent to practising neonatologists in India via an online survey tool between July to August 2021. Information pertaining to demographic data, diagnostic criteria and management strategies of PPHN was requested. The responses were collated and information processed.. There were 118 respondent NICUs (response rate 74%). The majority of neonatal units (65%) admitted an average of 1-3 patients of PPHN per month. Targeted neonatal echocardiography (TnECHO) was practised in 80% of the units. Most common management strategies being followed were pulmonary vasodilators (88.1%), inotropes (85.6%), conventional ventilation (68.6%) and high frequency ventilation (59.3%). The most preferred pulmonary vasodilator was sildenafil (79%) and inotropic agent was milrinone (32%). Only 25% of respondents reported use of iNO. None of the participating units used extracorporeal membrane oxygenation.. We found wide variability in management practices of PPHN across Indian NICUs. Non-selective pulmonary vasodilators are more widely used than iNO. There is an urgent need for structured TnECHO training programs and evidence based national guidelines for standardized management of PPHN as per availability of resources in India. Additional research on low cost alternative therapies to iNO in Indian settings might be helpful.

Topics: Administration, Inhalation; Humans; Hypertension, Pulmonary; Infant, Newborn; Intensive Care Units, Neonatal; Nitric Oxide; Persistent Fetal Circulation Syndrome; Sildenafil Citrate; Surveys and Questionnaires; Vasodilator Agents

The effectiveness of sildenafil in the management of pulmonary hypertension in congenital diaphragmatic hernia (CDH) has been reported but has not been systematically evaluated. Our studies have also demonstrated that intra-amniotic (IA) sildenafil administration improves pulmonary hypertension in CDH.. We evaluated the pharmacokinetics of sildenafil after IA administration in pregnant rabbits. Following maternal laparotomy, fetuses received IA injection of 0.8 mg of sildenafil. Maternal blood, amniotic fluid, and fetal tissues were collected at various time points. The concentrations of sildenafil and its major metabolite in samples were analyzed by liquid chromatography-mass spectrometry. To assess organ toxicity, 7 days after IA sildenafil administration, fetal organs were examined histologically.. After IA dosing, sildenafil was absorbed quickly with an absorption half-life of 0.03-0.07 h into the fetal organs. All the organs showed a maximum concentration within 1 h and the disposition half-life ranged from 0.56 to 0.73 h. Most of the sildenafil was eliminated from both mothers and fetuses within 24 h after a single dose. There was no histological evidence of organ toxicity in the fetuses after a single dose of IA administration of sildenafil.. IA sildenafil is rapidly absorbed into the fetus, distributes into the mother, and is eliminated by the mother without accumulation or fetal organ toxicity. This study confirms the feasibility and the safety of IA administration of sildenafil and enables future applications in the treatment of CDH fetuses.

Topics: Animals; Female; Fetus; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Lung; Pregnancy; Rabbits; Sildenafil Citrate

Phosphodiesterase-5 inhibitors (PDE5i) have been evaluated as a novel treatment for Alzheimer's disease and related dementias (ADRD), but two recent cohort studies have offered opposing conclusions.. We performed an unmatched case-control study using electronic medical records from a large healthcare system to evaluate the association of PDE5i use and ADRD in patients ≥65 years old.. Odds of PDE5i exposure were 64.2%, 55.7%, and 54.0% lower in patients with ADRD than controls among populations with erectile dysfunction, benign prostatic hyperplasia, and pulmonary hypertension, respectively. We observed odds ratios less than unity among males and females and with exposure to the PDE5i sildenafil (Viagra®) and tadalafil (Cialis®). We also evaluated the odds of exposure to two other common treatments for pulmonary hypertension: endothelin receptor antagonists (ERA) and calcium channel blockers (CCB). The odds of ERA exposure were 63.2% lower, but the odds of CCB exposure were 30.7% higher, in patients with ADRD than controls among the population with pulmonary hypertension.. Our results reconcile the opposing conclusions from the previous observational studies and support further research into using PDE5i for prevention and treatment of ADRD.

Topics: Aged; Alzheimer Disease; Case-Control Studies; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil

Persistent pulmonary hypertension of the newborn (PPHN) is a common pulmonary vascular disease during the neonatal period, and it is associated with a high clinical mortality rate and a poor prognosis. At present, the treatment of PPHN is based mainly on inhaled nitric oxide (iNO), high‑frequency ventilation, and pulmonary vasodilators. Sildenafil has gradually begun to be used in recent years for the treatment of PPHN and has exhibited some success; however, its detailed mechanism of action requires further elucidation. An animal model of neonatal pulmonary hypertension (neonatal rats, 48 h after birth, 10% O2, 14 days) as well as a cell model [human pulmonary artery smooth muscle cells (PASMCs), 4% O2, 60 h] were established. The effects of sildenafil on pulmonary hypertension in neonatal rats were evaluated by hematoxylin and eosin staining, immunofluorescence analysis, western blotting and PCR, and the changes in peroxisome proliferator‑activated receptor γ (PPARγ), transient receptor potential canonical (TRPC)1, TRPC6 and Ki67 expression levels were detected under hypoxic conditions. The results revealed that sildenafil reversed the increases in the right ventricular mean pressure and right ventricular hypertrophy index induced by hypoxia, and attenuated pulmonary arterial remodeling as well as PASMC proliferation. The inhibitory effects of sildenafil on TRPC expression and PASMC proliferation were attenuated by GW9662 and PPARγ small interfering RNA. In conclusion, sildenafil protects against hypoxia‑induced pulmonary hypertension and right ventricular hypertrophy in neonatal rats by upregulating PPARγ expression and downregulating TRPC1 and TRPC6 expression.

Topics: Animals; Animals, Newborn; Blood Pressure; Cell Proliferation; Down-Regulation; Female; Heart Ventricles; Humans; Hypertension, Pulmonary; Hypoxia; Ki-67 Antigen; Male; Myocytes, Smooth Muscle; PPAR gamma; Pulmonary Artery; Rats, Sprague-Dawley; Sildenafil Citrate; TRPC Cation Channels; Up-Regulation; Vascular Remodeling

Chronic treatment with sildenafil (SILD) is an effective protector on the development of cardiovascular complications of pulmonary hypertension (PH) and diabetes. However, to date, no studies have evaluated the effect of SILD on cardiopulmonary pathophysiology during PH secondary to type 1 diabetes.. The present study aimed to evaluate the beneficial effects of chronic SILD treatment on pulmonary arterial pressure, right ventricular hypertrophy (RVH) and cardiac autonomic dysfunction in rats with PH secondary to diabetes.. Male Sprague Dawley rats were randomly distributed into the control group (saline), diabetic group (60 mg/kg with streptozotocin), SILD-treated control group (20 mg/kg) and SILD-treated diabetic group.. After 8 weeks the type 1 diabetic animals presented PH, endothelial dysfunction of the pulmonary arteries, electrocardiographic alterations, RVH and overexpression of phosphodiesterase type 5 in the heart. In type 1 diabetic animals, SILD treatment prevented the development of PH, endothelial dysfunction and RVH. SILD treatment also prevented alterations in the corrected QT period and heart rate variability and prevented overexpression of phosphodiesterase type 5.. Our results indicate for the first time that SILD treatment prevents pulmonary arterial endothelial dysfunction, pulmonary hypertension, right ventricular hypertrophy and improves heart rate variability in type 1 diabetic rats.

Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Heart Rate; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Rats; Rats, Sprague-Dawley; Sildenafil Citrate

Extremely low gestational age newborns (ELGANs) represent an especially vulnerable population. Herein, we aimed to determine incidence and severity of pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH) in extremely immature ELGANs (gestational age: 23. In this prospective observational cohort study, we assessed BPD-PH by means of several echocardiography markers and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at 3 and 12 months of chronological age. In addition, we analyzed incidence and efficacy of pharmacologic treatment for BPD-PH.. At 3 months 15/34 ELGANs had echocardiographic evidence of BPD-PH, while at 12 months of age 6/34 still had PH. PH-targeted therapy consisted of sildenafil monotherapy in 11 and dual oral combination therapy (sildenafil and macitentan) in four ELGANs at 3 and 12 months.. 44% (15/34) of ELGANs developed BPD-PH. All received PH-targeted pharmacotherapy at 3 months, leading to hemodynamic improvements at 12 months in most infants.

Topics: Adult; Biomarkers; Bronchopulmonary Dysplasia; Child; Female; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Extremely Premature; Infant, Newborn; Pregnancy; Prospective Studies; Sildenafil Citrate; Young Adult

Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), can reduce cardiovascular events and mortality in patients with heart failure. A number of mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors. The purpose of this study was to determine whether dapagliflozin can improve pulmonary vascular remodelling and the efficacy of dapagliflozin as an add-on therapy to sildenafil in rats with pulmonary arterial hypertension (PAH).. A monocrotaline (MCT)-induced PAH rat model was used in our study. MCT-injected rats were randomly divided into four groups and treated for 3 weeks with daily per os treatment with vehicle, dapagliflozin (1 mg/kg/day), sildenafil (25 mg/kg/day), or a combination of dapagliflozin (1 mg/kg/day) and sildenafil (25 mg/kg/day). Haemodynamic measurements, histological analysis, enzyme-linked immunosorbent assay and western blotting analysis were employed to detect the changes in PAH rats after treatments.. Dapagliflozin significantly attenuated MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Dapagliflozin effectively decreased the thickening of pulmonary artery media and decreased the muscularization of pulmonary arterioles in PAH rats. Moreover, dapagliflozin attenuated nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in lung tissues and the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in plasma. However, dapagliflozin as an add-on therapy to sildenafil in rats with PAH did not show a more pronounced beneficial effect on right ventricular systolic pressure and pulmonary vascular remodelling in MCT rats than sildenafil alone.. Dapagliflozin reduces right ventricular systolic pressure and pulmonary vascular remodelling in a rat model of PAH. However, combination therapy with dapagliflozin and sildenafil was not more effective than monotherapy with sildenafil in PAH rats.

Topics: Animals; Benzhydryl Compounds; Disease Models, Animal; Familial Primary Pulmonary Hypertension; Glucosides; Humans; Hypertension, Pulmonary; Monocrotaline; Pulmonary Arterial Hypertension; Pulmonary Artery; Rats; Sildenafil Citrate; Vascular Remodeling

To evaluate the cost-utility of catheterization-obligate treatment in preterm infants with pulmonary hypertension, as compared with empiric initiation of sildenafil based on echocardiographic findings alone.. A Markov state transition model was constructed to simulate the clinical scenario of a preterm infant with echocardiographic evidence of pulmonary hypertension associated with bronchopulmonary dysplasia (BPD) and without congenital heart disease under consideration for the initiation of pulmonary vasodilator therapy via one of two modeled treatment strategies-empiric or catheterization-obligate. Transitional probabilities, costs and utilities were extracted from the literature. Forecast quality-adjusted life-years was the metric for strategy effectiveness. Sensitivity analyses for each variable were performed. A 1000-patient Monte Carlo microsimulation was used to test the durability of our findings.. The catheterization-obligate strategy resulted in an increased cost of $10 778 and 0.02 fewer quality-adjusted life-years compared with the empiric treatment strategy. Empiric treatment remained the more cost-effective paradigm across all scenarios modeled through one-way sensitivity analyses and the Monte Carlo microsimulation (cost-effective in 98% of cases).. Empiric treatment with sildenafil in infants with pulmonary hypertension associated with BPD is a superior strategy with both decreased costs and increased effectiveness when compared with catheterization-obligate treatment. These findings suggest that foregoing catheterization before the initiation of sildenafil is a reasonable strategy in preterm infants with uncomplicated pulmonary hypertension associated with BPD.

Topics: Bronchopulmonary Dysplasia; Cardiac Catheterization; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Sildenafil Citrate

Although sildenafil is used in dogs with severe pulmonary hypertension, they sometimes become resistant and clinical signs deteriorate over time. The objective of this study was to determine the benefits of adjunct ambrisentan therapy in dogs with sildenafil-refractory pulmonary hypertension. In 5 dogs with severe pulmonary hypertension with deteriorating clinical signs despite ongoing sildenafil treatment, adding ambrisentan improved appetite, activity, and respiratory functions. Although peak tricuspid valve regurgitation velocity, as measured by Doppler echocardiography, did not necessarily decrease after ambrisentan administration, there was improved partial pressure of arterial oxygen and the alveolar-arterial oxygen gradient, with no apparent side effects. We concluded that ambrisentan has potential as an adjunct treatment in dogs with pulmonary hypertension that are refractory to sildenafil therapy. Key clinical message: Ambrisentan improved clinical signs in dogs with sildenafil-refractory pulmonary hypertension.

Topics: Animals; Dog Diseases; Dogs; Hypertension, Pulmonary; Oxygen; Phenylpropionates; Pyridazines; Sildenafil Citrate

Sildenafil is widely used off-label in pediatric patients with pulmonary arterial hypertension (PAH). This study was conducted to characterize the pharmacokinetics (PK) of sildenafil in term and preterm neonates with PAH, by developing a population PK model, and to suggest appropriate doses to achieve clinically effective concentrations. A population PK modelling analysis was performed using sildenafil and its metabolite N-desmethyl sildenafil (DMS) concentration data from 19 neonates with PAH, whose gestational ages ranged 24-41 weeks. They received sildenafil orally at a dose of 0.5-0.75 mg/kg, four times a day. To investigate the appropriate sildenafil dose, simulations were conducted according to body weight which was significant covariate for sildenafil clearance. A one-compartment model with first-order absorption adequately described the PKs of sildenafil and DMS. Sildenafil clearance was expected to increase rapidly with increasing body weight. In the simulation, sildenafil doses > 1 mg/kg was required to achieve and maintain target concentrations of sildenafil and to expect timely clinical effects in term and preterm infants. These results could be utilized for the safer and more effective use of sildenafil in term and preterm infants.

Topics: Body Weight; Child; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Pulmonary Arterial Hypertension; Sildenafil Citrate

Pulmonary hypertension (PAH) is a proliferative disease of pulmonary blood vessels, but the pathogenesis of pulmonary hypertension is still unclear. This article explores the role of tumor necrosis factor-

Topics: Animals; Blood Coagulation; Disease Models, Animal; Drug Carriers; Hypertension, Pulmonary; Monocrotaline; Nanoparticles; Pulmonary Artery; Rats; Sildenafil Citrate; Thromboplastin; Tumor Necrosis Factor-alpha

Pulmonary hypertension (PH) is a progressive disorder lacking a validated and effective therapy which characterized by elevated pulmonary arterial pressure, vascular remodeling and eventual death. FDA approved sildenafil is being used as a first-line drug for PH, however, neither survival rates nor quality of life have been improved because of side effects and patient noncompliance. Thus, the exploration of novel therapeutic drugs is urgently needed. Astragaloside IV (ASIV) exhibits a protective effect on HPH, but its mechanisms of action is unclear.. CD4+T cell subsets, Tfh and Tfr cells, may contribute to the development of chronic hypoxia-induced PH (HPH). We hypothesized that ASIV could effectively ameliorates pulmonary vascular remodeling of HPH by restraining the Tfh cell response and expanding Tfr cell response.. HPH mice model was established by exposure to chronic hypoxia for 21 days. Mice were randomly assigned to six groups: NaCl group, model group, SN group (100 mg/kg of sildenafil), low-dose group (20 mg/kg of ASIV), medium-dose group (40 mg/kg of ASIV) and high-dose group (80 mg/kg of ASIV). Primary culture and identification of distal pulmonary artery smooth muscle cells (PASMCs) in mice were established. Here, we demonstrated that ASIV treatment could significantly ameliorate the increase of mean PAP, RV/ (LV+S) ratio and PAMT in HPH mice. ASIV inhibited Tfh cell differentiation and IL-21 production, but promoted Tfr cell differentiation and TGF-β, IL-10 production. Chronic hypoxia promoted germinal center B cell responses, which inhibited by ASIV. ASIV regulated Tfh and Tfr cell differentiation by inhibiting the phosphorylation of mTOR signaling pathway, and the effect of ASIV-H was better than that observed in the SN group. ASIV inhibited the proliferation, migration and adhesion of PASMCs in vitro. Moreover, ASIV significantly downregulated the protein level of RhoA and upregulated the protein level of p27 in PASMCs under hypoxic condition.. Collectively, ASIV may regulate Tfh and Tfr cell responses to subsequently repress pulmonary vascular remodeling and hypoxic pulmonary hypertension.

Topics: Animals; Hypertension, Pulmonary; Hypoxia; Mice; Pulmonary Artery; Quality of Life; Saponins; Sildenafil Citrate; T Follicular Helper Cells; Triterpenes; Vascular Remodeling

Pulmonary hypertension (PH) is a progressive and life-threatening disease with poor prognosis despite many advances in medical therapy over the past 20 years. Novel therapies which target on the underlying pathology of PH are still urgent to be met. TPN171H is a recently found new compound that exhibits potent pharmacological effects in PH via inhibiting phosphodiesterase type 5 (PDE-5). However, as one icariin derivative, the anti-inflammatory effects of TPN171H for treating PH are not clear. The present study was designed to investigate the therapeutical effect of TPN171H against inflammation in PH and reveal the underlying mechanism. Hypoxia and monocrotaline (MCT)-induced PH rat models were established, which were treated by oral administration of TPN171H (5, 25 mg/kg/d) or sildenafil (25 mg/kg/d). The right ventricle systolic pressure (RVSP), right ventricle hypertrophy index (RVHI) and vascular remodeling were measured. The results suggested that TPN171H significantly reduced RVSP and RVHI, and reversed pulmonary vascular remodeling in rats with both models. Furthermore, in in vivo and in vitro research, our data suggested that TPN171H remarkably suppressed cathepsin B-mediated NLRP3 inflammasome activation, which may contribute to its therapeutical function for PH.

Topics: Animals; Anti-Inflammatory Agents; Cathepsin B; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Inflammasomes; Inflammation; Monocrotaline; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Vascular Remodeling

Delayed diagnosis in children with a ventricular septal defect (VSD) is common in low- and middle-income countries. Consequently, these children present with elevated pulmonary vascular resistance (PVR) and pulmonary arterial hypertension (PAH). The study investigators introduced the double-flap valve VSD patch closure technique (DFV) in 1996 to reduce early postoperative risk. Long-term results are presented in this report.. This was a retrospective single-institution study of patients who underwent DFV between May 1996 and July 2015. Beginning in 2005, all candidates for DFV received sildenafil preoperatively and postoperatively. Preoperative catheterization data and operative, postoperative, hospital, and follow-up data were analyzed.. A total of 40 patients underwent the DFV procedure. Patients' demographics were comparable between the sildenafil and nonsildenafil groups. One of 39 patients (2.6%) was lost to follow-up. Early mortality was 2.5% (1 of 40), and late mortality was 2.6% (1 of 38). Sildenafil improved preoperative oxygen saturation, improved preoperative hemodynamics, and shortened postoperative ventilation time. In both groups, abnormal hemodynamic values improved with a 100% oxygen challenge. The median age at late follow-up was 26.3 years (interquartile range [25%, 75%], 20.9, 29.9 years), and the median time since operation was 19.2 years (interquartile range, 11.4, 22.7 years). Current discharge survival was 97.3%. A total of 18% of patients had severe PAH in late follow-up. Multivariate analysis revealed only a baseline PVR-to-systemic vascular resistance ratio of 0.8 or greater as a significant predictor of late severe PAH.. Long-term follow-up demonstrated that 60% of the patients will achieve normal or nearly normal pulmonary artery pressures. Furthermore, the study demonstrated that sildenafil improves preoperative hemodynamics and postoperative management. Children with VSD, elevated PVR, and PAH should not be denied operation.

Topics: Adolescent; Child; Familial Primary Pulmonary Hypertension; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Oxygen; Pulmonary Arterial Hypertension; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Vascular Resistance

Topics: Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Postoperative Period; Sildenafil Citrate

A 24-year-old woman, a baby-sitter with no known comorbidities, presented to the outpatient department with complaints of modified Medical Research Council grade IV breathlessness for 3 months, chest pain, and dry cough for 2 weeks. There was no known disease history, including respiratory, flu-like illness, or connective tissue disorder. There was no use of chemotherapeutic, oral contraceptive drugs, exposure to toxic substances, or smoking. A review of systems was negative for fever, arthralgia, myalgia, Raynaud phenomenon, skin thickening, rash, or leg swelling. The patient had no family history suggestive of a genetic syndrome.

Topics: Chest Pain; Computed Tomography Angiography; Cough; Diagnosis, Differential; Dyspnea; Echocardiography; Endothelin A Receptor Antagonists; Female; Hemangioma, Capillary; Humans; Hypertension, Pulmonary; Lung Neoplasms; Lung Transplantation; Mutation; Oxygen Inhalation Therapy; Phosphodiesterase 5 Inhibitors; Protein Serine-Threonine Kinases; Pulmonary Veno-Occlusive Disease; Pyrimidines; Respiratory Function Tests; Sildenafil Citrate; Sulfonamides; Young Adult

Pulmonary hypertension (PH) is a severe and often rapidly progressive disease with fatal outcome. Endothelial dysfunction in PH is associated with decreased nitric oxide production. After reviewing the mechanisms of action and the evidence base for specific therapy with phosphodiesterase 5 inhibitors (PDE-5) and soluble guanylate cyclase stimulators, a reseach review on switching from PDE-5 to riociguat is conducted. A potential advantage of riociguat is its independence from endogenous nitric oxide and from the other (besides PDE-5) isoenzymes of phosphodiesterases. The favorable efficacy profile of sildenafil has been proven for the main forms of pulmonary arterial hypertension, of riociguat for the main forms of pulmonary arterial hypertension and chronic thromboembolic PH. The clinical efficacy of replacing PDE-5 with riociguat has been demonstrated in uncontrolled trials and in the randomized controlled study REPLACE. The possibility of therapy optimization by switching from IFDE-5 to riociguat is fixed in the Russian (class and level of evidence B-3) and Eurasian (class and level of evidence IIb-B) clinical guidelines, as well as in the materials of the Cologne Expert Consensus. An additional argument for switching is the lower cost as compared to combination therapy in the Russian Federation. According to the Russian and Eurasian guidelines for PH and the Russian instructions for the use of riociguat, the drug should be taken at least 24 hours after sildenafil discontinuation.. Легочная гипертензия (ЛГ) тяжелое и часто быстро прогрессирующее заболевание с фатальным исходом. Эндотелиальная дисфункция при ЛГ сопровождается снижением продукции оксида азота. После рассмотрения механизмов действия и доказательной базы специфической терапии ингибиторами фосфодиэстеразы 5 (иФДЭ-5) и стимуляторами растворимой гуанилатциклазы проводится обзор исследований по переключению с иФДЭ-5 на риоцигуат. Потенциальным преимуществом риоцигуата является независимость от эндогенного оксида азота и других (помимо ФДЭ-5) изоферментов фосфодиэстераз. Благоприятный профиль эффективности силденафила доказан для основных форм легочной артериальной гипертензии, риоцигуата для основных форм легочной артериальной гипертензии и хронической тромбоэмболической ЛГ. Клиническая эффективность замены иФДЭ-5 на риоцигуат показана в неконтролируемых исследованиях и рандомизированном контролируемом исследовании REPLACE. Возможность оптимизации терапии за счет переключения с иФДЭ-5 на риоцигуат закреплена в российских (класс и уровень доказательности B-3) и евразийских (класс и уровень доказательности IIb-B) клинических рекомендациях, а также в материалах Кельнского консенсуса экспертов. Дополнительным аргументом за переключение в условиях Российской Федерации служит меньшая стоимость по сравнению с комбинированной терапией. Согласно российским и евразийским рекомендациям по ЛГ и российской инструкции по применению риоцигуата его прием следует начинать не ранее чем через 24 ч после отмены силденафила.

Topics: Humans; Hypertension, Pulmonary; Isoenzymes; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Phosphoric Diester Hydrolases; Pulmonary Arterial Hypertension; Randomized Controlled Trials as Topic; Sildenafil Citrate; Soluble Guanylyl Cyclase

Right ventricle (RV) dysfunction is a main determinant of morbidity and mortality in postcapillary pulmonary hypertension (PH). However, currently there are not available therapies. Since reduced nitric oxide (NO) availability and cyclic guanylate monophosphate (cGMP) levels are central in this disease, therapies targeting the NO pathway might have a beneficial effect on RV performance. In this regard, sildenafil has shown contradictory results. Our objective was to evaluate the effect of sildenafil on RV performance in an experimental pig model of postcapillary PH induced by a fixed banding of the venous pulmonary confluent. Animals were evaluated by right heart catheterization and cardiac magnetic resonance before randomization and after 8 weeks on sildenafil (n = 8) or placebo (n = 8), and myocardial tissues were analyzed with histology and molecular biology. At the end of the study, animals receiving sildenafil showed better RV performance as compared with those on placebo (improvement in RV ejection fraction of 7.3% ± 5.8% versus -0.6% ± 5.0%, P= 0.021) associated with less apoptotic cells and gene expression related with reduced oxidative stress and increased anti-inflammatory activity in the myocardium. No differences were observed in pulmonary hemodynamics. In conclusion, in a translational large animal model of chronic postcapillary PH, sildenafil improved RV systolic function independently of afterload. Further research with pharmacological approaches able to manipulate the NO-cGMP axis are needed to confirm this potential cardioprotective effect.

Topics: Animals; Disease Models, Animal; Heart Ventricles; Hypertension, Pulmonary; Sildenafil Citrate; Swine; Vasodilator Agents

Topics: Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelial Cells; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Elevated pulmonary vascular resistance remains a major problem for heart transplant (HT) candidate selection.. This study sought at assess the effect of pre-HT sildenafil administration in patients with fixed pulmonary hypertension.. This retrospective, single-center study included 300 consecutive, HT candidates treated between 2003 and 2013, in which 95 patients had fixed PH, and of these, 30 patients were treated with sildenafil and eventually received a transplant, forming Group A. Group B included 205 patients without PH who underwent HT. Pulmonary hemodynamics were evaluated before HT, as well as 1 week after and 1 year after HT. Survival was compared between the groups. In this study, a p value < 0.05 was considered statistically significant.. After treatment with sildenafil but before HT, PVR (-39%) and sPAP (-10%) decreased significantly. sPAP decreased after HT in both groups, but it remained significantly higher in group A vs. group B (40.3 ± 8.0 mmHg vs 36.5 ± 11.5 mmHg, p=0.022). One year after HT, sPAP was 32.4 ± 6.3 mmHg in group A vs 30.5 ± 8.2 mmHg in group B (p=0.274). The survival rate after HT at 30 days (97% in group A versus 96% in group B), at 6 months (87% versus 93%) and at one year (80% vs 91%) were not statistically significant (Log-rank p=0.063). After this first year, the attrition rate was similar among both groups (conditional survival after 1 year, Log-rank p=0.321).. In patients with severe PH pre-treated with sildenafil, early post-operative hemodynamics and prognosis are numerically worse than in patients without PH, but after 1 year, the medium to long-term mortality proved to be similar. (Arq Bras Cardiol. 2021; 116(2):219-226).. A resistência vascular pulmonar elevada ainda é um grande problema na seleção de candidatos ao transplante cardíaco.. Nosso objetivo foi avaliar o efeito da administração de sildenafila pré-transplante cardíaco em pacientes com hipertensão pulmonar fixa.. O estudo retrospectivo, de centro único, incluiu 300 candidatos a transplante cardíaco consecutivos tratados entre 2003 e 2013. Destes, 95 pacientes tinham hipertensão pulmonar fixa e, dentre eles, 30 pacientes foram tratados com sildenafila e acabaram passando pelo transplante, formando o Grupo A. O Grupo B incluiu 205 pacientes sem hipertensão pulmonar que passaram pelo transplante cardíaco. A hemodinâmica pulmonar foi avaliada antes do transplante, 1 semana e 1 ano após o transplante. A taxa de sobrevivência foi comparada entre os grupos. Neste estudo, um P valor < 0,05 foi considerado estatisticamente significativo.. Após o tratamento com sildenafila, mas antes do TxC, a RVP (-39%) e a PAPs (-10%) diminuíram significativamente. A PAPs diminuiu após o TxC em ambos os grupos, mas permaneceu significativamente alta no grupo A em relação ao grupo B (40,3 ± 8,0 mmHg versus 36,5 ± 11,5 mmHg, P=0,022). Um ano após o TxC, a PAPs era 32,4 ± 6,3 mmHg no Grupo A versus 30,5 ± 8,2 mmHg no Grupo B (P=0,274). O índice de sobrevivência após o TxC 30 dias (97% no grupo A versus 96% no grupo B), 6 meses (87% versus 93%) e um ano (80% versus 91%) após o TxC não foi estatisticamente significativo (Log-rank P=0,063). Depois do primeiro ano, o índice de mortalidade era similar entre os dois grupos (sobrevivência condicional após 1 ano, Log-rank p=0,321).. Nos pacientes com HP pré-tratados com sildenafila, a hemodinâmica pós-operatória inicial e o prognóstico são numericamente piores em pacientes sem HP, mas depois de 1 ano, a mortalidade em médio e longo prazo são semelhantes. (Arq Bras Cardiol. 2021; 116(2):219-226).

Topics: Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Retrospective Studies; Sildenafil Citrate; Treatment Outcome

Topics: Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Sildenafil Citrate

Sildenafil is a selective phosphodiesterase type-5 inhibitor that is increasingly used to treat pulmonary hypertension (PH) in neonates. Only little is known about the relation between the dose of sildenafil, plasma concentrations, and the degree of toxicity. Here, we present a young infant with congenital diaphragmatic hernia and PH who received an unintentional 10-fold overdose of oral sildenafil for 6 consecutive days. This overdose, compared to the therapeutic dose, resulted in increased plasma concentrations of sildenafil from 42 to 521 mcg/L and desmethylsildenafil from 81 to 393 mcg/L. However, the high exposure only led to diarrhea, without any other serious adverse events. This case describes the mild symptoms upon an overdose with the role of therapeutic drug monitoring to monitor exposure in relation to symptoms and therewith support clinical decision-making.

Topics: Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Pulmonary hypertension (PH) is a known co-morbidity in West Highland white terriers (WHWTs) affected with canine idiopathic pulmonary fibrosis (CIPF). The pulmonary vein-to-right pulmonary artery ratio (PV/PA) has recently been described for the detection of pre-capillary PH in dogs. The objective of the present study was to estimate the prevalence of PH at diagnostic, in WHWTs affected with CIPF, by using PV/PA, in comparison with a group of healthy breed-matched controls (CTRLs). Additional study objective was to explore whether the presence of PH at initial diagnosis of CIPF impacted survival time in dogs treated with sildenafil.. Twenty-five client-owned WHWTs presented with CIPF and 19 CTRLs were included in the study. PV/PA in either two-dimensional mode (2D) or time-motion mode or both were measured from cineloops in each dog. Dogs were classified according to PV/PA value into non/mild PH (PV/PA measured in 2D ≥ 0.7) or moderate/severe PH (PV/PA < 0.7). Survival data of WHWTs affected with CIPF were extracted from medical record to assess association between presence of PH at diagnosis and outcome. 60 % overall prevalence for moderate/severe PH was estimated in this cohort of WHWTs presented with CIPF vs. 5 % in CTRLS (P = 0.0002). The presence of moderate/severe PH at initial presentation was not associated with survival.. Results of the present study confirm a high prevalence of PH at diagnosis in WHWTs affected with CIPF and highlight the utility of PV/PA as a non-invasive surrogate for assessment of PH in this population.

Topics: Animals; Case-Control Studies; Dog Diseases; Dogs; Echocardiography; Genetic Predisposition to Disease; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Prevalence; Pulmonary Artery; Pulmonary Veins; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Topics: Animals; Arginine; Cyclic GMP; Hypertension, Pulmonary; Hypoxia; Male; Myocardium; Nitric Oxide; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Vasodilator Agents

We aimed to describe a case of prematurely born infant with accidental sildenafil overdose.. This was a retrospective case report followed with chart and literature review.. A prematurely born infant with moderate bronchopulmonary dysplasia, corrected congenital heart disease, and pulmonary hypertension presented with an accidental sildenafil overdose. Despite the relatively high dose in this medically frail infant and the long elimination half-life of sildenafil in infants, the symptoms of sildenafil overdose in our patient were only mild. After a short and uneventful period of observation in the hospital, the patient was discharged home.. Sildenafil overdose can cause serious symptoms such as hypotension. However, in our case, the sildenafil overdose was well tolerated, even by a young patient with underlying heart and lung disease. We show that choices in the management of sildenafil intoxication can be made based on the knowledge of sildenafil pharmacokinetics in young children.

Topics: Child; Child, Preschool; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Pulmonary Artery; Retrospective Studies; Sildenafil Citrate

Intravenous (IV) sildenafil may be administered as a continuous infusion or intermittent bolus dosing in infants with pulmonary hypertension (PH). We aimed to compare these delivery methods.. We retrospectively evaluated subjects less than 12 months old treated with IV sildenafil for PH. Vital signs, oxygen requirement, vasoactive-inotropic score (VIS), and echocardiogram results before and after sildenafil initiation, and the need for discontinuation due to side effects, were noted.. In this small cohort of infants treated with continuous or intermittent IV sildenafil, in the setting of different baseline characteristics between groups, there were no significant differences in changes in vital signs, VIS, FiO

Topics: Critical Illness; Humans; Hypertension, Pulmonary; Infant; Infusions, Intravenous; Prospective Studies; Retrospective Studies; Sildenafil Citrate

Impaired angiogenesis function in pulmonary artery endothelial cells (PAEC) contributes to persistent pulmonary hypertension of the newborn (PPHN). Decreased nitric oxide (NO) amounts in PPHN lead to impaired mitochondrial biogenesis and angiogenesis in the lung; the mechanisms remain unclear. We hypothesized that decreased cyclic guanosine monophosphate (cGMP)-PKG (protein kinase G) signaling downstream of NO leads to decreased mitochondrial biogenesis and angiogenesis in PPHN. PPHN was induced by ductus arteriosus constriction from 128-136 days' gestation in fetal lambs. Control animals were gestation-matched lambs that did not undergo ductal constriction. PAEC isolated from PPHN lambs were treated with the sGC (soluble guanylate cyclase) activator cinaciguat, the PKG activator 8-bromo-cGMP, or the PDE-V (PDE type V) inhibitor sildenafil. Lysates were immunoblotted for mitochondrial transcription factors and electron transport chain C-I (complex I), C-II, C-III, C-IV, and C-V proteins. The

Topics: Animals; Animals, Newborn; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Endothelial Cells; Female; Guanosine Monophosphate; Humans; Hypertension, Pulmonary; Infant, Newborn; Mitochondria; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Pregnancy; Pulmonary Artery; Sheep; Signal Transduction; Sildenafil Citrate

We present a 10-year-old boy with syncope who was found to have long-QT syndrome and severe Pulmonary Hypertension (PH) both in the absence of a secondary cause; to our knowledge, this is the first report with this unusual coexistence. His genetic tests were positive for hereditary hemorrhagic telangiectasia and Long QT Syndrome (LQTS) without any family history of PH or LQTS. We demonstrated that digital subtraction pulmonary angiography was more useful compared to CT angiogram to demonstrate pulmonary vascular changes which correlated with a noresponse to acute vasoreactivity testing during right heart catheterization. He has been stable for the last 2 years on Ambrisentan, Sildenafil, and Nadolol without recurrence of symptoms.

Topics: Angiography; Child; Echocardiography; Electrocardiography; Genetic Testing; Humans; Hypertension, Pulmonary; Long QT Syndrome; Male; Nadolol; Phenylpropionates; Pyridazines; Sildenafil Citrate; Syncope; Telangiectasia, Hereditary Hemorrhagic; Tomography, X-Ray Computed

We developed a pharmacokinetic model of intravenous sildenafil in newborns with congenital diaphragmatic hernia (CDH) to achieve a target plasma concentration of over 50 μg/l.. Twenty-three CDH newborns with pulmonary hypertension (64 blood samples) received intravenous sildenafil. Patients received a loading dose of 0.35 mg/kg (IQR 0.16 mg/kg) for 3 h, followed by a continuous infusion of 1.5 mg/kg/day (IQR 0.1 mg/kg/day). For model development, non-linear mixed modeling was used. Inter-individual variability (IIV) and inter-occasion variability were tested. Demographic and laboratory parameters were evaluated as covariates. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were used for model validation.. A two-compartment disposition model of sildenafil and a one-compartment disposition model of desmethyl sildenafil (DMS) was observed with IIV in sildenafil and DMS clearance and volume of distribution of sildenafil. NPDE and VPC revealed adequate predictability. Only postnatal age increased sildenafil clearance. This was partly compensated by a higher DMS concentration, which also has a therapeutic effect. In this small group of patients, sildenafil was tolerated well.. This model for sildenafil in CDH patients shows that concentration-targeted sildenafil dosing of 0.4 mg/kg in 3 h, followed by 1.6 mg/kg/day continuous infusion achieves appropriate sildenafil plasma levels.

Topics: Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Infusions, Intravenous; Models, Biological; Phosphodiesterase 5 Inhibitors; Retrospective Studies; Sildenafil Citrate; Tissue Distribution

A 6-month-old intact female Maltese dog was presented for acute onset of syncope.. The dog was presented for collapse upon excitement and exercise. It collapsed at discharge and suffered cardiopulmonary arrest. Echocardiography after resuscitation indicated severe pulmonary hypertension without evidence of intracardiac or extracardiac shunting. A presumptive diagnosis of congenital pulmonary hypertension was made.. Initial treatment with sildenafil was effective at relieving syncope, but the extent of pulmonary hypertension as determined by serial echocardiography was unchanged. Graded balloon atrial septostomy was performed as a palliative procedure. Follow-up echocardiography identified a patent interatrial communication with bidirectional shunting. The dog remained asymptomatic 18 months after treatment.. To the best of our knowledge, this study is the first report in the veterinary literature of graded balloon atrial septostomy performed for therapeutic purposes. Further studies are required to determine if this palliative procedure is a beneficial treatment option for dogs with congenital or severe refractory pulmonary hypertension.

Topics: Animals; Catheterization; Dog Diseases; Dogs; Female; Hypertension, Pulmonary; Palliative Care; Sildenafil Citrate; Vasodilator Agents

Prenatal closure of foramen ovale without CHD is a rarely reported entity. Therefore, clinical and echocardiographic findings are poorly defined in these patients. We report a patient with prenatal closure of foramen ovale that presented with severe pulmonary hypertension of the newborn and left ventricular failure. Judicious management strategies were utilised to successfully treat both life-threatening conditions.

Topics: Bosentan; Echocardiography; Female; Foramen Ovale; Heart Failure; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Pregnancy; Sildenafil Citrate; Treatment Outcome; Ultrasonography, Prenatal

Information regarding the pharmacokinetics of oral sildenafil in dogs with pulmonary hypertension is limited. In this study, we examined the pharmacokinetics of oral sildenafil in a canine model of chronic embolic pulmonary hypertension (CEPH). The CEPH model was developed by repeatedly injecting microspheres into the pulmonary arteries. The pharmacokinetics of oral sildenafil at 1, 2 and 4 mg/kg was evaluated using four dogs with pulmonary hypertension in the fasted state. The plasma concentrations of sildenafil were determined using high-performance liquid chromatography, and pharmacokinetic parameters were calculated using a noncompartmental analysis. Sildenafil was well tolerated in this study. Proportional increments in the maximum plasma concentration and area under the curve extrapolated to infinity at drug doses of 1, 2 and 4 mg/kg were detected using a power model analysis. No significant differences were observed among the three doses in the time to maximum plasma concentration. The mean residence time and elimination half-life were slightly but significantly higher at a dose of 4 mg/kg than at a dose of 1 mg/kg.

Topics: Administration, Oral; Animals; Area Under Curve; Disease Models, Animal; Dog Diseases; Dogs; Female; Hypertension, Pulmonary; Microspheres; Sildenafil Citrate

Topics: Antihypertensive Agents; Female; Heart Arrest; Heart Failure; Humans; Hypertension, Pulmonary; Middle Aged; Pulmonary Artery; Pulmonary Wedge Pressure; Risk Factors; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents; Ventricular Function, Left

Topics: Aged; Antihypertensive Agents; Coronary Artery Disease; Female; Fibromuscular Dysplasia; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sildenafil Citrate; Tadalafil; Vascular Fistula; Vasodilator Agents

Topics: Bosentan; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Insurance Coverage; Japan; Phenylpropionates; Prevalence; Prognosis; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Pyridazines; Pyrimidines; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Universal Health Insurance

Intravenous (IV) sildenafil, a phosphodiesterase type 5 inhibitor, is increasingly being used for the treatment of pulmonary hypertension (PH) in the paediatric population. Sildenafil (Revatio®) is approved for the treatment of pH in adults where it is administered as a bolus injection. However, in paediatrics it is used off-label and administered by continuous IV infusion. In the critically unwell child, limited IV access necessitates the administration of multiple IV infusions through a single IV lumen. The absence of compatibility data between sildenafil and other IV medications commonly used in this context necessitates the use of a dedicated IV line for sildenafil. The overall aim of this study was to establish the physical and chemical compatibility of sildenafil with commonly administered infusions in the paediatric and neonatal intensive care setting.. This study evaluated the chemical and physical compatibility of binary and multiple combinations (n = 42) of sildenafil with adrenaline, noradrenaline, milrinone, vasopressin and heparin. These were tested using three diluents (NaCl 0.9%w/v, Glucose 5%w/v, and Glucose 10%w/v) and two environmental conditions (room temperature and 37 °C) frequently encountered in paediatric or neonatal intensive care units. Prior to drug combination analysis, HPLC methods were developed and optimised to allow for the quantification of drugs in accordance with current pharmaceutical guidance. Binary and multiple drug mixtures of sildenafil were examined for physical and chemical compatibility to establish compatibility.. Of the drug combinations not containing heparin, all were deemed compatible with the exception of the five drug mix of Sildenafil 800 μg/mL, Milrinone 200 μg/mL, Vasopressin 0.4Units/mL, Noradrenaline 60 μg/mL, Adrenaline 60 μg/mL at 37 °C, in 10%w/v glucose. All binary or multi drug combinations containing heparin were deemed incompatible.. This research provides support and information to clinicians looking to co-administer sildenafil with other IV medicines thus removing the requirement to subject their patients to multiple intravenous cannula insertion points where IV access is restricted.. New evidence to support administration of sildenafil infusions in #PedsICU and #nicu- collaboration between @RCSIPharBioMol@FionaSOBrien1 and @OLCHCrumlin @RCSI_Irl @MoninneHowlett #CHI.

Topics: Administration, Intravenous; Drug Combinations; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Intensive Care, Neonatal; Pediatrics; Pharmaceutical Preparations; Sildenafil Citrate

Diabetic foot (DF), is one of the most serious and prevalent complications of diabetes mellitus (DM). Disruption in tissue oxygenation due to atherosclerosis in peripheral veins has an important place in DF development. In recent years, phosphodiesterase type 5 (PDE5) inhibitor drugs like sildenafil, which cause peripheral vasodilation, are used commonly in cases of erectile dysfunction, pulmonary hypertension and cardiac insufficiency. In that sense, PDE5 inhibitors, which cause vasodilation in peripheral veins, can increase blood build up in tissues of patients with DF and its stand-alone usage or its usage with already used treatments can increase tissue healing speed and quality.

Topics: Diabetes Mellitus; Diabetic Foot; Erectile Dysfunction; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Topics: Aged, 80 and over; Bosentan; Computed Tomography Angiography; Coronary Vessel Anomalies; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Scimitar Syndrome; Sildenafil Citrate; Treatment Outcome

Pulmonary vasodilators improve the functional capacity of some patients with pulmonary arterial hypertension. However, pulmonary vasodilators frequently fail to improve unequivocal endpoints of efficacy in patients with lower pulmonary arterial pressures who have been palliated with a Fontan procedure.. Haemodynamic measurements and the results of acute vasodilator testing in a subset of patients were reviewed to determine whether some patients acutely respond more favourably to sildenafil and might be candidates for precision care with a phosphodiesterase V inhibitor long term.. Heart catheterisation was performed in 11 patients with a Fontan procedure. Haemodynamic measurements were performed before and after treatment with intravenous sildenafil (mean 0.14, range 0.05-0.20 mg/kg). Results (mean ± standard deviation) were compared by paired and unpaired t-tests to identify statistically significant changes.. Sildenafil was acutely associated with changes in mean pulmonary arterial pressure, transpulmonary gradient, indexed blood flow, and indexed vascular resistance. Changes in mean pulmonary arterial pressure were greater for patients with a mean pulmonary arterial pressure greater than 14 mmHg compared to patients with a lower mean pulmonary arterial pressure. Changes in transpulmonary gradient were greater for patients with a transpulmonary gradient greater than 5 mmHg compared to patients with a lower transpulmonary gradient.. Sildenafil acutely decreases mean pulmonary arterial pressure and transpulmonary gradient and causes greater acute changes in patients with higher mean pulmonary arterial pressures and transpulmonary gradients. Haemodynamic measurements and vasodilator testing might help to guide precision care following Fontan palliation.

Topics: Administration, Intravenous; Adolescent; Adult; Blood Pressure; Cardiac Catheterization; Child; Child, Preschool; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Pulmonary Circulation; Retrospective Studies; Sildenafil Citrate; Utah; Vascular Resistance; Vasodilator Agents; Young Adult

We sought to determine the predictors of restoration of heart transplantation (HTx) candidacy in patients with systolic heart failure (HF) and reactive fixed pulmonary hypertension (RFPH) defined as pulmonary vascular resistance (PVR) > 2.5 Wood units (WU), transpulmonary gradient (TPG) > 12 mmHg or ≤2.5 WU with systolic arterial pressure ≤85 mmHg during vasoreactivity test, following sildenafil therapy.. Between 2007 and 2018 1136 patients were evaluated at our department as candidates for HTx. Thirty-five of them, who presented with systolic HF and were not eligible for HTx due to RFPH, were included in the study (31 men aged 55.1 ± 7.4 years). In all the patients sildenafil was introduced and up-titrated to a maximal tolerated dose in addition to optimal medical therapy. Patients were assessed at 3-6 months intervals.. During median 11 months (interquartile range 6-18 months) reduction of RFPH enabling qualification for HTx was observed in 62.9% patients. Higher baseline PVR (OR 0.32; 95% CI (0.14-0.74) p < 0.001), pulmonary artery systolic pressure (PASP) (OR 0.94, 95% CI (0.88-0.99) p = 0.05), mean artery pulmonary pressure (mPAP) (OR 0.87, 95% CI (0.77-0.98) p = 0.02) and TPG (OR 082, 95% CI (0.70-0.96) p = 0.003) were negative predictors of RFPH reduction with sildenafil therapy. In multivariable analysis, lower PVR (p = 0.02) was identified as an independent predictor of RFPH reduction following sildenafil therapy.. Sildenafil therapy can support PH reduction in systolic HF patients uneligible for HTx due to RFPH. Lower baseline PVR was identified as an independent predictor of PH reversibility with sildenafil enabling restoration of HTx candidacy.

Topics: Biomarkers; Cardiac Catheterization; Female; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Retrospective Studies; Sildenafil Citrate; Vascular Resistance; Vasodilator Agents

In children with single ventricle physiology, increased pulmonary vascular resistance may impede surgical progression or result in failing single ventricle physiology. The use of pulmonary vasodilators has been suggested as a potential therapy. However, knowledge on indication, dosage, and effect is limited. A retrospective case notes review of all (n = 36) children with single ventricle physiology, treated with pulmonary vasodilators by the UK Pulmonary Hypertension Service for Children 2004-2017. Therapy was initiated in Stage 1 (n = 12), Glenn (n = 8), or TCPC (n = 16). Treatment indications were high mean pulmonary arterial pressure, cyanosis, reduced exercise tolerance, protein-losing enteropathy, ascites, or plastic bronchitis. Average dose of sildenafil was 2.0 mg/kg/day and bosentan was 3.3 mg/kg/day. 56% had combination therapy. Therapy was associated with a reduction of the mean pulmonary arterial pressure from 19 to 14 mmHg (n = 17, p < 0.01). Initial therapy with one or two vasodilators was associated with an increase in the mean saturation from 80 to 85%, (n = 16, p < 0.01). Adding a second vasodilator did not give significant additional effect. 5 of 12 patients progressed from Stage 1 to Glenn, Kawashima, or TCPC, and 2 of 8 from Glenn to TCPC during a mean follow-up time of 4.7 years (0-12.8). Bosentan was discontinued in 57% and sildenafil in 14% of treated patients and saturations remained stable. Pulmonary vasodilator therapy was well tolerated and associated with improvements in saturation and mean pulmonary arterial pressure in children with single ventricle physiology. It appears safe to discontinue when no clear benefit is observed.

Topics: Adolescent; Arterial Pressure; Bosentan; Child; Child, Preschool; Drug Therapy, Combination; Exercise Tolerance; Female; Heart Defects, Congenital; Heart Ventricles; Humans; Hypertension, Pulmonary; Infant; Male; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; United Kingdom; Vascular Resistance; Vasodilator Agents

Sildenafil citrate causes vasodilatation, relaxation of the smooth muscle, and reduction of pulmonary arterial pressure. The latter property makes sildenafil citrate efficient for the treatment of cardiovascular diseases, including pulmonary arterial hypertension. Pediatric patients with pulmonary arterial hypertension are more susceptible to errors in drug administration than adults because of a lack of suitable drug dosages. Thus, the purpose of this study was to develop stable (chemically and microbiologically) sildenafil citrate drop liquid formulation, suitable for pediatric patients (including diabetics), ensuring safety during preparation and storing and improving palatability by using milk as a carrier for administration. The significant factors that affect the sildenafil solubility were evaluated by applying a Plackett-Burman design using two levels with six variables. The experiment showed that the type of buffer and glycerin content influenced the sildenafil solubility. The developed formulations proved to be stable for 6 months at all three assayed conditions (40± 2°C, 75 ± 5% RH; 25± 2°C, 60 ± 5% RH; and 4 ± 2°C). The microbiological tests fit with the requirement of the pharmacopeia at day 0 and 90 and even more at day 180. Finally, the palatability assay showed that 0.82 mL of the formulation containing buffer phosphate, 20% glycerin, and 4 mg mL

Topics: Adult; Child; Drug Compounding; Drug Stability; Humans; Hypertension, Pulmonary; Middle Aged; Sildenafil Citrate; Solubility; Solutions

The adult worms of Angiostrongylus vasorum reside in the pulmonary artery of dogs and can lead to cardiac, respiratory, and central neurologic signs. Due to luminal obstruction and perivascular inflammation of the pulmonary artery branches, pulmonary hypertension can arise. Pulmonary hypertension, in turn, can lead to severe damage of the right-sided cardiac structures, leading to right ventricular remodeling and tricuspid valve regurgitation.. An 8-year-old neutered female English Cocker Spaniel was presented to the author's institution because of abdominal distention and exercise intolerance. Ascites caused by congestive right-sided heart failure was found to be responsible for these problems. The underlying etiology of the right-sided heart failure was a severe pulmonary hypertension caused by Angiostrongylus vasorum infection. Echocardiography revealed, in addition to a severe concentric and eccentric right ventricular hypertrophy, right atrial and pulmonary trunk dilation, severe tricuspid valve regurgitation, and a systolic flail of the anterior leaflet of the tricuspid valve, resulting from ruptured chordae tendineae. As a coincidental finding, a congenital mitral stenosis was found. Oral therapy was initiated with daily administration of fenbendazole for 2 weeks along with daily administration of oral sildenafil until the re-check examination. At the 6-week re-check the dog showed full clinical and partial echocardiographic recovery, and both the blood antigen test for Angiostrongylus vasorum and the fecal Baermann larva isolation test were negative. When the sildenafil therapy was ceased after tapering the daily dosage, the owner reported recurrence of abdominal distension. Re-starting the sildenafil therapy resulted in resolution of this problem. The dog was reported to be clinically healthy with daily sildenafil administration 7 months after the initial presentation.. The present case report describes a dog where angiostrongylosis led to congestive right-sided heart failure resulting from severe pulmonary hypertension. The secondary right ventricular eccentric hypertrophy together with suspected papillary muscular ischemia were the suspected cause of the ruptured major tricuspid chordae tendineae, which led to a severe tricuspid valve regurgitation. Despite eradication of the worms, the severe pulmonary hypertension persisted. Treatment with daily oral sildenafil, a pulmonary arterial vasodilator, was enough to keep the dog free of clinically apparent ascites.

Topics: Angiostrongylus; Animals; Antinematodal Agents; Dog Diseases; Dogs; Female; Fenbendazole; Heart Failure; Heart Valve Diseases; Hypertension, Pulmonary; Sildenafil Citrate; Strongylida Infections; Tricuspid Valve; Vasodilator Agents

Diazoxide, a drug used to treat hyperinsulinemic hypoglycemia (HH), is associated with pulmonary hypertension (PH), as reported by the US Food and Drug Administration. However, no report has detailed the association between diazoxide dose and PH development. We report a case of an infant with HH, subsequently complicated by diazoxide-induced PH. When diazoxide was introduced, PH did not appear initially, but it developed during increased dosing. We monitored PH via regular echocardiography examinations. PH gradually improved with tapering of the diazoxide dose and disappeared after drug discontinuation. Our case suggests a diazoxide dose threshold might induce PH. Therefore, close echocardiography examinations should accompany diazoxide treatment.

Topics: Atrial Natriuretic Factor; Beckwith-Wiedemann Syndrome; Cardiac Catheterization; Congenital Hyperinsulinism; Deprescriptions; Diazoxide; Diuretics; Dose-Response Relationship, Drug; Echocardiography; Electrocardiography; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Natriuretic Peptide, Brain; Sildenafil Citrate; Vasodilator Agents

The effects of different doses of orally administered sildenafil on pulmonary haemodynamics in dogs with pulmonary hypertension (PH) have not been documented in an invasive and quantitative manner. In this study, we examined the effects of oral sildenafil using a canine model of chronic embolic PH (CEPH). This CEPH model was created by repeatedly injecting microspheres through a catheter into the pulmonary artery under general anaesthesia at regular weekly intervals over several months. The CEPH dogs received 1, 2 or 4 mg/kg of sildenafil orally twice a day for seven days. Then, haemodynamic measurements including pulmonary artery pressure (PAP), systemic artery pressure (SAP), pulmonary artery wedge pressure (PAWP), right atrial pressure (RAP) and cardiac output (CO) were obtained after seven days of sildenafil administration via right heart catheterisation and oscillometric blood pressure measurements. Sildenafil was well tolerated in this study. Sildenafil administered at doses of 2 and 4 mg/kg significantly decreased systolic PAP compared with before administration. In addition, all doses of sildenafil significantly decreased the mean and diastolic PAP. Furthermore, 4 mg/kg of sildenafil significantly decreased PAP compared with 1 mg/kg. Sildenafil also significantly decreased pulmonary vascular resistance without notable changes in SAP or systemic vascular resistance. The PAWP, RAP and CO did not increase significantly at any doses. In conclusion, the oral administration of sildenafil to CEPH models decreased PAP in a dose-dependent manner.

Topics: Administration, Oral; Animals; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Female; Hemodynamics; Hypertension, Pulmonary; Lung; Sildenafil Citrate; Vascular Resistance; Vasodilator Agents

Pulmonary arterial hypertension (PAH) causes pathological increase in pulmonary vascular resistance, leading to right-heart failure and eventual death. Previously, phosphodiesterase-10 (PDE10) was reported to be a promising target for PAH based on the studies with a nonselective PDE inhibitor papaverine, but little progress has been made to confirm the practical application of PDE10 inhibitors. To validate whether PAH is ameliorated by PDE10 inhibition rather than other PDE isoforms, here we report an integrated strategy to discover highly selective PDE10 inhibitors as chemical probes. Structural optimization resulted in a PDE10 inhibitor 2b with subnanomolar affinity and good selectivity of >45 000-fold against other PDEs. The cocrystal structure of the PDE10-2b complex revealed an important H-bond interaction between 2b and Tyr693. Finally, compound 2b significantly decreased the arterial pressure in PAH rats and thus validated the potential of PDE10 as a novel anti-PAH target. These findings suggest that PDE10 inhibition may be a viable treatment option for PAH.

Topics: Animals; Crystallography, X-Ray; Humans; Hypertension, Pulmonary; Male; Molecular Dynamics Simulation; Muscle, Smooth; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Platelet-Derived Growth Factor; Protein Binding; Protein Conformation; Rats

This study aims to assess the cost-effectiveness and budget impact of adopting sildenafil to the benefits package for the indication of pulmonary arterial hypertension (PAH), compared to beraprost.. Based on a societal perspective, a model-based economic evaluation was performed using local and international data to quantify the potential costs and health-related outcomes in terms of life years (LYs) and quality-adjusted life years (QALYs).. The economic model calculated the incremental cost-effectiveness ratio (ICER) per QALY gained for using sildenafil as first-line therapy compared to beraprost for the patient in functional class (FC) II and III, i.e. USD 3098 and USD 2827, respectively. The results indicated that in spite of sildenafil being more expensive than beraprost, generic sildenafil could potentially be a good value for money since ICER per QALY is below one times gross domestic product (GDP) per capita in Indonesia. Furthermore, budget impact analysis estimated that the incremental budget needed within 5 years for including sildenafil compared to beraprost for PAH patients starting in FC II and FC III was USD 436,775 and USD 3.6 million, respectively.. Compared to beraprost, sildenafil would be preferable for the treatment of PAH patients in FC II and FC III in Indonesia. The additional budget for adopting sildenafil compared to beraprost as the treatment of PAH in the benefits package was estimated at around USD 4.0 million.

Topics: Budgets; Cost-Benefit Analysis; Epoprostenol; Humans; Hypertension, Pulmonary; Indonesia; Sildenafil Citrate; Vasodilator Agents

Research comparing bosentan and macitentan in chronic thromboembolic pulmonary hypertension (CTEPH) is scarce, although macitentan might have superior pharmacologic properties. We present the first real-world, 2-year follow-up results and compare clinical outcomes of both drugs in CTEPH.. All consecutive, technical inoperable or residual CTEPH patients receiving bosentan or macitentan, diagnosed in our multidisciplinary team between January 2003 and January 2019, were included. We report and compare survival, clinical worsening (CW), adverse events, WHO FC, NT-proBNP and 6-min walking test (6MWT) until 2 years after medication initiation.. In total, 112 patients receiving bosentan or macitentan (58% female, mean age 62 ± 14 years, 68% WHO FC III/IV, 51% bosentan) could be included. Mean treatment duration was 1.9 ± 0.4 years for bosentan and 1.2 ± 0.6 years for macitentan. Two-year survival rate was 91% for bosentan and 80% for macitentan (HR mortality macitentan 1.85 [0.56-6.10], p = 0.31). Two-year CW-free survival was 81% and 58%, respectively (HR CW macitentan 2.16 [0.962-4.87], p = 0.06). Right atrial pressure, cardiac output (for mortality alone) and 6MWT lowest saturation were multivariate predictors at baseline. Overall adverse event rates were comparable and WHO FC, NT-proBNP and 6MWT distance improved similar for both drugs till 2-year follow-up.. CTEPH patients receiving bosentan or macitentan have improved clinical outcomes till 2-year follow-up, without significant differences in outcomes between both therapies.

Topics: Aged; Bosentan; Chronic Disease; Drug Therapy, Combination; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Survival Rate; Walk Test

Pulmonary hypertension causes substantial morbidity and mortality in infants. Although Food and Drug Administration approved to treat pulmonary arterial hypertension in adults, sildenafil is not approved for infants. We sought to describe sildenafil exposure and associated diagnoses and outcomes in infants.. Retrospective cohort of neonates discharged from more than 300 neonatal intensive care units from 2001 to 2016.. Sildenafil was administered to 1,336/1,161,808 infants (0.11%; 1.1 per 1,000 infants); 0/35,977 received sildenafil in 2001 versus 151/90,544 (0.17%; 1.7 per 1,000 infants) in 2016. Among infants <32 weeks' gestational age (GA) with enough data to determine respiratory outcome, 666/704 (95%) had bronchopulmonary dysplasia (BPD). Among infants ≥32 weeks GA, 248/455 (55%) had BPD and 76/552 (14%) were diagnosed with meconium aspiration. Overall, 209/921 (23%) died prior to discharge.. The use of sildenafil has increased since 2001. Exposed infants were commonly diagnosed with BPD. Further studies evaluating dosing, safety, and efficacy of sildenafil are needed.

Topics: Bronchopulmonary Dysplasia; Drug Utilization; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Male; Meconium Aspiration Syndrome; Retrospective Studies; Sildenafil Citrate; Vasodilator Agents

Currently, dual- or triple-drug combinations comprising different vasodilators are the mainstay for the treatment of pulmonary arterial hypertension (PAH). However, the patient outcome continues to be disappointing because the existing combination therapy cannot restrain progression of the disease. Previously, we have shown that when given as a monotherapy, long-acting inhaled formulations of sildenafil (a phosphodiesterase-5 inhibitor) and rosiglitazone (a peroxisome proliferator receptor-γ agonist) ameliorate PAH in rats. Thus, with a goal to develop a new combination therapy, we prepared and characterized poly(lactic-co-glycolic acid) (PLGA)-based long-acting inhalable particles of sildenafil and rosiglitazone. We then assessed the efficacy of the combinations of sildenafil and rosiglitazone, given in plain forms or as PLGA particles, in reducing mean pulmonary arterial pressure (mPAP) and improving pulmonary arterial remodeling and right ventricular hypertrophy (RVH) in Sugen 5416 plus hypoxia-induced PAH rats. After intratracheal administration of the formulations, we catheterized the rats and measured mPAP, cardiac output, total pulmonary resistance, and RVH. We also conducted morphometric studies using lung tissue samples and assessed the degree of muscularization, the arterial medial wall thickening, and the extent of collagen deposition. Compared with the plain drugs, given via the pulmonary or oral route as a single or dual combination, PLGA particles of the drugs, although given at a longer dosing interval compared with the plain drugs, caused more pronounced reduction in mPAP without affecting mean systemic pressure, improved cardiac function, slowed down right heart remodeling, and reduced arterial muscularization. Overall, PLGA particles of sildenafil and rosiglitazone, given as an inhaled combination, could be a viable alternative to currently available vasodilator-based combination therapy for PAH.

Topics: Administration, Inhalation; Animals; Drug Therapy, Combination; Heart Function Tests; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Rosiglitazone; Sildenafil Citrate; Vascular Remodeling

To assess the demographics, treatment algorithm, and outcomes in a large cohort of children treated with sildenafil.. A retrospective cohort study of children with pulmonary hypertension (PH) treated with sildenafil at a single institution between 2004 and 2015. Baseline and follow-up data collected by chart review.. There were 269 children included in this study: 47 with idiopathic pulmonary arterial hypertension, 53 with congenital heart disease, 135 with bronchopulmonary dysplasia, 24 with congenital diaphragmatic hernia, and 7 with other causes. Sildenafil was initial monotherapy in 84.8% and add-on therapy in 15.2%. Median follow-up time was 3.1 years (2  weeks-12.4 years). On follow-up, 99 (37%) remained on sildenafil or transitioned to tadalafil, 93 (35%) stopped sildenafil for improvement in PH, 54 (20%) died, and 20 (7%) were lost to follow-up. PH was most likely to improve in those with bronchopulmonary dysplasia, allowing for the discontinuation of sildenafil in 45%. Eighteen deaths were related to PH and 36 from other systemic causes. Two patients stopped sildenafil owing to airway spasm with desaturation. Overall survival was significantly lower in World Health Organization group 3 PH (bronchopulmonary dysplasia and congenital diaphragmatic hernia) vs group 1 (idiopathic pulmonary arterial hypertension and congenital heart disease), P = .02.. In this retrospective experience in children with mainly World Health Organization groups 1 and 3 PH, low-dose sildenafil was well-tolerated, safe, and had an acceptable side effect profile. Although patients with group 3 PH have high mortality, survivors have a high likelihood of PH improving.

Topics: Adolescent; Bronchopulmonary Dysplasia; Child; Child, Preschool; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Sildenafil Citrate; Tadalafil; Treatment Outcome; Vasodilator Agents

Topics: Hemodynamics; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Sildenafil Citrate

Pulmonary arterial hypertension is a fatal lung disease caused by the progressive remodeling of small pulmonary arteries (PAs). Sildenafil can prevent the remodeling of PAs, but conventional sildenafil formulations have shown limited treatment efficacy for their poor accumulation in PAs. Here, glucuronic acid (GlcA)-modified liposomes (GlcA-Lips) were developed to improve the delivery of sildenafil to aberrant over-proliferative PA smooth muscle cells via targeting the GLUT-1 (glucose transport-1), and, therefore, inhibiting the remodeling of PAs in a monocrotaline-induced PA hypertension model. GlcA-Lips encapsulating sildenafil (GlcA-sildenafil-Lips) had a size of 90 nm and a pH-sensitive drug release pattern. Immunostaining assay indicated the overexpression of GLUT-1 in PA smooth muscle cells. Cellular uptake studies showed a 1-fold increase of GlcA-Lips uptake by PA smooth muscle cells and pharmacokinetics and biodistribution experiments indicated longer blood circulation time of GlcA-Lips and increased ability to target PAs by 1-fold after 8 hours administration. Two-week treatment indicated GlcA-sildenafil-Lips significantly inhibited the remodeling of PAs, with a 32% reduction in the PA pressure, a 41% decrease in the medial thickening, and a 44% reduction of the right ventricle cardiomyocyte hypertrophy, and improved survival rate. Immunohistochemical analysis showed enhanced expression of caspase-3, after administration of GlcA-sildenafil-Lips, and reduced expression of P-ERK1/2 (phosphorylated ERK1/2) and HK-2 (hexokinase-2), and increased level of eNOS (endothelial nitric oxide synthase) and cyclic GMP (cGMP). In conclusion, targeted delivery of sildenafil to PA smooth muscle cells with GlcA-Lips could effectively inhibit the remodeling of PAs in the monocrotaline-induced PA hypertension.

Topics: Animals; Disease Models, Animal; Hypertension, Pulmonary; Immunohistochemistry; Liposomes; Male; Muscle, Smooth, Vascular; Nitric Oxide Synthase Type III; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Tissue Distribution; Vascular Remodeling; Vasodilator Agents; Ventricular Function, Right

Topics: Hemodynamics; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Sildenafil Citrate

The phosphodiesterase-5 inhibitor sildenafil was developed for the treatment of pulmonary hypertension. The authors investigated the efficacy and safety of sildenafil in the early postoperative period after mitral valve surgery in patients with pulmonary hypertension.. A double-blind, placebo-controlled randomized trial was performed.. The trial was performed in a single tertiary referral center.. Fifty consecutive patients who experienced pulmonary hypertension and underwent mitral valve surgery.. Patients were randomly assigned to the following 2 groups: 25 patients received 20 mg sildenafil every 8 hours, and the remaining 25 patients received placebo during the same period. Hemodynamic parameters were studied by using a pulmonary artery catheter at baseline and every 6 hours up to 36 hours.. Patients who received sildenafil showed a decrease in mean pulmonary pressure, from 32 ± 7 mmHg at baseline to 26 ± 3 mmHg after 36 hours, whereas no change was seen in patients who received placebo (mean pulmonary pressure 34 ± 6 mmHg at baseline and 35 ± 5 mmHg after 36 h) (p < 0.001). No significant changes in systemic hemodynamic and oxygenation were observed. Patients who received sildenafil compared with those who received placebo had a median mechanical lung ventilation time of 16 (10-31) hours versus 19 (13-41) hours (p = 0.431), intensive care unit stay of 74 (44-106) hours versus 91 (66-141) hours (p = 0.410), and a total hospitalization stay of 7 (5-10) days versus 11 (7-15) days (p = 0.009).. The immediate postoperative administration of sildenafil after mitral valve surgery is safe. Sildenafil demonstrates a favorable decreasing effect on pulmonary vascular pressure without systemic hypotension and ventilation-perfusion mismatch.

Topics: Aged; Double-Blind Method; Female; Follow-Up Studies; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Hypertension, Pulmonary; Male; Mitral Valve; Phosphodiesterase 5 Inhibitors; Postoperative Care; Prospective Studies; Pulmonary Wedge Pressure; Sildenafil Citrate; Time Factors; Treatment Outcome; Vascular Resistance

Topics: Cardiac Surgical Procedures; Humans; Hypertension, Pulmonary; Mitral Valve; Sildenafil Citrate; Vasodilator Agents

Topics: Antihypertensive Agents; Clinical Trials as Topic; Endothelin Receptor Antagonists; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Sildenafil Citrate; Vascular Remodeling

Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.

Topics: Animals; Dogs; Drug Design; Female; Half-Life; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Pyrimidines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Sildenafil Citrate; Structure-Activity Relationship; Substrate Specificity

Enteral sildenafil may be used in the intensive care unit for treatment of pulmonary arterial hypertension. We aimed to determine if initial enteral sildenafil dosing is safe in children receiving concurrent vasoactive infusions.. We performed a single-centre retrospective chart review that included patients less than 2 years of age in paediatric and cardiovascular intensive care units at an academic medical centre from 1 January, 2010 to 30 November, 2016. Included patients received concomitant enteral sildenafil and a continuously infused vasoactive agent. Exclusion criteria consisted of mechanical circulatory support, any form of dialysis, or a suspicion of septic shock at the time of sildenafil initiation. We sought to identify patients who developed worsening hemodynamic instability after initiation of enteral sildenafil defined as one or more of the following observations within 24 hours of sildenafil initiation: sildenafil discontinuation, total fluid bolus receipt >10 ml/kg, increased vasoactive support, epinephrine intravenous push administration, and/or the initiation of mechanical circulatory support.. Worsening hemodynamic instability was identified in 35% of the 130-patient cohort. Patients younger than 4 months were at increased risk of further hemodynamic instability compared with older patients (56% versus 44%, p = 0.0003) despite receiving lower median doses (1.28 mg/kg/day versus 1.78 mg/kg/day, p = 0.01).. Critically ill children receiving vasoactive infusions may be at increased risk for further hemodynamic instability after initiation of enteral sildenafil, particularly in younger patients. This population may benefit from lower starting enteral sildenafil doses of 0.25 mg/kg/dose or less every 8 hours to avoid further hemodynamic compromise.

Topics: Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Infusions, Intravenous; Intensive Care Units; Male; Retrospective Studies; Sildenafil Citrate; Vasodilator Agents

Pulmonary hypertension (PH) is a common clinical condition associated with morbidity and mortality in both humans and dogs. Sildenafil, a phosphodiesterase-5 (PDE5) inhibitor causing accumulation of cGMP, is frequently used for treatment of PH. The authors previously reported a PDE5A:E90K polymorphism in dogs that results in lower basal cyclic guanosine monophosphate (cGMP) concentrations than in wild-type dogs, which could contribute to variability in the efficacy of sildenafil. In this study, response to sildenafil therapy was evaluated in dogs with PH by comparing echocardiographic parameters, quality-of-life (QOL) score, and plasma cGMP concentrations before and after sildenafil therapy. Overall, tricuspid regurgitation estimated systolic pressure gradient (PG) and QOL score were significantly improved after sildenafil therapy, and the plasma cGMP concentration was significantly decreased. Dogs that had a heterozygous PDE5A status had a significantly worse QOL score when compared to the wildtype group after sildenafil treatment. The simple and multiple regression analyses revealed a significant but weak prediction for the percent reduction in QOL score with sildenafil treatment by plasma cGMP level and by the PDE5A:E90K polymorphic status. This study showed that sildenafil treatment improved PH in dogs, and the PDE5A:E90K polymorphism blunted the efficacy of sildenafil in terms of QOL improvement.

Topics: Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Electrocardiography; Female; Genotype; Hypertension, Pulmonary; Male; Polymorphism, Single Nucleotide; Quality of Life; Sildenafil Citrate

Portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis. Patients with severe PPHTN are contraindicated for liver transplant because of the associated risk of intraoperative acute right heart failure during reperfusion phase or massive volume infusion. Therefore, it has been recommended that patients with moderate to severe PPHTN undergo medical treatment to lower the pulmonary artery pressure before undergoing transplant. Herein, we report 3 patients with severe PPHTN who underwent sildenafil monotherapy before living donor liver transplant. None of the patients experienced associated adverse effects during sildenafil treatment, and the pulmonary artery pressure was effectively reduced before transplant. The first patient was diagnosed during anesthesia prior to transplant, and the mean pulmonary artery pressure was reduced by 34% after treatment. The second and third patients were followed-up with echography, and the estimated pulmonary artery systolic pressure were reduced by 34% and 47%, respectively. Pretransplant right heart catheterization also confirmed the reduction of the mean pulmonary artery pressure. Intraoperative hemodynamic parameters were stable, and the 3 patients were discharged uneventfully. After transplant, sildenafil was discontinued, and all patients remained in a stable clinical and functional status during follow-up.

Topics: Antihypertensive Agents; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Sildenafil Citrate; Vasodilator Agents

Topics: Adipose Tissue, Brown; Humans; Hypertension, Pulmonary; Infant, Extremely Premature; Infant, Newborn; Male; Neck; Sildenafil Citrate; Vasodilator Agents

In pulmonary hypertension (PH), hypoxia represents both an outcome and a cause of exacerbation. We addressed the question whether hypoxia adaptation might affect the mechanisms underlying PH alleviation through phosphodiesterase-5 (PDE5) inhibition.. Two-week hypoxia changed the body weight (- 31% vs. - 27%, respectively, P = NS), blood hemoglobin (+ 25% vs. + 27%, P = NS) and nitrates+nitrites (+ 175% vs. + 261%, P = 0.007), right ventricle fibrosis (+ 814% vs. + 317%, P < 0.0001), right ventricle hypertrophy (+ 84% vs. + 49%, P = 0.007) and systolic pressure (+ 108% vs. + 41%, P = 0.001), pulmonary vessel density (+ 61% vs. + 46%, P = NS), and the frequency of small (< 50 µm wall thickness) vessels (+ 35% vs. + 13%, P = 0.0001). Most of these changes were maintained for 4-week hypoxia, except blood hemoglobin and right ventricle hypertrophy that continued increasing (+ 52% vs. + 42%, P = NS; and + 104% vs. + 83%, P = 0.04). To further assess these observations, small vessel frequency was found to be linearly related with the right ventricle-developed pressure independent of hypoxia duration.. Thus, although hypoxia adaptation is not yet accomplished after 4 weeks, PH alleviation by PDE5 inhibition might nevertheless provide an efficient strategy for the management of this disease.

Topics: Animals; Blood Pressure; Heart; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Phosphodiesterase 5 Inhibitors; Rats; Rats, Sprague-Dawley; Sildenafil Citrate

Topics: Bronchoscopy; Child; Humans; Hypertension, Pulmonary; Sildenafil Citrate; Spasm; Tracheobronchomalacia

Topics: Child; Humans; Hypertension, Pulmonary; Sildenafil Citrate

Topics: A549 Cells; Aerosols; Animals; Cell Survival; Cytokines; Drug Compounding; Drug Stability; Drug Storage; Epithelial Cells; Humans; Hypertension, Pulmonary; Lipopolysaccharides; Macrophages, Alveolar; Metered Dose Inhalers; Nanoparticles; Particle Size; Poloxamer; Rats; Sildenafil Citrate

Topics: Administration, Oral; Animals; Crystallography, X-Ray; ERG1 Potassium Channel; Hypertension, Pulmonary; Microsomes, Liver; Models, Molecular; Molecular Structure; Phosphodiesterase 5 Inhibitors; Protein Conformation; Pulmonary Artery; Structure-Activity Relationship

The relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood.. The aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants.. We extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model.. We identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration-time curve over 24 hours (AUC24,SS) and maximum concentration of sildenafil (Cmax,SS,SIL) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC24,SS; 1.19 (0.78, 1.82) for Cmax,SS,SIL.. We found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil's safety profile in infants is warranted.

Topics: Administration, Oral; Cohort Studies; Female; Humans; Hypertension, Pulmonary; Hypotension; Infant; Infant, Newborn; Male; Multivariate Analysis; Phosphodiesterase 5 Inhibitors; Regression Analysis; Sildenafil Citrate

Pulmonary hypertension (PH) affects 1 in 6 infants with a birthweight <1,000 g (extremely low birthweight; ELBW) and is frequently associated with bronchopulmonary dysplasia (BPD). If untreated, the mortality rates of the disease are high.. The aim of this study was to characterize risk factors for PH in ELBW infants and to describe the timing of onset of the disease by setting up a screening program.. ELBW infants treated at the Department of Neonatology (level III neonatal intensive care unit at the University of Cologne Medical Centre, Germany) between January 2010 and March 2015 were included. Echocardiography screening for PH was performed either before discharge or if BPD was diagnosed. Additionally, infants had at least 1 echocardiographic scan after discharge. Survival with PH, age at diagnosis of PH, and risk factors associated with PH were assessed.. In total, 34/188 (18%) infants had PH. Of these, 14 (41%) were identified after discharge. Another 11 (32%) were diagnosed with PH without suffering from moderate or severe BPD. The risk factors for diagnosis of PH were moderate (odds ratio, OR 4 [2-8]) or severe BPD (OR 13 [2-71]), prolonged rupture of membranes >7 days (OR 5 [1-19]), and birthweight below the 3rd percentile (OR 3 [1-9]). All infants with PH before discharge and 50% diagnosed after discharge were treated with sildenafil (2.0 mg/kg/day). PH resolved and sildenafil was discontinued in all patients after a median duration of 13 months (IQR 8-20).. An echocardiographic screening program may help to identify infants with PH. Examinations should include all ELBW infants irrespective of the presence of BPD and be continued after discharge.

Topics: Birth Weight; Bronchopulmonary Dysplasia; Echocardiography; Female; Germany; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Extremely Low Birth Weight; Infant, Newborn; Intensive Care Units, Neonatal; Logistic Models; Male; Risk Factors; Severity of Illness Index; Sildenafil Citrate

Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively.. Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs. A hypoxic chamber was constructed in which the animals were placed in a conscious state. By reducing the inspired oxygen fraction (FiO. The new hypoxic chamber provided a stable hypoxic atmosphere during all experiments. The mean PAP under normoxic conditions was 15.8 ± 1.8 mmHg. Hypoxia caused a reliable increase in mean PAP (+ 12.2 ± 3.2 mmHg, p < 0.0001). Both, sildenafil (- 6.8 ± 4.4 mmHg) and ANP (- 6.4 ± 3.8 mmHg) significantly (p < 0.05) decreased PAP. Furthermore sildenafil and ANP showed similar effects on systemic hemodynamics. In subsequent studies, the in vitro effects and gene expression pattern of the two pathways were exemplified.. By combining the hypoxic environment with the telemetric approach, we could successfully establish a new acute PH model. Sildenafil and ANP demonstrated equal effects regarding pulmonary selectivity. This non-invasive model could help to rapidly screen pulmonary vasodilators with decreased animal burden.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Hypertension, Pulmonary; Hypoxia; Lung; Male; Pulmonary Artery; Sildenafil Citrate; Telemetry; Vasodilator Agents; Wakefulness

Incontinentia pigmenti (IP) is a rare inherited genodermatosis that usually involves the skin, and also teeth, oral cavity, central nervous system, eyes, blood with eosinophilia, and rarely skeletal system, breast, heart, and lungs. Skin lesions usually appear early, at birth or within the first 2 weeks of life, with four different phases tending to follow Blaschko lines that may overlap.. We report a rare case of a neonate with transient reversible pulmonary hypertension that presented at day 9 of life. She manifested increasing dyspnea and deterioration of respiratory dynamics with a serious pulmonary hypertension without a primary pulmonary disease. Hence, oxygen therapy at high flows and nitric oxide have been administered with an initial response, but, subsequently, because of the worsening of the respiratory activity, she underwent sildenafil and bosentan treatment with respiratory dynamics improvement and progressive decrease of the pulmonary pressures.. In literature only a few cases of cardiopulmonary anomalies in IP have been described with different outcomes, and these rare complications are probably underestimated by physicians. We could suppose that microangiopathic damages may have a critical role in endothelial alterations, and these processes are probably shared by multiple organs involved in IP and rarely by lungs and heart.

Topics: Antihypertensive Agents; Bosentan; Female; Humans; Hypertension, Pulmonary; Incontinentia Pigmenti; Infant, Newborn; Oxygen Inhalation Therapy; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

Sickle cell disease (SCD) is associated with intravascular hemolysis and oxidative inhibition of nitric oxide (NO) signaling. BAY 54-6544 is a small-molecule activator of oxidized soluble guanylate cyclase (sGC), which, unlike endogenous NO and the sGC stimulator, BAY 41-8543, preferentially binds and activates heme-free, NO-insensitive sGC to restore enzymatic cGMP production. We tested orally delivered sGC activator, BAY 54-6544 (17 mg/kg/d), sGC stimulator, BAY 41-8543, sildenafil, and placebo for 4-12 weeks in the Berkeley transgenic mouse model of SCD (BERK-SCD) and their hemizygous (Hemi) littermate controls (BERK-Hemi). Right ventricular (RV) maximum systolic pressure (RVmaxSP) was measured using micro right-heart catheterization. RV hypertrophy (RVH) was determined using Fulton's index and RV corrected weight (ratio of RV to tibia). Pulmonary artery vasoreactivity was tested for endothelium-dependent and -independent vessel relaxation. Right-heart catheterization revealed higher RVmaxSP and RVH in BERK-SCD versus BERK-Hemi, which worsened with age. Treatment with the sGC activator more effectively lowered RVmaxSP and RVH, with 90-day treatment delivering superior results, when compared with other treatments and placebo groups. In myography experiments, acetylcholine-induced (endothelium-dependent) and sodium-nitroprusside-induced (endothelium-independent NO donor) relaxation of the pulmonary artery harvested from placebo-treated BERK-SCD was impaired relative to BERK-Hemi but improved after therapy with sGC activator. By contrast, no significant effect for sGC stimulator or sildenafil was observed in BERK-SCD. These findings suggest that sGC is oxidized in the pulmonary arteries of transgenic SCD mice, leading to blunted responses to NO, and that the sGC activator, BAY 54-6544, may represent a novel therapy for SCD-associated pulmonary arterial hypertension and cardiac remodeling.

Topics: Anemia, Sickle Cell; Animals; Arterial Pressure; Disease Models, Animal; Enzyme Activation; Enzyme Activators; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Mice, Transgenic; Morpholines; Nitric Oxide; Pulmonary Artery; Pyrimidines; Sildenafil Citrate; Soluble Guanylyl Cyclase; Vasodilation; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Pressure; Ventricular Remodeling

Topics: Double-Blind Method; Heart Diseases; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Sildenafil Citrate

Pulmonary hypertension (PH) is an important contributor of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). Treatment options are limited, but sildenafil might improve oxygenation and PH in neonates with CDH.. Aim of this study is to assess effects of intravenous sildenafil on oxygenation and PH in neonates with CDH.. A retrospective chart review was performed in all neonates with CDH born in our institution between September 2012 and December 2014. Indication for sildenafil was an OI > 15, PH > 2/3 systemic pressure, or a difference in pre- and postductal oxygen saturation (≥8%). A sildenafil bolus was administered followed by a maintenance infusion of 1.6 mg/kg/d. Primary outcome was improved oxygenation after starting sildenafil. Patients were compared according to improvement in oxygenation (responder vs non-responder).. A total of 26 of 44 neonates were treated with intravenous sildenafil and in all sildenafil were initiated within the first 24 h of life (median age 3.1 h). Improved oxygenation was observed in 11 infants (42.3%). Among the 15 non-responders (57.6%) ECMO was started in 13 and two infants died without ECMO. Vasopressor support increased significantly during the first hours after commencing sildenafil in responders and non-responders. Echocardiographic indices demonstrated an effect on pulmonary arterial pressure within the first 24 h after starting sildenafil.. Treatment of neonates with intravenous sildenafil during the first day of life was associated with acute improvement in oxygenation in more than 40% of patients. However, a significant increase in vasopressor support was observed.

Topics: Extracorporeal Membrane Oxygenation; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Infusions, Intravenous; Phosphodiesterase 5 Inhibitors; Retrospective Studies; Sildenafil Citrate

Current treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V'/Q'). Hypoxia is also a well-known modulator of the nitric oxide (NO) pathway, and may therefore differentially affect the responses to phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators. So far, the effects of the sGC stimulator riociguat on HPV have been poorly characterized.. Contraction was recorded in pulmonary arteries (PA) in a wire myograph. Anesthetized rats were catheterized to record PA pressure. Ventilation and perfusion were analyzed by micro-CT-SPECT images in rats with pulmonary fibrosis induced by bleomycin.. The PDE5 inhibitor sildenafil and the sGC stimulator riociguat similarly inhibited HPV in vitro and in vivo. Riociguat was more effective as vasodilator in isolated rat and human PA than sildenafil. Riociguat was ≈3-fold more potent under hypoxic conditions and it markedly inhibited HPV in vivo at a dose that barely affected the thromboxane A2 (TXA2) mimetic U46619-induced pressor responses. Pulmonary fibrosis was associated with V'/Q' uncoupling and riociguat did not affect the V'/Q' ratio.. PDE5 inhibitors and sGC stimulators show a different vasodilator profile. Riociguat was highly effective and potentiated by hypoxia in rat and human PA. In vivo, riociguat preferentially inhibited hypoxic than non-hypoxic vasoconstriction. However, it did not worsen V'/Q' coupling in a rat model of pulmonary fibrosis.

Topics: Aged; Animals; Disease Models, Animal; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Pulmonary Fibrosis; Pyrazoles; Pyrimidines; Rats; Rats, Wistar; Sildenafil Citrate; Soluble Guanylyl Cyclase; Vasoconstriction; Vasodilator Agents; Ventilation-Perfusion Ratio

Topics: Bosentan; Child; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Sildenafil Citrate

A proportion of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) do not achieve treatment goals or experience side effects on their current therapy. In such cases, switching patients to a new drug while discontinuing the first may be a viable and appropriate treatment option. CAPTURE was designed to investigate how physicians manage the switching of patients to riociguat in real-world clinical practice. Observations from the study were used to assess whether recommendations in the riociguat prescribing information are reflected in clinical practice.. CAPTURE was an international, multicenter, uncontrolled, retrospective chart review that collected data from patients with PAH or inoperable or persistent/recurrent CTEPH who switched to riociguat from another pulmonary hypertension (PH)-targeted medical therapy. The primary objective of the study was to understand the procedure undertaken in real-world clinical practice for patients switching to riociguat.. Of 127 patients screened, 125 were enrolled in CAPTURE. The majority of patients switched from a phosphodiesterase type 5 inhibitor (PDE5i) to riociguat and the most common reason for switching was lack of efficacy. Physicians were already using the recommended treatment-free period when switching patients to riociguat from sildenafil, but a slightly longer period than recommended for tadalafil. In line with the contraindication, the majority of patients did not receive riociguat and PDE5i therapy concomitantly. Physicians also followed the recommended dose-adjustment procedure for riociguat.. Switching to riociguat from another PH-targeted therapy may be feasible in real-world clinical practice in the context of the current recommendations.

Topics: Aged; Aged, 80 and over; Chronic Disease; Drug Substitution; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Tadalafil

Topics: Administration, Oral; Adult; Antihypertensive Agents; Arterial Pressure; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Hypertension, Pulmonary; Liver Cirrhosis; Liver Transplantation; Pulmonary Artery; Pyrimidines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Treatment Outcome

Topics: Cyanosis; Ductus Arteriosus, Patent; Female; Humans; Hypertension, Pulmonary; Osteoarthropathy, Secondary Hypertrophic; Sildenafil Citrate; Vasodilator Agents; Young Adult

Pulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats.. An in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). In the in vivo experiments, PH was induced in male Wistar rats by a single intraperitoneal injection of 60 mg/kg MCT. Rats were divided into the following groups: control (saline injection only), MCT + vehicle, MCT + sildenafil, MCT + LASSBio 1359 and MCT + combination of sildenafil and LASSBio 1359. Fourteen days after the MCT injection, rats were treated daily with oral administration of the regimen therapies or vehicle for 14 days. Cardiopulmonary system function and structure were evaluated by echocardiography. RV systolic pressure and PA endothelial function were measured.. Isobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat PAs. Combined therapy with sildenafil and LASSBio 1359 but not monotreatment with low dosages of either sildenafil or LASSBio 1359 ameliorated all of PH related abnormalities in cardiopulmonary function and structure in MCT challenged rats.. The combination of sildenafil and LASSBio 1359 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to improve quality of life and outcomes for PH patients.

Topics: Adenosine A2 Receptor Agonists; Animals; Benzamides; Drug Synergism; Hydrazones; Hypertension, Pulmonary; Male; Monocrotaline; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Rats; Rats, Wistar; Sildenafil Citrate; Vasodilator Agents

A 12 year-old intact male Pembroke Welsh corgi weighing 10.8 kg was presented for evaluation of a 3-month history of dyspnea, and a 1-week history of exercise intolerance and anorexia. Severe hypoxemia (PaO

Topics: Animals; Blood Gas Analysis; Dog Diseases; Dogs; Fatal Outcome; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Sildenafil Citrate

Specific therapy for patients with PAH is associated with good outcomes. Little is known about the effect of this treatment in patients with Cpc-PH (PAPm ≥ 25 mmHg, PAWP > 15 mmHg, DPG ≥ 7 mmHg, and/or PVR > 3 WU). This study evaluates the outcome of treating patients with Cpc-PH using PAH specific therapy.. The primary outcome was survival. Secondary outcomes were WHO functional class and 6-minute walk distance (6-MWD).. Twenty-six patients with Cpc-PH (half with VHD and half with HF) received PAHST. Six patients did not tolerate treatment due to pulmonary edema. No predictors for treatment intolerance were identified. In twenty patients who tolerated the treatment, the mean WHO functional class improved from 2.70 ± 0.21 at initial assessment to 2.22 ± 0.21 (. PAHST may be beneficial in the treatment of Cpc-PH (both short and long term). Prospective randomized controlled trials of PAHST in this population are needed to assess its potential efficacy.

Topics: Analysis of Variance; Antihypertensive Agents; Bosentan; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents; Walking

Topics: Double-Blind Method; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Sildenafil Citrate

Topics: Double-Blind Method; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Sildenafil Citrate

Pulmonary hypertension associated with human immunodeficiency virus infection is an extremely rare disease in pediatrics; it requires a high clinical suspicion to reach a diagnosis. Its appearance poses an unfavorable prognostic, but early diagnosis and specific treatment can improve outcomes. We report the clinical case of a fifteen-year-old patient diagnosed with human immunodeficiency virus infection of vertical transmission, without antiretroviral treatment, with cough and progressive exertional dyspnea, associated with signs of right heart failure in which severe pulmonary hypertension was diagnosed. After discarding other causes, it was assumed pulmonary hypertension associated with human immunodeficiency virus infection. Treatment was performed with sildenafil with good response.. La hipertensión pulmonar asociada a la infección por virus de inmunodeficiencia humana es una enfermedad sumamente infrecuente en pediatría, por lo que requiere alta sospecha clínica para llegar a su diagnóstico. Su aparición es de pronóstico desfavorable, pero el diagnóstico precoz y el tratamiento específico pueden mejorar su evolución. Se presenta el caso clínico de un paciente de 15 años con diagnóstico de infección por virus de inmunodeficiencia humana de transmisión vertical, sin tratamiento antirretroviral, con tos y disnea de esfuerzo progresiva asociadas a signos de falla cardíaca derecha en el cual se diagnosticó hipertensión pulmonar grave. Luego de descartarse otras causas, se asumió la hipertensión pulmonar asociada a la infección por virus de inmunodeficiencia humana. Se realizó el tratamiento con sildenafil y presentó buena respuesta.

Topics: Adolescent; Heart Failure; HIV Infections; Humans; Hypertension, Pulmonary; Infectious Disease Transmission, Vertical; Male; Severity of Illness Index; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Topics: Angioplasty, Balloon; Cyclic Nucleotide Phosphodiesterases, Type 1; Drug Therapy, Combination; Endarterectomy; Epoprostenol; Genome-Wide Association Study; Hemodynamics; Humans; Hypertension, Pulmonary; Japan; Molecular Targeted Therapy; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Practice Guidelines as Topic; Pulmonary Embolism; Pyridazines; Randomized Controlled Trials as Topic; Registries; Sildenafil Citrate; Tadalafil

Topics: Administration, Oral; Age Factors; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Tadalafil

This study evaluated the incremental effect of riociguat on pulmonary hemodynamics in patients with inoperative or persistent chronic thromboembolic pulmonary hypertension (CTEPH) treated previously with sildenafil.. The retrospective study included 28 patients diagnosed with CTEPH who were ineligible for surgical treatment due to distal thrombi location or who suffered from persistent CTEPH after pulmonary endarterectomy and who were treated with sildenafil at a dose of 25 mg TID for a minimum of 3 months. Sildenafil was subsequently discontinued, and riociguat therapy was started with gradually increasing doses. Right heart catheterization was performed and WHO functional class (FC) was assessed in each patient at three time points: before starting sildenafil therapy (baseline), before the transition to riociguat, and after 3 to 6 months of therapy with riociguat.. Compared to baseline, the use of sildenafil and riociguat significantly decreased pulmonary vascular resistance (PVR) (10.47 ± 3.56 vs. 7.81 ± 3.58 Wood units, p < 0.001) and mean pulmonary arterial pressure (PAP) (54.1 ± 11.6 vs. 46.1 ± 13.2 mm Hg; p < 0.001) while increasing cardiac output (CO) (4.31 ± 0.88 vs. 4.85 ± 0.87 L/min; p = 0.007). Switching from sildenafil to riociguat reduced PVR by 14% (p = 0.005) and the mean PAP by 6% (p = 0.03) while increasing CO by 11% (p = 0,002). The number of patients with WHO FC III and IV symptoms decreased from 71,4% to 57,1% (p = 0,02) after the change from sildenafil to riociguat.. Replacing sildenafil with riociguat in patients with inoperable or persistent CTEPH may improve pulmonary hemodynamics and FC.

Topics: Aged; Aged, 80 and over; Chronic Disease; Drug Substitution; Enzyme Activators; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

To explore the effect of sildenafil combined with inhalational nitric oxide (NO) therapy on the curative effects and serum levels of hypoxia-inducible factor (HIF)-1α, endothelin-1 (ET-1), and calcium in persistent pulmonary hypertension of the newborn (PPHN).. Eighty-six patients with neonatal pulmonary hypertension treated in Xuzhou Children's Hospital from March 2015 to February 2016 were randomly divided into the observation group and control group, treated with sildenafil and sildenafil combined with inhalational NO, respectively. The clinical efficacy of newborns in the two groups was compared. Fraction of inspiration O2 (FiO2), Oxygen Index (OI), blood oxygen partial pressure (PaO2), blood oxygen saturation (SpO2), and pulmonary arterial pressure of newborns in the two groups were compared before treatment and 2 h, 12 h, and 24 h after treatment. The serum levels of HIF-1α, ET-1, and calcium of patients in the two groups were compared before treatment and 3, 5, 7 days after treatment.. The total effective rate of the observation group (95.34%) was significantly higher than that of the control group (74.41%) (p<0.05). After treatment, FiO2, OI, and pulmonary arterial pressure of patients in the two groups decreased, and the decrease in the observation group was significantly lower than in the control group (p<0.05). After treatment, PaO2 and SpO2 of patients in the observation group were higher than those of the control group. The levels of HIF-1α and ET-1 of patients in the two groups decreased and were significantly lower in the observation group compared with the control group. The levels of calcium of patients in the two groups increased and were significantly higher in the observation group than the control group (p<0.05).. Sildenafil combined with inhalational NO therapy for neonatal pulmonary hypertension can quickly improve oxygenation, effectively reduce pulmonary arterial hypertension, and is worthy of clinical application.

Topics: Administration, Inhalation; Calcium; Drug Therapy, Combination; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia-Inducible Factor 1, alpha Subunit; Infant, Newborn; Male; Nitric Oxide; Oxygen; Sildenafil Citrate

Topics: Early Termination of Clinical Trials; Female; Fetal Growth Retardation; Humans; Hypertension, Pulmonary; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Placenta; Pregnancy; Randomized Controlled Trials as Topic; Sildenafil Citrate; Withholding Treatment

Treprostinil, a potent vasodilator, is the treatment of choice for severe pulmonary arterial hypertension (PAH) during pregnancy. Its inhibition of platelet aggregation increases the risk of hemorrhage. In addition, anticoagulation therapy is widely used in pregnancy with PAH due to the hypercoagulable state. However, very little is known about the complications of anticoagulants' use in pregnancy with PAH.. A 27-year-old pregnant woman was admitted to the hospital at 32weeks with progressive dyspnea.. The pregnant was diagnosed with ventricular septal defect 12 years prior to presentation. Combining clinical manifestation with results of right heart catheterization (RHC) and echocardiography, it was consistent with severe World Health Organization (WHO) group I PAH.. Supportive treatment included supplemental oxygen, intravenous treprostinil, sildenafil and prophylactic anticoagulation.. Gastrointestinal bleeding is occurred in our patient when dalteparin were used in conjunction with treprostinil. Her care was further complicated refractory to usual conservative measures before delivery.. This case report illustrates the complexities that arise when prostacyclin therapies are combined with necessary anticoagulation in patients with PAH during pregnancy. More intention should play to the complications of anticoagulant in pregnancy with PAH during treprostinil therapy.

Topics: Adult; Anticoagulants; Antihypertensive Agents; Cardiovascular Agents; Dalteparin; Epoprostenol; Female; Gastrointestinal Hemorrhage; Humans; Hypertension, Pulmonary; Pregnancy; Pregnancy Complications, Cardiovascular; Sildenafil Citrate; Vasodilator Agents

Sildenafil already is administered during gestation in patients with pulmonary hypertension and is under evaluation as a treatment for several pregnancy complications, such as preeclampsia and intrauterine growth restriction. Animal studies have shown a potential therapeutic effect of the drug in fetuses with congenital diaphragmatic hernia, rescuing peripheral pulmonary vasculature, and airway phenotype. When considering this drug for evaluation in a clinical trial, data on effective human placental drug passage are required.. We quantified transplacental passage of sildenafil in the ex vivo dually perfused cotyledon model.. Six placentas that were collected after term delivery from healthy volunteers were cannulated and perfused dually. Sildenafil citrate was added to the maternal circulation at 2 different concentrations: 500 ng/mL, which represented the maximum tolerated concentration (n=3), and 50 ng/mL, which represented the therapeutic concentration (n=3). Samples were collected from both the fetal and the maternal reservoir at 0, 6, 30, 60, 90, 120, 150, and 180 minutes; the concentrations of sildenafil and its metabolite desmethyl-sildenafil were determined with the use of high performance liquid chromatography. The fetal/maternal concentration ratio was calculated for each timepoint. Transfer clearance was calculated as the rate of maternal to fetal passage/maternal concentration.. Sildenafil crossed the placenta at both maximal and therapeutic concentrations. Maternal and fetal levels reached a plateau at 90-120 minutes. Transfer clearance was the highest during the first hour of perfusion: 3.15 mL/min (range, 2.14-3.19 mL/min) for the maximum tolerated concentration and 3.07mL/min (range, 2.75-3.42 mL/min) for the therapeutic concentration (not significant). The fetomaternal concentration ratio significantly increased over time, up to 0.91±0.16 for the maximal concentration and 0.95±0.22 for the therapeutic concentration at the end of the perfusion (not significant). Desmethyl-sildenafil was not detected in any sample.. Sildenafil crosses the term placenta at a relatively high rate ex vivo, which suggests that there is sufficient placental transfer to reach clinically active fetal drug levels at the currently used maternal doses.

Topics: Antihypertensive Agents; Female; Humans; Hypertension, Pulmonary; Maternal-Fetal Exchange; Models, Biological; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Sildenafil Citrate

Topics: Disease Models, Animal; Hypertension, Pulmonary; Pulmonary Artery; Pyrazoles; Pyrimidines; Sildenafil Citrate; Ventricular Function, Right

With the non-selective vasodilating action, short half-life and first-pass metabolism of sildenafil (SC), local application in the lung for pulmonary arterial hypertension is of high demand. Although several nanosystems have been lately investigated, nanostructured lipid carriers (NLCs) give promises of potential safety, biodegradability and controlled drug release. In the current study, NLCs comprising either precirol, stearic acid or beeswax as solid lipid in presence of oleic acid as liquid lipid and PVA or poloxamer as emulsifier were prepared. Optimized NLCs (200-268 nm in size) were appraised versus SLNs both in vitro and in vivo. Precirol/PVA-based SLNs and NLCs ensued high entrapment efficiencies (EE > 95%) and controlled release behaviour over 6 h even though NLCs showed higher release profile. Stability studies at 4 °C indicated potential colloidal and entrapment stability over 3 months. Interestingly, NLCs demonstrated efficient nebulization, low interaction with mucin and higher viability of A549 cells (3-fold increase in IC

Topics: A549 Cells; Administration, Inhalation; Animals; Cell Survival; Delayed-Action Preparations; Diglycerides; Drug Carriers; Humans; Hypertension, Pulmonary; Lipids; Male; Nanostructures; Phosphodiesterase 5 Inhibitors; Polyvinyl Alcohol; Rats, Sprague-Dawley; Sildenafil Citrate

Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.

Topics: Animals; Catalytic Domain; CHO Cells; Chromones; Cricetulus; Cytochrome P-450 CYP1A2 Inhibitors; Drug Stability; ERG1 Potassium Channel; Female; Humans; Hypertension, Pulmonary; Male; Mice; Microsomes, Liver; Molecular Docking Simulation; Molecular Dynamics Simulation; Phosphodiesterase 5 Inhibitors; Pyrroles; Rats, Sprague-Dawley; Rats, Wistar; Sildenafil Citrate; Structure-Activity Relationship

Pulmonary arterial hypertension is characterized by pulmonary vascular proliferation and remodelling, leading to a progressive increase in pulmonary arterial resistance. Vasodilator properties of 3 different phosphodiesterase (PDE)-5 inhibitors alone and in combination with an endothelin (ET) receptor antagonist were compared in an ex vivo model.. Segments of human pulmonary arteries (PAs) and pulmonary veins (PVs) were harvested from lobectomy specimens. Contractile forces were determined in an organ bath. Vessels were constricted with norepinephrine (NE) to determine the effects of sildenafil, tadalafil and vardenafil and with ET-1 to assess the effects of bosentan.. All 3 PDE-5 inhibitors had no relevant effect on the basal tone of the vessels. Both sildenafil and vardenafil significantly (P < 0.0001) reduced the responses of the vessels to NE, whereas tadalafil was effective only in PA (P = 0.0009) but not in PV (P = 0.097). Sildenafil relaxed NE-preconstricted PV (P < 0.0001) but not PA (P = 0.143). Both tadalafil and vardenafil relaxed PA and PV significantly. Vardenafil appears to be the most potent of the PDE-5 inhibitors tested. Furthermore, we analysed the combination of bosentan and vardenafil in PA. Bosentan and vardenafil reduced ET-1 and NE induced vasoconstriction stronger than vardenafil alone (P ≤ 0.049).. Vardenafil caused the most consistent antihypertensive response in this ex vivo model. However, ET receptor antagonism appears to be an even more potent mechanism. A combination therapy using vardenafil and bosentan turned out to be an effective combination to lower vessel tension in PA.

Topics: Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Pulmonary Veins; Sildenafil Citrate; Sulfonamides; Tadalafil; Vardenafil Dihydrochloride; Vasodilation; Vasodilator Agents

Combination therapy with the phosphodiesterase type 5 inhibitors (PDE-5i) sildenafil or tadalafil and the endothelin receptor antagonists (ERA) bosentan, ambrisentan, or macitentan may cause mutual pharmacokinetic interactions in patients with pulmonary arterial hypertension (PAH).. The objective of this study was to analyze plasma drug concentrations in PAH patients receiving different combination treatments.. PAH patients receiving a stable combination treatment with ERA and PDE-5i with targeted dosage for at least 1 month were routinely assessed, including clinical parameters and plasma drug concentrations. Concentrations were normalized considering dose and time from last medication intake and presented as multiples of the expected mean (MoM) of the respective monotherapies.. A total of 125 PAH patients (84 female, 41 male, 57% idiopathic/heritable) were included. Sildenafil and tadalafil concentrations were lowest in combination with bosentan (MoM 0.44 ± 0.42, 95% confidence interval [CI] 0.30-0.57, and MoM 0.89 ± 0.53, 95% CI 0.50-1.28, respectively) compared to the combination with ambrisentan (MoM 1.3 ± 0.97, 95% CI 0.86-1.73, and MoM 1.67 ± 0.63, 95% CI 1.40-1.94, respectively) and macitentan (MoM 1.16 ± 0.87, 95% CI 0.86-1.46, and MoM 1.59 ± 0.99, 95% CI 0.80-2.38, respectively). The combination of sildenafil and bosentan led to more than twice the expected bosentan concentrations in 53.8%. Patients switching from sildenafil-bosentan to macitentan showed a significant increase in sildenafil concentrations (p < 0.001).. Only the combination with macitentan or ambrisentan led to targeted mean PDE-5i plasma concentrations and should therefore be preferred to combination with bosentan. Sildenafil-bosentan showed the strongest interaction, with low sildenafil and high bosentan concentrations. The study was not powered to analyze whether lower PDE-5i concentrations cause unsatisfying clinical response. However, plasma concentrations within a targeted range are desirable and may become of increasing importance.

Topics: Adult; Aged; Bosentan; Case-Control Studies; Drug Interactions; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Pyrimidines; Sildenafil Citrate; Sulfonamides; Tadalafil

In Australia, government-subsidised treatment of pulmonary arterial hypertension (PAH) is limited to monotherapy. Recent international guidelines advocate that initial combination therapy be considered for all symptomatic PAH patients.. To characterise 'real-life' outcomes in PAH patients initiated on monotherapy.. We performed a retrospective analysis of 100 consecutive PAH patients at a single centre who were commenced on monotherapy for PAH between 2004 and 2015. The composite clinical end-point of 'treatment failure' was prospectively defined as (i) >15% fall in 6-min walk distance (6MWD) on follow up, (ii) physician judgement of inadequate treatment response, (iii) adverse drug effect requiring cessation and (iv) death or transplantation.. At initiation of therapy, mean age was 54 ± 18 years, and underlying diagnoses included idiopathic (36%), connective tissue disease-associated (37%) and congenital heart disease-associated-PAH (25%). Baseline 6MWD was 360 ± 140 m, and 75% were in either the New York Heart Association functional classes III or IV. Over a median follow up of 38 months (interquartile range 20-67), 62% of the subjects met the criteria for a clinical failure event. Median time to monotherapy failure was 24 months (95% confidence interval 14-34), with death or transplantation being the most common clinical failure event. Estimated 1-, 3- and 5-year survival rates from time of treatment initiation were 92, 75 and 66%.. The majority of patients failed initial monotherapy therapy within 2 years of treatment initiation. Broader access to approved PAH agents is needed to enable combination therapy in line with evidence-based international guidelines.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Australia; Bosentan; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prospective Studies; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Treatment Failure; Young Adult

Topics: Cardiology; Child; Child Advocacy; Child Health; Dose-Response Relationship, Drug; Drug and Narcotic Control; Drug Development; Humans; Hypertension, Pulmonary; Mortality; Off-Label Use; Outcome Assessment, Health Care; Pediatrics; Randomized Controlled Trials as Topic; Sildenafil Citrate; Vasodilator Agents

Right-sided heart failure-often caused by elevated pulmonary arterial pressure-is a chronic and progressive condition with particularly high mortality rates. Recent studies and our current findings suggest that components of Wild garlic (

Topics: Allium; Animals; Biomarkers; Disease Models, Animal; Echocardiography; Heart Function Tests; Hypertension, Pulmonary; Lung; Male; Mass Spectrometry; Myocardium; Plant Extracts; Pulmonary Artery; Rats; Sildenafil Citrate

Bronchopulmonary dysplasia (BPD), a common complication of preterm birth, is associated with pulmonary hypertension (PH) in 25% of infants with moderate to severe BPD. Neonatal mice exposed to hyperoxia for 14d develop lung disease similar to BPD, with evidence of associated PH. The cyclic guanosine monophosphate (cGMP) signaling pathway has not been well studied in BPD-associated PH. In addition, there is little data about the natural history of hyperoxia-induced PH in mice or the utility of phosphodiesterase-5 (PDE5) inhibition in established disease. C57BL/6 mice were placed in room air or 75% O2 within 24h of birth for 14d, followed by recovery in room air for an additional 7 days (21d). Additional pups were treated with either vehicle or sildenafil for 7d during room air recovery. Mean alveolar area, pulmonary artery (PA) medial wall thickness (MWT), RVH, and vessel density were evaluated at 21d. PA protein from 21d animals was analyzed for soluble guanylate cyclase (sGC) activity, PDE5 activity, and cGMP levels. Neonatal hyperoxia exposure results in persistent alveolar simplification, RVH, decreased vessel density, increased MWT, and disrupted cGMP signaling despite a period of room air recovery. Delayed treatment with sildenafil during room air recovery is associated with improved RVH and decreased PA PDE5 activity, but does not have significant effects on alveolar simplification, PA remodeling, or vessel density. These data are consistent with clinical studies suggesting inconsistent effects of sildenafil treatment in infants with BPD-associated PH.

Topics: Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Guanylate Cyclase; Hyperoxia; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Mice; Mice, Inbred C57BL; Oxygen; Phosphodiesterase 5 Inhibitors; Pulmonary Alveoli; Pulmonary Artery; Signal Transduction; Sildenafil Citrate; Vascular Remodeling

Unilateral absent right pulmonary artery is a rare developmental anomaly that usually presents in late childhood and adolescence as recurrent respiratory tract infections, dyspnoea and haemoptysis. We report a case of a 2-day-old baby with respiratory distress and differential cyanosis. Echocardiogram showed pulmonary hypertension with absent right pulmonary artery. The findings were confirmed by CT angiogram. The baby improved with pulmonary vasodilators and antifailure medications.

Topics: Computed Tomography Angiography; Cyanosis; Diagnosis, Differential; Echocardiography; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Pulmonary Artery; Respiratory System Abnormalities; Sildenafil Citrate; Vasodilator Agents

Topics: Cyclic GMP; Drug Therapy, Combination; Endothelins; Enzyme Activators; Humans; Hypertension, Pulmonary; Molecular Targeted Therapy; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Precision Medicine; Pyrazoles; Pyrimidines; Signal Transduction; Sildenafil Citrate; Tadalafil

Pulmonary arterial hypertension (PAH) is a challenging disorder characterized by increasing pulmonary artery pressure, which is hard to treat.. This study was aimed to investigate the effects of bosentan, sildenafil and their combination.. Saline or MCT were applied to Wistar rats. By the development of PAH (4th week), MCT-given rats were treated orally with bosentan, sildenafil and combination of sildenafil and bosentan or placebo. ECHO examinations were performed. Tissues obtained from all of the rats were evaluated under an electron microscope.. Left ventricular end diastolic diameter significantly increased in sildenafil and combined groups. Sildenafil group revealed a significant decrease in RV pressure and wall thickness. Examination of lung revealed a significant amount of connective tissue formation and increase in inflammatory cells in all the groups except controls in the interalveolar septum. Examination of PA revealed an increase in connective tissue volume, hypertrophic changes and expansions in granular endoplasmic reticulum cisternaes in smooth muscle cells in active groups rather than in the controls. Unlike the controls, the examination of the RV revealed an enlargement of the sarcoplasmic reticulum cisternaes in some cells, due to the calcium increase.. Sildenafil and the combined therapy demonstrated to have more impact on pressure and the RV parameters in rats, with lower inflammatory findings in lung tissue (Fig. 6, Ref. 31).

Topics: Animals; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Phosphodiesterase 5 Inhibitors; Rats; Rats, Wistar; Sildenafil Citrate; Sulfonamides

Development of sarcoidosis-associated pulmonary hypertension (SAPH) significantly worsens prognosis in sarcoidosis patients. Unfortunately, there is no treatment of proven benefit for this condition. Medications used for treatment of pulmonary arterial hypertension are of great interest in this respect. Here, we report a case of a patient with severe SAPH treated with sildenafil. A significant, but only temporary improvement in functional status was observed, and the patient died of gradually progressing heart and respiratory failure while awaiting for lung transplantation.

Topics: Female; Humans; Hypertension, Pulmonary; Middle Aged; Sarcoidosis; Sarcoidosis, Pulmonary; Sildenafil Citrate; Vasodilator Agents

Hepatopulmonary syndrome and portopulmonary hypertension are complications of portal hypertension with opposing mechanisms that can coexist. Moderate portopulmonary hypertension, which is a contraindication to a liver transplant, must be managed with pulmonary vasodilators to normalize pulmonary arterial pressures before a transplant listing. Concomitant hepatopulmonary syndrome complicates the management of portopulmonary hypertension, as pulmonary vasodilators can theoretically exacerbate the intrapulmonary dilatation believed to cause hepatopulmonary syndrome. We describe a case of a post-liver transplant patient with concomitant hepatopulmonary syndrome and portopulmonary hypertension safely treated with sildenafil.

Topics: Antihypertensive Agents; Female; Hemodynamics; Hepatopulmonary Syndrome; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Circulation; Liver Transplantation; Middle Aged; Pulmonary Circulation; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

In our study, sildenafil alone and everolimus or alagebrium in combination with sildenafil were investigated in terms of their additional therapeutic and anti-remodeling activity in monocrotaline-induced pulmonary hypertension (PH) model in rats. In particular, the inter-relationships between PH and matrix metalloproteinases (MMPs) were investigated.. The pulmonary artery responses of male Sprague Dawley rats were recorded using myography, and the quantities and activities of MMPs were analyzed in homogenates of the pulmonary arteries and lungs by enzyme-linked immunosorbent assays, activity assays, and gelatin zymography techniques.. Our results indicated that the therapeutic effects of sildenafil were accompanied by its suppressor effects on MMP activity. It was also shown that everolimus or alagebrium in combination with sildenafil showed additional regulatory effects on MMPs as well as functional responses on pulmonary artery pressure. Therefore, the enzymes in the MMP superfamily are likely to be target molecules for the treatment of PH.. In conclusion, MMPs were involved in the pathogenesis of PH, and our results suggested that the addition of everolimus or alagebrium to sildenafil therapy may be beneficial in PH. Our results indicated that agents that limit pulmonary vascular hypertrophy and inflammation via their anti-remodeling effects significantly ameliorate mortality and morbidity in PH.

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Everolimus; Hypertension, Pulmonary; Male; Matrix Metalloproteinases; Monocrotaline; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Thiazoles; Vasodilator Agents

When bronchopulmonary dysplasia (BPD) is complicated by pulmonary hypertension (PH), morbidity and mortality are significantly increased. BPD-associated PH is not included in the current indications for PH medications. However, limited data demonstrate hemodynamic improvement and decreased mortality with PH-specific treatment. This report describes our 6-year experience treating BPD-associated PH with PH medications, mainly sildenafil.. The medical records of 20 infants diagnosed with BPD-associated PH at a tertiary pediatric pulmonary hypertension clinic in 2008-2014 were reviewed. Clinical improvement was defined as a decrease in Ross functional class by at least one degree. PH severity was classified by echocardiography as mild, moderate, or severe. Hemodynamic improvement was defined as a decrease in PH severity by at least one level.. Eighteen out of 20 patients were treated with PH medications: 12 sildenafil, 5 sildenafil and bosentan, and 1 bosentan. Median follow-up time was 2 years. Mean functional class significantly decreased from 3.2 ± 0.9 at diagnosis to 1.7 ± 0.9 at the last follow-up. Improvement in functional class was observed in 15/16 children (94%). Moderate or severe PH was found in 13/18 children (72%) at diagnosis, and in three (17%, all moderate PH) at the last follow-up. Improvement in PH class by echocardiography was demonstrated in 14/18 children (78%). The survival rate was 95%.. Treatment of BPD complicated by PH with PH-specific medications, mainly sildenafil, is associated with improvement in both clinical and hemodynamic parameters and a low mortality rate. Pediatr Pulmonol. 2017;52:77-83. © 2016 Wiley Periodicals, Inc.

Topics: Antihypertensive Agents; Bosentan; Bronchopulmonary Dysplasia; Child, Preschool; Drug Therapy, Combination; Echocardiography; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Treatment Outcome

To compare the occurrence of hypotension following administration of intermittent intravenous (IV) and enteral sildenafil for treatment of pulmonary hypertension (PH) in infants. We hypothesized there may be more adverse effects associated with intermittent IV sildenafil compared with enteral sildenafil.. This was a retrospective matched-cohort study conducted in a tertiary care children's hospital. Patients were included if they were less than 1 year of age and received intermittent sildenafil for PH. Exclusion criteria consisted of concurrent extracorporeal membrane oxygenation during the initiation of sildenafil, the utilization of sildenafil as a one-time dose, continuation of home-dosing regimen, or inclusion in the other cohort. A total of 40 patients were matched 1:1 based on postmenstrual age and primary diagnosis.. There was no statistically significant difference in the primary outcome, as 30% (6/20) of patients receiving IV sildenafil required a hypotension intervention compared with 10% (2/20) in the enteral cohort (P = 0.24). The majority of interventions occurred within 24 hr of the initiation of sildenafil with 4/6 patients (67%) in the IV group and 2/2 patients (100%) in the enteral group, respectively. Baseline mean arterial pressure was significantly lower in the IV patients that required an intervention compared with those that did not (44 ± 6.3 vs. 65 ± 13.4 mmHg, P = 0.0024).. There were no statistically significant differences in safety outcomes between intermittent IV and enteral sildenafil in infants with PH. Hemodynamic parameters should be monitored closely upon sildenafil initiation. Limitations include the retrospective nature and small sample size. Pediatr Pulmonol. 2017;52:232-237. © 2016 Wiley Periodicals, Inc.

Topics: Administration, Intravenous; Administration, Oral; Case-Control Studies; Drug Administration Routes; Drug Administration Schedule; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Hypotension; Infant; Infusions, Intravenous; Male; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

The stem bark of Terminalia arjuna (Roxb.) is widely used in Ayurveda in various cardiovascular diseases. Many animal and clinical studies have validated its anti-ischemic, antihypertensive, antihypertrophic and antioxidant effects. Pulmonary hypertension (PH) is a fatal disease which causes right ventricular hypertrophy and right heart failure. Pulmonary vascular smooth muscle hypertrophy and increased oxidative stress are major pathological features of PH. As available limited therapeutic options fail to reduce the mortality associated with PH, alternative areas of therapy are worth exploring for potential drugs, which might be beneficial in PH.. The effect of a standardised aqueous extract of the stem bark of Terminalia arjuna (Roxb.) in preventing monocrotaline (MCT)-induced PH in rat was investigated.. The study was approved by Institutional Animal Ethics Committe. Male Wistar rats (150-200g) were randomly distributed into five groups; Control, MCT (50mg/kg subcutaneously once), sildenafil (175µg/kg/day three days after MCT for 25 days), and Arjuna extract (TA125 and TA250 mg/kg/day orally after MCT for 25 days). PH was confirmed by right ventricular weight to left ventricular plus septum weight (Fulton index), right ventricular systolic pressure (RVSP), echocardiography, percentage medial wall thickness of pulmonary arteries (%MWT). Oxidative stress in lung was assessed by super oxide dismutase (SOD), catalase, reduced glutathione (GSH) and thiobarbituric acid reactive substance (TBARS). The protein expressions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX-1) in lung and gene expression of Bcl2 and Bax in heart were analyzed by Western blot and RT PCR respectively.. MCT caused right ventricular hypertrophy (0.58±0.05 vs 0.31±0.05; P<0.001 vs. control) and increase in RVSP (33.5±1.5 vs 22.3±4.7mm of Hg; P<0.001). Both sildenafil and Arjuna prevented hypertrophy and RVSP. Pulmonary artery acceleration time to ejection time ratio in echocardiography was decreased in PH rats (0.49±0.05 vs 0.32±0.06; P<0.001) which was prevented by sildenafil (0.44±0.06; P<0.01) and TA250 (0.45±0.06; P<0.01). % MWT of pulmonary arteries was increased in PH and was prevented by TA250. Increase in TBARS (132.7±18.4 vs 18.8±1.6nmol/mg protein; P<0.001) and decrease in SOD (58.4±14.1 vs 117.4±26.9U/mg protein; P<0.001) and catalase (0.30±0.05 vs 0.75±0.31U/mg protein; P<0.001) were observed in lung tissue of PH rats, which were prevented by sildenafil and both the doses of Arjuna extract. Protein expression of NOX1 was significantly increased in lung and gene expression of Bcl2/Bax ratio was significantly decreased in right ventricle in MCT-induced PH, both were significantly prevented by Arjuna and sildenafil.. Aqueous extract of Terminalia arjuna prevented MCT-induced pulmonary hypertension which may be attributed to its antioxidant as well as its effects on pulmonary arteriolar wall thickening.

Topics: Animals; Antihypertensive Agents; Antioxidants; bcl-2-Associated X Protein; Catalase; Disease Models, Animal; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Male; Medicine, Ayurvedic; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; Plant Bark; Plant Extracts; Plant Stems; Proto-Oncogene Proteins c-bcl-2; Pulmonary Artery; Rats; Rats, Wistar; Sildenafil Citrate; Terminalia; Water

Non-invasive estimates have suggested that asymptomatic BMPR2 mutation carriers may have an abnormal pulmonary vascular response to exercise and hypoxia. However, this has not been assessed with "gold standard" invasive measures.. Eight controls and 8 asymptomatic BMPR2 mutation carriers underwent cardiac magnetic resonance imaging with simultaneous invasive pressure recording during bicycle exercise in normoxia, hypoxia and after sildenafil administration. Abnormal pulmonary vascular reserve was defined as an increase in mean pulmonary artery pressure relative to cardiac output (P/Q slope) >3 mm Hg/liter/min.. During normoxic exercise, BMPR2 mutation carriers had a similar P/Q slope when compared with healthy subjects. Only 1 of 8 BMPR2 mutation carriers had a P/Q slope >3 mm Hg/liter/min. During exercise in hypoxia, 3 of 8 BMPR2 mutation carriers had P/Q slopes >3 mm Hg/liter/min compared with none of the controls. Sildenafil decreased the P/Q slope both in controls and BMPR2 mutation carriers. The exercise-induced increase in right ventricular ejection fraction was similar between groups. None of the BMPR2 mutation carriers developed pulmonary arterial hypertension within 2 (range 1.3 to 2.8) years.. The presence of a BMPR2 mutation, per se, is not associated with an abnormal pulmonary vascular and right ventricular functional response to exercise in asymptomatic individuals. Longer follow-up will be required to determine whether a P/Q slope of >3 mm Hg/liter/min during exercise in normoxia or hypoxia is a sign of pre-clinical disease expression.

Topics: Adult; Blood Gas Analysis; Bone Morphogenetic Protein Receptors, Type II; Cardiac Output; Case-Control Studies; Exercise Test; Female; Heterozygote; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Mutation; Pulmonary Circulation; Reference Values; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Ventricular Function, Right

The study provides the physicochemical characteristic of bosentan (BOS) in comparison to tadalafil (TA) and sildenafil citrate (SIL). Despite some reports dealing with thermal characteristic of SIL and TA, physicochemical properties of BOS have not been investigated so far. Recent clinical reports have indicated that the combination of bosentan and PDE-5 inhibitor can improve the effectiveness of pharmacotherapy of pulmonary arterial hypertension (PAH). However, in order to design personalized medicines for therapy of chronic rare diseases, detailed information on the thermal behaviour and solubility of each drug is indispensable. Thus, XRD, DSC and TGA-QMS analyses were applied to compare the properties of the drugs, their thermal stability as well as to identify the products of thermal degradation. The dehydration of BOS started at 70°C and was followed by the chemical degradation with the onset at 290°C. The highest thermal stability was stated for TA, which decomposed at ca. 320°C, whereas the lowest onset of the thermal decomposition process was stated for SIL, i.e. 190°C. The products of the drug decomposition were identified. FT-FIR was applied to study intra- and intermolecular interactions between the drug molecules. FT-MIR and Raman spectroscopy were used to examine the chemical structure of the drugs. Chemoinformatic tools were used to predict the polar surface area, pKa, or logP of the drugs. Their results were in line with solubility and dissolution studies.

Topics: Bosentan; Drug Design; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Rare Diseases; Sildenafil Citrate; Sulfonamides; Tadalafil

Topics: Administration, Inhalation; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Carriers; Drug Liberation; Drug Stability; Hypertension, Pulmonary; Lipids; Mucins; Nanoparticles; Nebulizers and Vaporizers; Particle Size; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Solubility; Sterilization

The stability of sildenafil in combination with heparin and dopamine was evaluated.. A stability-indicating high-performance liquid chromatography method with ultraviolet detection was developed for sildenafil citrate and validated. The method was applied to the investigation of sildenafil alone, sildenafil with heparin, sildenafil with dopamine, and sildenafil with heparin and with dopamine, all in 5% dextrose injection at room temperature and under refrigeration for 30 days. Samples of 100 μL were pulled from each storage bottle on each sampling day, diluted in mobile phase, and assayed in duplicate. Samples were tested on days 0, 1, 2, 3, 4, 5, 7, 9, 12, 14, 21, and 30. Each preparation was visually inspected for precipitation and color change. The percent recovery in each study sample was determined by comparing the peak area of sildenafil in the sample with the peak area of sildenafil from a freshly prepared 100-μg/mL standard in mobile phase.. The sildenafil alone, sildenafil with heparin, and sildenafil with dopamine remained within 90-110% of the expected sildenafil potency for at least 30 days at both temperatures. The preparation of sildenafil with both heparin and dopamine fell below 90% potency after 3 days at room temperature and 21 days in the refrigerator.. Sildenafil prepared in 5% dextrose injection alone, with heparin, and with dopamine retained over 90% potency after 30 days of storage at room temperature and under refrigeration. Sildenafil prepared with both heparin and dopamine had a potency of <90% after 3 days of storage at room temperature and 21 days of storage under refrigeration.

Topics: Anticoagulants; Chemistry, Pharmaceutical; Child; Chromatography, High Pressure Liquid; Dopamine; Drug Combinations; Drug Stability; Drug Storage; Glucose; Heparin; Humans; Hypertension, Pulmonary; Infant, Newborn; Refrigeration; Sildenafil Citrate; Temperature; Time Factors

Topics: Heart Failure; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Sulfones; Vasodilator Agents

The practice of treating PAH patients with oral or intravenous sildenafil suffers from the limitations of short dosing intervals, peripheral vasodilation, unwanted side effects, and restricted use in pediatric patients. In this study, we sought to test the hypothesis that inhalable poly(lactic-co-glycolic acid) (PLGA) particles of sildenafil prolong the release of the drug, produce pulmonary specific vasodilation, reduce the systemic exposure of the drug, and may be used as an alternative to oral sildenafil in the treatment of PAH. Thus, we prepared porous PLGA particles of sildenafil using a water-in-oil-in-water double emulsion solvent evaporation method with polyethyleneimine (PEI) as a porosigen and characterized the formulations for surface morphology, respirability, in-vitro drug release, and evaluated for in vivo absorption, alveolar macrophage uptake, and safety. PEI increased the particle porosity, drug entrapment, and produced drug release for 36h. Fluorescent particles showed reduced uptake by alveolar macrophages. The polymeric particles were safe to rat pulmonary arterial smooth muscle cell and to the lungs, as evidenced by the cytotoxicity assay and analyses of the injury markers in the bronchoalveolar lavage fluid, respectively. Intratracheally administered sildenafil particles elicited more pulmonary specific and sustained vasodilation in SUGEN-5416/hypoxia-induced PAH rats than oral, intravenous, or intratracheal plain sildenafil did, when administered at the same dose. Overall, true to the hypothesis, this study shows that inhaled PLGA particles of sildenafil can be administered, as a substitute for oral form of sildenafil, at a reduced dose and longer dosing interval.

Topics: Administration, Inhalation; Administration, Oral; Animals; Drug Carriers; Humans; Hypertension, Pulmonary; Lactic Acid; Macrophages, Alveolar; Male; Microspheres; Muscle, Smooth, Vascular; Particle Size; Phosphodiesterase 5 Inhibitors; Polyethyleneimine; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Porosity; Pulmonary Artery; Rats, Sprague-Dawley; Sildenafil Citrate; Surface Properties; Vasodilator Agents

To study the concentration of the asymmetrical dimethyl-L-arginine (ADMA) in patients with pulmonary arterial hypertension (PAH) commbination with congenital heart disease (CHD) and its clinical value as a biomaker for diagnosis and prognosis.
 Methods: A total of 100 patients with CHD and 25 healthy adult subjects were recruited. CHD patients were divided into three groups: normal pulmonary arterial pressure group (group A, n=25), mild-to-moderate PAH group (group B, n=25), severe PAH group (group C, n=50). Twenty patients in Group C were treated with sildenafil and followed up for 6 months. The clinical data, including echocardiographic measurements, hemodynamic parameters and ADMA levels, for all subjects were collected.
 Results: The ADMA concentrations in patients with CHD-PAH significantly increased compared with that in the CHD patients without PAH or the health controls, and the ADMA concentrations in CHD patients with severe PAH were significantly higher than that in the CHD patients with mild-to-moderate PAH; serum ADMA concentration was correlated with mean pulmonary arterial pressure (mPAP) (r=0.61, P<0.001) and pulmonary vascular resistance (PVR) (r=0.417, P<0.001) in CHD patients; when using AMDA>0.485 µmol/L as criteria for diagnosis of CHD-PAH, the specificity was 82.7% and the sensitivity was 92.0%; the pulmonary arterial pressure significantly decreased after sildenafil therapy for 6 months, same as the ADMA levels.
 Conclusion: Plasma ADMA could be used as a biomarker to identify PAH in patients with CHD and as a prognosic index to reflect the sildenafil treatment effect.. 目的：研究血浆不对称二甲基精氨酸(asymmetrical dimethyl-L-arginine，ADMA)作为先天性心脏病(congenital heart disease，CHD)相关肺动脉高压(pulmonary arterial hypertension，PAH)患者诊断、分层与随访指标的应用价值。
方法：收集湘雅二医院心血管内科2013年10月至2014年10月经超声心动图证实的CHD患者(n=100)，将其分为3组：无PAH组、轻中度PAH组、重度PAH组；重度PAH组又分为动力型亚组、艾森曼格综合征前期亚组、艾森曼格综合征亚组；同时收集健康成人作为对照组(n=25)；对20例阻力型患者使用西地那非治疗后随访6个月。采集入选病例所有临床一般情况、心脏彩色超声检查和心导管检查结果，检测血浆ADMA浓度。结果：轻中度PAH组血浆ADMA水平显著高于无PAH组及对照组(均P<0.001)；重度PAH组血浆ADMA水平显著高于无PAH组及对照组(均P<0.001)；无PAH组血浆ADMA水平与对照组无统计学差异(P=0.209)；在重度PAH组中，艾森曼格综合征亚组患者血浆ADMA水平显著高于动力型亚组(P<0.001)；ADMA水平与平均肺动脉压(mPAP)，全肺阻力(PVR)呈显著正相关(r分别为0.61，0.417，P<0.001)；血浆ADMA浓度0.485 µmol/L时诊断CHD合并重度PAH敏感度为92.0%，特异性为82.7%(P<0.001)；20例阻力型PAH患者使用西地那非治疗6个月后，肺动脉压力得到改善(P=0.001)，血浆ADMA水平显著降低(P<0.01)。结论：血浆ADMA水平可作为早期识别CHD-PAH的无创性筛查指标，在一定程度上反映西地那非治疗效果，有望成为CHD-PAH患者重要的随访指标。.

Topics: Adult; Arginine; Biomarkers; Echocardiography; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Prognosis; Sensitivity and Specificity; Sildenafil Citrate

In congenital heart disease, severity of pulmonary hypertension and operability is defined by noninvasive parameters (clinical history, physical examination, and echocardiography) and sometimes, cardiac catheterization. We investigated how circulating levels of inflammatory mediators correlate with such parameters in a young pediatric population (age, 2.0 months to 3.1 years) and the effects of preoperative pulmonary vasodilator therapy with sildenafil. Cytokines were analyzed in serum using chemiluminescence signals. In the whole patient group (n = 47), interleukin 17E, a Th2 immune response mediator increased with increasing age, considered as a parameter of disease severity (R

Topics: Child, Preschool; Cytokines; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Male; Sildenafil Citrate; Vasodilator Agents

Aim of this study was to investigate the potential effects of sildenafil on the function of endothelial cells from patients with congenital heart disease with pulmonary hypertension (CHDPH). Patients who are diagnosed as CHD with PH (n=30) or without PH (n=30), and 30 healthy persons (control) were enrolled in this study. The 30 CHDPH cases were separated into two groups, one was given aspirin while the other received aspirin and sildenafil. An ELISA assay was used to detect the biological indexes for endothelial cells. Furthermore, 24 male New Zealand white rabbits were used to construct the CHDPH model. The signal pathway-related protein expression was analyzed using RT-PCR and western blotting. Compared to that in healthy people, levels for flowmediated dilatation (FDM), NO, and adiponectin (APN) were significantly decreased while endothelin (ET-1) was significantly increased in CHD patients, while their levels were drastically changed in CHDPH patients (P<0.01). Besides, no significant differences for expression levels including FDM, APN, NO, and ET-1 was observed in CHDPH patients receiving aspirin. But the levels for FDM, APN, NO, and ET-1 were significantly changed in CHDPH patients after treatment with sildenafil for 3 months (P<0.01). The mRNA and protein levels for JNK1/2, MAPK, and NF-κB were significantly increased in CHDPH rabbits compared to the control (P<0.01), but their levels were significantly suppressed by the sildenafil application compared to the CHDPH group (P<0.01). Taken together, our study suggested that sildenafil may play a protective role on endothelial function via suppressing the JNK and NF-κB signal pathways in CHDPH patients.

Topics: Adiponectin; Animals; Aspirin; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Healthy Volunteers; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; NF-kappa B; Nitric Oxide; Platelet Aggregation Inhibitors; Rabbits; Signal Transduction; Sildenafil Citrate; Vasodilation; Vasodilator Agents

Tadalafil is a selective Phosphodiesterase-5 inhibitor that has been reported to have vasodilatory and antiproliferative effects on the pulmonary artery. In this study we evaluated the safety and efficacy of oral tadalafil in children with pulmonary arterial hypertension (PAH).. This open label study, prospective and interventional was carried out in 25 known patients aged 2 month-5 years in 3 medical centers in Iran, between March 2013-Jun 2014. Tadalafil suspension was administrated at 1 mg/kg daily for all patients. Hemodynamic and safety parameters were assessed at baseline and then monthly for a total of 4 visits.. 19 patients received tadalafil as initial therapy, in all visits significant improvements in mean pulmonary arterial pressure were observed (p<0.01). Of the 25 patients, 6 (24%) had been on sildenafil for longer than 6 months. After transition from sildenafil to tadalafil clinical improvement was noted (p<0.05). Administration of tadalafil suspension was generally safe and well tolerated. Nausea was the most frequently reported adverse events which occurred in 3 patients during treatment.. Oral tadalafil was administered easily and tolerated well and improved mean pulmonary artery pressure (MPAP) in children with PAH, which suggests that oral tadalafil may be more effective and safer than sildenafil in the treatment of PAH.

Topics: Administration, Oral; Arterial Pressure; Child, Preschool; Female; Humans; Hypertension, Pulmonary; Infant; Iran; Male; Phosphodiesterase 5 Inhibitors; Prospective Studies; Sildenafil Citrate; Tadalafil

Despite the beneficial effects of barberry (Berberis integerrima Berberidaceae) on decreasing systemic hypertension, its influence has not been investigated on pulmonary hypertension.. The objective of this study is to examine the effect of barberry fruit, on monocrotaline-induced pulmonary hypertension.. Nine groups were arranged as follows: the control group, the monocrotaline (M) group, the barberry groups with doses of 50, 100, and 200 (mg/kg), the M plus barberry groups, and the M plus sildenafil group. Two weeks after a single injection of monocrotaline (60 mg/kg, s.c.), barberry water extracts or sildenafil (30 mg/kg/d) were gavaged daily for 2 weeks. At the end of the 4th week, hemodynamic, biochemical, and histopathological parameters were assessed.. In comparison with the M group, barberry (200 mg/kg) or sildenafil significantly reduced the right ventricular systolic pressure (RVSP) (22.95 ± 1.78 mm Hg and 30.71 ± 1.64 mm Hg, versus 41.28 ± 1.5 mm Hg), right ventricular hypertrophy (RVH) (0.39 ± 0.03 and 0.42 ± 0.02, versus 0.57 ± 0.02), and the medial wall thickness (MWT) (4.56 ± 0.15 µm and 5.97 ± 0.19 µm, versus 7.02 ± 0.43 µm). Barberry or sildenafil had no significant effect on the plasma level of endothelin-1, glutathione peroxidase, and the malondialdehide of lung.. 200 mg/kg of barberry has an improving effect on the monocrotaline-induced pulmonary hypertension. This effect was stronger than that of the sildenafil's and may have been mediated through mechanisms other than the modulation of the endothelin-1 or redox system.

Topics: Animals; Berberis; Dose-Response Relationship, Drug; Hypertension, Pulmonary; Male; Microvessels; Plant Extracts; Rats; Rats, Wistar; Sildenafil Citrate; Treatment Outcome; Vascular Remodeling; Vasodilator Agents

Direct vasodilator delivery to the airways enables a selective therapy of pulmonary hypertension (PH). However, short-term effects of the applied medication require multiple daily inhalations. Controlled release formulations (polymeric nanomedicines) offer the potential of prolonging drug effects within the respiratory tract, thereby reducing the number of necessary inhalations. In the model of U46619-elicited PH, sildenafil and two sildenafil-loaded polymeric submicron particle formulations were evaluated for their pharmacodynamic and pharmacokinetic characteristics and acute tolerability. Lung-delivered sildenafil caused a selective dose-dependent decline of the pulmonary arterial pressure and vascular resistance. Compared to the transient pharmacodynamic effect observed for sildenafil, the same dose of nanoencapsulated sildenafil resulted in prolongation, but not augmentation, of the pulmonary vasodilatation. An extended pharmacokinetic profile was observed for nanoencapsulated sildenafil, and nanomedicines revealed no acute toxicity. The amplification of pulmonary vasodilatory response caused by nanoencapsulation of sildenafil offers an intriguing approach to ameliorate the therapy of PH. From the Clinical Editor: Pulmonary hypertension usually results in right heart failure long term. Current medical therapy includes the use of potent vasodilators such as sildenafil. In this article, the authors investigated the use of nanoencapsulated formulation for sustained delivery via inhalation route. An extended pharmacokinetic profile was seen for this nanoformulation with little side effects. It is hoped that clinical application of this would come to fruition soon.

Topics: Administration, Inhalation; Animals; Delayed-Action Preparations; Diffusion; Hypertension, Pulmonary; Nanocapsules; Pulmonary Circulation; Rabbits; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

To examine the effect of sildenafil therapy on development of severe retinopathy of prematurity (ROP) requiring surgical intervention in premature infants.. We identified premature infants who were discharged from Pediatrix Medical Group neonatal intensive care units from 2003 to 2012 and who received an ophthalmologic exam. We matched each infant exposed to sildenafil before first eye exam to three nonexposed infants using propensity scoring to control for differences in baseline infant characteristics. We evaluated the association between sildenafil exposure and development of severe ROP using conditional logistic regression.. Of the 57 815 infants meeting inclusion criteria, 88 were exposed to sildenafil. We matched 81/88 (92%) sildenafil-exposed with 243 nonexposed infants. There was no difference in the proportion of infants who developed severe ROP in the sildenafil-exposed vs nonexposed groups (17/81 (21%) vs 38/243 (16%), P=0.27). On adjusted analysis, there was no difference in severe ROP in the sildenafil-exposed vs nonexposed infants (odds ratio=1.46, 95% confidence interval=0.76 to 2.82, P=0.26).. We did not observe an association between risk of severe ROP and sildenafil exposure before first eye exam in this cohort of premature infants.

Topics: Bronchopulmonary Dysplasia; Diagnostic Techniques, Ophthalmological; Female; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Premature; Infant, Very Low Birth Weight; Male; Medical Records, Problem-Oriented; Retinopathy of Prematurity; Risk Assessment; Risk Factors; Sildenafil Citrate; Statistics as Topic; United States; Vasodilator Agents

Tetralogy of Fallot (TOF) with pulmonary atresia (PA) and multiple aortopulmonary collaterals (MAPCAs) is a rare and severe form of congenital heart disease with poor prognosis. Aortopulmonary collaterals expose pulmonary arterioles to systemic pressure resulting in pulmonary hypertension (PH). To date, reports regarding the role of PH medications in this population are sparse. The objective of this study was to assess the effect of PH medications in patients with TOF, PA and MAPCAs or similar anatomy, with emphasis on symptoms, echocardiography and invasive hemodynamics. A retrospective review was performed for patients at a single tertiary care pediatric center. Twelve of 66 patients were treated with PH medications (18 %), and eight of these patients had adequate follow-up for further analysis. Median age at last follow-up was 6 years (range 1.4-21 years). Median length of therapy with PH medication was 4 years (range 0.3-17 years). PH medications included sildenafil, bosentan, ambrisentan, inhaled treprostinil and prostacyclin infusion. PH therapy was associated with improvement in symptoms in all patients and improvement in PH by hemodynamic measures in the majority of patients. All patients underwent at least one cardiac intervention by catheterization or surgery while taking PH medication. Two patients died from non-PH-related causes. The remaining six patients are alive and remain on PH medication. This review indicates that PH medications are well tolerated by this patient group and provide symptomatic improvement. Further studies are required to determine whether PH medications provide long-term survival benefit for patients with complex congenital heart disease.

Topics: Abnormalities, Multiple; Adolescent; Antihypertensive Agents; Bosentan; Catheterization; Child; Child, Preschool; District of Columbia; Echocardiography; Female; Hemodynamics; Hospitals, Pediatric; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Lung; Male; Phenylpropionates; Pulmonary Artery; Pulmonary Atresia; Pyridazines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Tertiary Care Centers; Tetralogy of Fallot; Young Adult

Topics: Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Sildenafil Citrate

This study aims to compare the lifetime costs and health outcomes of both first-line and sequential combination treatments with standard treatment for pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) (PAH-CHD) patients.. A cost-utility analysis was performed using a Markov model based on a societal perspective. One-way and probabilistic sensitivity analyses were performed to investigate the effect of parameter uncertainty.. As first-line treatments, both beraprost (incremental cost-effectiveness ratio (ICER) = 192,752 and 201,308 Thai baht (THB) per quality-adjusted life year (QALY) gained) and sildenafil (ICER = 249,770 and 226,802 THB per QALY gained) seemed cost-effective for PAH-CHD patients aged ≤30 years in functional classes II and III, respectively, while no treatment was cost-effective for the sequential combination therapy.. Sildenafil should be included in the National Drug List of Essential Medicines as the first-line treatment for PAH-CHD, and its price per dose should be negotiated to be reduced by 43-57%.

Topics: Adult; Budgets; Cost-Benefit Analysis; Drug Costs; Drugs, Essential; Epoprostenol; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Markov Chains; Quality-Adjusted Life Years; Sildenafil Citrate; Thailand; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a rare multifactorial disease with an unfavorable prognosis. Sildenafil therapy can improve functional capacity and pulmonary hemodynamics in PAH patients. Nowadays, it is increasingly recognized that the effects of sildenafil are pleiotropic and may also involve changes of the pro-/antioxidant balance, lipid peroxidation and autonomic control. In present study we aimed to assess the effects of sildenafil on the fatty acids (FAs) status, level of hydroxynonenal (HNE) and heart rate variability (HRV) in PAH patients. Patients with PAH were characterized by an increase in HNE and changes in the FAs composition with elevation of linoleic, oleic, docosahexanoic acids in phospholipids as well as reduced HRV with sympathetic predominance. Sildenafil therapy improved exercise capacity and pulmonary hemodynamics and reduced NT-proBNP level in PAH. Antioxidant and anti-inflammatory effects of sildenafil were noted from the significant lowering of HNE level and reduction of the phopholipid derived oleic, linoleic, docosahexanoic, docosapentanoic FAs. That was also associated with some improvement of HRV on account of the activation of the neurohumoral regulatory component. Incomplete recovery of the functional metabolic disorders in PAH patients may be assumed from the persistent increase in free FAs, reduced HRV with the sympathetic predominance in the spectral structure after treatment comparing to control group. The possibilities to improve PAH treatment efficacy through mild stimulation of free radical reactions and formation of hormetic reaction in the context of improved NO signaling are discussed.

Topics: Adult; Aldehydes; Fatty Acids; Female; Heart Rate; Humans; Hypertension, Pulmonary; Lipid Peroxidation; Male; Nitric Oxide; Oxidative Stress; Sildenafil Citrate; Young Adult

This study had 2 goals: (1) to identify clinical and demographic characteristics associated with sildenafil exposure for infants with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH); and (2) to characterize hospital-specific treatment frequency, age at first administration, and length of sildenafil treatment.. This retrospective cohort study used data from the Pediatric Health Information System to determine variables associated with sildenafil exposure and between-hospital variations in sildenafil utilization patterns. The study included infants with BPD-PH who were discharged between January 1, 2006, and December 31, 2013.. Within 36 US pediatric hospitals, 3720 infants were diagnosed with BPD, of whom 598 (16%) also had a diagnosis of PH (BPD-PH). Among infants with BPD-PH, 104 infants (17%) received sildenafil. The odds for sildenafil treatment among infants born between 25 and 26 weeks' gestational age (GA) and <24 weeks' GA, respectively, were 2.26 (95% confidence interval [CI]: 1.20-4.24) and 3.21 (95% CI: 1.66-6.21) times those of infants born at 27 to 28 weeks' GA. Severity of BPD correlated with sildenafil exposure, with adjusted odds ratios (ORs) for moderate BPD (OR: 3.03 [95% CI: 1.03-8.93]) and severe BPD (OR: 7.56 [95% CI: 2.50-22.88]), compared with mild BPD. Greater rates of sildenafil exposure were observed among small for GA neonates (OR: 2.32 [95% CI: 1.21-4.46]). The proportion of infants with BPD-PH exposed to sildenafil varied according to hospital (median: 15%; 25th-75th percentile: 0%-25%), as did the median duration of therapy (52 days; 25th-75th percentile: 28-109 days).. The odds of sildenafil treatment were greatest among the most premature infants with severe forms of BPD. The frequency and duration of sildenafil exposure varied markedly according to institution. Patient-centered trials for infants with BPD-PH are needed to develop evidence-based practices.

Topics: Bronchopulmonary Dysplasia; Cohort Studies; Female; Gestational Age; Hospitals, Pediatric; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Male; Needs Assessment; Outcome and Process Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Practice Patterns, Physicians'; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; United States

In recent years, a significant number of costly oral therapies have become available for the treatment of pulmonary arterial hypertension (PAH). Funding decisions for these therapies requires weighing up their effectiveness and costs.. The aim of this study was to assess the cost effectiveness of monotherapy with oral PAH-specific therapies versus supportive care as initial therapy for patients with functional class (FC) II and III PAH in Canada.. A cost-utility analysis, from the perspective of a healthcare system and based on a Markov model, was designed to estimate the costs and quality-adjusted life-years (QALYs) associated with bosentan, ambrisentan, riociguat, tadalafil, sildenafil and supportive care for PAH in treatment-naïve patients. Separate analyses were conducted for cohorts of patients commencing therapy at FC II and III PAH. Transition probabilities, based on the relative risk of improving and worsening in FC with treatment versus placebo, were derived from a recent network meta-analysis. Utility values and costs were obtained from published data and clinical expert opinion. Extensive sensitivity analyses were conducted.. Analysis suggests that sildenafil is the most cost-effective therapy for PAH in patients with FC II or III. Sildenafil was both the least costly and most effective therapy, thereby dominating all other treatments. Tadalafil was also less costly and more effective than supportive care in FC II and III; however, sildenafil was dominant over tadalafil. Even given the uncertainty within the clinical inputs, the probabilistic sensitivity analysis showed that apart from sildenafil and tadalafil, the other PAH therapies had negligible probability of being the most cost effective.. The results show that initiation of therapy with sildenafil is likely the most cost-effective strategy in PAH patients with either FC II or III disease.

Topics: Administration, Oral; Cost-Benefit Analysis; Humans; Hypertension, Pulmonary; Markov Chains; Quality-Adjusted Life Years; Sildenafil Citrate; Tadalafil

Combination therapy is frequently used to treat patients with pulmonary hypertension but few studies have compared treatment regimens. This study examined the long-term effect of different combination regimens of inhaled iloprost and oral sildenafil on survival and disease progression.. This was a retrospective study of patients in the Giessen Pulmonary Hypertension Registry who received iloprost monotherapy followed by addition of sildenafil (iloprost/sildenafil), sildenafil monotherapy followed by addition of iloprost (sildenafil/iloprost), or upfront combination therapy (iloprost + sildenafil). The primary outcome was transplant-free survival (Kaplan-Meier analysis). When available, haemodynamic parameters and 6-minute-walk distance were evaluated.. Overall, 148 patients were included. Baseline characteristics were similar across treatment groups; however, the iloprost + sildenafil cohort had higher mean pulmonary vascular resistance and pulmonary arterial pressure than the others. Transplant-free survival differed significantly between groups (P = 0.007, log-rank test). Cumulative transplant-free survival was highest for patients who received iloprost/sildenafil (1 year survival: iloprost/sildenafil, 95.1%; sildenafil/iloprost, 91.8%; iloprost + sildenafil, 62.9%); this group also remained on monotherapy significantly longer than the sildenafil/iloprost group (median 17.0 months vs 7.0 months, respectively; P = 0.004). Compared with pre-treatment values, mean 6-minute-walk distance increased significantly for all groups 3 months after beginning combination therapy.. In this observational study of patients with pulmonary hypertension receiving combination therapy with iloprost and sildenafil, cumulative transplant-free survival was highest in those who received iloprost monotherapy initially. However, owing to the size and retrospective design of this study, further research is needed before making firm treatment recommendations.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Cohort Studies; Disease Progression; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Kaplan-Meier Estimate; Lung Transplantation; Male; Middle Aged; Registries; Retrospective Studies; Sildenafil Citrate; Survival Rate; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a rare, progressive, fatal vascular disorder. Genetic predisposition plays vital roles in the development of PAH, with most mutations being identified in genes involved in the transforming growth factor beta (TGF-β) signaling pathways. Defects in the BMP9 gene have been documented in hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, which is occasionally associated with PAH. Selective enhancement of endothelial BMPR2 with BMP9 reverses pulmonary arterial hypertension.. We report the case of a 5-year-old Hispanic boy who was diagnosed with severe PAH and right heart failure at 3 years of age. During his stay in the pediatric intensive care unit, treatment was initiated with inhaled nitric oxide and intravenous epoprostenol; he subsequently was transitioned to treprostinil, sildenafil, and prophylactic enoxaparin. Now, two years later, the child is asymptomatic on sildenafil, bosentan, subcutaneous treprostinil, and warfarin. Genetic screening revealed a novel homozygous nonsense mutation in the BMP9 gene (c.76C > T; p.Gln26Ter). The child had no telangiectasias or arteriovenous malformations; family history also was negative. Subsequent parental testing showed both parents were heterozygous for the same mutation, indicating that the child inherited the BMP9 mutant allele from each parent.. To our knowledge, this is the first report of a BMP9 mutation in a patient with PAH. The homozygous nonsense mutation may account for the early onset and severity of PAH in this patient and also fit the 'two-hit' model we proposed previously. The absence of clinical symptoms for PAH in the parents may be due to incomplete penetrance or various expressivities of the BMP9 mutations. Our study expands the spectrum of phenotypes related to BMP9 mutations.

Topics: Anticoagulants; Antihypertensive Agents; Bosentan; Child, Preschool; Codon, Nonsense; Epoprostenol; Growth Differentiation Factor 2; Growth Differentiation Factors; Homozygote; Humans; Hypertension, Pulmonary; Male; Mexican Americans; Sildenafil Citrate; Sulfonamides; Vasodilator Agents; Warfarin

Topics: Bronchopulmonary Dysplasia; Humans; Hypertension, Pulmonary; Infant, Extremely Premature; Infant, Newborn; Outcome Assessment, Health Care; Sildenafil Citrate; Vasodilator Agents

The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the C825T polymorphism in the G-protein β3 subunit gene (GNB3) are associated with the efficacy of phosphodiesterase-5 inhibitor (PDE-5I) in erectile dysfunction. In addition, GNB3 genotypes could be associated with clinical worsening in pulmonary hypertension (PH) treated with PDE-5I. However, no studies have described the synergistic effects of gene polymorphisms on drug efficacy in patients with PH.. We aimed to examine the effects of combined ACE/GNB3 polymorphisms on the efficacy of PDE-5I in patients with PH.. This was a retrospective uncontrolled study. Ninety patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH) were treated with PDE-5I. Freedom from clinical worsening and pre- and post-treatment parameters, including the 6-min walk distance (6MWD) and serum brain natriuretic peptide (BNP) levels, were compared between patients with ACE/GNB3 II/TT and non-II/TT genotypes.. Time to clinical worsening was significantly longer in patients with the II/TT genotype than in those with the non-II/TT genotype (5-year freedom from clinical worsening: 100 vs. 48.8%, respectively; p = 0.018), even in patients with CTEPH alone. Post-treatment 6MWD and BNP levels in patients with the II/TT genotype tended to be better than those in patients with the non-II/TT genotype. The ACE/GNB3 genotype was a significant predictor of clinical worsening, even after adjusting for pulmonary vascular resistance and 6MWD.. ACE and GNB3 polymorphisms may synergistically influence the efficacy of PDE-5I in patients with PH.

Topics: Adult; Aged; Female; Heterotrimeric GTP-Binding Proteins; Humans; Hypertension, Pulmonary; INDEL Mutation; Male; Middle Aged; Peptidyl-Dipeptidase A; Phosphodiesterase 5 Inhibitors; Polymorphism, Genetic; Retrospective Studies; Sildenafil Citrate; Tadalafil; Treatment Outcome

Topics: Adult; Age Distribution; Aged; Anticoagulants; Bosentan; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Incidence; Latvia; Male; Middle Aged; Phenylpropionates; Prevalence; Pulmonary Embolism; Pyrazoles; Pyridazines; Pyridones; Registries; Rivaroxaban; Sex Distribution; Sildenafil Citrate; Sulfonamides; Vasodilator Agents; Warfarin; Young Adult

The present study aimed to evaluate the preventive effect of sildenafil treatment on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. Fifty-four 12-week-old male Sprague-Dawley rats were injected with MCT or saline solution (MCT-injected rats: n=36; saline: n=18). Serial echocardiography and right ventricular systolic pressure (RVSP) measurements via a cardiac catheter were performed at 2, 4 and 6 weeks after the injection. After injection of MCT, rats received oral sildenafil (MCT/sildenafil group: n=18) or no treatment (MCT group: n=18) until undergoing echocardiography and cardiac catheterization. RVSP in the MCT/sildenafil group was lower than that in the MCT group at 4 (P<0.001) and 6 weeks (P<0.001). The septal curvature was improved in the MCT/sildenafil group compared with the MCT group. This finding showed that sildenafil prevented flattening of the interventricular septum because of right ventricular pressure overload. The ratio of peak trans-tricuspid early diastolic wave velocity to active filling with atrial systolic velocity showed that sildenafil improved diastolic function. Tricuspid annular plane systolic excursion and tricuspid annular systolic velocity in the MCT/sildenafil group did not show preserved myocardial contraction after administration of sildenafil. Administration of sildenafil leads to a reduction in RVSP and improvement in cardiac function in rats with PH induced by MCT. The vasodilatory action of sildenafil improves right ventricular diastolic function, but the intrinsic, positive, inotropic effect of sildenafil is minimal.

Topics: Administration, Ophthalmic; Animals; Echocardiography; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; Pulmonary Artery; Rats, Sprague-Dawley; Sildenafil Citrate; Vasodilator Agents; Ventricular Function, Right

Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met.This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III-IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8).All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively.Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Diethylpropion; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Patient Safety; Phenylpropionates; Pyridazines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Tadalafil; Time Factors; Treatment Outcome

Sildenafil improves the 6-min walking distance in patients with idiopathic pulmonary fibrosis (IPF) and right-sided ventricular systolic dysfunction.We analysed the previously unexplored role of sildenafil on vasoconstriction and remodelling of pulmonary arteries from patients with IPF and pulmonary hypertension (PH) ex vivo Pulmonary arteries from 18 donors without lung disease, nine IPF, eight PH+IPF and four PH patients were isolated to measure vasodilator and anti-contractile effects of sildenafil in isometric organ bath. Ventilation/perfusion was explored in an animal model of bleomycin lung fibrosis.Sildenafil relaxed serotonin (5-HT) pre-contracted pulmonary arteries in healthy donors and IPF patients and, to a lesser extent, in PH+IPF and PH. Sildenafil inhibited 5-HT dose-response contraction curve mainly in PH+IPF and PH, but not in healthy donors. Sildenafil did not impair the ventilation/perfusion mismatching induced by bleomycin. Pulmonary arteries from PH+IPF patients showed a marked expression of phosphodiesterse-5 and extracellular matrix components. Sildenafil inhibited pulmonary artery endothelial and smooth muscle cell to mesenchymal transition by inhibition of extracellular regulated kinases 1 and 2 (ERK1/2) and SMAD3 phosphorylation.These results suggest an absence of direct relaxant effect and a prominent anti-contractile and anti-remodelling role of sildenafil in PH+IPF pulmonary arteries that could explain the beneficial effects of sildenafil in IPF with PH phenotype.

Topics: Animals; Bleomycin; Disease Models, Animal; Endothelium, Vascular; Extracellular Matrix; Fibroblasts; Humans; Hypertension, Pulmonary; Lung; Male; Myocytes, Smooth Muscle; Myofibroblasts; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Rats; Rats, Wistar; Serotonin; Signal Transduction; Sildenafil Citrate; Transforming Growth Factor beta1; Vasoconstriction; Vasodilator Agents

Persistent pulmonary hypertension of the newborn (PPHN) is the most common neonatal form and mostly reversible after a few days with improvement of the underlying pulmonary condition. When pulmonary hypertension (PH) persists despite adequate treatment, the severity of parenchymal lung disease should be assessed by chest CT. Pulmonary vein stenosis may need to be ruled out by cardiac catheterisation and lung biopsy, and genetic workup is necessary when alveolar capillary dysplasia is suspected. In PPHN, optimisation of the cardiopulmonary situation including surfactant therapy should aim for preductal SpO2between 91% and 95% and severe cases without post-tricuspid-unrestrictive shunt may receive prostaglandin E1 to maintain ductal patency in right heart failure. Inhaled nitric oxide is indicated in mechanically ventilated infants to reduce the need for extracorporal membrane oxygenation (ECMO), and sildenafil can be considered when this therapy is not available. ECMO may be indicated according to the ELSO guidelines. In older preterm infant, where PH is mainly associated with bronchopulmonary dysplasia (BPD) or in term infants with developmental lung anomalies such as congenital diaphragmatic hernia or cardiac anomalies, left ventricular diastolic dysfunction/left atrial hypertension or pulmonary vein stenosis, can add to the complexity of the disease. Here, oral or intravenous sildenafil should be considered for PH treatment in BPD, the latter for critically ill patients. Furthermore, prostanoids, mineralcorticoid receptor antagonists, and diuretics can be beneficial. Infants with proven or suspected PH should receive close follow-up, including preductal/postductal SpO2measurements, echocardiography and laboratory work-up including NT-proBNP, guided by clinical improvement or lack thereof.

Topics: Acute Disease; Administration, Inhalation; Bronchopulmonary Dysplasia; Cardiac Catheterization; Chronic Disease; Consensus; Constriction, Pathologic; Endothelium-Dependent Relaxing Factors; Extracorporeal Membrane Oxygenation; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Lung Diseases; Nitric Oxide; Persistent Fetal Circulation Syndrome; Phosphodiesterase 5 Inhibitors; Pulmonary Veins; Sildenafil Citrate; Tomography, X-Ray Computed

Acute pulmonary hypertension (PH) complicates the course of several cardiovascular, pulmonary and other systemic diseases in children. An acute rise of RV afterload, either as exacerbating chronic PH of different aetiologies (eg, idiopathic pulmonary arterial hypertension (PAH), chronic lung or congenital heart disease), or pulmonary hypertensive crisis after corrective surgery for congenital heart disease, may lead to severe circulatory compromise. Only few clinical studies provide evidence on how to best treat children with acute severe PH and decompensated RV function, that is, acute RV failure. The specific treatment in the intensive care unit should be based on the underlying pathophysiology and not only be focused on so-called 'specific' or 'tailored' drug therapy to lower RV afterload. In addition therapeutic efforts should aim to optimise RV preload, and to achieve adequate myocardial perfusion, and cardiac output. Early recognition of patients at high risk and timely initiation of appropriate therapeutic measures may prevent the development of severe cardiac dysfunction and low cardiac output. In patients not responding adequately to pharmacotherapy, (1) novel surgical and interventional techniques, temporary mechanical circulatory support with extracorporeal membrane oxygenation, (2) pumpless lung assist devices (3) and/or lung or heart-lung transplantation should be timely considered. The invasive therapeutic measures can be applied in a bridge-to-recovery or bridge-to-lung transplant strategy. This consensus statement focuses on the management of acute severe PH in the paediatric intensive care unit and provides an according treatment algorithm for clinical practice.

Topics: Acute Disease; Administration, Inhalation; Administration, Intravenous; Adolescent; Cardiac Output; Child; Consensus; Critical Care; Disease Management; Disease Progression; Endothelium-Dependent Relaxing Factors; Extracorporeal Membrane Oxygenation; Heart-Lung Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Intensive Care Units, Pediatric; Lung Transplantation; Nitric Oxide; Oxygen Inhalation Therapy; Phosphodiesterase 5 Inhibitors; Prostaglandins; Sildenafil Citrate; Vasodilator Agents; Ventricular Dysfunction, Right

Topics: Activin Receptors, Type II; Female; Humans; Hypertension, Pulmonary; Middle Aged; Mutation, Missense; Pedigree; Pulmonary Arterial Hypertension; Sildenafil Citrate; Telangiectasis; Treatment Outcome; Vasodilator Agents

In 2010, the congenital diaphragmatic hernia (CDH) EURO Consortium published a standardized neonatal treatment protocol. Five years later, the number of participating centers has been raised from 13 to 22. In this article the relevant literature is updated, and consensus has been reached between the members of the CDH EURO Consortium. Key updated recommendations are: (1) planned delivery after a gestational age of 39 weeks in a high-volume tertiary center; (2) neuromuscular blocking agents to be avoided during initial treatment in the delivery room; (3) adapt treatment to reach a preductal saturation of between 80 and 95% and postductal saturation >70%; (4) target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical ventilation to be the optimal initial ventilation strategy, and (6) intravenous sildenafil to be considered in CDH patients with severe pulmonary hypertension. This article represents the current opinion of all consortium members in Europe for the optimal neonatal treatment of CDH.

Topics: Clinical Protocols; Consensus; Europe; Expert Testimony; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Monitoring, Physiologic; Postnatal Care; Practice Guidelines as Topic; Respiration, Artificial; Sildenafil Citrate

The aim of this study was to investigate possible functional and structural ocular changes caused by chronic sildenafil therapy to treat pulmonary arterial hypertension (PAH).. Case-control study included patients with pulmonary arterial hypertension: chronically using sildenafil and without sildenafil treatment. A comprehensive ophthalmologic exam including ectoscopy, extrinsic ocular motility, logMAR visual acuity measurement, contrast sensitivity test, color test, anterior segment biomicroscopy, Schirmer test 1, intraocular pressure, fundus exam under pupil dilation, fundus pictures, time domain and spectral domain optical coherence tomography, ocular Doppler ultrasound were performed. Full-field electroretinography (ERG) was tested for each eye in a subgroup of sildenafil-treated patients.. Twenty patients from each group were tested. Bilateral severe keratitis was found in seven (35 %) patients under sildenafil therapy. Lacrimal film break-up time (BUT) was significantly reduced (p = 0.006 respectively) and Doppler ultrasound showed a reduced resistance index of the central retinal artery in the group of sildenafil users (p = 0.019). No diffuse retinal functional abnormalities were found in ERG in treated patients. Visual acuity, contrast sensitivity and color discrimination were normal in both groups. No abnormalities were found in both time-domain and spectral-domain OCT for retinal parameters.. One-third of the treated PAH group showed severe bilateral keratitis. This finding could be related to connective tissue abnormalities usually present in patients with this condition that might be exacerbated with the sildenafil usage. The resistance index of the central retinal artery was diminished in the chronic users group and it could be associated to the vasodilation caused by the medication in the choroidal vessels. An ophthalmic assessment for these patients is recommended to diagnose and treat possible ocular surface and choroidal blood flow abnormalities caused by sildenafil.

Topics: Adult; Aged; Blood Flow Velocity; Case-Control Studies; Electroretinography; Female; Humans; Hypertension, Pulmonary; Keratitis; Lacrimal Apparatus Diseases; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Retinal Artery; Retinal Diseases; Sildenafil Citrate; Ultrasonography, Doppler, Color; Visual Acuity

Presence of pulmonary hypertension (PH) and right ventricular dysfunction worsens prognosis in patients with chronic heart failure (CHF). Preclinical and clinical studies suggest a role for the impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway in both PH and CHF. Hence, we examined the effects of the NO-sGC-cGMP pathway modulation by the PDE5 inhibitor sildenafil or sGC stimulator riociguat on pulmonary hemodynamics and heart function in a murine model of secondary PH induced by transverse aortic constriction.. C57Bl/6N mice were subjected to transverse aortic constriction (TAC) for 6weeks to induce left heart failure and secondary PH and were subsequently treated with either sildenafil (100mg/kg/day) or riociguat (10mg/kg/day) or placebo for 2weeks.. Six weeks after surgery, TAC induced significant left ventricular hypertrophy and dysfunction associated with development of PH. Treatment with riociguat and sildenafil neither reduced left ventricular hypertrophy nor improved its function. However, both sildenafil and riociguat ameliorated PH, reduced pulmonary vascular remodeling and improved right ventricular function.. Thus, modulation of the NO-sGC-cGMP pathway by the PDE5 inhibitor sildenafil or sGC stimulator riociguat exerts direct beneficial effects on pulmonary hemodynamics and right ventricular function in the experimental model of secondary PH due to left heart disease and these drugs may offer a new therapeutic option for therapy of this condition.

Topics: Animals; Cyclic GMP; Disease Models, Animal; Heart Function Tests; Humans; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Pyrazoles; Pyrimidines; Signal Transduction; Sildenafil Citrate; Soluble Guanylyl Cyclase; Treatment Outcome

Severe pulmonary hypertension may following ibuprofen administration for ductal closure.. An extremely preterm infant who developed severe pulmonary hypertension unresponsive to inhaled nitric oxide after ibuprofen administration.. Pulmonary hypertension reversed after the administration of oral sildenafil, but the infant died due to complications related to bronchopulmonary dysplasia.. Sildenafil may have a role in treatment of severe pulmonary hypertension after ibuprofen treatment for ductal closure.

Topics: Humans; Hypertension, Pulmonary; Ibuprofen; Infant, Newborn; Male; Sildenafil Citrate; Vasodilator Agents

The objective of this study is to assess sildenafil and N-desmethyl sildenafil (DMS) exposure in infants receiving sildenafil for the treatment of pulmonary hypertension (PH).. Data were collected from six infants receiving sildenafil for the treatment of PH and plasma samples were collected at the time of routine laboratory blood draws. The echocardiography results were assessed for improvement in right ventricular (RV) hypertension following sildenafil treatment.. The median (range) sildenafil and DMS concentrations were 27.4 ng ml(-1) (2.6 to 434.0) and 105.5 ng ml(-1) (3.6 to 314.0), respectively. The median metabolite-to-parent ratio was higher in infants receiving co-medications that can induce cytochrome P450 (CYP) enzymes (5.2 vs 0.7). The echocardiography results showed improvement in RV hypertension for the majority of infants (5/6).. The concentrations of sildenafil and DMS were within the previously observed ranges. Our results suggest that caution may be warranted when CYP-related co-medications are administered during sildenafil treatment for PH.

Topics: Bronchopulmonary Dysplasia; Echocardiography; Female; Humans; Hypertension, Pulmonary; Infant; Infant, Extremely Premature; Male; North Carolina; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Ventricular Function, Right

The present study was designed to prepare sildenafil carrier free dry powder inhalation (DPI) formulation for the treatment of idiopathic pulmonary arterial hypertension (IPAH). Sildenafil DPI formulations were fabricated by spray drying technique. The ideal formulation was optimized using different solvent type (methanol, dimethyformamide and water), concentration (5 and 50 mg/mL) and pH (2 and 7.4) of feed solution. Particles size distribution, morphology and crystallinity of fabricated microparticles were evaluated by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) methods, respectively. The aerosolization efficiency of formulations were assessed by next generation impactor equipped with an Aerolizer. Results indicated that evaluated variables had great impacts on powder characteristics which significantly influenced aerosolization performance of formulations. The aerosolized fraction of formulations was improved from 2 to 70% by changing in solvent type and drug concentration in spray dryer feeding solution. Aerosolization performance of powders were well correlated and interpreted by their morphologies as depicted from SEM images. DSC results also indicated that crystallinity of all formulations were reduced by spray drying procedure. Optimization of spray drying technique for production of Sildenafil carrier free DPI formulation in this study may pave a way for locally treatment of IPAH.

Topics: Aerosols; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Dry Powder Inhalers; Hypertension, Pulmonary; Microscopy, Electron, Scanning; Particle Size; Powders; Sildenafil Citrate; Solvents; Vasodilator Agents

We report a 14-month-old child with persistent truncus arteriosus and crossed pulmonary arteries. The potential advantage of crossed pulmonary artery arrangement in achieving surgical correction is discussed.

Topics: Abnormalities, Multiple; Anastomosis, Surgical; Cardiomegaly; Cardiopulmonary Bypass; Combined Modality Therapy; Dobutamine; Female; Humans; Hypertension, Pulmonary; Infant; Milrinone; Pulmonary Artery; Sildenafil Citrate; Truncus Arteriosus, Persistent; Vascular Surgical Procedures

Topics: Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adult; Female; Humans; Hypertension, Pulmonary; Nerve Fibers; Optic Neuropathy, Ischemic; Phosphodiesterase 5 Inhibitors; Retinal Ganglion Cells; Scotoma; Sildenafil Citrate; Tomography, Optical Coherence; Visual Acuity; Visual Field Tests; Visual Fields

This study aimed to investigate the potential effects of sildenafil on pulmonary hypertension (PH) in the monocrotaline (MCT)-induced PH rat. Twenty-four, 12-week-old, male Sprague-Dawley rats were injected with MCT or saline solution. After injection of MCT, rats received oral sildenafil immediately (early-phase treatment group: E group), 4 weeks after injection (late-phase treatment group: L group) or no treatment (MCT group) until 6 weeks after injection. Serial echocardiography and right ventricular systolic pressure (RVSP) measurements via a cardiac catheter were performed. RVSP was reduced in the E and L groups compared with the MCT group. Echocardiography indicated that sildenafil therapy prevents an increase in RVSP and preserves diastolic function, and this effect is not dependent on timing of initiation of therapy.

Topics: Animals; Echocardiography; Hypertension, Pulmonary; Male; Monocrotaline; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Ventricular Function, Right; Ventricular Pressure

To investigate expression changes and role of Gα11 protein in the processes of muscularization of non-muscular pulmonary arterioles and effect of sildenafil intervention in rats with pulmonary arterial hypertension (PAH).. Thirty SD rats were randomly divided into three groups, including normal control group, monocrotaline (MCT) group and sildenafil group; PAH model was prepared with 50 mg/kg MCT treatment for 4 weeks in the MCT group, and these rats were treated by 25 mg/kg sildenafil for 2 weeks after PAH formation in the sildenafil group, and the normal control group were treated with the equal amounts of physiological saline instead of monocrotaline; pulmonary artery pressure was measured with jugular vein catheterization; hematoxylin and eosin (HE) staining method was used to detect the pulmonary arteriolar morphology and vascular tissue parameters; expression of the target Gα11 protein, vascular smooth muscle marker osteopontin (OPN) and proliferation marker proliferating cell nuclear antigen (PCNA) was detected by Western blot.. Pulmonary artery mean pressure (mPAP), non-muscular pulmonary arterioles wall thickness index (TI) and area index (AI) of the MCT group were higher than those of the normal control group[(27.43±3.97) vs (11.93±1.52) mmHg (1 mmHg=0.133 kPa), 0.49±0.07 vs 0.31±0.09 and 0.74±0.05 vs 0.45±0.10](all P<0.05), and meanwhile the expression levels of Gα11 and the related proteins including OPN and PCNA were significantly enhanced. mPAP, TI and AI[(18.59±1.44) mmHg, 0.39±0.09 and 0.56±0.04]of the sildenafil group were all lower than those of the MCT group (all P<0.05), and furthermore, expressions of Gα11, OPN and PCNA also reduced in line with these changes.. Gα11 protein plays a role in the development of PAH and pulmonary non-muscular arteriole muscularization, and sildenafil effectively suppresses PAH and pulmonary vascular remodeling by inhibiting Gα11 expression.

Topics: Animals; Arterioles; Familial Primary Pulmonary Hypertension; GTP-Binding Protein alpha Subunits, Gq-G11; Hypertension, Pulmonary; Lung; Monocrotaline; Muscle, Smooth, Vascular; Osteopontin; Piperazines; Random Allocation; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypoplasia and hypertension is a leading cause of morbidity and mortality in congenital diaphragmatic hernia (CDH). The etiologic insult occurs early in gestation highlighting the potential of prenatal interventions. We evaluated prenatal pharmacologic therapies in the nitrofen CDH model.. Olive oil or nitrofen were administered alone or with dexamethasone (DM), sildenafil, or DM+sildenafil to pregnant rats. Newborn pups were assessed for lung function, structure and pulmonary artery (PA) flow and resistance.. Prenatal DM treatment of CDH pups increased alveolar volume density (Vva), decreased interalveloar septal thickness, increased tidal volumes and improved ventilation without improving oxygenation or PA resistance. Sildenafil decreased PA resistance and improved oxygenation without improving ventilation or resulting in significant histologic changes. DM+sildenafil decreased PA resistance, improved oxygenation and ventilation while increasing Vva and decreasing interalveolar septal and pulmonary arteriole medial wall thickness. Lung and body weights were decreased in pups treated with DM and/or sildenafil.. Prenatal DM or sildenafil treatment increased pulmonary compliance and decreased pulmonary vascular resistance respectively, and was associated with improved neonatal gas exchange but had a detrimental effect on lung and fetal growth. This study highlights the potential of individual and combined prenatal pharmacologic therapies for CDH management.

Topics: Animals; Arterioles; Body Weight; Dexamethasone; Female; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Lung; Olive Oil; Organ Size; Oxygen; Phenyl Ethers; Pregnancy; Pregnancy, Animal; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Respiratory Function Tests; Respiratory Physiological Phenomena; Sildenafil Citrate; Stroke Volume; Trachea

In dogs with canine monocytic ehrlichiosis (CME), respiratory signs are uncommon and clinical and radiographic signs of interstitial pneumonia are poorly described. However, in human monocytic ehrlichiosis, respiratory signs are common and signs of interstitial pneumonia are well known. Pulmonary hypertension (PH) is classified based on the underlying disease and its treatment is aimed at reducing the clinical signs and, if possible, addressing the primary disease process. PH is often irreversible, but can be reversible if it is secondary to a treatable underlying etiology. CME is currently not generally recognized as one of the possible diseases leading to interstitial pneumonia and secondary PH in dogs. Only one case of PH associated with CME has been reported worldwide.. A seven-year-old, male intact, mixed breed dog was presented with 2 weeks history of lethargy and dyspnea. The dog previously lived in the Cape Verdean islands. Physical examination showed signs of right-sided congestive heart failure and poor peripheral perfusion. Thoracic radiography showed moderate right-sided cardiomegaly with dilation of the main pulmonary artery and a mild diffuse interstitial lung pattern with peribronchial cuffing. Echocardiography showed severe pulmonary hypertension with an estimated pressure gradient of 136 mm Hg. On arterial blood gas analysis, severe hypoxemia was found and complete blood count revealed moderate regenerative anemia and severe thrombocytopenia. A severe gamma hyperglobulinemia was also documented. Serology for Ehrlichia canis was highly positive. Treatment with oxygen supplementation, a typed packed red blood cell transfusion and medical therapy with doxycycline, pimobendan and sildenafil was initiated and the dog improved clinically. Approximately 2 weeks later, there was complete resolution of all clinical signs and marked improvement of the PH.. This report illustrates that CME might be associated with significant pulmonary disease and should be considered as a possible differential diagnosis in dogs presenting with dyspnea and secondary pulmonary hypertension, especially in dogs that have been in endemic areas. This is important because CME is a treatable disease and its secondary lung and cardiac manifestations may be completely reversible.

Topics: Animals; Antiparasitic Agents; Dog Diseases; Dogs; Doxycycline; Ehrlichiosis; Heart Failure; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Pyridazines; Radiography, Thoracic; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Topics: Adult; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Male; Pyrimidines; Sildenafil Citrate; Sulfonamides; Thalassemia; Vasodilator Agents

Topics: Humans; Hypertension, Pulmonary; Optic Neuropathy, Ischemic; Risk Factors; Sildenafil Citrate

This study investigated the potential value of serum high mobility group box-1 (HMGB1) level in the diagnosis, staging and treatment response of patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD).. This was a single-center prospective study in 106 CHD patients. Serum HMGB1 levels were measured by enzymelinked immunosorbent assay. HMGB1 levels were significantly increased in patients with PAH compared to patients without PAH (P<0.01) and healthy controls (P<0.001). HMGB1 levels significantly correlated with pulmonary arterial pressure (P<0.001) and pulmonary vascular resistance (PVR) (P<0.001). In patients with severe PAH, HMGB1 levels were significantly higher in patients with Eisenmenger syndrome (ES) than in patients exhibiting low PVR (P<0.001). Severe PAH and ES was identified by serum HMGB1 with a cutoff value of 13.62ng/mL (P<0.001) with a specificity of 82.8% and a sensitivity of 90%, and a cutoff value of 21.62ng/mL (P=0.001) with a specificity of 85.2% and a sensitivity of 64.3%, respectively. HMGB1 levels were significantly decreased after sildenafil therapy for 6months (P<0.01).. Our study suggests that serum HMGB1 level may be used as a biomarker to identify PAH in CHD patients, assess pulmonary vascular remodeling, and evaluate the treatment response to sildenafil.

Topics: Adult; Biomarkers; Case-Control Studies; Eisenmenger Complex; Enzyme-Linked Immunosorbent Assay; Female; Heart Defects, Congenital; HMGB1 Protein; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prospective Studies; Sensitivity and Specificity; Severity of Illness Index; Sildenafil Citrate; Treatment Outcome; Vascular Resistance; Young Adult

Pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants remains a serious concern and continues to cause significant morbidity despite improvements in both quality of life and survival for patients. One of the potential agents that might help is sildenafil citrate, a phosphodiesterase-V inhibitor used a first line therapy for idiopathic PH. However, only limited evidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. The evidence and current knowledge is presented for sildenafil alone and in combination with other disease modifying agents to treat PH in the presence of BPD. We have previously suggested that sildenafil appears to be safe and possibly effective in this condition. We present the evidence that if continued until PH resolution, there might be reduced mortality in this debilitating disease.

Topics: Bronchopulmonary Dysplasia; Humans; Hypertension, Pulmonary; Infant; Sildenafil Citrate; Vasodilator Agents

Topics: Altitude Sickness; Humans; Hypertension, Pulmonary; Japan; Mountaineering; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

A 25-year-old, male mealy Amazon parrot (Amazona farinose) with a history of polycythemia, hepatomegaly, and epistaxis was evaluated for progressive lethargy and anorexia. Clinical laboratory testing revealed severe polycythemia (71%), hypophosphatemia (1.6 mg/dL), and mild hypokalemia (2.8 mEq/L). Radiographs showed marked hepatomegaly and loss of air sac space. Despite supportive treatments, the bird's condition deteriorated, and it developed ataxia, was unable to fly, and became oxygen dependent. An echocardiogram, including an air bubble study, revealed a right-to-left atrial shunt and presumed pulmonary arterial hypertension. The bird was started on periodic phlebotomy (5-10 mL/kg q6wk) to reduce packed cell volume and sildenafil citrate (2.5 mg/kg PO q8h) for treatment of suspected pulmonary arterial hypertension. One week later, the patient was weaned off oxygen, and 24 days after initial presentation, the parrot was returned to its outdoor exhibit. Intermittent periods of increased respiratory rate and effort have been reported but have resolved without additional treatments. Epistaxis, once common in this bird, has not been noted since initiating treatment with sildenafil citrate 15 months ago.

Topics: Amazona; Animals; Bird Diseases; Hypertension, Pulmonary; Male; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Pulmonary artery hypertension (PAH) is a significant cause of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). The phosphodiesterase-5 inhibitor sildenafil may be beneficial as a pulmonary vasodilator in CDH. Use of oral preparations of sildenafil may be restricted by feeding delays and intolerance. This study assessed the cardiorespiratory effects of a newly available intravenous (IV) preparation of sildenafil in CDH.. The objective of the article is to assess the acute effects of IV sildenafil infusion on myocardial function, pulmonary artery pressure (PAP), and oxygenation in infants with CDH.. Retrospective case review of infants with CDH who received continuous IV sildenafil. Physiological and echocardiographic data were reviewed to obtain oxygenation index (OI), PAP, patent ductus arteriosus (PDA) flow, myocardial tissue Doppler velocities, and right ventricular output (RVO) at 48 hours presildenafil, and at 24 to 48 hours and 72 to 96 hours after commencing IV sildenafil.. A total of nine infants received IV sildenafil at a dose of 100 to 290 μg/kg/h after CDH repair but before enteral feeding. Pre-IV sildenafil PAP was ≥ systemic blood pressure in all infants, systolic and diastolic right ventricular myocardial velocities were impaired. After 72 to 96 hours of IV sildenafil, OI and Fio 2 were significantly reduced. Ratio of right-to-left to left-to-right PDA flow was > 1 pre-IV sildenafil and < 1 post-IV sildenafil.. IV sildenafil infusion was associated with improved oxygenation. Prospective trials of IV sildenafil are required to determine effects on longer term outcome.

Topics: Blood Flow Velocity; Blood Pressure; Cardiac Output; Coronary Circulation; Female; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infusions, Intravenous; Male; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Retrospective Studies; Sildenafil Citrate; Ultrasonography; Vasodilator Agents

Sarcoidosis is a pleomorphic disease that can present with pulmonary hypertension (PH). What little information is available about the association of these two diseases comes mainly from small series of patients scheduled for transplant. We present 4 cases of mild pulmonary involvement in whom right catheterisation was performed and PH-specific therapy was administered. After obtaining written consent, a genetic study was performed that showed mutations in PH-related genes in 3 of the patients. This is the first study of its kind to yield genetic information for this type of PH.

Topics: Bone Morphogenetic Protein Receptors, Type II; Bosentan; Disease Progression; Epoprostenol; Fatal Outcome; Female; Humans; Hypertension, Pulmonary; Kv1.5 Potassium Channel; Male; Middle Aged; Mutation; Phenylpropionates; Point Mutation; Pyridazines; Respiratory Function Tests; RNA, Messenger; Sarcoidosis; Sildenafil Citrate; Sulfonamides; Tadalafil; Treatment Outcome

Two phosphodiesterase-type 5 (PDE-5) inhibitors, sildenafil and tadalafil, are approved for treatment of pulmonary arterial hypertension (PAH). It has not yet been observed if transition from sildenafil to tadalafil is beneficial in patients suffering from adverse reactions. Aim of this study was to analyze safety and long-term effects in PAH patients whose treatment was transitioned from sildenafil to tadalafil due to intolerable side-effects.. A retrospective analysis of PAH-patients who were stable on sildenafil for >3 months and transitioned to tadalafil due to adverse events was performed. Data collected included demographics, PAH-etiology, WHO-functional class, 6 min walking distance (6MWD), echocardiography, lung function tests, and NTproBNP pre-transition and 3, 6, and 12 months post-transition.. Included were 13 PAH patients (8 females mean age 64 ± 10 years) who had been on sildenafil for a mean of 12 ± 8.4 months. In six patients (46.1 %) a switch to tadalafil was feasible and resulted in tolerable side effects and a stable clinical course with improvement of symptoms, 6MWD, stable echocardiographic findings, and NTproBNP-levels during a follow-up of 11 ± 3 months. In 5 out of 13 patients (38.5 %) adverse events occurred under tadalafil as well and therapy with PDE-5 inhibitors was discontinued. In two patients (15.4 %) sildenafil-treatment could be successfully restarted after an intermittent switch to tadalafil.. The observations of this study indicate that a transition of sildenafil to tadalafil in case of intolerable side effects is a reasonable therapy option in about 50 % of the patients. These results should be verified by a larger prospective study.

Topics: Aged; Antihypertensive Agents; Arterial Pressure; Carbolines; Drug Substitution; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Tadalafil; Time Factors; Treatment Outcome

Chronic neonatal pulmonary hypertension frequently culminates in right ventricular (RV) failure and death. In juvenile rats, RV systolic dysfunction secondary to chronic hypoxia is rescued by systemic treatment with a Rho kinase (ROCK) inhibitor. To explore the relationship between ROCK inhibitor-mediated decreases in pulmonary vascular resistance and pressure, RV hypertrophy, and systolic dysfunction, we compared the effects of systemically administered to inhaled (pulmonary-selective) ROCK inhibitor on RV systolic function. Rat pups were exposed to air or hypoxia (13% O2) from Postnatal Days 1 to 21 and received rescue treatment with aerosolized fasudil (200 mM) for 15 minutes three times daily or intraperitoneal Y27632 (15 mg/kg twice daily) from Days 14 to 21. Chronic hypoxia differentially increased RhoA and ROCK activity in the right, but not left, cardiac ventricle. Inhaled ROCK inhibitor normalized pulmonary vascular resistance and caused regression of RV hypertrophy and pulmonary arterial wall remodeling but did not improve RV systolic dysfunction (decreased stroke volume and tricuspid annular plane systolic excursion). Systemic, but not inhaled, ROCK inhibitor normalized up-regulated ROCK and phosphodiesterase 5 activities in the right ventricle. Treatment with sildenafil (100 mg/kg/d intraperitoneally from Days 14 to 21) improved RV systolic function. Collectively, these data indicate that pressure unloading and regressed arterial and cardiac remodeling did not lead to recovery of systolic function while right ventricular ROCK activity remained increased. Right ventricle-specific up-regulation of RhoA/ROCK activity is critical to hypoxia-mediated systolic dysfunction, in part by regulating the activity of phosphodiesterase 5.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Piperazines; Purines; Rats; rho-Associated Kinases; rhoA GTP-Binding Protein; Sildenafil Citrate; Sulfonamides; Vascular Resistance; Ventricular Dysfunction, Right

Topics: Aged; Atrial Fibrillation; Biological Availability; Catheter Ablation; Echocardiography; Female; Heart Atria; Humans; Hypertension, Pulmonary; Pulmonary Wedge Pressure; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a sickness with high rate of mortality that consists of elevation in pressure of the vessels through which blood flows to the lung. Sildenafil is a therapeutic option for the treatment of PAH in children for the fact that it relaxes the blood vessels and thereby improves pulmonary blood flow. The aim was to analyze the clinical behavior of an extemporaneous formulation of sildenafil as a therapeutic option in children with PAH, twelve children with PAH were studied. The ages and weights of the children ranged from 5 to 15 years and from 13 to 27 kg. All patients received a capsule of 1 mg/kg of sildenafil prepared as extemporaneous formulation in the pharmacology laboratory. Blood levels of sildenafil were analyzed in order to evaluate its availability of developed formulation. Management has derived from physiopathological knowledge and clinical presentations of patients. The mean maximum concentration was 550 ng/ml which is greater than levels reported in adults. Moreover, a therapeutic monitoring of sildenafil was carried out in order to establish an adequate therapeutic range for children and to show that dosages prepared extemporaneously meet the therapeutic needs for the management of PAH. With an average follow-up of once every 2 months, it was found that the evolution of the patients was favorable and without adverse effects that could put their life at risk. The management of PAH with sildenafil prepared as extemporaneous formulation might be considered as a good therapeutic option.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Compounding; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Sildenafil Citrate; Time Factors; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is one of the long-term complications of HIV infection. The incidence of HIV-PAH is estimated at 0.5% of HIV-infected individuals. The mechanism by which infection leads to full-blown PAH is unknown. We describe a 44-year-old female patient with HIV infection diagnosed in 2004. Pulmonary hypertension was diagnosed in 2006. Seven months after the first cardiovascular clinical signs had started, the patient was referred to hospital because she was in New York Heart Association functional class IV. She commenced treatment with sildenafil. After increasing the sildenafil dose to ensure therapeutic drug levels over 24 h, the PAH and physical performance of the patient improved significantly. Our experience confirms long-term benefits of sildenafil monotherapy in PAH-HIV adult patients with improvements in symptoms and echocardiographic findings.

Topics: Adult; Female; HIV Infections; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

We describe two cases of pulmonary arterial hypertension (PAH) that occurred under dasatinib treatment and were resolved after dasatinib discontinuation. Two patients with chronic phase chronic myeloid leukemia (CML) were switched to dasatinib therapy because of hematological progress while receiving imatinib. These patients had New York Heart Association (NYHA) functional class II dyspnea with elevated right ventricular systolic pressure (RVSP), which progressed under dasatinib treatment. After dasatinib treatment was discontinued, subjective symptoms were improved to NYHA functional class I and the follow-up transthoracic Doppler echocardiography showed improved RVSP. Treatment with an alternate tyrosine kinase inhibitor was initiated and had been continued without development of dyspnea or elevation of RVSP. This report suggests that dasatinib can cause the reversible PAH, therefore, routine cardiopulmonary evaluation before and during treatment with dasatinib may be needed in CML patients with clinical manifestations.

Topics: Adult; Antihypertensive Agents; Antineoplastic Agents; Calcium Channel Blockers; Dasatinib; Diuretics; Humans; Hypertension, Pulmonary; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Sildenafil Citrate; Vasodilator Agents

Symptoms in patients with chronic thromboembolic pulmonary hypertension (CTEPH) predominantly occur during exercise, while haemodynamic assessment is generally performed at rest. We hypothesised that exercise imaging of RV function would better explain exercise limitation and the acute effects of pulmonary vasodilator administration than resting measurements.. Fourteen patients with CTEPH and seven healthy control subjects underwent cardiopulmonary testing to determine peak exercise oxygen consumption (VO2peak) and ventilatory equivalent for carbon dioxide (VE/VCO2) at the anaerobic threshold. Subsequently, cardiac MRI was performed at rest and during supine bicycle exercise with simultaneous invasive measurement of mean pulmonary arterial pressure (mPAP) before and after sildenafil.. During exercise, patients with CTEPH had a greater increase in the ratio of mPAP relative to cardiac output (CO) than controls (6.7 (5.1-8.7) vs 0.94 (0.86-1.8) mm Hg/L/min; p < 0.001). Stroke volume index (SVi) and RVEF increased during exercise in controls, but not in patients with CTEPH (interaction p < 0.001). Sildenafil decreased the mPAP/CO slope and increased SVi and RVEF in patients with CTEPH (p < 0.05) but not in controls. In patients with CTEPH, RVEF reserve correlated moderately with VO2peak (r = 0.60; p = 0.030) and VE/VCO2 (r = -0.67; p = 0.012). By contrast, neither VO2peak nor VE/VCO2 correlated with resting RVEF.. Exercise measures of RV function explain much of the variance in the exercise capacity of patients with CTEPH while resting measures do not. Sildenafil increases SVi during exercise in patients with CTEPH, but not in healthy subjects.

Topics: Chronic Disease; Exercise; Exercise Test; Female; Heart Ventricles; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Oxygen Consumption; Piperazines; Pulmonary Embolism; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vasodilator Agents; Ventricular Function, Right

Topics: Adult; Antihypertensive Agents; Female; Humans; Hypertension, Pulmonary; Sildenafil Citrate; Vasodilator Agents; Ventricular Dysfunction, Right

Topics: Bronchopulmonary Dysplasia; Echocardiography; Humans; Hypertension, Pulmonary; Infant, Newborn; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfonamides; Treatment Outcome

This study investigated the clinical value of plasma asymmetrical dimethyl-L-arginine (ADMA) level in the diagnosis, staging, and treatment response in congenital heart disease (CHD) patients with pulmonary arterial hypertension (PAH). This was a single-center prospective observational study in 80 CHD patients. Plasma ADMA levels were measured by enzyme-linked immunosorbent assay. Plasma ADMA levels were significantly increased in CHD patients with PAH compared with CHD patients without PAH (P < 0.01) and healthy controls (P < 0.001). In CHD patients with severe PAH, plasma ADMA levels were significantly higher in patients with Eisenmenger's syndrome (ES) than in patients exhibiting low pulmonary vascular resistance (P < 0.001). The plasma ADMA levels significantly correlated with pulmonary arterial pressure (P < 0.001) and pulmonary vascular resistance (P < 0.001) in patients with CHD. Severe PAH was identified by plasma ADMA with a cutoff value of 0.485 μmol/L (P < 0.001) with a specificity of 82.8 % and a sensitivity of 90 %. ES was identified by plasma ADMA with a cutoff value of 0.85 μmol/L (P < 0.05) with a specificity of 85.2 % and a sensitivity of 64.3 %. ADMA levels were significantly decreased after sildenafil therapy for 6 months compared with before therapy levels (0.91 ± 0.22 vs. 0.57 ± 0.30, P < 0.01). Our study suggests that plasma ADMA level may be used as a biomarker for identifying PAH in patients with CHD, assessing pulmonary vascular remodeling, and evaluating the treatment response of CHD patients with PAH to sildenafil.

Topics: Adult; Arginine; Biomarkers; Female; Follow-Up Studies; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies; Pulmonary Artery; Sildenafil Citrate; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Young Adult

Sildenafil is a pulmonary anti-hypertensive agent whose action could be modified by different fractions of inspired oxygen (FiO2). We compared the effects of pure oxygen (FiO2 > 90%) or room air (21% FiO2) on the cardiopulmonary actions of sildenafil in sheep with acute pulmonary embolism (APE).. Thirty-two anesthetized, mechanically ventilated sheep (34.9 ± 5.4 kg), were randomly distributed into four groups (n = 8 per group): FiO2 > 90% without intervention; APE induced by microspheres with FiO2 > 90%, followed 30 min later by placebo (Emb90); or APE followed 30 min later by intravenous sildenafil (0.7 mg/kg over 30 min) with FiO2 > 90% (Emb + Sild90) or 21% FiO2 (Emb + Sild21) [Corrected]. Variables were recorded until 30 min after the end of treatment administration.. Microsphere injection increased (P < 0.05) mean pulmonary artery pressure (MPAP) in all embolized groups (111-140% higher than that of baseline). Compared with values recorded 30 min after induction of APE (E30), sildenafil induced greater decreases in MPAP in the Emb + Sil90 group than in the Emb + Sil21 group (23% and 14% lower than E30, respectively). Hypotension (mean arterial pressure < 60 mm Hg) was precipitated by sildenafil due to systemic vasodilation in the Emb + Sil21 group. Embolization lowered the PaO2/FiO2 ratio and increased venous admixture, but sildenafil did not alter the oxygenation impairment induced by APE.. Sildenafil induces a more consistent pulmonary anti-hypertensive effect and causes less interference with the systemic circulation with the concomitant use of pure oxygen than that with room air in the APE setting.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cardiac Output; Heart Rate; Hypertension, Pulmonary; Oxygen; Piperazines; Pulmonary Embolism; Pulmonary Wedge Pressure; Purines; Respiratory Mechanics; Sheep; Sildenafil Citrate; Sulfonamides; Vascular Resistance

Topics: Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Sildenafil Citrate; Vasodilator Agents

Bronchopulmonary dysplasia (BPD) is associated with a high incidence of pulmonary artery hypertension (PAH) and is frequently treated with sildenafil. The objective was to investigate the echocardiographic and clinical efficacy and safety of sildenafil in this setting. The hypothesis was that treatment would result in significant echocardiographic and clinical improvements. This was a retrospective study of the cohort of infants who were born between 2004 and 2012 and administered sildenafil as in-patients for BPD-associated PAH. Medical records and archived echocardiographic data were reviewed. Twenty-two infants fulfilled the inclusion criteria and had a mean (±SD) gestation age and birth weight of 25.6 (±1.3) weeks and 631 (±181) g, respectively. Six (27 %) infants died before discharge (predominantly due to respiratory failure; in three of them, a concomitant viral respiratory infection was thought to be an aggravating factor). Amongst survivors, no mortality was noted up to 1 year follow-up. Significant improvement in echocardiographic markers of pulmonary hypertension was noted in the echocardiogram performed 27.5 days (interquartile range 24, 31) post-initiation of therapy, two thirds showing ≥20 % decline in the right ventricular systolic pressure. Left ventricular fractional shortening did not alter significantly. At initiation, all infants had 'severe' BPD. The fraction of inspired oxygen (FiO2) decreased significantly from 0.57 (SE ± 0.05) to 0.42 (SE ± 0.03) (p = 0.02), and no significant alteration was noted over the timeframe in mean pCO2 (64.4 ± 3.3 to 63.2 ± 3.3 mmHg). The number of infants needing endotracheal intubation and mechanical ventilation decreased (from 3 to 1) over the same time. No serious adverse effects were noted.. Sildenafil therapy was associated with a significant improvement in the echocardiographic markers of PAH and a reduction in FiO2. The medication was well tolerated.

Topics: Blood Pressure; Bronchopulmonary Dysplasia; Echocardiography; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Phosphodiesterase 5 Inhibitors; Retrospective Studies; Sildenafil Citrate; Time Factors; Treatment Outcome; Ventricular Function, Left

Patients with normalized mean pulmonary artery pressure (mPAP) after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) do not always regain normal exercise capacity. We evaluated right ventricular function, its interaction with both pulsatile and resistive afterload, and the effect of sildenafil during exercise in these patients.. Fourteen healthy controls, 15 CTEPH patients, and 7 patients with normalized resting mPAP (≤25 mm Hg) post-PEA underwent cardiopulmonary exercise testing, followed by cardiac magnetic resonance imaging with simultaneous invasive mPAP measurement during incremental supine cycling exercise. Peak oxygen consumption and peak heart rate were significantly reduced in post-PEA and CTEPH patients compared to controls. The mPAP-cardiac output slope was steeper in post-PEA patients than in controls and similar to CTEPH. Relative to controls, resting right ventricular ejection fraction was reduced in CTEPH, but not in post-PEA patients. In contrast, peak exercise right ventricular ejection fraction was reduced both in post-PEA and CTEPH patients. Exercise led to reduction of pulmonary arterial compliance in all groups. Nevertheless, resting pulmonary arterial compliance values in CTEPH and post-PEA patients were even lower than those in controls at peak exercise. In post-PEA patients, sildenafil did not affect resting hemodynamics nor right ventricular function, but decreased the mPAP/cardiac output slope and increased peak exercise right ventricular ejection fraction.. Exercise intolerance in post-PEA patients is explained by abnormal pulmonary vascular reserve and chronotropic incompetence. The mPAP/cardiac output slope and pulmonary arterial compliance are sensitive measures demonstrating abnormal resistive and pulsatile pulmonary vascular function in post-PEA patients. These abnormalities are partially attenuated with sildenafil.

Topics: Adult; Aged; Arterial Pressure; Bicycling; Case-Control Studies; Catheterization, Swan-Ganz; Chronic Disease; Compliance; Endarterectomy; Exercise Test; Exercise Tolerance; Female; Heart Rate; Hemodynamics; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Predictive Value of Tests; Pulmonary Artery; Pulmonary Embolism; Recovery of Function; Risk Factors; Sildenafil Citrate; Stroke Volume; Treatment Outcome; Ventricular Function, Right; Young Adult

This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed.

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Nicorandil; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Pyridazines; Rats, Wistar; Recovery of Function; Severity of Illness Index; Sildenafil Citrate; Vasodilator Agents; Ventricular Dysfunction, Right; Ventricular Function, Right

Pulmonary arterial hypertension (PAH) can be a complication in patients with connective tissue disease (CTD). Although the phosphodiesterase-5 inhibitor sildenafil shows evidence of efficacy and tolerability among patients with PAH associated with CTD in clinical trials, no studies have examined the association between its use and health care resource utilization in clinical practice. The objective of this study was to assess the associations between the use of sildenafil and health care resource utilization, specifically days of hospitalization, in a population with PAH associated with CTD.. A retrospective, matched, case-control analysis was conducted using data from a commercial claims database. Patients with a claim dated between 2003 and 2009 were selected. Cases and controls were matched on age, sex, and baseline total days of hospitalization. A longitudinal, zero-inflated, negative binomial model was used for analyzing the data after control for age, sex, region, Charlson comorbidity score, and use of PAH-specific medication other than sildenafil.. A total of 420 individuals, 210 cases and 210 controls, were included in the sample. The sample was 85.71% women, and the mean age was 57.6 years. Estimates for variances of an intercept random effect (5.08 × 10(-13)) and for a time-variable random effect (2.84 × 10(-16)) were both essentially zero. Thus a zero-inflated negative binomial model without random effects was used. When individuals were not using sildenafil, each 1-month interval was associated with a 2.8% increase in the mean number of days of hospitalization. In contrast, when individuals were using sildenafil, each 1-month interval was associated with a decrease of 3.3% in days of hospitalization.. In this data analysis of the association between sildenafil use and days of hospitalization among individuals with PAH associated with CTD in a large-scale population, sildenafil use in the treatment of PAH associated with CTD was associated with reduced days of hospitalization during the year after the initiation of treatment.

Topics: Adult; Aged; Connective Tissue Diseases; Female; Health Resources; Hospitalization; Humans; Hypertension, Pulmonary; Length of Stay; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Retrospective Studies; Sildenafil Citrate; United States; Vasodilator Agents

Sildenafil, a phosphodiesterase-5 inhibitor, is a controversial treatment option for pulmonary arterial hypertension (PAH), a significant complication of bronchopulmonary dysplasia (BPD). The objective of this study was to evaluate the use of sildenafil in infants with PAH secondary to BPD. This was a retrospective review of medical records of all premature infants with PAH associated with BPD treated with sildenafil between January 2009 and May 2013 in a level 3 neonatal intensive care unit. The primary outcomes were clinical response (20 % decreases in respiratory support score or oxygen requirements) and echocardiographic response (20 % decrease in tricuspid regurgitation gradient or change of at least 1° of septal flattening). Twenty-three infants were included in the study. Significant echocardiographic and clinical responses were, respectively, observed in 71 and 35 % of cases. Most clinical responses were observed in the first 48 h of treatment, and the median time to an echocardiographic response was of 19 days. The median dose of sildenafil used was 4.4 mg/kg/day, with a median time to reach the maximum dose of 9 days. Transient hypotension was the primary reported side effect, and it was observed in 44 % of our study population. Sildenafil treatment in patients with PAH secondary to BPD was associated with an echocardiographic improvement in the majority of patients, whereas clinical improvement was observed in a minority of patients. Many infants presented with transient hypotension during the course of the treatment. Further prospective studies are required to better assess safety and efficacy of this treatment in this population.

Topics: Bronchopulmonary Dysplasia; Dose-Response Relationship, Drug; Echocardiography; Female; Humans; Hypertension, Pulmonary; Hypotension; Infant; Infant, Newborn; Intensive Care, Neonatal; Male; Oxygen; Phosphodiesterase 5 Inhibitors; Respiratory Rate; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Tricuspid Valve Insufficiency

Closure of congenital atrial communications in the presence of either severe pulmonary arterial hypertension (PAH) with pulmonary-to-systemic (right-to-left) shunting, or severe left ventricular (LV) non-compliance with left-to-right shunting is often considered prohibitive. Thus, the recognition of durable reversibility of these physiologic conditions is crucial. We describe a hemodynamic conundrum in a patient with five septal communications in whom the coexistence of unmasked bidirectional physiologic shunting, severe PAH, and worsening left-sided overload dissuaded initial closure. We report our strategy for hemodynamic evaluation and successful closure of all defects.

Topics: Balloon Occlusion; Cardiac Catheterization; Dyspnea; Echocardiography, Transesophageal; Heart Septal Defects, Atrial; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Septal Occluder Device; Sildenafil Citrate; Ventricular Dysfunction, Left

Pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) affect 25-35% of premature infants with significant bronchopulmonary dysplasia (BPD), increasing morbidity and mortality. We sought to determine the role of phosphodiesterase 5 (PDE5) in the right ventricle (RV) and left ventricle (LV) in a hyperoxia-induced neonatal mouse model of PH and RVH. After birth, C57BL/6 mice were placed in room air (RA) or 75% O2 (CH) for 14 days to induce PH and RVH. Mice were euthanized at 14 days or recovered in RA for 14 days or 42 days prior to euthanasia at 28 or 56 days of age. Some pups received sildenafil or vehicle (3 mg·kg(-1)·dose(-1) sc) every other day from P0. RVH was assessed by Fulton's index [RV wt/(LV + septum) wt]. PDE5 protein expression was analyzed via Western blot, PDE5 activity was measured by commercially available assay, and cGMP was measured by enzyme-linked immunoassay. Hyperoxia induced RVH in mice after 14 days, and RVH did not resolve until 56 days of age. Hyperoxia increased PDE5 expression and activity in RV, but not LV + S, after 14 days. PDE5 expression normalized by 28 days of age, but PDE5 activity did not normalize until 56 days of age. Sildenafil given during hyperoxia prevented RVH, decreased RV PDE5 activity, and increased RV cGMP levels. Mice with cardiac-specific overexpression of PDE5 had increased RVH in RA. These findings suggest normal RV PDE5 function is disrupted by hyperoxia, and elevated PDE5 contributes to RVH and remodeling. Therefore, in addition to impacting the pulmonary vasculature, sildenafil also targets PDE5 in the neonatal mouse RV and decreases RVH.

Topics: Animals; Animals, Newborn; Antihypertensive Agents; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Down-Regulation; Heart Ventricles; Hyperoxia; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Mice, Inbred C57BL; Mice, Transgenic; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Second Messenger Systems; Sildenafil Citrate; Sulfonamides; Time Factors; Ventricular Function, Right; Ventricular Remodeling

We describe the case of a 54-year-old man who presented with exertional dyspnea and fatigue that had worsened over the preceding 2 years, despite a normally functioning bioprosthetic aortic valve and stable, mild left ventricular dysfunction (left ventricular ejection fraction, 0.45). His symptoms could not be explained by physical examination, an extensive biochemical profile, or multiple cardiac and pulmonary investigations. However, abnormal cardiopulmonary exercise test results and a right heart catheterization-combined with the use of a symptom-limited, bedside bicycle ergometer-revealed that the patient's exercise-induced pulmonary artery hypertension was out of proportion to his compensated left heart disease. A trial of sildenafil therapy resulted in objective improvements in hemodynamic values and functional class.

Topics: Antihypertensive Agents; Cardiac Catheterization; Exercise; Exercise Test; Exercise Tolerance; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Point-of-Care Testing; Predictive Value of Tests; Sildenafil Citrate; Stroke Volume; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Amlodipine; Antihypertensive Agents; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Macular Edema; Metoprolol; Middle Aged; Phosphodiesterase 5 Inhibitors; Retinal Detachment; Sildenafil Citrate; Vision Disorders

Topics: Blood Transfusion; Bosentan; Diagnostic Imaging; Dobutamine; Ductus Arteriosus, Patent; Eisenmenger Complex; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Menorrhagia; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Tomography, X-Ray Computed; Vasodilator Agents; Young Adult

Ascorbic acid bound to KMUP-1 and sildenafil were examined for their antioxidant effects on vascular endothelium growth factor (VEGF) and endothelium nitric oxide synthase (eNOS) in hypoxic pulmonary artery (PA). Inhaled KMUP-1 and oral sildenafil released NO from eNOS. The effect of buffered l-ascorbic acid, alone and bound to KMUP-1 or sildenafil, for treating pulmonary arterial hypertension (PAH) is unclear. In this study, the antioxidant capacity of ascorbic acid increased the beneficial effects of KMUP-1 on PAH. KMUP-1A and sildenafil-A (5 mg/kg/d) were administered to hypoxic PAH rats. Pulmonary artery blood pressure, and VEGF, Rho kinase II (ROCK II), eNOS, soluble guanylate cyclase (sGC-α), and protein kinase G expression in lung tissues were measured to link PAH and right ventricular hypertrophy. Hypoxic rats had higher pulmonary artery blood pressure, greater PA medial wall thickness and cardiac weight, and a higher right ventricle/left ventricle + septum [RV/(LV+S)] ratio than normoxic rats. Oral KMUP-1A or sildenafil-A for 21 days in hypoxia prevented the rarefaction of eNOS in immunohistochemistry (IHC), reduced the IHC of VEGF in PAs, restored eNOS/protein kinase G/phosphodiesterase 5A; unaffected sGC-α and inactivated ROCK II expression were also found in lung tissues. In normoxic PA, KMUP-1A/Y27632 (10μM) increased eNOS and reduced ROCK II. ROCK II/reactive oxidative species was increased and eNOS was reduced after long-term hypoxia for 21 days. KMUP-1A or Y27632 blunted ROCK II in short-term hypoxic PA at 24 hours. l-Ascorbic acid + l-sodium ascorbate (40, 80μM) buffer alone directly inhibited the IHC of VEGF in hypoxic PA. Finally, KMUP-1A or sildenafil-A reduced PAH and associated right ventricular hypertrophy.

Topics: Amides; Animals; Ascorbic Acid; Endothelium, Vascular; Hypertension, Pulmonary; Hypoxia; Male; Nitric Oxide Synthase Type III; Piperidines; Pulmonary Artery; Pyridines; Rats; Sildenafil Citrate; Vascular Endothelial Growth Factors; Xanthines

Sildenafil, a phosphodiesterase-5 inhibitor used to treat pulmonary hypertension, may have effects on pulmonary vessel structure and function. We evaluated the effects of sildenafil in a cigarette smoke (CS)-exposed model of chronic obstructive pulmonary disease (COPD).42 guinea-pigs were exposed to cigarette smoke or sham-exposed and treated with sildenafil or vehicle for 12 weeks, divided into four groups. Assessments included respiratory resistance, pulmonary artery pressure (PAP), right ventricle (RV) hypertrophy, endothelial function of the pulmonary artery and lung vessel and parenchymal morphometry.CS-exposed animals showed increased PAP, RV hypertrophy, raised respiratory resistance, airspace enlargement and intrapulmonary vessel remodelling. CS exposure also produced wall thickening, increased contractility and endothelial dysfunction in the main pulmonary artery. CS-exposed animals treated with sildenafil showed lower PAP and a trend to less RV hypertrophy than CS-exposed only animals. Furthermore, sildenafil preserved the intrapulmonary vessel density and attenuated the airspace enlargement induced by CS. No differences in gas exchange, respiratory resistance, endothelial function and vessel remodelling were observed.We conclude that in this experimental model of COPD, sildenafil prevents the development of pulmonary hypertension and contributes to preserve the parenchymal and vascular integrity, reinforcing the notion that the nitric oxide-cyclic guanosine monophosphate axis is perturbed by CS exposure.

Topics: Animals; Disease Models, Animal; Guinea Pigs; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Sildenafil Citrate; Tobacco Smoke Pollution

Recent vasodilating drugs have improved prognosis of Pulmonary arterial hypertension (PAH). Some reports describe the merits of combination therapies for PAH, and this study evaluated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5i) combination therapy, using sildenafil and tadalafil, for multi-drug-resistant PAH.. We retrospectively analyzed 7 consecutive refractory patients with PAH administered either sildenafil 60 mg or tadalafil 40 mg as well as both ERA and prostanoid as combination therapies. All were started on the dual PDE5i (sildenafil and tadalafil at maximum dose).. Treatment was generally well tolerated without severe adverse events. On completion of the study, the seven patients received right heart catheterization and the 6-minute walk test (6WMT) 9.6 ± 1.4 months after initiation of the dual PDE5i therapy, showing significant improvements in hemodynamic parameters and exercise tolerance. Mean pulmonary arterial pressure and pulmonary vascular resistance decreased from 47.9 ± 9.7 to 41.7 ± 9.2 mmHg (P = 0.004) and 9.3 ± 2.7 to 6.7 ± 2.9 mmHg (P = 0.018), respectively. Cardiac index and 6MWT also increased from 2.8 ± 0.9 to 3.1 ± 0.8 L/min/m(2) (P = 0.026) and 353 ± 60 to 382 ± 62 m (P = 0.014), respectively.. The findings support dual PDE5i therapy as a new treatment option for refractory PAH.

Topics: Adult; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pilot Projects; Prostaglandins; Pulmonary Wedge Pressure; Pyridazines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Tadalafil; Treatment Outcome; Vascular Resistance; Young Adult

Pulmonary arterial hypertension is a severe disease with a complex pathogenesis, for which combination therapy is an attractive option.This study aimed to assess the impact of sequential combination therapy on both short-term responses and long-term outcomes in a real-world setting.Patients with idiopathic/heritable pulmonary arterial hypertension, or pulmonary arterial hypertension associated with congenital heart disease or connective tissue disease and who were not meeting treatment goals on either first-line bosentan or sildenafil monotherapy, were given additional sildenafil or bosentan and assessed after 3-4 months. Double combination therapy significantly improved clinical and haemodynamic parameters, independent of aetiology or the order of drug administration. Significant improvements in functional class were observed in patients with idiopathic/heritable pulmonary arterial hypertension. The 1-, 3- and 5-year overall survival estimates were 91%, 69% and 59%, respectively. Patients with pulmonary arterial hypertension associated with connective tissue disease had significantly poorer survival rates compared to other aetiologies (p<0.003).The favourable short-term haemodynamic results and good survival rates, observed in patients receiving both bosentan and sildenafil, supports the use of sequential combination therapy in patients failing on monotherapy in a real-world setting.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Bosentan; Cause of Death; Child; Connective Tissue Diseases; Drug Therapy, Combination; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Italy; Kaplan-Meier Estimate; Male; Middle Aged; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Survival Rate; Treatment Outcome; Vasodilator Agents; Young Adult

Pulmonary artery hypertension (PAH) is devastating disease that has very serious outcomes. Dysregulated angiogenesis is one of the main responsible courses in pathophysiology of disease. Our experimental research intends to find out and compare the angiogenic effects of medications used sildenafil, iloprost, and bosentan in the treatment of PAH.. This study was performed in Department of Biochemistry and Cancer and Stem Cell Research Laboratory of our institutes between August and October 2014. Angiogenic activity of sildenafil, iloprost, and bosentan were examined in vivo in chick chorioallantoic membrane (CAM) model and in vitro tube formation assay of human umbilical vein endothelial cells (HUVECs). Proliferative activity of these three agents was also determined through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on HUVECs.. In CAM assay, when compared to the control and drug groups, treatment with sildenafil solutions resulted in a significant dose-dependent increase (budding, sprouting, extravasation) on CAM vessel growth. While there was no significant proliferative effect with iloprost and bosentan, presence of sildenafil caused a statistically significant proliferation on HUVECs following 24 and 48 h incubation (p < 0.05) compared to the control group. Comparing the tube length/area ratio values, there was statistically significant increase in sildenafil group with respect to the other 2 groups (p < 0.05). Iloprost and bosentan did not show a significant effect.. The results provide evidence that sildenafil but not iloprost and bosentan induces angiogenesis in vitro and in vivo. Dysregulated angiogenesis, as an important pathophysiological part in the progression of PAH, may be triggered by the chronic ingestion of sildenafil in the long treatment period and may cause negative effects.

Topics: Angiogenesis Inducing Agents; Animals; Bosentan; Cell Proliferation; Chick Embryo; Dose-Response Relationship, Drug; Human Umbilical Vein Endothelial Cells; Humans; Hypertension, Pulmonary; Iloprost; Sildenafil Citrate; Sulfonamides

Hoarseness is a common phenomenon that can be caused by uncommon pathology. One seldom cause is Ortner's syndrome, a rare cardiovocal disease that can lead to hoarseness due to left recurrent laryngeal nerve palsy induced by mechanical compression of the nerve by cardiovascular structures. This case report describes a case of a 41-year-old woman with sudden onset of hoarseness. The patient had known pulmonary hypertension and Eisenmenger's syndrome.

Topics: Adult; Antihypertensive Agents; Cardiac Catheterization; Eisenmenger Complex; Female; Hoarseness; Humans; Hypertension, Pulmonary; Laryngoscopy; Phenylpropionates; Piperazines; Pulmonary Artery; Purines; Pyridazines; Recurrent Laryngeal Nerve; Sildenafil Citrate; Sulfonamides; Syndrome; Tomography, X-Ray Computed; Vocal Cord Paralysis

Topics: Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Topics: Antihypertensive Agents; Bosentan; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

There is no recommendation for treating pulmonary hypertension (PH) when associated with chronic obstructive pulmonary disease (COPD).. To evaluate the effect of PH-specific therapy in patients with COPD.. All successive patients with severe PH [mean pulmonary arterial pressure (mPAP) ≥35 mm Hg] and COPD, who received specific PH medication and who underwent right heart catheterization at baseline and after 3-12 months of treatment, were analyzed from a prospective database.. Twenty-six patients were included with a median follow-up of 14 months. Mean forced expiratory volume in 1 s was 57 ± 20% of predicted, and mean forced expiratory volume in 1 s/forced vital capacity was 47 ± 12%. Dyspnea was New York Health Association classification stage (NYHA) II in 15%, NYHA III in 81% and NYHA IV in 4%. First-line treatments were endothelin receptor antagonists in 11 patients, phosphodiesterase-5 inhibitors in 11 patients, calcium blocker in 1 patient, combination therapy in 3 patients including 2 with a prostanoid. After 6 ± 3 months, pulmonary vascular resistance decreased from 8.5 ± 3 to 6.6 ± 2 Wood units (p < 0.001), with significant improvement of cardiac index from 2.44 ± 0.43 to 2.68 ± 0.63 liters × min × m-2 (p = 0.015) and mPAP from 48 ± 9 to 42 ± 10 mm Hg (p = 0.008). There was no significant difference in dyspnea, 6-min walking distance, echocardiographic parameters or N-terminal pro-brain natriuretic peptide levels. There was no significant difference in arterial oxygen saturation after 3-12 months of treatment.. Specific PH medications may improve hemodynamic parameters in COPD patients with severe PH. Appropriate prospective randomized studies are needed to evaluate the potential long-term clinical benefit of treatment.

Topics: Aged; Bosentan; Cohort Studies; Comorbidity; Female; Follow-Up Studies; France; Hemodynamics; Hospitals, University; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Statistics, Nonparametric; Sulfonamides; Treatment Outcome; Vascular Resistance; Vasodilator Agents

To describe clinical canine patients with naturally occurring pulmonary hypertension and radiographic pulmonary alveolar infiltrates before and after treatment with sildenafil.. Ten client-owned dogs.. A retrospective analysis of dogs with echocardiographically-determined pulmonary hypertension and pulmonary alveolar infiltrates on thoracic radiographs was performed before (PRE) and after (POST) sildenafil therapy. Clinical scores, pulmonary alveolar infiltrate scores and tricuspid regurgitation gradients were analyzed PRE and POST sildenafil.. Pulmonary alveolar infiltrates associated with pulmonary hypertension developed in a diffusely patchy distribution (10/10). Sixty percent of dogs had a suspected diagnosis of interstitial pulmonary fibrosis as the etiology of pulmonary hypertension. Median PRE clinical score was 4 (range: 3-4) compared to POST score of 0 (0-2) (p = 0.005). Median alveolar infiltrate score PRE was 10 (5-12) compared to POST score of 4 (0-6) (p = 0.006). Median tricuspid regurgitation gradient PRE was 83 mmHg (57-196) compared to 55 mmHg POST (33-151) (p = 0.002).. A subset of dogs with moderate to severe pulmonary hypertension present with diffuse, patchy alveolar infiltrates consistent with non-cardiogenic pulmonary edema. The typical clinical presentation is acute dyspnea and syncope, often in conjunction with heart murmurs suggestive of valvular insufficiency. This constellation of signs may lead to an initial misdiagnosis of congestive heart failure or pneumonia; however, these dogs clinically and radiographically improve with the initiation of sildenafil.

Topics: Animals; Dog Diseases; Dogs; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pulmonary Alveoli; Pulmonary Fibrosis; Sildenafil Citrate

The study investigates whether combination therapy of sildenafil with imatinib at a low dose (20 mg/kg) further ameliorates pulmonary hypertension (PH) in rats. The effects on right ventricle pressure (RVP), and right ventricle hypertrophy (RVH) were assessed in experimental monocrotaline (MCT)-induced pulmonary hypertension. Combined therapy reversed the MCT-induced increase in RVP more than each drug alone and decreased RV hypertrophy (RV/LV+ S ratio), significantly. Such additive effects toward improvement of PH may result from both pharmacodynamic and pharmacokinetic drug-drug interactions, however, further studies are required to assess its mechanistic background.

Topics: Animals; Blood Pressure; Heart Rate; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Imatinib Mesylate; Male; Monocrotaline; Protein Kinase Inhibitors; Rats; Rats, Wistar; Sildenafil Citrate; Vasodilator Agents

Sildenafil citrate (SC) nebulization solution has the potential to treat pulmonary hypertension by delivering high concentration directly to the respiratory system while minimizing systemic drug exposure and associated toxicity. The objective of the present study was to evaluate the potential toxicity of aerosolized SC (inhaled) in Sprague dawley rats for 28 days.. The rats were randomly divided into five groups (n = 6). Placebo (normal saline) was inhaled to group I (control). Group II was exposed to therapeutic dose (TD): 20 mg/kg, while group 3 and group 4 were exposed to 3 TD and 6 TD, respectively, till 28 days and toxicokinetic parameters were evaluated in group V. The particle size of the nebulized solution of SC (1%) was measured by using Anderson Cascade Impactor. At the end of experiment, all animals were sacrificed. Endpoints used to evaluate potential toxicity of inhaled sildenafil citrate were clinical observations, body weight, and clinical pathology along with broncho-alveolar lavage (BAL) Fluid investigation.. ACI study has shown that more than 70% aerosolized drug particles were in submicron range (0.3-0.5 μm). There was no systemic toxicity or clinically limiting local respiratory toxicity associated with inhalation exposure to SC nebulization solution at 6 TD. No significant changes were observed in the level of different blood and BALF parameters in treated groups in comparison to control. Histopathological examination revealed no abnormal findings in the animals of treated group. The data demonstrate that aerosolized sildenafil citrate is well tolerated in rats and suggest its use in humans.

Topics: Administration, Inhalation; Aerosols; Animals; Hypertension, Pulmonary; Inhalation Exposure; Lung; Male; Particle Size; Rats; Rats, Sprague-Dawley; Sildenafil Citrate

Recent imaging studies demonstrated the usefulness of quantitative computed tomographic (CT) analysis assessing pulmonary hypertension (PH) in patients with chronic obstructive lung disease (COPD-PH). The aim of this study was to investigate whether it would be also valuable for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH.. We analyzed a correlation between the extent of cystic destruction (LAA%) and total cross-sectional areas of small pulmonary vessels less than 5 mm(2) (%CSA <5) in many CT slices from each of four COPD-PH patients before and after the initiation of pulmonary vasodilator. To evaluate those generalized data from patients with COPD, we evaluated multiple slices from 42 patients whose PH was not clinically suspicious. We also selected five PH patients with idiopathic interstitial pneumonia (IIP-PH) and analyzed serial changes of pulmonary artery enlargement (PA:A ratio).. In 42 COPD patients without PH, LAA% had a statistically significant negative correlation with %CSA <5. However, three of four COPD-PH patients manifested no such correlation. In two patients, clinical findings were dramatically improved after the initiation of pulmonary vasodilator. Notably, LAA% and %CSA <5 in those patients correlated significantly after its treatment. In COPD-PH, the PA:A ratio was significantly decreased after the initiation of pulmonary vasodilator therapy (1.25 ± 0.13 vs. 1.13 ± 0.11, p = 0.019), but not in IIP-PH.. Our study demonstrates that the use of quantitative CT analysis is a plausible and beneficial tool for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH.

Topics: Aged; Bosentan; Endothelin Receptor Antagonists; Exercise Test; Female; Forced Expiratory Volume; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Artery; Pulmonary Diffusing Capacity; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Sildenafil Citrate; Sulfonamides; Tadalafil; Tomography, X-Ray Computed; Vasodilator Agents; Vital Capacity

Endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitors (PDE5I) are long-term therapeutics for the treatment of pulmonary arterial hypertension (PAH). Their interindividual pharmacokinetic variability is remarkably large, and despite the seriousness of the disease, nonadherence is occurring. Therefore, methods to monitor sufficient circulating drug levels are essential. The objectives of this study were to develop and validate dried blood spot (DBS) assays for the quantification of ambrisentan, bosentan, sildenafil, tadalafil, and their main metabolites. We also quantified the influence of different hematocrit levels and assessed the correlation of simultaneously taken capillary whole blood (DBS) and venous plasma samples. The aliquot punches were extracted by liquid/liquid extraction followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) quantification methods. All assays fulfilled the requirements of the FDA and EMA guidelines for assay validation with a lower limit of quantification of 2.5 ng/mL for the ERAs, 5 ng/mL for sildenafil, and 10 ng/mL for tadalafil. All analytes were stable for at least 147 days when stored on DBS filter paper cards at room temperature in the dark. Due to poor distribution into erythrocytes, drug concentrations in DBS were always lower than in plasma, resulting in conversion factors of 1.58 for ambrisentan and sildenafil and 1.52 for bosentan and tadalafil.

Topics: Bosentan; Chromatography, Liquid; Dried Blood Spot Testing; Humans; Hypertension, Pulmonary; Limit of Detection; Phenylpropionates; Pyridazines; Reproducibility of Results; Sildenafil Citrate; Sulfonamides; Tadalafil; Tandem Mass Spectrometry

To investigate the application and value of pulmonary artery catheterization (PAC) in pregnant patients with pulmonary hypertension (PH).. The clinical data of pregnant patients with PH who were treated between 2006 and 2014 in surgical intensive care unit (SICU) at Capital Medical University affiliated Beijing Anzhen Hospital were retrospectively analysed. The differences of the clinical characteristics and outcome between PAC inserted patients and PAC not inserted patients were compared.. The systolic pulmonary artery pressure (sPAP) measured by preoperative echocardiography has no significant difference between the PAC inserted patients [(103.0 ± 24.1) mmHg (1 mmHg = 0.133 kPa)] and PAC not inserted patients [(96.4 ± 27.3) mmHg; P = 0.175]. SPAP may be overestimated or underestimated by echocardiography compared with PAC with a gap from -38.4 mmHg to 49.5 mmHg. The rates of idiopathic pulmonary arterial hypertension (20.0% vs 3.2%) and continuous use of epidural anesthesia (89.1% vs 65.1%) were higher in PAC inserted patients compared with PAC not inserted patients. Norepinephrine, dobutamine, sildenafil, alprostadil, iloprost and low molecular weight heparin were more widely used in PAC inserted patients. The mortality rate and the rates of low birth weight (63.9% vs 30.6%) and very low birth weight infants (19.4% vs 13.9%) were all higher in PAC inserted patients, while the rate of induced abortion was lower in this group (5.5% vs 17.5%). The length of stay in surgical intensive care unit [6.0 (5.0) d vs 1.0 (3.0) d], postoperative length of stay [8.0 (6.0) d vs 8.0 (4.0) d] and total hospital costs [43 999.22 (38 267.27) RMB vs 14 878.24 (10 564.47) RMB] were all higher in PAC inserted patients. The incidence rate of PAC related complications was 7.3%.. In moderate or severe PH pregnant patients with severe clinical symptoms, perioperative insertion of PAC helps to monitor the perinatal pulmonary arterial pressure(PAP) and guide treatment, potentially improving clinical outcomes and lowering the short term mortality. PAC can't be replaced by echocardiography in measuring PAP.

Topics: Beijing; Case-Control Studies; Catheterization, Swan-Ganz; Echocardiography; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Infant; Intensive Care Units; Peripartum Period; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pulmonary Artery; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

To investigate the effect of sildenafil on the survival of patients with pulmonary arterial hypertension (PAH) associated with connective tissue diseases (CTD), who have been followed up at the Rheumatology Expert Center.. A total of 16 patients (all women) with PAH associated with CTD, who had been admitted to the V. A. Nasonova Research Institute of Rheumatology in 2013-2015, were examined. PAH corresponded to Functional Class II in the majority of the patients. After the diagnosis was verified by catheterization of the right heart and pulmonary artery, all the patients received original sildenafil (a phosphodiesterase type 5 inhibitor, a potent vasodilator, the efficiency of which was proven in patients with PAH) at a dose of 20 mg thrice daily. Survival rates and time to clinical deterioration were estimated during a prospective follow-up).. Three-year survival rates were 94% in the study group and 25% in the group of historical control (p < 0.05). The time to clinical deterioration was associated with the duration of the follow-up and hemodynamic parameters (right atrial pressure and changes in vascular resistance within 4 months after therapy initiation).. The administration of sildenafil substantially improves survival in patients with PAH associated with CTD as compared with the historical control. The identification of poor prognostic factors in this cohort of patients and early diagnosis will favor the personification of therapy for the fatal manifestation of CTD.. Цель исследования. Изучить влияние силденафила на выживаемость пациентов с легочной артериальной гипертонией (ЛАГ), ассоциированной с системными заболеваниями соединительной ткани (СЗСТ), наблюдаемыми в ревматологическом экспертном центре. Материалы и методы. Обследовали 16 женщин с ЛАГ-СЗСТ, госпитализированных в ФГБНУ НИИР им. В.А.Насоновой в 2013-2015 гг. У большинства ЛАГ соответствовала II функциональному классу. После подтверждения диагноза при катетеризации правых отделов сердца и легочной артерии все пациентки получали оригинальный силденафил (ингибитор фосфодиэстеразы 5-го типа, мощный вазодилататор, эффективность которого доказана у пациентов с ЛАГ) 20 мг 3 раза в день. В процессе проспективного наблюдения оценивали выживаемость и время наступления клинического ухудшения. Результаты. Трехлетняя выживаемость в обследуемой группе составила 94%, в то время как в группе 'исторического' контроля - 25% (р<0,05). Время до наступления клинического ухудшения связано с длительностью наблюдения и гемодинамическими параметрами (давление в правом предсердии и динамика легочного сосудистого сопротивления в течение 4 мес от начала терапии). Заключение. Применение силденафила существенно улучшает выживаемость пациенток ЛАГ-СЗСТ по сравнению с 'историческим' контролем. Выявление факторов неблагоприятного прогноза у данной категории больных, а также ранняя диагностика будут способствовать персонификации терапии этого фатального проявления СЗСТ.

Topics: Adult; Aged; Comorbidity; Connective Tissue Diseases; Female; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase 5 Inhibitors; Prospective Studies; Sildenafil Citrate; Treatment Outcome

Pulmonary hypertension (PH) occurs in 25 to 35% of premature infants with significant bronchopulmonary dysplasia (BPD). Neonatal mice exposed to 14 days of hyperoxia develop BPD-like lung injury and PH. To determinne the impact of hyperoxia on pulmonary artery (PA) cyclic guanosine monophosphate (cGMP) signaling in a murine model of lung injury and PH, neonatal C57BL/6 mice were placed in room air, 75% O2 for 14 days (chronic hyperoxia [CH]) or 75% O2 for 24 hours, followed by 13 days of room air (acute hyperoxia with recovery [AHR]) with or without sildenafil. At 14 days, mean alveolar area, PA medial wall thickness (MWT), right ventricular hypertrophy (RVH), and vessel density were assessed. PA protein was analyzed for cGMP, soluble guanylate cyclase, and PDE5 activity. CH and AHR mice had RVH, but only CH mice had increased alveolar area and MWT and decreased vessel density. In CH and AHR PAs, soluble guanylate cyclase activity was decreased, and PDE5 activity was increased. In CH mice, sildenafil attenuated MWT and RVH but did not improve mean alveolar area or vessel density. In CH and AHR PAs, sildenafil decreased PDE5 activity and increased cGMP. Our results indicate that prolonged hyperoxia leads to lung injury, PH, RVH, and disrupted PA cGMP signaling. Furthermore, 24 hours of hyperoxia causes RVH and disrupted PA cGMP signaling that persists for 13 days. Sildenafil reduced RVH and restored vascular cGMP signaling but did not attenuate lung injury. Thus, hyperoxia can rapidly disrupt PA cGMP signaling in vivo with sustained effects, and concurrent sildenafil therapy can be protective.

Topics: Animals; Cyclic GMP; Guanosine Monophosphate; Hyperoxia; Hypertension, Pulmonary; Lung; Lung Injury; Mice; Mice, Inbred C57BL; Piperazines; Pulmonary Artery; Purines; Signal Transduction; Sildenafil Citrate; Sulfones

Sildenafil citrate is a selective phosphodiesterase-5 inhibitor used for the treatment for erectile dysfunction and pulmonary hypertension. The delivery of sildenafil directly to the lung could have several advantages over conventional treatments for pulmonary hypertension because of the local delivery, a more rapid onset of response, and reduced side effects. The major problem of sildenafil citrate is its limited solubility in water. Sildenafil citrate was complexed with cyclodextrins (CDs) to enhance its water solubility prior to development as an inhaled preparation. Four sildenafil citrate inhaled formulations were prepared with the aid of HP-β-CD (#1), α-CD (#2) and γ-CD (#3) and their effects were compared with the formulations without CDs (#4). The sildenafil citrate pressurized metered dose inhalers (pMDI) used ethanol as a solvent, PEG400 as a stabilizing agent, sorbitan monooleate as a surfactant and HFA-134a as a propellant. All formulations consisted of sildenafil citrate equivalent to a sildenafil content of 20μg/puff. These products were evaluated according to a standard guideline of inhalation products. Vasodilation testing was performed to investigate the efficacy of sildenafil pMDIs in relieving a vasoconstricted umbilical blood vessel of the chicken egg embryo. The sildenafil contents of the pMDI formulations #1-#3 were within the acceptance criteria (80-120%). The emitted doses (ED) were 102.3±11.5%, the fine particle fractions (FPF) were 60.5±5.6% and the mass median aerodynamic diameters (MMAD) were 2.3±0.3μm. The vasodilatory activity of those formulations reduced umbilical blood pressure by 67.1-73.7% after treatment by intravenous injection whereas only a 50.1-58.0% reduced blood pressure was obtained after direct spraying of the sildenafil pMDI containing CDs. With sildenafil formulations of a pMDI without CD the blood pressure was reduced by only 39.0% (P-value<0.05). The available sildenafil in the blood vessels of chicken egg embryos after spraying sildenafil-CDs pMDIs was within the range of 751-825ng/mL which was much higher than that of a sildenafil only pMDI.

Topics: Animals; Blood Pressure; Blood Vessels; Chemistry, Pharmaceutical; Chick Embryo; Cyclodextrins; Drug Carriers; Excipients; Hypertension, Pulmonary; Metered Dose Inhalers; Piperazines; Purines; Sildenafil Citrate; Solubility; Sulfones; Umbilical Cord; Vasodilation; Vasodilator Agents

The objective of this study is to evaluate the safety and tolerability of the pharmacological treatment of pulmonary hypertension in pediatric patients. It is a retrospective, longitudinal, observational study on pediatric patients undergoing treatment with pulmonary targeted therapies. 63 patients were included (51% male), with a median age of 3.4 years (IQR, 3.6 months-10 years) and a median weight 13 kg (IQR, 6-30 kg). Congenital heart disease was the etiology of pulmonary hypertension in the majority of cases (n = 33) and 28 patients were in NYHA functional class III-IV. The most commonly used drug was sildenafil (n = 79, 56%), followed by bosentan (n = 27, 23%), and a combination of both (n = 14, 41%). 34 patients had adverse reactions (54%) with an incidence rate of 1.02 per patient per year. The most commonly reported reactions were gastrointestinal symptoms (22%) and spontaneous erections (22%) in males. Nine severe adverse reactions (10%) occurred, requiring eight treatment withdrawal and one hospital admission. Treatment with targeted therapies for pulmonary hypertension is safe in the pediatric population. Severe ADRs were uncommon both in monotherapy and in combination therapy. Combination therapy was associated with a higher rate of ADRs. We observed similar survival rates in children receiving sildenafil doses according to the European Medicines Agency (EMA) recommendations or higher.

Topics: Antihypertensive Agents; Bosentan; Child; Child, Preschool; Drug Therapy, Combination; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Longitudinal Studies; Male; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension and secondary pleural effusion have been reported in association with long-term therapy with the multi-tyrosine kinase inhibitor dasatinib, approved for the treatment of chronic myeloid leukemia. Here, we present the case of a 50-year-old man, diagnosed with chronic myeloid leukemia in August 2003, who developed pulmonary arterial hypertension after > 4 years of treatment with dasatinib. The complete remission of pulmonary arterial hypertension following dasatinib discontinuation suggests an etiological role of the drug in its development, although the administration of sildenafil may have played a therapeutic role.

Topics: Dasatinib; Humans; Hypertension, Pulmonary; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Kinase Inhibitors; Purines; Pyrimidines; Sildenafil Citrate; Sulfones; Thiazoles

Both sildenafil and bosentan have been used clinically to treat pulmonary arterial hypertension. As these substances target different pathways to modulate vasoconstriction, we investigated the combined effects of both drug classes in isolated human pulmonary vessels.. Segments of pulmonary arteries (PA) and veins (PV) were harvested from 51 patients undergoing lobectomy. Contractile force was determined isometrically in an organ bath. Vessels were constricted with norepinephrine (NE) to determine effects of sildenafil. They were constricted with ET-1 to assess effects of bosentan, and with NE and ET-1 to evaluate the combination of both substances.. Sildenafil (1E-5 M) significantly reduced maximum constriction by NE of both PA (13.0 ± 11.1 vs. 34.9 ± 7.6% relative to KCl induced constriction; n = 6; p < 0.001) and PV (81.2 ± 34.2 vs 121.6 ± 20.8%; n = 6; p < 0.01) but did not affect basal tones. Bosentan (1E-5 M) significantly reduced maximum constriction of PV (56.6 ± 21.5 vs. 172.1 ± 30.0%; n = 6; p < 0.01) by ET-1 and led to a small but insignificant decrease of basal tone (p = 0.07). Bosentan almost completely abolished constriction of PA (1.0 ± 0.9 vs. 74.7 ± 25.7 %; n = 6; p < 0.001) by ET-1, but did not affect basal tone. Bosentan (1E-7 M) significantly attenuated combined ET-1/NE dose-response curves in PA (93.1 ± 47.4 vs. 125.3 ± 41.0%; n = 12; p < 0.001) whereas the effect of sildenafil (1E-5 M) was less pronounced (103.6 ± 20.2%; p < 0.05). Simultaneous administration of both substances showed a significantly greater reduction of maximum constriction in PA compared to individual administration (64.6 ± 26.3 %; p < 0.001).. Sildenafil only at its highest concentration was effective in suppressing NE induced pulmonary vessel contraction. Bosentan was able to completely suppress ET-1 induced contraction of PA and strongly attenuated contraction of PV. The present data suggest a benefit of sildenafil/bosentan combination therapy as they affect different pathways and may allow lower dosages.

Topics: Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Norepinephrine; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasoconstriction

Pulmonary arterial hypertension (PAH) is a progressive disease. In recent years, phosphodiesterase type 5 inhibitors such as sildenafil have been used to treat this disease in children. Recently, tadalafil has been used in adults with similar efficacy but it has been used less often in children. This experimental study was carried out in 18 known patients aged 4-24 years in the Emam Hossein Hospital of Isfahan, Iran. All patients had been taking sildenafil for a few months to years. Patients underwent echocardiographic study, the 6-minute walk test (6MWT), and non-invasive pulse oximetry before and after the 6MWT. These tests were repeated again after sildenafil had been switched to tadalafil for 6 weeks. After 6 weeks of tadalafil prescription, the severity of some of the patients' symptoms decreased, but the New York Heart Association class of the patients did not change more. Mean ± standard deviation (SD) oxygen saturation while taking sildenafil and after 6 weeks of tadalafil were significantly different (p = 0.005). Furthermore, mean ± SD oxygen saturation after the 6MWT while taking sildenafil and after 6 weeks of tadalafil were significantly different (p = 0.036). The mean ± SD distances walked in this test while taking sildenafil and tadalafil were significantly different (p = 0.005). No significant side effects were seen; 15 patients continued tadalafil. Tadalafil may be a safe drug to treat children and young adults with PAH. We did not observe any significant side effects during usage; it improves functional capacity and oxygen saturation better than sildenafil in these patients, and requires fewer daily doses than sildenafil.

Topics: Adolescent; Adult; Carbolines; Child; Child, Preschool; Dose-Response Relationship, Drug; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Tadalafil; Treatment Outcome; Walking; Young Adult

A simultaneous, selective, sensitive, and rapid liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of bosentan, ambrisentan, sildenafil, and tadalafil in 50μL of human blood plasma. Diluted plasma samples were extracted using a solid-phase extraction procedure with 2% formic acid and methanol. The four drugs were separated by high-performance liquid chromatography using a C18 column and an isocratic mobile phase running at a flow rate of 0.2mL/min for 5min. The drugs were detected by a tandem mass spectrometer with electrospray ionization using deuterated compounds as internal standards. Calibration curves were generated over the linear concentration range of 2-1000ng/mL in plasma with a lower limit of quantification of 2ng/mL for all compounds. Finally, this validated method was applied to a clinical pharmacokinetic study in pediatric patients with pulmonary arterial hypertension (PAH) following the oral administration of PAH drugs. These results indicate that this method is suitable for assessing the risk/benefit of combination therapy in the pediatric population and useful for therapeutic drug monitoring for PAH treatment.

Topics: Bosentan; Carbolines; Child; Child, Preschool; Chromatography, Liquid; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Infant; Male; Phenylpropionates; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Tadalafil; Tandem Mass Spectrometry

Pulmonary hypertension (PHT) and the resulting right ventricle dysfunction are important risk factors in patients who undergo cardiac surgery. The treatment of PHT and right ventricle dysfunction should be focused on maintaining the correct right ventricle after load, improving right ventricle function and reducing the right ventricle pre-load and therefore reducing pulmonary vascular resistance by means of vasodilators. A combined therapy of vasodilators and medicines which have different mechanisms of action, is becoming an option for the treatment of PHT. We present a 65 year old woman that suffered from mitral regurgitation, aortic valve disease, tricuspid and ascending aortic dilation with 115mmHg of pulmonary artery pressure (by ultrasound evaluation). The patient was operated on of mitral, aortic valve and tricuspid plastia and proximal aortic artery plastia as well. Previosly to surgery the patient suffered right ventricle dysfunction and PHT and was treated with nitric oxide, intravenous sildenafil and levosimendan. Subsequent evolution was satisfactory, PHT being controlled, without arterial hypotension nor respiratory alterations.

Topics: Aged; Aorta; Dobutamine; Drug Synergism; Drug Therapy, Combination; Female; Heart Valve Prosthesis Implantation; Humans; Hydrazones; Hypertension, Pulmonary; Nitric Oxide; Norepinephrine; Postoperative Complications; Pyridazines; Sildenafil Citrate; Simendan; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Right

In paediatric pulmonary arterial hypertension (PAH), the effectiveness of add-on combination PAH-therapy has not yet been systematically studied. The purpose of this study was to determine the effect of sildenafil add-on therapy in paediatric PAH patients treated with bosentan.. In this observational study within a national paediatric patient cohort, follow-up data of 24 consecutive paediatric PAH patients initially treated with bosentan monotherapy and prospectively followed at the Dutch national referral centre for paediatric PAH in 2007-2013, were reviewed. Patients received add-on sildenafil therapy in case of clinical worsening.. Fifteen children received add-on sildenafil therapy; nine remained on bosentan monotherapy. Patient characteristics, 6-minute walk distance (6MWD), WHO functional class (WHO-FC), N-terminal pro-Brain Natriuretic Peptide (NT-proBNP), and haemodynamic measurements at bosentan start were similar in both patient groups. In children with clinical worsening, sildenafil add-on therapy improved 6MWD at 5, 10, 15 and 21 months of follow-up, improved WHO-FC at 10, 15 and 21 months and stabilised NT-proBNP. Patients who received add-on sildenafil therapy had more advanced disease progression during bosentan monotherapy. Despite that, they had better or, at least, no worse survival compared to patients who remained on bosentan monotherapy.. In children with PAH, sildenafil add-on therapy indicated by clinical deterioration on bosentan monotherapy, was associated with a significant improvement of WHO-functional class and 6MWD. Despite clinical deterioration on bosentan monotherapy, patients receiving sildenafil add-on therapy, had either better or, at least, no worse survival than patients remaining on bosentan monotherapy.

Topics: Adolescent; Age Factors; Antihypertensive Agents; Bosentan; Child; Cohort Studies; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Netherlands; Piperazines; Purines; Secondary Care Centers; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

This study was performed to examine the effectiveness and safety of oral sildenafil and inhaled iloprost in term newborns with persistent pulmonary hypertension of the newborn (PPHN).. Oral sildenafil and inhaled iloprost were administered to 27 and 20 neonates, respectively, for treatment of persistent pulmonary hypertension. All patients were term infants at 37 gestational weeks or older. In the sildenafil group, 14 patients had meconium aspiration syndrome, 8 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, 1 had transient tachypnea, and 1 had idiopathic PPHN. In the iloprost group, 9 patients had meconium aspiration syndrome, 7 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, and 1 had transient tachypnea. Sildenafil citrate was administered via an oral feeding tube. Iloprost was administered endotracheally to patients on mechanical ventilation using a jet nebulizer.. Iloprost appeared to be more effective than sildenafil in the treatment of PPHN with regard to time to adequate clinical response, ventilatory parameters, duration of drug administration, duration of mechanical ventilation, duration of return to normal values of respiratory failure indices, use of MgSO4 as a second vasodilator and requirement for support with inotropic agents. We observed no side effects on blood pressure or homeostasis in any of the patients in the iloprost group. Systemic hypotension was significantly elevated in the sildenafil group. Four and three infants died of PPHN in the sildenafil and iloprost groups, respectively. Pulmonary systolic arterial pressure decreased to normal levels in the remaining 40 patients, and they were discharged from hospital.. We suggested that inhaled iloprost may be a safe and effective treatment choice in newborn infants with persistent pulmonary hypertension. In cases where treatment with inhaled iloprost, ECMO or INO is not possible, oral sildenafil can be an alternative therapy option in the treatment of PPHN.

Topics: Administration, Oral; Female; Humans; Hypertension, Pulmonary; Hypoxia-Ischemia, Brain; Iloprost; Infant, Newborn; Male; Meconium Aspiration Syndrome; Nebulizers and Vaporizers; Pneumonia; Retrospective Studies; Sildenafil Citrate; Tachypnea; Vasodilator Agents

Mutations in the TMEM70 are the most common cause of nuclear ATP synthase deficiency resulting in a distinctive phenotype characterized by severe neonatal hypotonia, hypertrophic cardiomyopathy (HCMP), facial dysmorphism, severe lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria (3-MGA).. We collected 9 patients with genetically confirmed TMEM70 defect from 8 different families. Six were homozygous for the c.317-2A>G mutation, 2 were compound heterozygous for mutations c.317-2A>G and c.628A>C and 1 was homozygous for the novel c.701A>C mutation. Generalized hypotonia, lactic acidosis, hyperammonemia and 3-MGA were present in all since birth. Five patients presented acute respiratory distress at birth requiring intubation and ventilatory support. HCMP was detected in 5 newborns and appeared a few months later in 3 additional children. Five patients showed a severe and persistent neonatal pulmonary hypertension (PPHN) requiring Nitric Oxide (NO) and/or sildenafil administration combined in 2 cases with high-frequency oscillatory (HFO) ventilation. In 3 of these patients, echocardiography detected signs of HCMP at birth.. PPHN is a life-threatening poorly understood condition with bad prognosis if untreated. Pulmonary hypertension has rarely been reported in mitochondrial disorders and, so far, it has been described in association with TMEM70 deficiency only in one patient. This report further expands the clinical and genetic spectrum of the syndrome indicating PPHN as a frequent and life-threatening complication regardless of the type of mutation. Moreover, in these children PPHN appears even in the absence of an overt cardiomyopathy, thus representing an early sign and a clue for diagnosis.

Topics: Cardiomyopathy, Hypertrophic; Child, Preschool; Female; Humans; Hyperammonemia; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Membrane Proteins; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones

The C825T polymorphism in the G protein β3 subunit gene (GNB3) influences the efficacy of sildenafil in patients with erectile dysfunction. The effects of this polymorphism on the therapeutic response to sildenafil in patients with pulmonary hypertension remains unknown. To investigate whether the GNB3C825T polymorphism is associated with the clinical efficacy of sildenafil in patients with pulmonary hypertension.. Fifty-nine patients (age: 55.6 ± 13.3 [SD] yrs., mean pulmonary arterial pressure (Ppa): 52 ± 11 mmHg) with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension were treated with sildenafil. The pre- and post-treatment parameters, including pulmonary hemodynamics measured using right heart catheterization, the systolic pulmonary arterial pressure estimated on Doppler echocardiography (sPA), the six-minute walk distance (6MWD) and freedom from clinical worsening, were compared between the patients with the TT and CT/CC genotypes.. The pretreatment parameters were not significantly different between the two groups, with the exception of a lower mean Ppa in the TT group. The post-treatment World Health Organization (WHO) class was significantly better (p=0.03) and the 6MWD values trended toward improvement in the TT genotype patients compared with that observed in the CC/CT genotype patients (p=0.05). The time to clinical worsening was significantly longer in the TT genotype patients than in the CC/CT genotype patients (3-year freedom from clinical worsening: 83.1% vs. 46.0%, p=0.02), while the TT genotype was found to be a significant predictor of freedom from clinical worsening, even after adjusting for the baseline mean Ppa.. The GNB3 C825T polymorphism influences the efficacy of sildenafil in patients with pulmonary hypertension.

Topics: Adult; Aged; Cohort Studies; Female; Genetic Association Studies; Heterotrimeric GTP-Binding Proteins; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Polymorphism, Single Nucleotide; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilation

 Pulmonary hypertension (PH) is a fatal disease characterized by pulmonary artery (PA) remodeling, elevated PA pressure and right ventricular (RV) failure. It has been previously demonstrated that treatment with a Rho-kinase inhibitor, fasudil, ameliorates PH in animal models. Here, whether combination therapy with fasudil and sildenafil further ameliorates PH in rats was examined..  PH was induced in Sprague-Dawley rats by the use of a single subcutaneous monocrotaline (MCT) injection, which caused PA remodeling, elevated RV systolic pressure (RVSP), and RV hypertrophy (RVH). While fasudil and sildenafil monotherapy inhibited the development of MCT-induced PH in the prevention and treatment protocols, their combination therapy further improved RVSP and RVH. Moreover, a histological examination demonstrated significant improvements of PA remodeling in the combination group compared with the monotherapy groups. An echocardiographic examination also revealed significant reduction in RV diameter in the combination group compared with the monotherapy groups. Mechanistic experiments revealed significant inhibition of Rho-kinase activity in PA trunk, lung and RV tissues in the combination group as well as in the monotherapy groups. Finally, the combination therapy markedly improved the long-term survival compared with the monotherapy groups..  These results indicate that the combination therapy with fasudil and sildenafil shows the synergistic effects through the inhibition of Rho-kinase activity for the treatment of PH.  

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Calcium Channel Blockers; Drug Therapy, Combination; Hypertension, Pulmonary; Male; Monocrotaline; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones

Patients with severe pulmonary arterial hypertension (PAH) in New York Heart Association (NYHA) functional class (FC) III/IV have a poor prognosis, despite survival benefits being demonstrated with intravenous epoprostenol. In this pilot study, the efficacy and safety of a triple combination therapy regimen in patients with severe PAH was investigated. Data from newly diagnosed NYHA FC III/IV PAH patients (n=19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil) were collected retrospectively from a prospective registry. Significant improvements in 6-min walk distance and haemodynamics were observed after 4 months' triple combination therapy in 18 patients (p<0.01); 17 patients had improved to NYHA FC I or II. One patient was not included in the month 4 assessment (due to an emergency lung transplant in month 3). At the final evaluation (mean ± sd 32 ± 19 months), all 18 patients had sustained clinical and haemodynamic improvement. Overall survival estimates for the triple combination cohort were 100% at 1, 2 and 3 years. Expected survival calculated from the French equation was 75% (95% CI 68-82%), 60% (95% CI 50-70%) and 49% (95% CI 38-60%) at 1, 2 and 3 years, respectively. This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Prognosis; Purines; Registries; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Young Adult

A 43-year-old man presented with dyspnea on exertion. Right heart catheterization demonstrated pulmonary arterial hypertension (PAH). He was treated with bosentan, sildenafil and intravenous epoprostenol. Despite the administration of such intensive therapy, the patient's condition deteriorated to a World Health Organization functional class (WHO-FC) of IV. He participated in a clinical trial of imatinib for PAH. After three months of treatment with imatinib, the chest X-ray and echocardiography findings improved, and the WHO-FC class was III. One year after, however, the PAH worsened again, and the patient died 2.6 years after the first diagnosis. At autopsy, patchy capillary proliferation was observed in the lungs. The definitive diagnosis was pulmonary capillary hemangiomatosis.

Topics: Adult; Antihypertensive Agents; Antineoplastic Agents; Autopsy; Benzamides; Bosentan; Cardiac Catheterization; Dyspnea; Echocardiography; Epoprostenol; Fatal Outcome; Hemangioma, Capillary; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Lung; Lung Neoplasms; Male; Piperazines; Purines; Pyrimidines; Radiography, Thoracic; Sildenafil Citrate; Sulfonamides; Treatment Failure

Topics: Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Right ventricular (RV) function immediately after left ventricular assist device (LVAD) implantation is a crucial prognostic factor. RV failure is linked to increased mortality and worse outcome. A phosphodiesterase 5 inhibitor, sildenafil, was shown to decrease pulmonary vascular resistance and pulmonary artery pressure post-LVAD. We report on a series of heart failure patients, and the effect of sildenafil on the incidence of RV failure after LVAD implantation. We retrospectively analyzed the data of end-stage heart failure patients who underwent LVAD implantation with pulmonary hypertension and RV dysfunction prior to surgery. Patients were divided into two groups; group 1: patients who received sildenafil perioperatively, and group 2: patients who did not receive sildenafil. Hemodynamic and echographic data were collected before and after surgery. Fourteen patients were included, 8 patients in group 1 and 6 in group 2. Sildenafil was administered with a mean dose of 56.2 ± 9.4 mg in group 1 and was able to significantly reduce right heart failure incidence, and to demonstrate a significant reduction in pulmonary vascular resistance, pulmonary artery pressure, transpulmonary gradient, and a significant increase in cardiac output. In conclusion, sildenafil seems to have a promising role perioperatively in preventing acute RV failure postsurgery in patients with RV dysfunction and pulmonary hypertension, requiring LVAD therapy.

Topics: Adult; Cardiac Output; Female; Heart Failure; Heart-Assist Devices; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Ventricular Dysfunction, Right

Interstitial lung diseases (ILD) are often associated with pulmonary hypertension (PH). This study aimed to evaluate the therapeutic benefit of phosphodiesterase-5 (PDE-5) inhibitors in pulmonary hypertension secondary to ILD.. Patients with ILD and PH were treated with sildenafil or tadalafil. Right heart catheterization was performed before and after a minimum of 3-month treatment. In addition, lung function, 6-min walk distance (6MWD) and plasma brain natriuretic peptide (BNP) concentration were assessed.. Ten ILD patients (three female, mean age 64.4 ± 9.0 years, six with idiopathic pulmonary fibrosis (IPF), four with hypersensitivity pneumonitis, (HP)) with significant precapillary PH (mean pulmonary artery pressure (PAPm) ≥ 25 mmHg, pulmonary vascular resistance (PVR) > 280 dyn*s*cm(-5) ; pulmonary artery wedge pressure (PAWPm) ≤ 15 mmHg) were treated with either sildenafil (n = 5) or tadalafil (n = 5). Pulmonary haemodynamics were severely impaired at baseline (PAPm 42.9 ± 5.4 mmHg; cardiac index (CI) 2.7 ± 0.6 L/min/m2; PVR 519 ± 131 dyn × sec × cm(-5)). After mean follow-up of 6.9 ± 5.8 months an increase in CI (2.9 ± 0.7 L/min/m2 , P = 0.04) and a decrease in PVR (403 ± 190 dyn × sec × cm(-5) , P = 0.03) were observed. 6MWD and BNP did not change significantly.. Our data suggest that treatment with PDE-5 inhibitors improves pulmonary haemodynamic patients with PH secondary to ILD.

Topics: Aged; Aged, 80 and over; Carbolines; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Middle Aged; Natriuretic Peptide, Brain; Phosphodiesterase 5 Inhibitors; Pilot Projects; Piperazines; Purines; Respiratory Function Tests; Sildenafil Citrate; Sulfonamides; Tadalafil; Walking

Pulmonary hypertension (PH) is a disease with a poor prognosis characterized by a vascular remodeling process and an increase in pulmonary vascular resistance. While a variety of reports demonstrated that exercise training exerts beneficial effects on exercise performance and quality of life in PH patients, it is not known how physical exercise affects vascular remodeling processes occurring in hypoxia-induced PH. Therefore, we investigated the effect of individualized exercise training on the development of hypoxia-induced PH in mice. Training effects were compared with pharmacological treatment with the phosphodiesterase 5 inhibitor Sildenafil or a combination of training plus Sildenafil. Trained mice who received Sildenafil showed a significantly improved walking distance (from 88.9 ± 8.1 to 146.4 ± 13.1 m) and maximum oxygen consumption (from 93.3 ± 2.9 to 105.5 ± 2.2% in combination with Sildenafil, to 102.2 ± 3.0% with placebo) compared with sedentary controls. Right ventricular systolic pressure, measured by telemetry, was at the level of healthy normoxic animals, whereas right heart hypertrophy did not benefit from training. Most interestingly, the increase in small pulmonary vessel muscularization was prevented by training. Respective counterregulatory processes were detected for the nitric oxide-soluble guanylate cyclase-phosphodiesterase system. We conclude that individualized daily exercise can prevent vascular remodeling in hypoxia-induced PH.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Exercise Therapy; Exercise Tolerance; Gene Expression; Hypertension, Pulmonary; Hypoxia; Lung; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Physical Conditioning, Animal; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Ventricular Pressure

Among phosphodiesterase type 5 inhibitors, tadalafil offers clinicians a once-daily alternative to 3 times daily sildenafil for the treatment of pulmonary arterial hypertension (PAH). This study assessed the safety and patient satisfaction with conversion from sildenafil to tadalafil.. In this multicenter, prospective, 6-month study, patients with PAH were instructed to take their last dose of sildenafil in the evening and initiate tadalafil 40 mg/d the next morning. Patients completed the Treatment Satisfaction Questionnaire for Medication at baseline and 30, 90, and 180 days after transition to assess PAH symptoms and patient satisfaction. Safety was assessed on the basis of recorded adverse events (AEs).. Of the 35 patients who met the study criteria, 56% were receiving ≥2 PAH therapies. At the time of transition, the sildenafil dose ranged from 40 to 300 mg/d, with 20% of the patients on >20 mg of sildenafil 3 times daily. Transition to tadalafil was generally well tolerated, and the incidence of common AEs, except for myalgia, appeared to decrease over time on tadalafil therapy. Five (14%) patients switched back to sildenafil. A greater percentage of patients were satisfied than were dissatisfied after conversion to tadalafil (55% vs 19% at 90 days), while 26% felt about the same degree of satisfaction. Conversion to tadalafil resulted in significant improvement in patient ratings of therapy convenience.. Transition of patients from sildenafil to tadalafil was usually well tolerated, with improved convenience and may enhance treatment satisfaction.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Arterial Pressure; Carbolines; Drug Substitution; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Patient Satisfaction; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Surveys and Questionnaires; Tadalafil; Time Factors; Treatment Outcome; United States; Vasodilator Agents; Young Adult

Topics: Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

A predictor of neonatal mortality in infants with congenital diaphragmatic hernia (CDH) is disrupted pulmonary vascular development, clinically expressed as pulmonary hypertension.. To determine if prenatal corticosteroids and phosphodiesterase-5 (PDE-5) inhibitors have a beneficial effect on pulmonary vascular development in CDH lungs.. We induced CDH in fetal rats by giving nitrofen. We then exposed them to dexamethasone or to sildenafil. We separated them into three groups: (1) DEX, 4 pregnant rats received dexamethasone at days E16, E18 and E20; (2) SILD, 4 pregnant rats received sildenafil and L-arginine between E14 and E22, and (3) placebo. We then analyzed the lung of each fetus with CDH at E22. We examined the number of arterioles and arteries, and their percent of medial wall thickness (%MWT).. We obtained 30 CDH-positive fetuses. We analyzed 3,560 arterioles and 211 arteries. SILD showed a significant increase in the number of arterioles, but no significant increase in the number of arteries. No change was noted in the arteriolar %MWT. In contrast, DEX showed significant decreases in the number of arterioles and arteries and a significant increase in %MWT.. PDE-5 inhibitors may improve pulmonary arteriolar development in fetuses with CDH. In contrast, prenatal corticosteroids could have deleterious effects on arteriolar and arterial development in CDH lungs.

Topics: Actins; Animals; Animals, Newborn; Dexamethasone; Female; Glucocorticoids; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Immunohistochemistry; Neovascularization, Physiologic; Phosphodiesterase 5 Inhibitors; Piperazines; Platelet Endothelial Cell Adhesion Molecule-1; Pregnancy; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfonamides; Tunica Intima

Unresponsive pulmonary hypertension (PH) implies poor posttransplant outcomes. Data on late adaptation of the right ventricle (RV) are still few. This study evaluated three-yr RV function and remodeling, exercise capacity, and hemodynamic data in a selected group of patients initially disqualified because of PH. Between May 2005 and December 2009, 31 consecutive patients were qualified for oral sildenafil because of unresponsive PH at baseline right heart catheterization (RHC). After a 12-wk trial, RHC disclosed PH reversibility (mean PVR: 5.41 ± 3 Wood units, mean TPG 14.5 ± 5.6 mmHg, and mean systolic PAP 68.9 ± 15.1 mmHg), allowing listing even though as high-risk procedures. All patients underwent heart transplantation. RV failure developed in three patients (9.6%), and hospital mortality was 3.2%. Protocol RHC disclosed pulmonary hemodynamic profile normalization within the third postoperative month, allowing weaning from sildenafil in the 30 hospital survivors. One- and three-yr RHCs confirmed stable PH reversal (n = 26, all three-yr survivors). Parameters of late RV function and remodeling proved satisfactory. Parameters of functional capacity (Vo2 peak 19.7 ± 3.6 mL/kg/min and slope VE/Vco2 34.8 ± 2.7) proved homogeneous to those measured in transplant recipients with normal preoperative pulmonary artery pressure. Oral sildenafil is effective in allowing candidacy, safe transplantation, and long-term survival in PH recipients initially disqualified.

Topics: Administration, Oral; Allografts; Cardiac Catheterization; Exercise Tolerance; Female; Follow-Up Studies; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Prognosis; Prospective Studies; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Transplant Recipients; Vasodilator Agents; Ventricular Function, Right

This study investigates whether endothelin-1 (ET-1) mediates monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) and right ventricular hypertrophy (RVH), and if so, whether the G-protein coupled receptor antagonist KMUP-1 (7-{2-[4-(2-chlorobenzene)piperazinyl]ethyl}-1,3-dimethylxanthine) inhibits ET-1-mediated PA constriction and the aforementioned pathological changes. In a chronic rat model, intraperitoneal MCT (60 mg/kg) induced PAH and increased PA medial wall thickening and RV/left ventricle + septum weight ratio on Day 21 after MCT injection. Treatment with sublingual KMUP-1 (2.5 mg/kg/day) for 21 days prevented these changes and restored vascular endothelial nitric oxide synthase (eNOS) immunohistochemical staining of lung tissues. Western blotting analysis demonstrated that KMUP-1 enhanced eNOS, soluble guanylate cyclase, and protein kinase G levels, and reduced ET-1 expression and inactivated Rho kinase II (ROCKII) in MCT-treated lung tissue over long-term administration. In MCT-treated rats, KMUP-1 decreased plasma ET-1 on Day 21. KMUP-1 (3.6 mg/kg) maximally appeared at 0.25 hours in the plasma and declined to basal levels within 24 hours after sublingual administration. In isolated PA of MCT-treated rats, compared with control and pretreatment with l-NG-nitroarginine methyl ester (100 μM), KMUP-1 (0.1-100 μM) inhibited ET-1 (0.01 μM)-induced vasoconstriction. Endothelium-denuded PA sustained higher contractility in the presence of KMUP-1. In a 24-hour culture of smooth muscle cells (i.e., PA smooth muscle cells or PASMCs), KMUP-1 (0.1-10 μM) inhibited RhoA- and ET-1-induced RhoA activation. KMUP-1 prevented MCT-induced PAH, PA wall thickening, and RVH by enhancing eNOS and suppressing ET-1/ROCKII expression. In vitro, KMUP-1 inhibited ET-1-induced PA constriction and ET-1-dependent/independent RhoA activation of PASMCs. In summary, KMUP-1 attenuates ET-1-induced/ET-1-mediated PA constriction, and could thus aid in the treatment of PAH caused by MCT.

Topics: Animals; Blood Pressure; Body Weight; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Endothelin-1; Guanylate Cyclase; Heart Rate; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; In Vitro Techniques; Male; Monocrotaline; Nitric Oxide Synthase Type III; Piperazines; Piperidines; Pulmonary Artery; Purines; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfonamides; Vasoconstriction; Xanthines

Sildenafil, a phospohodiesterase-5 inhibitor, is widely used to treat pulmonary hypertension in infants with bronchopulmonary dysplasia despite a lack of evidence to support either safety or efficacy and US FDA advice against its use.

Topics: Bronchopulmonary Dysplasia; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Antihypertensive Agents; Arteriovenous Malformations; Bone Morphogenetic Protein Receptors, Type II; Bosentan; Disease Progression; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Mutation; Pedigree; Piperazines; Pulmonary Artery; Pulmonary Veins; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension is a progressive disease of diverse origin with devastating consequences in adults as well as in children. The phosphodiesterase 5 inhibitor sildenafil successfully lowers pulmonary vascular resistance. However, because of its poor enteral absorption, resulting in ineffective plasma concentrations, responses in infants and children are often erratic.. We report the cases of two Caucasian boys, one born at term (case 1) and one aged 2.5 years (case 2), who had structural cardiac and pulmonary defects accompanied by symptomatic pulmonary hypertension. They received sildenafil enterally and sublingually and also intravenously in one of them. Plasma samples were taken at various time points to determine the plasma concentrations of sildenafil and its partially active metabolite. Sildenafil and N-desmethyl sildenafil were quantified using a validated liquid chromatography/mass spectrometry method. Oxygen partial pressure was determined from routine arterial blood gas samples.. In agreement with previous observations in adults, we found that sublingual sildenafil was more extensively absorbed in our two pediatric patients. After sublingual administration, sildenafil plasma concentrations increased by 314% to 361% compared to enteral dosing. Concurrently, the metabolic ratio increased, suggesting not only that the overall absorption was enhanced but also that first-pass metabolism was partially bypassed. In case 2, the free fraction of sildenafil was 0.9%, which is considerably less than in adults (4%), suggesting that, in case 2, higher plasma concentration would have been needed to achieve effects similar to those in adults. Sublingual sildenafil appears to be a promising alternative route of administration in children with poor enteral absorption.

Topics: Administration, Sublingual; Biological Availability; Child, Preschool; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Liver Cirrhosis, Biliary; Liver Transplantation; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PH) is associated with high mortality due to right ventricular failure and hypoxia, therefore to understand the mechanism by which pulmonary vascular remodeling initiates these processes is very important. We used a well-characterized monocrotaline (MCT)-induced rat PH model, and analyzed lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, and phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-κB activation in order to elucidate the mechanisms by which sildenafil's protective effect in PH is exerted. Besides its protective effect on lung morphology, sildenafil suppressed multiple cytokines involved in neutrophil and mononuclear cells recruitment including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2α/β, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1α, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, and MIP-3α. NF-κB activation and phosphorylation were also attenuated by sildenafil. Furthermore, sildenafil reduced extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation while enhanced activation of the cytoprotective Akt pathway in PH. These data suggest a beneficial effect of sildenafil on inflammatory and kinase signaling mechanisms that substantially contribute to its protective effects, and may have potential implications in designing future therapeutic strategies in the treatment of pulmonary hypertension.

Topics: Active Transport, Cell Nucleus; Animals; Cell Nucleus; Chemokines; Enzyme Activation; Hypertension, Pulmonary; Lung; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; NF-kappa B; Piperazines; Proto-Oncogene Proteins c-akt; Purines; Rats; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

Pulmonary arterial hypertension (PAH) in scleroderma (SSc) patients is a devastating complication with high mortality if untreated. Early recognition and specific treatment of PAH may improve outcome. Regular interval screening for PAH is generally recommended in scleroderma patients especially with the availability of emerging new therapies. The aim of this study is to determine the self-reported screening and treatment practices for SSc-PAH amongst rheumatologists in New Zealand (NZ).. An anonymous online questionnaire survey was emailed to all rheumatologists in New Zealand.. Responses were received from 65% (39/60) of rheumatologists. The majority of patients had limited SSc (lcSSc) (57%) versus diffuse SSc (dcSSc) (34%). Twelve percent of patients had PAH. Eighty-two percent of rheumatologists screened for PAH in all SSc patients regardless of symptoms. The most commonly used screening modalities were pulmonary function tests (PFT) (97%) followed by clinical examination (95%) and echocardiogram (TTE) (92%). The majority of rheumatologists performed screening tests on a yearly basis (80% used PFT and 64% used TTE). A right heart catheter was used to confirm PAH in 70% of patients. Sixty-four percent of rheumatologists extend screening interval time if their patients were clinically stable. The most common PAH-specific therapy used was sildenafil (57%) followed by bosentan (19%). Sixty-four percent of rheumatologists supported a national PAH-SSc screening guideline.. This study has shown a wide variability of how NZ rheumatologists screen for PAH in scleroderma patients. The development of a PAH-SSc guideline for screening and diagnosis may help standardise treatment practices in NZ.

Topics: Anticoagulants; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Echocardiography; Electrocardiography; Exercise Test; Humans; Hypertension, Pulmonary; Mass Screening; New Zealand; Physical Examination; Piperazines; Practice Patterns, Physicians'; Purines; Respiratory Function Tests; Rheumatology; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Surveys and Questionnaires; Vasodilator Agents

Severe pulmonary hypertension (PH) often develops in patients with pulmonary Langerhans cell histiocytosis (PLCH). Supplemental oxygen treatment is often used, whereas pulmonary arterial hypertension-specific vasodilators are generally considered hazardous because of the possible development of pulmonary edema and deterioration of hypoxia. In the present report, we herein describe a PLCH patient with severe PH in whom sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, substantially improved the pulmonary hemodynamics before lung transplantation. An immunohistochemical study of the resected lung revealed positive staining for PDE5 on the diseased pulmonary arteries. These observations suggest that sildenafil can be a promising therapeutic option for PH in patients with PLCH.

Topics: Biopsy; Diagnosis, Differential; Hemodynamics; Histiocytosis, Langerhans-Cell; Humans; Hypertension, Pulmonary; Lung; Lung Transplantation; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Preoperative Care; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Tomography, X-Ray Computed; Young Adult

Pulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). The sildenafil can regulate the Connexin (Cx) 43 in the PASMCs and thus inhibit the PASMCs proliferation and the remodeling of pulmonary arterial. However, how sildenafil exert regulation in the Cx40 in the PASMCs in PAH remains unclear.. Using the rat PAH model induced by the monocrotoline, we demonstrated that the Cx40 in the PASMCs is down-regulated in the PAH. The sildenafil promotes the up-regulation of Cx40 in the PASMCs via bone morphogenetic protein (BMP) signaling, accompanied by an anti-proliferative response in PASMCs. Inhibition of the BMP axis reverses the up-regulation of Cx40 and anti-proliferation of the sildenafil in these cells. In monocrotaline-induced PAH rat models, which display reduced levels of BMP signaling, this study further indicates that the BMP-Cx40 axis is activated in lungs following the sildenafil treatment. Furthermore, we also find in vitro that sildenafil increases the Cx40 expression of PASMCs isolated from MCT-PAH rats and inhibit the proliferation of these cells. These phenomenon are reversed by LDN-193189, the antagonist of type II receptor for bone morphogenetic protein (BMPR2) treatment, providing strong evidence for the protect effect of sildenafil and the BMP-Cx40 axis involvement.. Taken together, these data suggest the sildenafil activate BMP-Cx40 signaling in the PAH. This axis may be a potential therapeutic target in PAH.

Topics: Animals; Blotting, Western; Bone Morphogenetic Proteins; Connexins; Disease Models, Animal; Gap Junction alpha-5 Protein; Hypertension, Pulmonary; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Signal Transduction; Sildenafil Citrate; Sulfonamides; Vascular Remodeling; Vasodilator Agents

Pulmonary hypertension (PH) is the most important complication of congenital diaphragmatic hernia (CDH) and still has a high mortality rate. The aim of this study was to evaluate the effectiveness of inhaled nitric oxide therapy in PH due to CDH.. Hospital records of children who had undergone inhaled nitric oxide therapy for PH due to CDH between June 2009 and December 2011 were reviewed.. Twenty-nine patients had a diagnosis of CDH at the time of study, and eight of these patients underwent nitric oxide therapy because of failure of conventional ventilation techniques, which was successful in five of these patients. Patients who had a good overall outcome of nitric oxide therapy experienced rapid improvement (pretreatment, mean PaO2 = 44.8 mmHg; after the first hour of therapy, mean PaO2 = 96.8 mmHg), whereas patients with no response did not have a similar course (pretreatment, PaO2 = 37 mmHg; after the first hour, PaO2 = 54.6 mmHg).. Inhaled nitric oxide therapy seems to increase survival in PH due to CDH. No predictive parameters to orient patient selection could be identified; however, the early response seemed to predict the overall outcome. Good results in our series were attributed to routine use of sildenafil and dopamine, along with the nitric oxide inhalation.

Topics: Administration, Inhalation; Cardiotonic Agents; Combined Modality Therapy; Dopamine; Drug Therapy, Combination; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Infusions, Intravenous; Intubation, Gastrointestinal; Nitric Oxide; Oxygen; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Sildenafil is a potent and selective inhibitor of phosphodiesterase-5 (PDE5) and is considered first-line therapy for erectile dysfunction. Nowadays, Sildenafil is used extensively throughout the world on patients with pulmonary hypertension. However, few studies have evaluated the possible side effects of chronic Sildenafil treatment on the male reproductive system, specifically in the prostate. In the present study, it was demonstrated via morphological and ultrastructural analysis that chronic treatment with Sildenafil induced an enhancement of the glandular activity of the prostate. In addition, mice treated with Sildenafil showed a significant increase in testosterone serum levels. However, no statistically significant differences were observed in nitric oxide serum levels, or in sGC, eNOS, PSA and TGF-β prostatic expression. In conclusion, the present study suggests that chronic use of Sildenafil does not cause evident prostatic damage, and therefore, can be used pharmacologically to treat a variety of disorders.

Topics: Animals; Erectile Dysfunction; Humans; Hypertension, Pulmonary; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type III; Piperazines; Prostate; Prostate-Specific Antigen; Purines; Sildenafil Citrate; Sulfonamides; Testosterone; Transforming Growth Factor beta

Pulmonary arterial hypertension (PAH) that occurs in the setting of cirrhosis and portal hypertension is referred to as portopulmonary hypertension (PPHTN). Liver transplantation (LTx) is curative, but the presence of moderate-to-severe PPHTN may be a contraindication for transplantation because of the elevated risk of peri- and post-transplantation morbidity and mortality. We report a successful liver transplantation in a patient with liver cirrhosis after treatment of moderate-to-severe PPHTN with a combination of the dual endothelin receptor antagonist bosentan and the specific phosphodiesterase-5 inhibitor sildenafil.

Topics: Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Transplantation; Male; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

There is considerable interest in the pleiotropic effects of statins and their potential role in the treatment of pulmonary hypertension. Previous experimental findings indicate that a combination of lipophilic statins with phosphodiesterase type-5 inhibitor, sildenafil, can offer preventive effects on rat monocrotaline-induced pulmonary hypertension. The present study is aimed to assess whether therapeutic regimen provides any benefits. Seven days after pulmonary hypertension induction, hydrophilic rosuvastatin and sildenafil were given for 14 days to male Wistar outbred rats. Right ventricular pressure, right ventricle mass and three biomarkers were evaluated after 21 days: brain natriuretic peptide, high-density lipoprotein cholesterol and vascular endothelial growth factor. The present study demonstrates that administration of hydrophilic statin with sildenafil results in reduction of pulmonary vascular remodeling and right ventricular pressure. The results of biochemical measurements may suggest that statins play a positive role in right ventricle function or the process of angiogenesis in pulmonary hypertension development.

Topics: Animals; Antihypertensive Agents; Arterial Pressure; Biomarkers; Cholesterol, HDL; Disease Models, Animal; Drug Therapy, Combination; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Natriuretic Peptide, Brain; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Purines; Pyrimidines; Rats, Wistar; Rosuvastatin Calcium; Sildenafil Citrate; Sulfonamides; Time Factors; Vascular Endothelial Growth Factor A; Vascular Remodeling; Vasodilator Agents; Ventricular Function, Right; Ventricular Pressure

A 38-year-old male was diagnosed with unrepaired ventricular septal defect associated with severe pulmonary arterial hypertension, cyanosis, and significant exercise intolerance. His echocardiogram showed right ventricular dysfunction and moderate pericardial effusion with no signs of cardiac tamponade. He was treated with an intensive course of inhaled iloprost and sildenafil. He showed a dramatic clinical response; his saturation went up from 60% on admission to 90% on minimal oxygen with significant improvement in his symptoms and signs of heart failure and total resolution of pericardial effusion. On follow up 3 and 6 weeks later, he was stable and could walk 360 meters in a 6 minutes walk test with disappearance of pericardial effusion. With unavailability of intravenous prostacyclin, we have shown in this case that intensive administration of inhaled iloprost could be used intensively as a rescue therapy in severe cases of pulmonary arterial hypertension with excellent results. 

Topics: Administration, Inhalation; Adult; Exercise Test; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Iloprost; Male; Pericardial Effusion; Pericarditis; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vasodilator Agents

Study of pulmonary hypertension (PAH) during pregnancy has characteristics of the high risk factors for patient death and its clinical characteristics.. Death in patients with clinical data was collected from January 2006 to October 2013 in Beijing Anzhen Hospital Affiliated to Capital Medical University treated 8 cases of pregnancy complicated with PAH in hospital. According to the mechanism of PAH patients will be divided into two categories, Idiopathic pulmonary arterial hypertension (IPAH) in 4 cases, 4 cases of secondary PAH [are secondary to congenital heart disease, also known as congenital heart disease associated PAH (CHD-PAH)]. Analyze the clinical features of 8 cases of patients and pregnancy outcome.. (1) In 8 patients, 4 cases were IPAH, none of them with primary diseases, and they were complicated with severe tricuspid regurgitation. 4 cases were CHD-PAH, all with Eisenmenger's syndrome. 8 patients were not preconception counseling and regular prenatal examination. (2) The pregestational cardiac function of 8 cases was grade I-II, and it was grade III-IV on admission. The estimation pressure (sPAP) of pulmonary artery systolic by echocardiography was 101 mmHg (1 mmHg = 0.133 kPa). In 8 patients, 7 cases were in pregnancy 27 weeks and beyond for treatment since the clinical symptoms increased, 1 case of pregnant 18 weeks for treatment caused by the increased clinical symptoms. (3) In 8 patients, 1 patient with CHD- PAH secondary to patent ductus arteriosus, its sPAP was 170 mmHg, dead at 12 hours after admission; the remaining 7 cases termination with cesarean section. 4 patients with IPAH were continuous epidural anesthesia, including 1 case for the intraoperative PAH crisis and respiratory and cardiac arrest with general anesthesia, 3 cases of CHD- PAH patients in 1 case with continuous epidural anesthesia, 2 cases of general anesthesia.(4) In 8 patients, 7 cases of median death time were 3 days after delivery, including 4 cases of IPAH patients death for 2.5 days after delivery; the causes of death were PAH crisis and heart failure. Time of death in 4 cases of CHD-PAH, 1 case was dead at 12 hours after admissions, the remaining 3 cases median death time were 13 days after delivery; the death causes for 4 cases of CHD-PAH were PAH crisis and multiple organ failure. (5) In 8 patients, 1 patient with CHD-PAH secondary to patent ductus arteriosus in gestational week 31 stillbirths occur. 1 case of pregnant 19 weeks had treatment of caesarean operation, the remaining 6 cases respectively at 28-30 weeks of gestation live birth, neonatal survival. (6) Before delivery, 4 cases of IPAH and 3 cases of CHD-PAH patients treated with alprostadil, iloprost, sildenafil, reduction of pulmonary artery pressure treatment, 1 case of CHD-PAH patient was dead after 12 hours in hospital, no drug treatment.. (1) PAH in patients need for consultation prior to conception, pregnancy must conduct regular prenatal examination, symptoms occur during pregnancy, the cardiac function was significantly decreased, and no improvement of drug treatment should be early terminated the pregnancy. (2) Compared with the pregnant women with CHD- PAH, faster progress and poor prognosis in patients with IPAH disease. (3)The patients during cesarean operation or intrapartumare easy to cause PAH crisis and heart failure or multiple organ failure. Taking active measures to maintain stability of hemodynamics is the key to prevent the occurrence of death of pregnant women with PAH.

Topics: Anesthesia, General; Cesarean Section; Delivery, Obstetric; Echocardiography; Familial Primary Pulmonary Hypertension; Female; Gestational Age; Heart Defects, Congenital; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Maternal Mortality; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pulmonary Artery; Purines; Risk Factors; Sildenafil Citrate; Sulfonamides

To evaluate the effects of bosentan, sildenafil, and combined therapy on the cardiovascular system using impedance cardiography (ICG) in rats with monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH).. Seventy male Wistar-albino rats were randomized into five groups. A single dose of MCT was given to all rats, except to the control group. After 4 weeks, bosentan, sildenafil, and combined treatment was started and lasted for 3 weeks. The last group that developed PAH did not receive any medication. Echocardiographic evaluation was performed to determine the PAH development. Thoracic fluid content index (TFCI), stroke volume index (SI), heart rate (HR), cardiac index (CI), and myocardial contractility index (IC) were determined. All procedures were performed at the baseline and after 4 and 7 weeks.. Echocardiographic parameters showed that the all MCT-injected rats developed PAH. There were no significant inter- and intra-group differences in TFCI, SI, and IC (P>0.05), but at the 7th week, CI value in the sildenafil-treated PAH rats was significantly higher than in other groups and HR of PAH rats with combined therapy was significantly lower than in other groups.. PAH did not have an effect on LV function of rats, or if it did, the effect was compensated by physiological processes. Also, sildenafil treatment deteriorated the LV cardiac index.

Topics: Animals; Blood Pressure; Bosentan; Cardiography, Impedance; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Endothelin Receptor Antagonists; Heart Ventricles; Hypertension, Pulmonary; Male; Monocrotaline; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Purines; Rats, Wistar; Sildenafil Citrate; Sulfonamides

Eisenmenger syndrome (ES) occurs as the most advanced form of pulmonary arterial hypertension (PAH) in patients with congenital heart disease. In this study, we aimed to evaluate the management of ES patients, follow-up and specific PAH treatment applying and clinical outcomes during 5 years.. During the period of the month between May 2008 and 2013 ES female patients were included in the study and followed an average for 5 years. Clinical findings, brain natriuretic peptide levels, transthoracic and right heart catheterization findings, 6-min walking test distance were recorded. PAH specific treatment as bosentan, iloprost and sildenafil was given to patients according to guidelines. The patients were evaluated with 3 months intervals as requirement for hospitalization, combination treatment, and mortality.. A total of 12 patients were included in the study. All of the patients were women, the mean age was 36.5. As prognostic echocardiographic data, the patients had high pulmonary artery pressure (109.81 ± 24.94 mmHg) related with increased right ventricular wall thickness, elevated right atrial pressure, severe pulmonary regurgitation in 40%, shortened pulmonary acceleration time, diminished myocardial tissue Doppler velocities of the left and right ventricles, increased right atrium area/left atrial area ratio (1.35 ± 0.40), lower right ventricular fractional area change. During the follow-up period of 5 years, a total of 16 events occurred. Combination treatment was required in 8 patients.. Eisenmenger syndrome is a multi-system affecting disease and due to high morbidity and mortality risk patients with ES should be followed by specialized centers. PAH specific treatment improves the disease course and survival of patients.

Topics: Adult; Antihypertensive Agents; Bosentan; Echocardiography; Eisenmenger Complex; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Laser-Doppler Flowmetry; Piperazines; Pulmonary Wedge Pressure; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Turkey

We aimed to study whether pulmonary arterial distensibility (PAD) correlates with hemodynamic parameters in chronic thromboembolic pulmonary hypertension (CTEPH) using electrocardiogram (ECG)-gated 320-slice multidetector computed tomography (MDCT).. ECG-gated 320-slice MDCT and right heart catheterization (RHC) was performed in 53 subjects (60.6±11.4 years old; 37 females) with CTEPH. We retrospectively measured the minimum and maximum values of the cross sectional area (CSA) of the main pulmonary artery (mainPA), right pulmonary artery (rtPA), and left pulmonary artery (ltPA) during one heartbeat. PAD was calculated using the following formula: PAD = [(CSAmaximum-CSAminimum)/CSAmaximum]×100(%). The correlation between hemodynamic parameters and PAD was assessed. Mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were 40.8±8.7 mmHg and 8.3±3.0 wood units, respectively. PAD values were as follows: mainPA (14.0±5.0%), rtPA (12.8±5.6%), and ltPA (9.7±4.6%). Good correlations existed between mainPAD, with mPAP (r = -0.594, p<0.001) and PVR (r = -0.659, p<0.001). The correlation coefficients between rtPAD and ltPAD with pulmonary hemodynamics were all lower or equal than for mainPAD.. PAD measured using ECG-gated 320-slice MDCT correlates with pulmonary hemodynamics in subjects with CTEPH. The mainPA is suitable for PAD measurement.

Topics: Aged; Chronic Disease; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multidetector Computed Tomography; Oxygen Inhalation Therapy; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Risk Factors; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vascular Capacitance; Vasodilator Agents

Sildenafil is used for the treatment of pediatric pulmonary hypertension. A dried blood spot (DBS)-based LC-MS method for sildenafil quantitation was developed and applied to a group of patients.. DBS showed high portability and stability of samples, and the method was selective and linear for quantitation of sildenafil (5-3,000 ng/ml) and N-desmethyl-sildenafil (3-1,500 ng/ml). After a single oral dose of sildenafil (1 mg/kg), method evidenced poor metabolism in these patients.. The method was successfully applied in peripheral blood and can be used for both pharmacokinetics and therapeutic drug monitoring. DBS proved to have advantages during sample translation and preservation of analytes. Data suggest that hazardous blood sildenafil levels may be reached in this population.

Topics: Child; Child, Preschool; Chromatography, High Pressure Liquid; Dried Blood Spot Testing; Drug Monitoring; Female; Half-Life; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Tandem Mass Spectrometry; Vasodilator Agents

The use of intermittent i.v. sildenafil dosing in three patients with pulmonary hypertension (PH) and limited venous access is reported.. One preterm infant with PH in addition to bronchopulmonary dysplasia and two full-term neonates with PH after congenital diaphragmatic hernia repairs were successfully treated for PH with adjunctive intermittent i.v. sildenafil. sildenafil dosages ranged from 0.4 to 2 mg/kg every six hours. Infusion periods ranged from one to three hours. The longer infusion periods were used to minimize the risk of hypotension during infusion, with continued efficacy assessment between dosing intervals by monitoring ongoing oxygenation saturation trends and oxygen requirements when the drug was not infusing. Treatment duration ranged from 5 to 50 days. Decreases or fluctuations in systemic blood pressure were noted at the beginning of treatment, but minimal interventions were required to maintain blood pressure, which generally increased during extended treatment. Fraction of inspired oxygen requirements were decreased or remained stable during each patient's first dose, and the need for respiratory support decreased over time, with improvements in oxygenation and prevention of continual life-threatening desaturation episodes. PH eventually resolved in each patient, based on improvements in serial echocardiographic studies with decreased requirements for inhaled nitric oxide, oxygen, and mechanical ventilation. All three patients required weaning from sildenafil treatment, suggesting a potential for rebound respiratory insufficiency with abrupt discontinuation of sildenafil.. Intermittent i.v. sildenafil dosing provided a well-tolerated, practical, and potentially effective treatment for PH in three patients when enteral intake was undesirable and when there was a need to conserve available venous access.

Topics: Disease Management; Drug Administration Schedule; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infusions, Intravenous; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

A 51-year-old woman (Case A) who had suffered from pulmonary Langerhans' cell granulomatosis for four years presented with progressive exertional dyspnea. A 39-year-old man (Case B) with pulmonary Langerhans' cell granulomatosis for eight years presented with right heart failure.. In Case A we found fixed airflow obstruction, hypoxemia, pulmonary fibrosis, bronchiectasis, severe precapillary pulmonary hypertension and a reduced right ventricular function, in Case B moderate airflow obstruction, hypoxemia, pulmonary fibrosis, emphysema and severe precapillary pulmonary hypertension.. Pulmonary hypertension due to pulmonary Langerhans' cell granulomatosis was assumed in both patients. After treatment with sildenafil, the woman has experienced long-term improvement for 2.5 years so far. An initially planned lung transplantation was therefore postponed. During inhaled iloprost the man also showed hemodynamic and clinical improvement and was stable for several years. Five years later recurrent right heart failure required an increase in iloprost dose; lung transplantation was then performed.. Although no approved drug is available for pulmonary hypertension in Langerhans' cell granulomatosis specific targeted therapies can lead to hemodynamic and long-term clinical improvement. Treatment could be helpful for selected patients with pulmonary hypertension in Langerhans' cell granulomatosis.

Topics: Adult; Drug Therapy, Combination; Female; Histiocytosis, Langerhans-Cell; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) still cannot be cured effectively, hence the search for novel treatments continues. The effects of sildenafil (25 mg/kg body weight) and fasudil (30 mg/kg body weight) given alone or in combination, on normalization of right ventricular pressure (RVP), right ventricle mass, as well as the levels of several biomarkers (HDL-C, BNP, VEGF-A), were assessed in a rat model of monocrotaline (MCT)-induced PAH. MCT (60 mg/kg body weight) induced clear PAH in male Wistar rats. After 21 days, a significant decrease in RVP accompanied by a reduction of right ventricular hypertrophy - a significant decrease in the right ventricle/left ventricle plus septum ratio - as a result of sildenafil or fasudil administration was assessed. The administration of fasudil and sildenafil alone or in combination caused a significant decrease in plasma BNP level as compared to MCT-treated rats. Fasudil alone or with sildenafil, but not sildenafil alone, significantly increased HDL-C level as compared to MCT-treated rats. Fasudil and sildenafil given alone or in combination caused a significant increase in plasma VEGF-A level as compared to rats exposed to MCT.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Cholesterol, HDL; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; Natriuretic Peptide, Brain; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Kinase Inhibitors; Purines; Rats; Rats, Wistar; rho-Associated Kinases; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor A

A retrospective analysis of the records of all the patients of pulmonary arterial hypertension with pregnancy at AIIMS, New Delhi, India, to study maternal and perinatal outcome and to compare outcome between severe and mild pulmonary arterial hypertension.. A retrospective analysis was carried out of 30 pregnancies in women with pulmonary arterial hypertension (PAH) who delivered at ≥ 28 weeks of gestation from July 2006 through July 2012 at a tertiary care center in India. Pulmonary artery blood pressure (PABP) during the first trimester of pregnancy or before pregnancy was considered to define PABP as severe or mild, with severe cases having systolic PABP >50 mmHg on echocardiography.. Out of 30 patients, 14 patients had severe PAH and 16 patients had mild PAH. Women with severe PAH had a significantly higher incidence of preterm delivery (11 vs. 3, P < 0.05), small for gestational age infants (10 vs. 2, P < 0.05) and cardiac complications (6 vs. 1, P < 0.05) compared to women with mild PAH. There was maternal mortality in a patient with Eisenmenger syndrome. In women with severe PAH and mild PAH, PABP increased in later pregnancy from 63.14 ± 7.6 to 71.57 ± 7.9 mmHg (P < 0.05) and from 40.37 ± 3.6 to 41.69 ± 4.1 mmHg (P < 0.05), respectively.. Pregnancy in women with severe PAH is associated with higher maternal morbidity and adverse fetal outcome compared to pregnancy in women with mild PAH.

Topics: Adult; Arrhythmias, Cardiac; Arterial Pressure; Birth Weight; Cesarean Section; Echocardiography; Eisenmenger Complex; Familial Primary Pulmonary Hypertension; Female; Gestational Age; Heart Failure; Humans; Hypertension, Pulmonary; India; Infant, Newborn; Infant, Small for Gestational Age; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pregnancy Trimester, First; Pregnancy Trimester, Third; Premature Birth; Purines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfones; Vasodilator Agents; Young Adult

Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.

Topics: Adolescent; Antihypertensive Agents; Bosentan; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Incidence; Infant; Infant, Newborn; Male; Piperazines; Product Surveillance, Postmarketing; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; United States; United States Food and Drug Administration; Vasodilator Agents

Sildenafil, usually a well-tolerated drug traditionally used for erectile dysfunction (ED), was recently approved for pulmonary arterial hypertension. In the literature, there are few cases of hemoptysis following sildenafil use for ED; however, to our knowledge, we are reporting the first case of hemoptysis following sildenafil use for pulmonary hypertension. We are documenting a case of a 90-year-old male patient who was admitted to the intensive care unit with hemoptysis and respiratory failure two weeks after he was started on sildenafil.

Topics: Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Drug Therapy, Combination; Hemoptysis; Humans; Hypertension, Pulmonary; Intensive Care Units; Male; Patient Admission; Piperazines; Purines; Respiratory Insufficiency; Sildenafil Citrate; Sulfones; Vasodilator Agents

Intravenous (IV) prostacyclin (epoprostanol) and its analogs (iloprost and treprostinil) are effective in treating pulmonary artery hypertension (PAH). Although prostacyclins are available for inhaled and subcutaneous delivery, IV administration of prostacyclins, sometimes in combination with other agents, such as bosentan or sildenafil, is considered the most aggressive method to manage PAH. This report attempts to help clinicians determine when to initiate IV treatment of PAH and when to refer a patient with PAH to a center for treatment. IV prostacyclin therapy initiation is suggested when patients exhibit World Health Organization functional class IV symptoms. The Registry to EValuate Early And Long-term Pulmonary Arterial Hypertension disease management (REVEAL) risk calculator can help determine a patient's 1-year mortality with PAH and characterize the clinical course, treatment, and predictors of outcomes in patients with PAH. Referring physicians can screen their patients for PAH and refer even before the diagnosis has been confirmed so that the center can facilitate the diagnostic process and provide suggestions for initial therapy selection and provide other collaborative and supportive services. Alternatively, the physician can diagnose and initiate early therapy with a plan to involve the pulmonary hypertension center at the need for IV therapy or consideration for transplantation, working closely with the patient to ensure stability. Physicians and pulmonary centers must develop good methods of communication to ensure effective diagnosis and management.

Topics: Disease Management; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Platelet Aggregation Inhibitors; Purines; Referral and Consultation; Sildenafil Citrate; Sulfones; Vasodilator Agents

There has been no established medical therapy to ameliorate pulmonary hypertension (PH) owing to left heart disease (LHD-PH). It has recently been shown that the left ventricular assist device (LVAD) can improve LHD-PH and therefore has the potential to become a major bridge tool for heart transplantation (HTx). However, some patients still have persistent PH even after LVAD treatment. It is essential to demonstrate the reversibility of end-organ dysfunction, including PH, prior to implantable LVAD treatment, especially in Japan, because implantable LVAD treatment is indicated only as bridge to transplantation. Here we report a patient with LHD-PH whose PH was demonstrated to be reversible by the acute pulmonary vasoreactivity test (APVT) with nitrogen monoxide (NO) and the phosphodiesterase-5 inhibitor sildenafil. Both inhaled NO and sildenafil reduced pulmonary vascular resistance, but pulmonary capillary wedge pressure was increased by NO, which was conversely decreased under increased cardiac output by sildenafil. After the patient was listed as an HTx recipient, pulmonary vascular resistance recovered down to an acceptable range with LVAD treatment. Based on these findings, we suggest that the APVT with sildenafil may be a useful and safe tool to predict improvement of PH after LVAD treatment.

Topics: Adult; Cardiomyopathy, Dilated; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Piperazines; Prosthesis Implantation; Purines; Sildenafil Citrate; Sulfones

We investigated if soluble guanylate cyclase stimulation either alone or in combination with phosphodiesterase-5 (PDE5) inhibition could prevent pressure overload-induced right ventricular (RV) hypertrophy and failure.. The soluble guanylate cyclase stimulator BAY 41-2272 (BAY, 10 mg · kg⁻¹ · d⁻¹) either alone or in combination (BAY + SIL) with a PDE5 inhibitor sildenafil (SIL, 100 mg · kg⁻¹ · d⁻¹) was examined for prevention of RV hypertrophy and failure in Wistar rats (n = 73) operated by pulmonary trunk banding.. All treatments failed to inhibit the development of RV hypertrophy and failure. In the BAY and BAY + SIL groups, there was an increased mortality. Mean arterial blood pressure was lowered and cardiac output increased in the BAY + SIL group. Systolic RV pressure was increased in the BAY and BAY + SIL groups possibly because of an inotropic response and/or increased venous return.. Stimulation of soluble guanylate cyclase by BAY 41-2272 alone or in combination with sildenafil failed to prevent the development of RV hypertrophy and failure in rats subjected to pulmonary trunk banding. An increased mortality was observed in animals treated by BAY 41-2272 alone and in combination with sildenafil.

Topics: Animals; Blood Pressure; Cardiac Output; Cyclic GMP; Disease Models, Animal; Disease Progression; Enzyme Activators; Guanylate Cyclase; Heart Failure; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrazoles; Pyridines; Random Allocation; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfones; Survival Analysis

Right ventricular (RV) dysfunction, caused by severe pulmonary hypertension (PH), is associated with high mortality because of RV failure. However, some patients can suffer from sudden cardiac death (SCD). We hypothesized that severe PH can cause RV arrhythmogenesis, leading to SCD. We sought to investigate arrhythmogenesis in PH. Optical mapping analysis (OMP) with an electrophysiological study (EPS) and pathological examination were performed in a monocrotaline (MCT)-induced rat PH model. Rats were injected with MCT (60 mg/kg), and OMP was performed in isolated Langendorff-perfused hearts. OMP revealed abnormal RV conduction delays and abnormal patterns, along with elevated RV pressure. In addition, impaired action potential duration dispersion (APDd), an index of myocardial repolarization instability, was observed only in the RVs with severe PH. The EPS demonstrated that lethal arrhythmias were induced by burst pacing to the RV when deteriorated APDd became evident. This arrhythmogenesis was inhibited by combination treatment with sildenafil and beraprost (SIL + BERA). RT-PCR showed an mRNA up-regulation of Type I collagen and down-regulation of connexin-43 in the RV at 5 weeks after MCT injection. Pathological examination revealed pulmonary vascular remodeling and RV hypertrophy with interstitial fibrosis, which was substantially reduced by SIL + BERA. Immunohistochemistry also revealed connexin-43 degradation in the RVs with severe PH. In contrast, connexin-43 was well preserved, and no lethal arrhythmias were induced by burst pacing to the RV in the absence of PH after SIL + BERA. In conclusion, RV electrical remodeling, including impaired APDd, causes arrhythmogenesis in severe PH, potentially associated with SCD attributable to PH.

Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Collagen Type I; Connexin 43; Death, Sudden, Cardiac; Drug Therapy, Combination; Epoprostenol; Gene Expression Regulation; Heart; Humans; Hypertension, Pulmonary; Male; Monocrotaline; Organ Culture Techniques; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Right; Ventricular Remodeling; Voltage-Sensitive Dye Imaging

Drug-induced ototoxicity, particularly those involving phosphodiesterase type 5 (PDE-5) inhibitors, is considered to be rare and to our knowledge such an adverse effect has not been reported in Canada. Here we present a case of a 77-year old man initiated on a sildenfil regimen for the treatment of pulmonary hypertension, who developed sudden bilateral hearing loss after taking sildenafil, in the setting of high dose furosemide and diltiazem. We outline the likely interplay of patient characteristics, drug synergy and drug-drug interactions in the development of his ototoxicity. Importantly, given the extent and popularity of PDE-5 inhibitors for erectile dysfunction as well as a newer therapeutic option for pulmonary hypertension, clinicians should be aware of the risk for drug-induced ototoxicity, particularly in the setting of concomitant loop diuretics and CYP3A4 inhibiting medications.

Topics: Aged; Canada; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Diltiazem; Diuretics; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Enzyme Inhibitors; Furosemide; Hearing Loss; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

In recent times, paediatric pulmonary arterial hypertension management has been transformed to focus on disease modifying strategies that improve both quality of life and survival, rather than just symptom palliation. Sildenafil, a phosphodiesterase-V inhibitor, has been at the centre of this. Despite controversial beginnings, its success in treating pulmonary arterial hypertension has led to its consideration for related pathologies such as persistent pulmonary hypertension of the newborn and bronchopulmonary dysplasia, as well as the development of a range of alternative formulations. However, this has caused its own controversy and confusion regarding the use of sildenafil in younger patients. In addition, recent data regarding long-term mortality and the repeal of US drugs approval have complicated the issue. Despite such setbacks, sildenafil continues to be a major component of the contemporary care of paediatric pulmonary hypertension in a variety of contexts, and this does not seem likely to change in the foreseeable future.

Topics: Child; Drug Approval; Drug Interactions; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Practice Guidelines as Topic; Purines; Sildenafil Citrate; Sulfones

Tadalafil, a once-daily phosphodiesterase type 5 inhibitor (PDE-5I), offers clinicians an alternative to sildenafil, a 3-times-daily (t.i.d.) PDE-5I for treatment of pulmonary arterial hypertension (PAH). However, there are limited data describing the risks and benefits or recommended methodology of switching patients from sildenafil to tadalafil.. Chart reviews were conducted on all World Health Organization group 1 patients on sildenafil for ≥ 3 months who transitioned to tadalafil with documented clinic visits and 6-min walk tests on both drugs. Most patients were transitioned by discontinuing sildenafil after the evening dose and initiating tadalafil 40 mg/day the next day. Data collected included demographics, PAH etiology, diagnostic hemodynamics, 6-min walk distance (6MWD), PDE-5I side effects, and concomitant medications. Data on B-type natriuretic peptide (BNP) levels were available for most patients also receiving endothelin receptor antagonists (ERAs).. Medical records from 98 patients were evaluated. Most patients (92%) were on sildenafil for > 1 year, and 78% were receiving sildenafil 80-100 mg t.i.d. Ninety-seven percent of patients (95/98) were successfully transitioned and maintained on 40 mg/day. With a mean duration on tadalafil therapy of 243 ± 127 days at the time of analysis, 6MWD was unchanged. Patient-reported adverse events included headache (4%) and heartburn (2%). There was minimal change in BNP levels in the subset of patients receiving an ERA concomitantly.. Transition from sildenafil to tadalafil 40 mg/day appears feasible without clinical deterioration or intolerable side effects. This study provides guidance to physicians considering transition from sildenafil to tadalafil for selecting patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carbolines; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Tadalafil

Chronic hypoxia induces an increased production of nitric oxide (NO) in pulmonary prealveolar arterioles. Bioavailability of the NO in the pulmonary vessels correlates with concentration of L-arginine as well as activity of phosphodiesterase-5 enzyme (PDE-5). We tested a hypothesis whether a combination of L-arginine and PDE-5 inhibitor sildenafil has an additive effect in reduction of the hypoxic pulmonary hypertension (HPH) in rats. Animals were exposed to chronic normobaric hypoxia for 3 weeks. In the AH group, rats were administered L-arginine during chronic hypoxic exposure. In the SH group, rats were administered sildenafil during chronic hypoxic exposure. In the SAH group, rats were treated by the combination of L-arginine as well as sildenafil during exposure to chronic hypoxia. Mean PAP, structural remodeling of peripheral pulmonary arterioles (%DL) and RV/LV+S ratio was significantly decreased in the SAH group compared to hypoxic controls even decreased compared to the AH and the SH groups in first two measured parameters. Plasmatic concentration of cGMP and NOx were significantly lower in the SAH group compared to hypoxic controls. We demonstrate that NO synthase substrate L-arginine and phosphodiesterase-5 inhibitor sildenafil administered in combination are more potent in attenuation of the HPH compared to a treatment by substances given alone.

Topics: Animals; Arginine; Blood Pressure; Drug Synergism; Drug Therapy, Combination; Hypertension, Pulmonary; Hypoxia; Male; Piperazines; Pulmonary Gas Exchange; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Sildenafil is used to treat pulmonary hypertension (PAH) in infants with congenital diaphragmatic hernia (CDH). However, data to guide sildenafil dosing and weaning are limited. This is concerning in light of a recent report describing increased risk associated with high-dose sildenafil regimens in non-CDH PAH. A retrospective cohort study of sildenafil usage, dosing, and weaning in infants with CDH was conducted at the authors' institution. The findings show that 17 % (19/122) of infants were discharged receiving sildenafil at a median dose of 8 mg/kg/day (range 2.91-5.78 mg/kg/day). The weaning rate was 0.1 mg/kg/week (range 0.01-0.5 mg/kg/week). The infants ceased therapy after a median of 343 days. At the age of 1 year, 29 % were receiving sildenafil at a dose higher than 1.5 mg/kg/day. One infant died of severe PAH. Sildenafil therapy at discharge is common in severe CDH. Variation in dosing and weaning rates highlights the need for standardized assessment and treatment of PAH after discharge to optimize the benefits and minimize the adverse effects of sildenafil.

Topics: Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Patient Discharge; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Vasodilation; Weaning

Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is a rare disease (incidence and prevalence rates of approximately one and six cases per million inhabitants, respectively) with different clinical phenotypes. A group of diverse conditions manifest pulmonary arterial hypertension (PAH) and share similar pathological and/or clinical findings with IPAH. By definition, IPAH is diagnosed only after alternative diagnoses have been ruled out. Extensive investigation is needed to determine if PAH is associated with thyroid diseases, infectious diseases, autoimmune conditions, exposure to certain drugs (particularly anorexigens), certain genetic mutations, and so on. The presence of genetic abnormalities and risk factors (such as specific drug exposures) reinforces the "multiple hit" concept for the development of pulmonary hypertension. Fortunately, within the past two decades, therapeutic options have become available for IPAH, resulting in improved survival and clinical outcomes. At least seven different compounds have been registered for PAH treatment. However, even with aggressive PAH-specific therapy, mortality rates remain high (∼40% at 5 years). Given the high mortality rates, the use of combinations of agents that work by different pathways has been advocated (either as "add-on" therapy or initial "up front" therapy). Further, new therapeutic agents and treatment strategies are on the near horizon, aiming to further improve survival from the remarkable progress already seen.

Topics: Aminorex; Antihypertensive Agents; Appetite Depressants; Bosentan; Dasatinib; Epoprostenol; Familial Primary Pulmonary Hypertension; Fenfluramine; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Iloprost; Phenylpropionates; Piperazines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridazines; Pyrimidines; Risk Factors; Sildenafil Citrate; Sulfonamides; Sulfones; Thiazoles; Vasodilator Agents

Topics: Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Normal pulmonary vascular development in infancy requires maintenance of low pulmonary vascular resistance after birth, and is necessary for normal lung function and growth. The developing lung is subject to multiple genetic, pathological and/or environmental influences that can adversely affect lung adaptation, development, and growth, leading to pulmonary hypertension. New classifications of pulmonary hypertension are beginning to account for these diverse phenotypes, and or pulmonary hypertension in infants due to PPHN, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). The most effective pharmacotherapeutic strategies for infants with PPHN are directed at selective reduction of PVR, and take advantage of a rapidly advancing understanding of the altered signaling pathways in the remodeled vasculature.

Topics: Bosentan; Bronchopulmonary Dysplasia; Hernia, Diaphragmatic; Humans; Hypertension, Pulmonary; Infant, Newborn; Milrinone; Nitric Oxide; Piperazines; Prostaglandins; Purines; Signal Transduction; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance

An 84-year-old woman with pulmonary hypertension (PH) secondary to chronic pulmonary thromboembolism suffered from continuous warfarin dependent bleeding from sigmoid colon cancer. Sigmoidectomy was scheduled to control continuous bleeding. Six hours after discontinuation of anticoagulant therapy for elective sigmoidectomy, the patient showed hypoxia, pulmonary thromboembolism and pulmonary hypertension with right ventricular systolic pressure (RVSP) of 81 mmHg. The operation was postponed and heparin was infused. Since two-day heparinization therapy did not improve PH, oral administration of sildenafil citrate 60 mg daily was initiated. Seven days after initiation of sildenafil administration, RVSP decreased to 49 mmHg without improvement of hypoxia. Sigmoidectomy was performed under general anesthesia. The patient showed severe hypotension managed with noradrenaline and dopamine infusion during and after surgery, resulting from interaction between sildenafil and vasodilators. The patient was discharged 36 days after the operation without complications.

Topics: Aged, 80 and over; Colon, Sigmoid; Female; Humans; Hypertension, Pulmonary; Perioperative Care; Piperazines; Pulmonary Embolism; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adolescent; Child; Child, Preschool; Databases, Factual; Drug Utilization; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Infant; Off-Label Use; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; United States

Topics: Antihypertensive Agents; Cardiac Surgical Procedures; Female; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Aged; Ascites; Cardiac Catheterization; Diagnosis, Differential; Echocardiography; Female; Humans; Hypertension, Pulmonary; Hypoxia; Oxygen; Piperazines; Purines; Scleroderma, Limited; Sildenafil Citrate; Sulfones; Vasodilator Agents; Weight Loss

Early closure of a large ventricular septal defect before the onset of elevated pulmonary vascular resistance is important. Pulmonary hypertensive events might cause significant morbidity or mortality, even when closure is performed after infancy. Therefore, treatment of pulmonary hypertension after surgery may be the most important issue affecting the prognosis. We describe successful treatment of pulmonary hypertension in a 25-year-old woman after closure of large ventricular septal defect, with inhaled nitric oxide, sildenafil, and bosentan.

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Bosentan; Cardiac Surgical Procedures; Drug Therapy, Combination; Female; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

We report a case of an elderly woman with heart failure with preserved ejection fraction and pulmonary hypertension (HFpEF-PH), refractory to conventional therapy for left heart failure and successfully treated by sildenafil.

Topics: Aged; Female; Heart Failure; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Patients with inoperable chronic thromboembolic pulmonary hypertension (Inop-CTEPH) treated with conventional therapy have a poor survival. We compare the 3-year survival between those treated with conventional therapy and those treated with conventional therapy and a combination of novel drugs. We also evaluate the clinical course. A total of 34 Inop-CTEPH consecutive patients were evaluated from 1991 to 2009 including right heart catheterization (RHC) and perfusion lung scan (PLS): 7 underwent surgical treatment while 27 were confirmed inoperable. Of these 27 patients, 12 evaluated from 1991 to 2003 (Group 1) were treated with conventional therapy and 15 evaluated from 2004 to 2009 (Group 2) were treated with conventional and novel therapies. At baseline, no group difference emerged at RHC. Based on clinical course, novel drugs and oxygen supplementation were given to patients of Group 2. Seven of these who had worse clinical course repeated RHC and four of them also PLS during therapy. Those without repeat RHC had baseline pulmonary artery mean pressure and brain natriuretic peptide (NT-proBNP) lower and mixed venous saturation (SvO2) and exercise test higher (p = 0.022, 0.015, 0.044 and 0.003, respectively). During therapy, those with repeat RHC had total pulmonary vascular resistance reduced (p = 0.012), base excess increased (p = 0.002) and significant redistribution of pulmonary blood flow at PLS. At the 3-year follow-up, survival was 86% in Group 2 and 31% in Group 1 (p = 0.031). In Inop-CTEPH patients, the clinical course may help to select drugs and the level of oxygen supply that can improve hemodynamics, gas exchange and long-term survival.

Topics: Acid-Base Equilibrium; Aged; Antihypertensive Agents; Blood Gas Analysis; Bosentan; Cardiac Output; Chronic Disease; Drug Therapy, Combination; Exercise Test; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Male; Middle Aged; Oxygen Consumption; Oxygen Inhalation Therapy; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; Thiophenes; Thromboembolism; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is an increasingly recognised serious illness with insidious onset, delayed diagnosis, complex diagnostic algorithms and poor prognosis, but with recently available effective treatments.. To efficiently diagnose and to offer treatment for PAH, we established a multidisciplinary service in 2005, where patients attend a clinic staffed by specialists in cardiology, respiratory medicine, rheumatology and immunology in a tertiary referral hospital setting.. We studied the first 200 patients referred. Serology, echocardiography, lung function tests, high-resolution computed tomography, World Health Organisation Class determination and 6-min walk tests and/or right heart catheterisation were performed, as clinically indicated.. Of the 200 patients seen, 66 had confirmed pulmonary hypertension (mean pulmonary artery pressure > 25 mmHg) diagnosed on echocardiography ± right heart catheterisation. Of these patients, 58 had catheter-proven PAH (mean pulmonary artery pressure > 25 mmHg with mean wedge pressure < 15 mmHg). Underlying diagnoses for the confirmed PAH patients were idiopathic (32), scleroderma-associated (14), other connective tissue disease (4) and associated with congenital heart disease (8). Patients with confirmed PAH were commenced on PAH-specific therapy--initially bosentan in the majority but sildenafil, and iloprost were occasionally used initially for patient-specific reasons. Median time from when the patient first called the clinic to prescription of therapy was 16 days (interquartile range; 0-31 days). All surviving patients with PAH have attended for regular 6-monthly follow-up visits with a 100% retention rate up to 4 years.. A multidisciplinary clinic can provide efficient diagnosis and rapid triage to PAH-specific therapy, if appropriate. Retention rates remain high, at follow up.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allergy and Immunology; Bosentan; Cardiac Catheterization; Cardiology; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Kaplan-Meier Estimate; Male; Mass Screening; Middle Aged; Outpatient Clinics, Hospital; Patient Care Team; Piperazines; Prospective Studies; Pulmonary Medicine; Purines; Rheumatology; Sildenafil Citrate; Sulfonamides; Sulfones; Tertiary Care Centers; Ultrasonography; Young Adult

A 1-year-old boy who had left isomerism and corrected transposition of the great arteries (c-TGA) with moderate-sized ventricular septal defect, severe pulmonary artery hypertension (PAH), and pulmonary vascular disease with significant right-to-left shunting received a diagnosis of type 2 Abernethy malformation, which was partly responsible for disproportionate PAH in the child. The malformation was treated by plugging of the portosystemic shunt. Follow-up cardiac catheterization on sildenafil demonstrated significant left-to-right shunting (2.16:1) and a fall in pulmonary vascular resistance, making surgical correction possible. This case highlights the importance of searching for additional rare causes of PAH in patients with congenital heart diseases when the degree of pulmonary hypertension is disproportional to the defect size.

Topics: Abnormalities, Multiple; Cardiac Catheterization; Cardiac Surgical Procedures; Disease Progression; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Heterotaxy Syndrome; Humans; Hypertension, Pulmonary; Infant; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Topics: Child; Child, Preschool; Fontan Procedure; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension (PH) is a life-threatening disease that causes endothelial dysfunction in the pulmonary vascular bed. Systemic endothelial dysfunction has also been reported in PH. This study compared the systemic and pulmonary vascular responses and some blood biomarkers of endothelial function in monocrotaline (MCT)-induced PH of rats. It also investigated the effect of sildenafil and iloprost treatment. MCT application induced elevation in the right ventricular pressures of the rat heart that had been reversed by sildenafil and iloprost treatment. Acetylcholine-induced endothelium-dependent relaxations of the isolated pulmonary artery were decreased in the PH group and this failure was reversed by sildenafil and iloprost treatment. Acetylcholine-induced endothelium-dependent relaxations of the isolated thoracic aorta were similar in all groups. Serotonin-induced contractions of the pulmonary artery were augmented by PH. In the isolated aorta, serotonin-stimulated contraction was not different in the control and MCT groups, but sildenafil and iloprost treatment decreased serotonin responses. The nitric oxide (NO) level in systemic circulation was not significantly changed by PH. However, sildenafil and iloprost treatments caused a decrease in the plasma level of NO. Asymmetric dimethylarginine levels in plasma were significantly decreased after MCT application and were not recovered by sildenafil and iloprost treatment. Total antioxidant capacity and H2S level of plasma were similar in all groups. Results of this study showed that MCT-induced PH caused specific toxic effects on pulmonary vasculature without any functional effects on the aorta. In addition, it was also demonstrated that sildenafil and iloprost treatments were effective in the MCT-induced PH.

Topics: Animals; Aorta, Thoracic; Arginine; Disease Models, Animal; Endothelium, Vascular; Hydrogen Sulfide; Hypertension, Pulmonary; Iloprost; Male; Monocrotaline; Nitric Oxide; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

The purpose of this study was to review the patient characteristics and management of 56 cases of high altitude pulmonary edema at the Pheriche Himalayan Rescue Association Medical Aid Post, and to measure the use of medications in addition to descent and oxygen.. In a retrospective case series, we reviewed all patients diagnosed clinically with high altitude pulmonary edema during the 2010 Spring and Fall seasons. Nationality, altitude at onset of symptoms, physical examination findings, therapies administered, and evacuation methods were evaluated.. Of all patients, 23% were Nepalese, with no difference in clinical features compared with non-Nepalese patients; 28% of all patients were also suspected of having high altitude cerebral edema. Symptoms developed in 91% of all patients at an altitude higher than the aid post (median altitude of onset of 4834 m); 83% received oxygen therapy, and 87% received nifedipine, 44% sildenafil, 32% dexamethasone, and 39% acetazolamide. Patients who were administered sildenafil, dexamethasone, or acetazolamide had presented with significantly lower initial oxygen saturations (P ≤ .05). After treatment, 93% of all patients descended; 38% descended on foot without a supply of oxygen.. A significant number of patients presenting to the Pheriche medical aid post with high altitude pulmonary edema were given dexamethasone, sildenafil, or acetazolamide in addition to oxygen, nifedipine, and descent. This finding may be related to perceived severity of illness and evacuation limitations. Although no adverse effects were observed, the use of multiple medications is not supported by current evidence and should not be widely adopted without further study.

Topics: Acetazolamide; Altitude Sickness; Dexamethasone; Emergency Treatment; Female; Humans; Hypertension, Pulmonary; Male; Mountaineering; Nepal; Nifedipine; Oxygen Inhalation Therapy; Piperazines; Purines; Retrospective Studies; Seasons; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a rare disease with a predilection for young women that is associated with right ventricular failure and premature death. PAH can complicate pregnancy with hemodynamic instability or sudden death during parturition and postpartum. Our aim was to examine the impact of PAH on pregnancy outcomes in the modern era.. We conducted a retrospective evaluation of pregnant patients with PAH managed between 1999 and 2009 at five US medical centers. Patient demographics, medical therapies, hemodynamic measurements, manner of delivery, anesthetic administration, and outcomes were assessed.. Among 18 patients with PAH, 12 continued pregnancy and six underwent pregnancy termination. Right ventricular systolic pressure in patients managed to parturition was 82 ± 5 mm Hg and in patients with pregnancy termination was 90 ± 16 mm Hg. Six patients underwent pregnancy termination at mean gestational age of 13 ± 1.0 weeks with no maternal deaths or complications. Twelve patients elected to continue their pregnancy and were hospitalized at 29 ± 1.4 weeks. PAH-specific therapy was administered to nine (75%) at time of delivery consisting of sildenafil, IV prostanoids, or combination therapy. All parturients underwent Cesarean section at 34 weeks with one in-hospital death and one additional death 2 months postpartum for maternal mortality of 16.7%.. Compared with earlier reports, maternal morbidity and mortality among pregnant women with PAH was reduced, yet maternal complications remain significant and patients should continue to be counseled to avoid pregnancy.

Topics: Adult; Anesthetics; Blood Pressure; Cesarean Section; Disease Management; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Prostaglandins; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Survival Rate; Vasodilator Agents

To elucidate left ventricular function in pulmonary hypertension, we measured parameters of left ventricular as well as right ventricular function by echocardiography in 11 patients with pulmonary hypertension (idiopathic pulmonary artery hypertension in 4, chronic thromboembolic pulmonary hypertension in 5, and other pulmonary hypertension in 2). The percent change in these parameters 6 months after treatment with pulmonary artery vasodilators (beraprost in 8 and sildenafil in 3) was assessed. There was a correlation between the relative change in right ventricular systolic pressure (RVSP) and the relative changes in left ventricular outflow tract velocity-time integral (r = -0.730, P = 0.011) and mitral valve velocity-time integral (r = -0.621, P = 0.041). However, there was no correlation between the relative change in RVSP and the relative changes in left ventricular ejection fraction, left ventricular diastolic dimension, and systolic blood pressure. The relative change in RVSP was also correlated with the relative change in early diastolic myocardial velocity at the medial mitral annulus (r = -0.675, P = 0.023). Reduction of RVSP by pulmonary artery vasodilators might increase left ventricular preload, leading to an increase in stroke volume. Right ventricular load reduction might improve left ventricular diastolic function in patients with pulmonary hypertension, possibly through altered interventricular septal performance.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Diastole; Echocardiography, Doppler; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Linear Models; Male; Middle Aged; Mitral Valve; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Systole; Time Factors; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right; Ventricular Function, Left; Ventricular Function, Right; Ventricular Pressure

Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable pulmonary arterial hypertension (PAH), and BMPR-II deficiency contributes to idiopathic and experimental forms of PAH. Sildenafil, a potent type-5 nucleotide-dependent phosphodiesterase inhibitor, is an established treatment for PAH, but whether sildenafil affects bone morphogenetic protein (BMP) signaling in the pulmonary circulation remains unknown.. Studies were undertaken in human pulmonary arterial smooth muscle cells (PASMCs) and in vivo in the monocrotaline rat model of PAH. In PASMCs, sildenafil enhanced BMP4-induced phosphorylation of Smad1/5, Smad nuclear localization, and Inhibitor of DNA binding protein 1 gene and protein expression. This effect was mimicked by 8-bromo-cyclic GMP. Pharmacological inhibition or small interfering RNA knockdown of cyclic GMP-dependent protein kinase I inhibited the effect of sildenafil on BMP signaling. In functional studies, we observed that sildenafil potentiated the antiproliferative effects of BMP4 on PASMC proliferation. Furthermore, sildenafil restored the antiproliferative response to BMP4 in PASMCs harboring mutations in BMPR-II. In the monocrotaline rat model of PAH, which is characterized by BMPR-II deficiency, sildenafil prevented the development of pulmonary hypertension and vascular remodeling, and partly restored Smad1/5 phosphorylation and Inhibitor of DNA binding protein 1 gene expression in vivo in monocrotaline exposed rat lungs.. Sildenafil enhances canonical BMP signaling via cyclic GMP and cyclic GMP-dependent protein kinase I in vitro and in vivo, and partly restores deficient BMP signaling in BMPR-II mutant PASMCs. Our findings demonstrate a novel mechanism of action of sildenafil in the treatment of PAH and suggest that targeting BMP signaling may be beneficial in this disease.

Topics: Animals; Antihypertensive Agents; Binding Sites; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type II; Bone Morphogenetic Proteins; Cell Proliferation; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Disease Models, Animal; Dose-Response Relationship, Drug; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Inhibitor of Differentiation Protein 1; Male; Monocrotaline; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Phosphodiesterase 5 Inhibitors; Phosphorylation; Piperazines; Promoter Regions, Genetic; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; RNA Interference; Signal Transduction; Sildenafil Citrate; Smad1 Protein; Smad5 Protein; Sulfones; Transfection; Vasodilator Agents

Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.

Topics: Disease Progression; Drug Monitoring; Humans; Hypertension, Pulmonary; Piperazines; Product Surveillance, Postmarketing; Purines; Sildenafil Citrate; Sulfones; United States; United States Food and Drug Administration; Vasodilator Agents

Pulmonary hypertension (PH) is an infrequently reported complication after hematopoietic stem cell transplantation, and its etiology and therapeutic strategies, especially in infants, remain unclear. We report a case of severe PH that developed in an infant with acute leukemia following administration of busulfan as a preconditioner for cord blood transplantation; the case was successfully treated with sildenafil and beraprost, which to our knowledge is the first reported successful use of this regimen in PH following transplantation for infantile leukemia. From a review of all previous reports, use of busulfan in infants may raise the risk of developing PH, and unlike definitive pulmonary veno-occlusive disease, PH in this subgroup may be reversible by early detection and treatment.

Topics: Cord Blood Stem Cell Transplantation; Echocardiography; Epoprostenol; Humans; Hypertension, Pulmonary; Infant; Leukemia; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Treatment Outcome; Vasodilator Agents

Bronchopulmonary dysplasia (BPD) of very preterm infants is a multifactorial chronic lung disease and its incidence has not decreased despite improvements in neonatal intensive care, including lung protective strategies. Pulmonary hypertension (PH) can complicate the course of BPD. Mortality in infants with BPD-associated PH is thought to be very high, but its incidence is unknown and a standard diagnostic and therapeutic strategy has not been well defined. In this article, we will first describe the current knowledge on the BPD-associated PH and the current treatments available for this pathology. We will then present the HTP-DBP Study, carried out in Paris (France) starting in 2012. The diagnosis of PH is suspected on echocardiographic criteria, but cardiac catheterization is considered the gold standard for diagnosis and evaluation of the severity of PH. Moreover, pulmonary vasoreactivity testing is used to guide the management of patients with PH. The pathogenesis of BPD-associated PH is poorly understood and even less is known about appropriate therapy. Today, optimizing ventilation and reducing the pulmonary vascular tone with specific pulmonary vasodilatator drugs are the main goals in treating HTP-associated DBP. Animal studies and a few clinical studies suggest that medications targeting the nitric oxide (NO) signaling pathway (NO inhalation, oral sildenafil citrate) could be effective treatments for BPD-associated PH, but they have not been approved for this indication. The HTP-DBP study is a French multicenter prospective observational study. The objective is to evaluate the frequency of BPD-associated PH, to describe its physiopathology, its severity (morbidity and mortality), and the effectiveness of current treatments.

Topics: Administration, Inhalation; Bronchodilator Agents; Bronchopulmonary Dysplasia; Cardiac Catheterization; Familial Primary Pulmonary Hypertension; France; Humans; Hypertension, Pulmonary; Incidence; Infant, Extremely Premature; Infant, Newborn; Nitric Oxide; Piperazines; Positive-Pressure Respiration; Prospective Studies; Purines; Risk Factors; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

A 23-week-old baby, born at 26(+2) weeks, presented to the hospital with critical respiratory failure, which was impossible to stabilize. She had unstable oxygen saturations between 35% and 95%. A presumptive diagnosis of bronchopulmonary dysplasia with associated pulmonary hypertensive crisis was made. In the absence of inhaled nitric oxide, 2 oral doses of 1 mg/kg sildenafil were given, with a dramatic improvement 30 to 45 minutes later. Her oxygenation index fell from 43 to 14. She made a full recovery and was discharged from the hospital 2 weeks later.

Topics: Administration, Oral; Bronchopulmonary Dysplasia; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Heart Arrest; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Intubation, Gastrointestinal; Oxygen; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Respiratory Insufficiency; Sildenafil Citrate; Sulfones; Vasodilator Agents

We hypothesized that the long-term therapeutic effect of combined sildenafil and bone marrow-derived endothelial progenitor cells (BMDEPCs) on monocrotaline (MCT)-induced rat pulmonary arterial hypertension (PAH) is superior to either treatment alone.. Male Sprague-Dawley rats (n = 40) were equally divided into normal controls, MCT (65 mg/kg, subcutaneously) only, MCT + sildenafil (25 mg/kg/day, orally), MCT + BMDEPCs (2.0 × 10(6) autologous cells, intravenously) and MCT + sildenafil+ BMDEPCs. BMDEPCs and sildenafil were given on day 21 after MCT administration. Animals were sacrificed by day 90 after MCT administration.. The apoptotic (caspase 3, Bax) and inflammatory (tumor necrosis factor-α, matrix metalloproteinase-9) biomarkers in right ventricle and lung and pulmonary expressions of fibrotic biomarkers (transforming growth factor-β, p-Smad3) and connexin 43 protein were lower in monotherapy groups (i.e., MCT + sildenafil and MCT + BMDEPCs) and further decreased in normal controls and combined treatment groups (i.e., MCT + sildenafil + BMDEPCs) compared with untreated animals (i.e., MCT only) (all P < 0.01). Expressions of anti-fibrotic biomarkers (bone morphogenetic protein-2, p-Smad1/5) and numbers of alveolar sacs and arterioles in lung were higher in monotherapy groups and further increased in normal controls and combined treatment groups compared with untreated animals (all P < 0.005). In right ventricle, connexin 43 and α-myosin heavy chain (MHC) expressions were higher in the monotherapy groups and further elevated in normal controls and combined treatment groups compared with untreated animals, whereas β-MHC exhibited the opposite pattern (all P < 0.01). Right ventricular systolic pressure and weight were lower in the monotherapy animals and further reduced in normal controls and combined treatment groups compared with untreated animals (all P < 0.0001).. Combined therapy with BMDEPCs and sildenafil was superior to either treatment alone in attenuating rodent MCT-induced PAH.

Topics: Animals; Cell- and Tissue-Based Therapy; Combined Modality Therapy; Endothelial Cells; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Male; Monocrotaline; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Stem Cell Transplantation; Stem Cells; Sulfones; Time; Vasodilator Agents

A young male patient reported for evaluation of progressive easy fatigability, accompanied by a recent history of recurrent haemoptysis. His clinical examination was unremarkable except for evidence of pulmonary arterial hypertension (PAH). Routine investigations (haemogram, coagulogram, serological tests for connective tissue disorders and a sputum Ziehl Neelsen stain for acid-fast bacilli) were normal. Two-dimensional echocardiography suggested PAH (pulmonary artery systolic pressure-67 mm Hg), whereas the 64-slice spiral CT pulmonary angiogram showed a dilated main pulmonary artery along with bilateral arteriovenous malformations. Cardiac catheterisation performed subsequently confirmed the presence of PAH. On the basis of the above findings, a diagnosis of hereditary haemorrhagic telangiectasia (HHT) complicated with PAH was made, and the patient was started on oral sildenafil therapy to which he responded well. This rare complication of HHT, which requires a high degree of suspicion for diagnosis, is discussed.

Topics: Echocardiography; Familial Primary Pulmonary Hypertension; Fatigue; Hemoptysis; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Telangiectasia, Hereditary Hemorrhagic; Tomography, X-Ray Computed; Vasodilator Agents; Young Adult

Topics: Aged; Antihypertensive Agents; Arterial Pressure; Benzazepines; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Infusions, Parenteral; Ivabradine; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prostaglandins; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

We report a rare case of diffuse systemic sclerosis (SSc) evolving into diffuse SSc/systemic lupus erythematosus (SLE) overlap syndrome. A 15-year-old boy was diagnosed as diffuse SSc with initial presentations of Raynaud's phenomenon and skin tightening. He underwent Chinese herbal treatment and clinical symptoms deteriorated in the following 3 years. On admission to our ward, serositis with pleural effusion, severe pulmonary fibrosis with moderate pulmonary hypertension, swallowing difficulty, and polyarthritis were observed. Autoantibody profiles revealed concurrence of anti-double-stranded DNA, anti-Smith, anti-topoisomerase I, and anti-ribonucleoprotein antibodies. The patient fulfills the criteria for both diffuse SSc and SLE. After drainage for pleural effusion accompanied by oral prednisolone and sildenafil, there were improvement of respiratory distress, swallowing difficulty, and pulmonary hypertension. In conclusion, connective tissue diseases may overlap with each other during the disease course. Serial follow-up for clinical symptoms as well as serological changes is recommended.

Topics: Adolescent; Antihypertensive Agents; Arthritis; Autoantibodies; Biomarkers; Deglutition Disorders; Disease Progression; Drainage; Drugs, Chinese Herbal; Glucocorticoids; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Male; Piperazines; Pleural Effusion; Prednisolone; Pulmonary Fibrosis; Purines; Raynaud Disease; Scleroderma, Diffuse; Serositis; Sildenafil Citrate; Sulfones; Treatment Outcome

Sildenafil and bone marrow-derived endothelial progenitor cells (BMDEPCs) have been shown to ameliorate monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in the rat. We test whether combined sildenafil and BMDEPC treatment exerts additional protection against MCT-induced PAH in rats.. Male Sprague-Dawley rats were randomized to receive saline injection only (group 1), MCT (70 mg/kg) only (group 2), MCT plus autologous BMDEPC (2.0×10(6) cells) transplantation (group 3), MCT with sildenafil (30 mg/kg/day) (group 4), and MCT with combined BMDEPCs-sildenafil (30 mg/kg/day) (group 5). Intravenous BMDEPC and oral sildenafil were given on day 3 after MCT administration. Hemodynamics were analyzed using Labchart software, whereas cellular and molecular parameters were measured using flow cytometry, real-time PCR, TUNEL assay, Western blot, and immunohistochemical staining.. By day 35 following MCT treatment, lower expression of connexin43, protein kinase C-ε, Bcl-2, and endothelial nitric oxide synthase and higher expression of tumor necrosis factor-α and caspase 3 were found in right ventricle (RV) and lung in group 2 compared with other groups (all p<0.05). The number of alveolar sacs and lung arterioles were also lower in group 2 than in other groups (all p<0.05). Furthermore, RV systolic pressure (RVSP), RV weight, and RV-to-final body weight ratio were substantially increased in group 2 than in other groups, and notably higher in groups 3 and 4 than in groups 1 and 5 (all p<0.0001).. Combined therapy with autologous BMDEPC and sildenafil is superior to either BMDPEC or sildenafil alone for preventing MCT-induced PAH.

Topics: Animals; Combined Modality Therapy; Endothelial Cells; Hypertension, Pulmonary; Male; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Stem Cell Transplantation; Sulfones; Vasodilator Agents

In our study, we investigated the efficacy of everolimus in combination with sildenafil on hemodynamic and morphological parameters in rats with monocrotaline-induced pulmonary hypertension (PH). Right ventricular pressure (RVP), right ventricular hypertrophy, and the response to vasoconstrictor and vasodilator agents in pulmonary arteries as evaluated by myography and histopathological changes were compared among the groups. RVP and right ventricle/body weight ratios were increased in non-treated monocrotaline groups versus the controls; these increased ratios were decreased in the treated groups and were similar to control values. The contractile responses to endothelin-1 in the pulmonary arteries were decreased in the non-treated monocrotaline groups versus the control. In the treatment groups, contractile responses were similar to those in the controls. Responses to acetylcholine and sodium nitroprusside relaxation were decreased in non-treated monocrotaline groups but were improved significantly in the everolimus groups. Upon histopathological examination, the vascular hypertrophy and cardiac hypertrophy observed in monocrotaline groups were improved by the sildenafil and everolimus treatment. In particular, these improvements became remarkable, including the inflammatory changes, in the everolimus treatment groups. In the light of these results, sildenafil and everolimus in combination were more effective than sildenafil treatment alone in reversing the remodelling process without any cardiovascular toxic effects in the monocrotaline-induced PH model.

Topics: Acetylcholine; Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin-1; Everolimus; Female; Hypertension, Pulmonary; Monocrotaline; Nitroprusside; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sirolimus; Sulfones; Vasoconstrictor Agents; Vasodilator Agents; Ventricular Dysfunction, Right; Ventricular Remodeling

The objective of this study is to determine the effects that sildenafil citrate has on gas exchange in infants with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH).. A retrospective review was performed from 2005 to 2009. Infants treated with sildenafil citrate for greater than 48  h were included. Standard patient data was collected, including echocardiogram, inspired oxygen and systemic blood pressure, before and during administration of sildenafil citrate.. Sildenafil citrate was used in 21 preterm infants with BPD-associated PH. A significant reduction in estimated right ventricular peak systolic pressure was seen after initiation of sildenafil citrate, with the majority of infants showing no improvement in gas exchange at 48  h of treatment. Four infants died during treatment.. Sildenafil citrate reduced estimated pulmonary artery pressures, but this reduction was not reflected in improved gas exchange within the first 48  h.

Topics: Bronchopulmonary Dysplasia; Female; Gestational Age; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Gas Exchange; Purines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome

Contractility of the peritubular smooth muscle layer ensures the transit of immotile spermatozoa through the epididymal duct to acquire their fertilizing capacity. Atrial natriuretic peptide (ANP) and nitric oxide (NO) affect contractility via cGMP signals that are controlled by phosphodiesterases (PDEs). Sildenafil inhibits the cGMP-hydrolyzing PDE5 and thereby promotes relaxation of smooth muscle cells. While sildenafil is increasingly used in young patients for the treatment of pulmonary hypertension, virtually no knowledge exists about PDEs in the epididymis. Western blotting, immunohistochemistry and RT-PCR analyses after laser capture microdissection localized PDE5 to smooth muscle cells, but not to epithelial cells, of the epididymal duct in man and rat. Sildenafil, ANP and NO significantly slowed spontaneous contractions of rat epididymal duct segments in organ bath studies. Sildenafil effects were additive to ANP and NO. Long-term exposure to sildenafil in vivo did not change the PDE5 expression or the observed contractility pattern with the rapid relaxing response toward ANP, NO and sildenafil. Data demonstrate that PDE5 is an important member of cGMP signaling pathways regulating the finely orchestrated process of epididymal duct contractility and suggest, however, that in the epididymis side effects of therapeutically used sildenafil are unlikely.

Topics: Adult; Aged; Aged, 80 and over; Animals; Atrial Natriuretic Factor; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Epididymis; Humans; Hypertension, Pulmonary; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Organ Culture Techniques; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sildenafil Citrate; Sulfones

Polymeric nanoparticles meet the increasing interest for drug delivery applications and hold great promise to improve controlled drug delivery to the lung. Here, we present a series of investigations that were carried out to understand the impact of formulation variables on the nebulization performance of novel biodegradable sildenafil-loaded nanoparticles designed for targeted aerosol therapy of life-threatening pulmonary arterial hypertension. Narrowly distributed poly(D,L-lactide-co-glycolide) nanoparticles (size: ∼200 nm) were prepared by a solvent evaporation technique using poly(vinyl alcohol) (PVA) as stabilizer. The aerodynamic and output characteristics using the Aeroneb Pro nebulizer correlated well with the dynamic viscosity of the employed fluids for nebulization. The nebulization performance was mainly affected by the amount of employed stabilizer, rather than by the applied nanoparticle concentration. Nanoparticles revealed physical stability against forces generated during aerosolization, what is attributed to the adsorbed PVA layer around the nanoparticles. Sildenafil was successfully encapsulated into nanoparticles (encapsulation efficiency: ∼80%). Size, size distribution and sildenafil content of nanoparticles were not affected by nebulization and the in vitro drug release profile demonstrated a sustained sildenafil release over ∼120 min. The current study suggests that the prepared sildenafil-loaded nanoparticles are a promising pharmaceutical for the therapy of pulmonary arterial hypertension.

Topics: Administration, Inhalation; Aerosols; Antihypertensive Agents; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Drug Stability; Excipients; Hypertension, Pulmonary; Kinetics; Lactic Acid; Nanoparticles; Nanotechnology; Nebulizers and Vaporizers; Particle Size; Phosphodiesterase 5 Inhibitors; Piperazines; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polyvinyl Alcohol; Purines; Sildenafil Citrate; Solubility; Solvents; Spectrophotometry, Ultraviolet; Sulfones; Technology, Pharmaceutical; Vasodilator Agents; Viscosity

Topics: Bronchopulmonary Dysplasia; Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones

Right ventricular (RV) failure (RVF) is the main cause of death in patients with pulmonary artery hypertension (PAH). Sildenafil, a phosphodiesterase type 5 inhibitor, was approved recently for treatment of PAH patients. However, the mechanisms underlying RV contractile malfunction and the benefits of sildenafil on RV function are not well understood. We aimed to investigate the following: (1) the ultrastructural and excitation-contraction coupling alterations underlying PAH-induced RVF; (2) whether the ultrastructural changes are reversible; and (3) the mechanisms underlying the therapeutic benefits of sildenafil in PAH-RVF. We used a single injection of monocrotaline in Wistar rats to induce pulmonary vascular proliferation, which led to PAH and RVF. RV myocytes displayed severe transverse (T)-tubule loss and disorganization, as well as blunted and dys-synchronous sarcoplasmic reticulum Ca(2+) release. Sildenafil prevented and reversed the monocrotaline-induced PAH and LV filling impairment. Early intervention with sildenafil prevented RV hypertrophy and the development of RVF, T-tubule remodeling, and Ca(2+) handling dysfunction. Although late treatment with sildenafil did not reverse RV hypertrophy in animals with established RVF, RV systolic function was improved. Furthermore, late intervention partially reversed both the impairment of myocyte T-tubule integrity and Ca(2+) handling protein and sarcoplasmic reticulum Ca(2+) release function in monocrotaline-treated rats. In conclusion, PAH-induced increase in RV afterload causes severe T-tubule remodeling and Ca(2+) handling dysfunction in RV myocytes, leading to RV contractile failure. Sildenafil prevents and partially reverses ultrastructural, molecular, and functional remodeling of failing RV myocytes. Reversal of pathological T-tubule remodeling, although incomplete, is achievable without the regression of RV hypertrophy.

Topics: Animals; Calcium; Disease Models, Animal; Excitation Contraction Coupling; Heart Failure; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Microscopy, Confocal; Monocrotaline; Myocardial Contraction; Myocytes, Cardiac; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Treatment Outcome; Ventricular Dysfunction, Right; Ventricular Remodeling

Pulmonary hypertension associated with pregnancy carries a poor prognosis. We describe successful maternal-foetal outcome for a 30-year-old woman who was found to have severe pulmonary hypertension, human immunodeficiency virus (HIV) and an atrial septal defect. Prior to delivery, she was managed with subcutaneous enoxaparine, sildenafil, nitric oxide, careful maintenance of a euvolemic status and antiretroviral therapy. She was planned for an elective Caesarean section to reduce the risk of maternal-foetal HIV transmission, but went into labour in the coronary care unit. During delivery, antibiotic prophylaxis was given, although there was insufficient time for intravenous zidovudine. Peripartum, the patient was continued on nitric oxide and subcutaneous enoxaparine. She was eventually weaned off the nitric oxide and recovered well.

Topics: Anti-HIV Agents; Anticoagulants; Enoxaparin; Female; Heart Septal Defects, Atrial; HIV Infections; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Infectious; Pregnancy Outcome; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Zidovudine

Sildenafil is increasingly used for the therapy of pulmonary arterial hypertension (PAH) in HIV infected patients. However, concerns exist about pharmacokinetic interactions between sildenafil and protease inhibitors (PI); in particular, ritonavir has been shown to increase sildenafil AUC and Cmax by several folds. The aim of our study was to determine the plasma levels of sildenafil and PI in two HIV patients with PAH treated with antiretroviral therapy including ritonavir-boosted PI. Our patients both experienced sildenafil Cmax above 500 ng/mL; however, they did not report any significant adverse reactions to sildenafil during the follow-up period. Therapeutic drug monitoring of sildenafil should be taken in consideration during treatment in order to avoid overdosage.

Topics: Adult; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Ritonavir; Sildenafil Citrate; Sulfones; Vasodilator Agents

This study aimed to investigate the safety, tolerability, and effects of tadalafil on children with pulmonary arterial hypertension (PAH) after transition from sildenafil or after tadalafil received as initial therapy. A total of 33 pediatric patients with PAH were retrospectively evaluated. Of the 33 patients, 29 were switched from sildenafil to tadalafil. The main reason for the change from sildenafil was once-daily dosing. The average dose of sildenafil was 3.4 ± 1.1 mg/kg/day, and that of tadalafil was 1.0 ± 0.4 mg/kg/day. For 14 of the 29 patients undergoing repeat catheterization, statistically significant improvements were observed after transition from sildenafil to tadalafil in terms of mean pulmonary arterial pressure (53.2 ± 18.3 vs. 47.4 ± 13.7 mmHg; p < 0.05) and pulmonary vascular resistance index (12.2 ± 7.0 vs 10.6 ± 7.2 Units/m(2); p < 0.05). Clinical improvement was noted for four patients treated with tadalafil as initial therapy. The side effect profiles were similar for the patients who had transitioned from sildenafil to tadalafil including headache, nausea, myalgia, nasal congestion, flushing, and allergic reaction. Two patients discontinued tadalafil due to migraine or allergic reaction. One patient receiving sildenafil had no breakthrough syncope after transition to tadalafil. Tadalafil can be safely used for pediatric patients with PAH and may prevent disease progression.

Topics: Adolescent; Carbolines; Cardiac Output; Child; Child, Preschool; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Statistics, Nonparametric; Sulfones; Tadalafil; Treatment Outcome; Vascular Resistance

Topics: Animals; Carbolines; Disease Models, Animal; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Penile Erection; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Vascular Diseases; Vasodilator Agents

Topics: Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

It is believed that growth factors play an important role in vascular remodeling that is evident in pulmonary hypertension (PH) pathogenesis. In the present study, the vascular endothelial growth factor (VEGF) levels in serum and pulmonary artery samples of rats have been analyzed with monocrotaline (MCT)-induced PH after treatments with iloprost, bosentan, and sildenafil. Serum VEGF and pulmonary artery VEGF levels were found to be significantly lower in MCT groups compared with control groups and significantly higher in treatment groups compared with MCT groups. In conclusion, treatment strategies directed at increasing VEGF levels may be reasonable in PH management.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Female; Hypertension, Pulmonary; Iloprost; Monocrotaline; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfonamides; Sulfones; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vasodilator Agents

Pulmonary hypertension remains a major clinical problem despite current therapies. In this study, we examine for the first time a novel pharmacological target, smooth muscle myosin, and determine if the smooth muscle myosin inhibitor, CK-2019165 (CK-165) ameliorates pulmonary hypertension.. Six domestic female pigs were surgically instrumented to measure pulmonary blood flow and systemic and pulmonary vascular dynamics. Pulmonary hypertension was induced by hypoxia, or infusion of the thromboxane analog (U-46619, 0.1 µg/kg/min, i.v.). In rats, chronic pulmonary hypertension was induced by monocrotaline.. CK-165 (4 mg/kg, i.v.) reduced pulmonary vascular resistance by 22±3 and 28±6% from baseline in hypoxia and thromboxane pig models, respectively (p<0.01 and 0.01), while mean arterial pressure also fell and heart rate rose slightly. When CK-165 was delivered via inhalation in the hypoxia model, pulmonary vascular resistance fell by 17±6% (p<0.05) while mean arterial pressure and heart rate were unchanged. In the monocrotaline model of chronic pulmonary hypertension, inhaled CK-165 resulted in a similar (18.0±3.8%) reduction in right ventricular systolic pressure as compared with sildenafil (20.3±4.5%).. Inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antihypertensive Agents; Dose-Response Relationship, Drug; Epoprostenol; Female; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Monocrotaline; Nitroprusside; Piperazines; Pulmonary Artery; Purines; Rats; Sildenafil Citrate; Smooth Muscle Myosins; Sulfones; Swine; Vascular Resistance; Vasoconstriction; Vasodilator Agents

The perioperative management of pulmonary hypertension in a patient with Eisenmenger syndrome, the most advanced form of associated pulmonary artery hypertension (PAH), who required a sigmoidectomy is presented. The treatment for pulmonary hypertension was switched from oral sildenafil to intravenous epoprostenol to avoid the unexpected discontinuation of vasodilation during the perioperative period. The scheduled perioperative conversion should be considered for patients with severe PAH undergoing major abdominal surgery to ensure the stabilization of pulmonary and systemic hemodynamics.

Topics: Administration, Oral; Antihypertensive Agents; Colectomy; Eisenmenger Complex; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Perioperative Care; Piperazines; Purines; Sigmoid Neoplasms; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil was the only phosphodiesterase-5 inhibitor available for the treatment of pulmonary arterial hypertension (PAH) until the approval and availability of once-daily tadalafil. Since no direct comparative study is likely to be performed between these agents, we sought to evaluate the feasibility of transitioning stable PAH patients from sildenafil to tadalafil.. The primary end point was continuation on tadalafil without clinical deterioration. A functional outcome through an evaluation of serial change in the 6-min walk test distance (6MWD) was also performed.. Thirty-five patients on sildenafil qualified for the analysis, of which 85.7 % (30/35) were successfully transitioned. The remaining 14.3 % (5/30) (failure group) were switched back to sildenafil due to worsening symptoms. The mean pretransition 6MWD was 363 m, with an average change in the success group of +16.4 m (range = -64 to +140 m) compared to -45 m (range = -123 to +32 m) in the failure group at 1-3 months post switch (p = 0.02). All 30 patients in the success group remained on tadalafil, with an average improvement in the 6MWD of +37.04 m (range = -36.5 to +236.5 m) at 12 months post switch. The failure group had a higher daily sildenafil dose (180 vs. 115.5 mg; p = 0.06), with 42.8 % of patients at the highest sildenafil dose failing the transition.. The transition from sildenafil to tadalafil is safe and generally well tolerated. Patients with more severe disease and those on higher doses of sildenafil are more likely to fail the transition and should be monitored closely post switch.

Topics: Adult; Aged; Carbolines; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfones; Tadalafil; Treatment Outcome; Vasodilator Agents; Young Adult

We report a case of priapism in a 6-month-old boy of African descent who had been receiving intravenous sildenafil, a phosphodiesterase-5 inhibitor. An orthotopic cardiac transplantation had been performed at 6 months of age, 2 months after he had received a Berlin heart. The pre-, peri-, and postoperative care required multiple transfusions, and postoperative pulmonary hypertension required treatment with intravenous sildenafil. He developed a series of prolonged, semitumescent erections (30-180 minutes) that resolved spontaneously without the need for urologic intervention. Subsequent investigations revealed he was a carrier of a sickle cell gene. Although the precise etiology of the prolonged penile erection is unclear, it was likely secondary to the use of sildenafil and the sickle cell trait.

Topics: Heart Transplantation; Humans; Hypertension, Pulmonary; Infant; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Purines; Sickle Cell Trait; Sildenafil Citrate; Sulfones

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal-transduction pathway is impaired in many cardiovascular diseases, including pulmonary arterial hypertension (PAH). Riociguat (BAY 63-2521) is a stimulator of sGC that works both in synergy with and independently of NO to increase levels of cGMP. The aims of this study were to investigate the role of NO-sGC-cGMP signaling in a model of severe PAH and to evaluate the effects of sGC stimulation by riociguat and PDE5 inhibition by sildenafil on pulmonary hemodynamics and vascular remodeling in severe experimental PAH.. Severe angioproliferative PAH was induced in rats by combined exposure to the vascular endothelial growth factor receptor antagonist SU5416 and hypoxia (SUHx). Twenty-one days thereafter rats were randomized to receive either riociguat (10 mg/kg/day), sildenafil (50 mg/kg/day) or vehicle by oral gavage, for 14 days until the day of the terminal hemodynamic measurements. Administration of riociguat or sildenafil significantly decreased right ventricular systolic pressure (RVSP). Riociguat significantly decreased RV hypertrophy (RVH) (0.55 ± 0.02, p<0.05), increased cardiac output (60.8 ± .8 mL/minute, p<0.05) and decreased total pulmonary resistance (4.03 ± 0.3 mmHg min(-1) ml(-1) 100 g BW, p<0.05), compared with sildenafil and vehicle. Both compounds significantly decreased the RV collagen content and improved RV function, but the effects of riociguat on tricuspid annular plane systolic excursion and RV myocardial performance were significantly better than those of sildenafil (p<0.05). The proportion of occluded arteries was significantly lower in animals receiving riociguat than in those receiving vehicle (p<0.05); furthermore, the neointima/media ratio was significantly lower in those receiving riociguat than in those receiving sildenafil or vehicle (p<0.05).. Riociguat and sildenafil significantly reduced RVSP and RVH, and improved RV function compared with vehicle. Riociguat had a greater effect on hemodynamics and RVH than sildenafil.

Topics: Animals; Apoptosis; Blood Pressure; Blotting, Western; Caspase 3; Cell Proliferation; Cyclic GMP; Guanylate Cyclase; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Immunohistochemistry; Indoles; Lung; Male; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrazoles; Pyrimidines; Pyrroles; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfones; Time Factors; Treatment Outcome

We present a case of pulmonary arterial hypertension (PAH), which is potentially related to treatment with dasatinib (Sprycel(®)). A 61-year-old woman, who had been treated with dasatinib for 27 months for chronic myeloid leukemia (CML), visited our hospital complaining of dyspnea. In right heart catheterization, her mean pulmonary arterial pressure was 35 mmHg. After other possible etiologies to cause PAH were excluded, the patient was diagnosed as a dasatinib-related PAH. As notified by U.S. Food and Drug Administration (FDA) in October 2011, we recommend routine cardiopulmonary evaluation before and during treatment with dasatinib in CML patients in terms of the adverse effects of PAH.

Topics: Dasatinib; Echocardiography; Electrocardiography; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Middle Aged; Piperazines; Protein Kinase Inhibitors; Purines; Pyrimidines; Sildenafil Citrate; Sulfones; Thiazoles; Treatment Outcome; Vasodilator Agents; Withholding Treatment

Elevated pulmonary vascular resistance (PVR) in heart transplant (HT) candidates is associated with poor survival after HT. This study assessed the effect of peri-operative sildenafil administration on pulmonary hemodynamics and clinical outcomes in patients with advanced heart failure who were considered high-risk for HT because of elevated PVR and transpulmonary gradient (TPG).. The study included 119 consecutive patients who underwent HT between 2004 and 2011. Fifteen patients (Group A) had severe pulmonary hypertension (PH), defined as mean pulmonary pressure (MPAP)>25 mm Hg and PVR>2.5 Wood units (WU), and/or TPG>12 mm Hg after vasodilator test or the continuous administration of inotropics drugs, and 104 patients (Group B) were without severe PH. Group A received sildenafil therapy. Pulmonary hemodynamics were evaluated before HT with and without sildenafil therapy. Right catheterization was performed early after HT with sildenafil therapy and late after HT without sildenafil. Survival after HT was compared between the groups.. The sildenafil dosage was 109±42 mg/day during 163±116 days before HT. After sildenafil therapy MPAP, PVR, and TPG decreased from 43.9±12.5 to 33.4±5.8 mm Hg, 5.0±1.1 to 3.0±1.6 WU, and 17.3±3.2 to 10.2±4.1 mm Hg, respectively (p<.01). All patients underwent successful HT. Sildenafil dosage was 140±70 mg/day for 43±45 days after HT. There were no differences in PVR and TPG with sildenafil therapy early after HT and without sildenafil 6 months after HT. Survival after HT was similar between the groups.. Sildenafil therapy before and after HT in patients with severe PH is associated with improved pulmonary hemodynamics and successful HT, without an increase in post-HT mortality.

Topics: Female; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Perioperative Period; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Phosphodiesterase type 5 inhibitors such as sildenafil, vardenafil, and tadalafil are a class of drugs used primarily in the treatment of erectile dysfunction. Sildenafil and tadalafil are also approved for the treatment of pulmonary hypertension. The aim of this study was to develop and validate a procedure for the detection and quantification of these 3 drugs and some of their metabolites in human blood plasma.. After liquid-liquid extraction of 0.5 mL of blood plasma using diethyl ether-ethyl acetate (1:1), the analytes sildenafil, norsildenafil, vardenafil, norvardenafil, and tadalafil were separated using a Shimadzu Prominence High-Performance Liquid Chromatography System (C18 separation column, gradient elution, and a total flow of 0.5 mL/min). They were detected using an AB Sciex 3200 Q-Trap LC-MS-MS System (electrospray ionization and multiple reaction monitoring mode). The method was fully validated according to international guidelines.. The assay was found to be selective for the tested compounds. It was linear from 5 to 1000 ng/mL for sildenafil, from 2 to 700 ng/mL for norsildenafil, from 0.5 to 350 ng/mL for vardenafil, from 0.5 to 200 ng/mL for norvardenafil, and from 5 to 1000 ng/mL for tadalafil. The recoveries were generally more than 50%. Matrix effects were not observed. Accuracy, repeatability, and intermediate precision were within the required limits (<15% or <20% near the limit of quantification). No instability was observed after repeated freezing and thawing or in processed samples.. A liquid chromatography-tandem mass spectrometry assay for the determination of sildenafil, norsildenafil, vardenafil, norvardenafil, and tadalafil in human blood plasma was developed and validated. It has proven to be selective, linear, accurate, and precise for all studied drugs. The method has also proven to be applicable for forensic cases and for therapeutic drug monitoring.

Topics: Adult; Aged; Antihypertensive Agents; Biotransformation; Carbolines; Chromatography, High Pressure Liquid; Drug Monitoring; Familial Primary Pulmonary Hypertension; Forensic Toxicology; Humans; Hypertension, Pulmonary; Imidazoles; Limit of Detection; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Reproducibility of Results; Sildenafil Citrate; Spectrometry, Mass, Electrospray Ionization; Sulfones; Tadalafil; Tandem Mass Spectrometry; Triazines; Vardenafil Dihydrochloride

We report a case of a 37-years-old man, affected by thalassemia major, hypogonadotropic hypogonadism, chronic HCV-hepatitis, diabetes mellitus, severe osteoporosis, prior septic pulmonary embolism and pulmonary artery hypertension was performed a long-term treatment with high-dose of sildenafil (120 mg/die) with reduction of pulmonary arterial systolic pressure and of the dyspnea.

Topics: Adult; beta-Thalassemia; Comorbidity; Hepatitis, Viral, Human; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Little is known concerning the degree to which initiation of sildenafil for pulmonary arterial hypertension (PAH) impacts patterns of healthcare utilization and costs.. Using a large US health insurance claims database, we identified all patients with evidence of PAH (ICD-9-CM diagnosis codes 416.0, 416.8) who received sildenafil between 1/1/2005 and 9/30/2008. Date of the first-noted prescription for sildenafil was designated the "index date," and claims data were compiled for all study subjects for 6 months prior to their index date ("pretreatment") and 6 months thereafter ("follow-up"); patients with incomplete data during either of these periods were excluded. Healthcare utilization and costs were then compared between pretreatment and follow-up for all study subjects.. A total of 567 PAH patients were identified who began therapy with sildenafil and met all other study entry criteria. Mean (SD) age was 52 (10) years; 73% were women. Healthcare utilization was largely unchanged between pretreatment and follow-up, the only exceptions being decreases in the mean number of emergency department visits (from 0.7 to 0.5 per patient; p<0.01) and the percentage of patients hospitalized (from 35% to 29%; p=0.01). The mean cost of all PAH-related medication was $7139 during pretreatment and $14,095 during follow-up (sildenafil cost during follow-up= $5236); exclusive of PAH-related medications, however, total healthcare costs decreased modestly (from $30,104 to $27,605) (p<0.01 for all comparisons).. The cost of sildenafil therapy may be partially offset by reductions in other healthcare costs.

Topics: Adult; Clinical Coding; Cohort Studies; Delivery of Health Care; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Health Care Costs; Humans; Hypertension, Pulmonary; Insurance Claim Reporting; Insurance Claim Review; Male; Middle Aged; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; United States; Vasodilator Agents

A patient with pulmonary arterial hypertension secondary to systemic sclerosis was successfully treated with sitaxentan prior to its worldwide withdrawal (because of hepatotoxicity concerns), but then ironically experienced acute hepatic dysfunction during substitute bosentan therapy, and was eventually stabilised on a phosphodiesterase-5 inhibitor.

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Liver; Liver Function Tests; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Safety-Based Drug Withdrawals; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes

  Several cellular pathways are implicated in the pathogenesis of pulmonary arterial hypertension (PAH) and attempts to arrest disease progression with a single drug would not be expected to succeed in the medium term. In clinical practice, combination therapy is often used in patients deteriorating on monotherapy, despite the absence of firm evidence from randomized controlled controls..   From January 2005 to August 2009, 112 patients with World Health Organisation Functional Class (FC) II-IV PAH deteriorating on monotherapy received non-parenteral combination therapy at six Australian PAH expert hospitals. Combination therapy included bosentan, sitaxentan, ambrisentan, iloprost and sildenafil. Data were prospectively collected for survival status, 6-min walk distance, FC and echocardiographic parameters at the start of monotherapy through to commencement of combination therapy and at 6-monthly intervals thereafter..   After varying periods of monotherapy (18.7±13.4onths), survival estimates on combination therapy were 88%, 71% and 61% for the additional 1, 2 and 3years respectively. Survival on dual therapy in patients with idiopathic PAH/familial PAH was 93% at 1year and 79% at 2years, and for scleroderma-related PAH, 72% at 1 year and 48% at year 2 after initiation of combination therapy. In survivors, dual therapy reversed the deterioration in FC, from 3.1±0.6 on monotherapy to 2.2±0.6 at 12months. Similarly, dual therapy improved 6-min walk distance from 316±119m to 406±129m at 12months, and sequential echocardiography demonstrated a fall in pulmonary artery systolic pressure and improved right ventricular function..   Dual non-parenteral therapy appears safe and effective and should be considered for PAH patients who are deteriorating on monotherapy to improve long-term outcomes.

Topics: Adult; Aged; Australia; Bosentan; Cooperative Behavior; Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Piperazines; Prospective Studies; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; Young Adult

We report on the successful treatment with sildenafil of a unique case of severe chronic thromboembolic pulmonary hypertension which developed as a late complication in a 71-year-old heart transplant recipient, with focus on the potential therapeutic challenges encountered in the management of such a peculiar association of clinical conditions.

Topics: Aged; Antihypertensive Agents; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Embolism; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Pulmonary hypertension as a frequent complication of left heart disease (PH-LHD) is characterized by lung endothelial dysfunction and vascular remodeling. Although PH-LHD contributes to morbidity and mortality in heart failure, established therapies for PH-LHD are lacking. We tested the effect of chronic sildenafil treatment in an experimental model of PH-LHD.. In Sprague-Dawley rats, PH-LHD was induced by supracoronary aortic banding. Oral sildenafil treatment (60 mg/kg daily) was initiated after 7 days, and lung endothelial function (n=5), vascular remodeling, and right ventricular function (n=11 each) were analyzed 9 weeks after banding. As compared with sham-operated controls, aortic banding induced pulmonary hypertension and lung endothelial dysfunction evident as lack of endothelial nitric oxide production and endothelium-dependent vasodilation. These changes were associated with an increased pulmonary vascular resistance, medial thickening, and biventricular cardiac hypertrophy. Sildenafil treatment largely attenuated these pathological changes and was not associated with detectable adverse effects pertinent to lung vascular barrier function, edema formation, or systemic hemodynamics.. Our data identify sildenafil as a promising therapy for PH-LHD. In light of its documented protective effects at the myocardial level in heart failure, sildenafil presents a particularly attractive strategy in that it simultaneously targets cardiac remodeling and secondary PH-LHD.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endothelium, Vascular; Heart Failure, Diastolic; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Lung; Male; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Time Factors; Vascular Resistance; Vasodilation; Ventricular Function, Left; Ventricular Function, Right

Topics: Chemical and Drug Induced Liver Injury; Contraindications; Endothelin A Receptor Antagonists; Familial Primary Pulmonary Hypertension; Fatal Outcome; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Jaundice; Liver Failure, Acute; Piperazines; Purines; Sildenafil Citrate; Sulfones; Thiophenes; Vasodilator Agents; Young Adult

Topics: Adult; Contrast Media; Coronary Circulation; Diagnosis, Differential; Echocardiography; Humans; Hypertension, Pulmonary; Hypoxia; Male; Piperazines; Pulmonary Circulation; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sodium Chloride; Sulfones; Tomography, X-Ray Computed; Vasodilator Agents

We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409 · (1 - 0.0377 · (AGE - 3.81)) · WT L/h and 0.175 h(-1), respectively.

Topics: Adolescent; Age Factors; Aryl Hydrocarbon Hydroxylases; Asian People; Bayes Theorem; Body Weight; Bosentan; Child; Child, Preschool; Computer Simulation; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Drug Interactions; Familial Primary Pulmonary Hypertension; Female; Genotype; Heart Failure; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Liver-Specific Organic Anion Transporter 1; Male; Models, Biological; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Piperazines; Polymorphism, Single Nucleotide; Purines; Sildenafil Citrate; Solute Carrier Organic Anion Transporter Family Member 1B3; Sulfonamides; Sulfones

Endothelin receptor antagonists are used to treat idiopathic pulmonary arterial hypertension (IPAH), but human pulmonary arterial endothelin receptor expression is not well defined. We hypothesised that disease and treatment would modify normal receptor distribution in pulmonary resistance arteries of children. Using immunohistochemistry and semiquantitative analysis, we investigated endothelin receptor subtypes A and B (ET(A) and ET(B), respectively), and endothelial nitric oxide synthase (eNOS) expression in peripheral pulmonary arteries of tissue from untreated children with IPAH (n=7), following extended combined bosentan and epoprostenol therapy (n=5) and from normal subjects (n=5). Clinical, haemodynamic and pathological abnormalities were severe and advanced in all IPAH cases. ET(A) was detected in pulmonary arterial endothelial cells of all normal and diseased tissue and cultured cells. Endothelial ET(A), ET(B) and eNOS expression was reduced in patent, plexiform and dilatation lesions of untreated cases, but in treated cases, ET(A) and ET(B) were normal and eNOS increased. In smooth muscle, ET(A) expression was reduced in treated cases but ET(B) expression increased in all arteries of both treated and untreated cases. In summary, ET(A) is expressed on human pulmonary arterial endothelium. In IPAH, combination treatment with bosentan and epoprostenol had a more marked influence on endothelin receptor expression of endothelial than smooth muscle cells.

Topics: Adolescent; Antihypertensive Agents; Bosentan; Child; Child, Preschool; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelium, Vascular; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Muscle, Smooth, Vascular; Nifedipine; Nitric Oxide Synthase Type III; Piperazines; Pulmonary Artery; Purines; Receptor, Endothelin A; Receptor, Endothelin B; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

While new pharmacological approaches have been demonstrated to effectively manage PH in adults, few reports have addressed PH treatment in neonates and infants. This case report describes the successful management of severe PH secondary to bronchopulmonary dysplasia, respiratory syncytial virus infection, and hypoxia in a preterm 4-month-old with the long-term use of orally administered sildenafil and inhaled iloprost.

Topics: Administration, Inhalation; Administration, Oral; Bronchopulmonary Dysplasia; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Hypoxia; Iloprost; Infant; Infant, Newborn; Infant, Premature; Male; Piperazines; Purines; Respiratory Syncytial Virus Infections; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Therapy with sildenafil has been shown to decrease pulmonary vascular resistance and may improve functional status in patients with interstitial pneumonia (IP) and pulmonary hypertension (PH). Patients with IP and PH defined by a mean pulmonary artery pressure (MPAP) of > or = 25mm Hg on right-heart catheterization were followed up in an open-label study of sildenafil. A multilateral evaluation was conducted before, and after 3 months of therapy. We studied 11 patients [8 men and 3 women, mean age 66.5] 6 of whom had IPF (1 with usual interstitial pneumonia {UIP}), 2 with IIP, and 3 with collagen-vascular disease interstitial pneumonia (CVD-IP). The mean modified Medical Research Council (MRC) score was 3.0 +/- 0.89, baseline dyspnea index (BDI) score was 4.5 +/- 1.9, % VC was 58.7 +/- 15.6%, percentage of carbon monoxide diffusing capacity (%DLco) was 20.0 +/- 10.9%, six-minute walk distance (6MWD) was 269.8 +/- 105.5m, shuttle walking test (SWT) was 179.1 +/- 99.7m, St. George Respiratory Questionnaire (SGRQ) was 70.9 +/- 15.6, mean pulmonary artery pressure (MPAP) was 33.8 +/- 7.61mm Hg, and pulmonary vascular resistance index (PVRI) was 658.9 +/- 236.1 dynes x s x cm(-5) x m2. After 3 months of therapy, improvements in BDI (< or = -1), 6MWD (> or = 20%), SWT (> or = 20%), and SGRQ (< or = -7) were observed in 4, 2, 3, and 6 patients, respectively. Improvements in MPAP (< or = - 20%) and PVRI (< or = -20%) were observed in 2 and 3 patients, respectively. No parameter showed statistically significant differences. We conclude that sildenafil may improve dyspnea, exercise tolerance and health-related quality of life (QOL) in some IP patients with PH.

Topics: Aged; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

We describe the case of a woman who presented to the intensive care unit with acute respiratory failure that required mechanical ventilation. She had severe pulmonary hypertension secondary to interstitial lung disease, and her history included sarcoidosis and tuberculosis. She was dependent on inhaled nitric oxide (INO) to maintain safe arterial oxygen saturation and could not be weaned from mechanical ventilation. Echocardiography revealed a patent foramen ovale with substantial right-to-left shunt, which probably contributed to her hypoxemia. Sildenafil enabled weaning from INO and substantially reduced the flow through the patent foramen ovale. She was successfully extubated and discharged home. To our knowledge, this is the first report of weaning from INO and mechanical ventilation in a patient with both severe secondary pulmonary hypertension and a right-to-left shunt through a patent foramen ovale.

Topics: Aged; Bronchodilator Agents; Comorbidity; Dyspnea; Female; Foramen Ovale, Patent; Humans; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Respiratory Insufficiency; Sarcoidosis, Pulmonary; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventilator Weaning

The development of bronchial hyperreactivity (BHR) subsequent to precapillary pulmonary hypertension (PHT) was prevented by acting on the major signalling pathways (endothelin, nitric oxide, vasoactive intestine peptide (VIP) and prostacyclin) involved in the control of the pulmonary vascular and bronchial tones.. Five groups of rats underwent surgery to prepare an aorta-caval shunt (ACS) to induce sustained precapillary PHT for 4 weeks. During this period, no treatment was applied in one group (ACS controls), while the other groups were pretreated with VIP, iloprost, tezosentan via an intraperitoneally implemented osmotic pump, or by orally administered sildenafil. An additional group underwent sham surgery. Four weeks later, the lung responsiveness to increasing doses of an intravenous infusion of methacholine (2, 4, 8 12 and 24 μg/kg/min) was determined by using the forced oscillation technique to assess the airway resistance (Raw).. BHR developed in the untreated rats, as reflected by a significant decrease in ED50, the equivalent dose of methacholine required to cause a 50% increase in Raw. All drugs tested prevented the development of BHR, iloprost being the most effective in reducing both the systolic pulmonary arterial pressure (Ppa; 28%, p = 0.035) and BHR (ED50 = 9.9 ± 1.7 vs. 43 ± 11 μg/kg in ACS control and iloprost-treated rats, respectively, p = 0.008). Significant correlations were found between the levels of Ppa and ED50 (R = -0.59, p = 0.016), indicating that mechanical interdependence is primarily responsible for the development of BHR.. The efficiency of such treatment demonstrates that re-establishment of the balance of constrictor/dilator mediators via various signalling pathways involved in PHT is of potential benefit for the avoidance of the development of BHR.

Topics: Administration, Oral; Airway Resistance; Analysis of Variance; Animals; Antihypertensive Agents; Blood Pressure; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelins; Hypertension, Pulmonary; Iloprost; Infusion Pumps, Implantable; Infusions, Parenteral; Lung; Lung Volume Measurements; Male; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Prostaglandins I; Purines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Signal Transduction; Sildenafil Citrate; Sulfones; Tetrazoles; Time Factors; Vasoactive Intestinal Peptide; Vasodilator Agents

Lung hypoplasia and persistent pulmonary hypertension of the newborn limit survival in congenital diaphragmatic hernia (CDH). Unlike other diseases resulting in persistent pulmonary hypertension of the newborn, infants with CDH are refractory to inhaled nitric oxide (NO). Nitric oxide mediates pulmonary vasodilatation at birth in part via cyclic GMP production. Phosphodiesterase type 5 (PDE5) limits the effects of NO by inactivation of cyclic GMP. Because of the limited success in postnatal management of CDH, we hypothesized that antenatal PDE5 inhibition would attenuate pulmonary artery remodeling in experimental nitrofen-induced CDH.. Nitrofen administered at embryonic day 9.5 to pregnant rats resulted in a 60% incidence of CDH in the offspring and recapitulated features seen in human CDH, including structural abnormalities (lung hypoplasia, decreased pulmonary vascular density, pulmonary artery remodeling, right ventricular hypertrophy), and functional abnormalities (decreased pulmonary artery relaxation in response to the NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide). Antenatal sildenafil administered to the pregnant rat from embryonic day 11.5 to embryonic day 20.5 crossed the placenta, increased fetal lung cyclic GMP and decreased active PDE5 expression. Antenatal sildenafil improved lung structure, increased pulmonary vessel density, reduced right ventricular hypertrophy, and improved postnatal NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide-induced pulmonary artery relaxation. This was associated with increased lung endothelial NO synthase and vascular endothelial growth factor protein expression. Antenatal sildenafil had no adverse effect on retinal structure/function and brain development.. Antenatal sildenafil improves pathological features of persistent pulmonary hypertension of the newborn in experimental CDH and does not alter the development of other PDE5-expressing organs. Given the high mortality/morbidity of CDH, the potential benefit of prenatal PDE5 inhibition in improving the outcome for infants with CDH warrants further studies.

Topics: Animals; Body Weight; Brain; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Female; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Lung; Nitric Oxide; Phenyl Ethers; Phosphodiesterase 5 Inhibitors; Piperazines; Pregnancy; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones

The patency of foramen ovale (FO) in fetal circulation is very important, and premature closure of FO could be associated with several pathological conditions.. We report a patient in whom premature closure of FO in fetal life was associated with late clinical onset of mitral valve stenosis and subsequent development of irreversible pulmonary hypertension (PH).. The patient showed persistent PH after birth, which completely regressed at the age of 8 months. However, the patient developed heart failure due to mitral valve lesions (hammock valve) at the age of 11 months and underwent artificial valve replacement. The patient subsequently developed severe PH, which was refractory to anti-PH therapy with sildenafil and bosentan in addition to home oxygen.. This case illustrates that mitral stenosis can be overlooked during early neonatal life, and thus emphasizes the need for close follow-up for potential existence of mitral stenosis and later clinical manifestation in patients with premature FO closure even when initial careful examination of the mitral valves does not indicate any abnormalities. In addition, premature closure of FO could cause pulmonary vascular disease, which may lead to later development of irreversible PH.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Fetal Diseases; Foramen Ovale; Heart Failure; Heart Valve Prosthesis Implantation; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Mitral Valve Stenosis; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Failure; Ultrasonography, Doppler, Pulsed; Ultrasonography, Prenatal; Vasodilator Agents

Sildenafil, an orally administered phosphodiesterase type 5 (PDE-5) inhibitor, was known for enhancing the downstream effects of NO. It was approved for treatment in patients with pulmonary arterial hypertension (PAH). Recently, a generic sildenafil (Unison Laboratories, Thailand) was proved to have the same bioequivalent as in the original formula. The authors conducted a 12-week case series to study the efficacy and safety of Elonza (generic sildenafil) in PAH patients.. Comparison of both hemodynamic data from cardiac catheterization and clinical outcome such as six minute walk test (6MWT) were performed to assess the efficacy of generic sildenafil at the dosage of 50 mg given orally three times daily in patients with PAH over a 12 weeks period.. There were 20 patients whose average age was 31.4 +/- 14.3 years old (13-58) and their average weight was 48.1 +/- 11.9 kg (31-79). There were three idiopathic pulmonary artery hypertensions (IPAH) and 17 congenital left to right shunts. There was a 15.1% decrease in pulmonary vascular resistance index (PVRi) from 20.5 +/- 13.9 to 17.4 +/- 2.9 Wood unit m2 at the end of 12 weeks (p = 0.044). The ratio of pulmonary to systemic vascular resistance (PVR/SVR) was also decreased from 0.71 +/- 0.57 to 0.52 +/- 0.41 (p = 0.014). 6MWT increased significantly from 271 +/- 59 meters (m) at baseline to 297 +/- 48 m, 307 +/- 43 m and 321 +/- 52 m at week 2, 6 and 12, respectively (p = 0.01). There was no significant change in other hemodynamic parameter, Borg dyspnea score, and functional class.. At the end of the 12-week treatment, a 50 mg three times daily of generic sildenafil given to patients with PAH was shown to have benefit on decreasing PVRi, PVR/SVR ratio. There was also an increase in mean average of 6MWT at the end of 12 weeks.

Topics: Administration, Oral; Adolescent; Adult; Asian People; Cardiac Catheterization; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Generic; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Thailand; Treatment Outcome; Vasodilator Agents; Young Adult

Topics: Adult; Aged; Aged, 80 and over; Female; Heart Failure, Systolic; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Motor Activity; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome

Pulmonary hypertension associated with pediatric congenital heart defects is a major cause of postoperative morbidity and death. Sildenafil has been combined with inhaled nitric oxide to treat pulmonary hypertension. We retrospectively studied the pre- and postoperative effects of oral sildenafil as monotherapy in children with pulmonary hypertension who underwent surgery to correct congenital cardiac defects. From September 2005 through November 2009, 38 children with moderate-to-severe pulmonary arterial hypertension (pulmonary arterial/aortic pressure ratio, >0.7) underwent cardiac surgery at our institution. Fifteen patients were given sildenafil (0.35 mg/kg, every 4 hr) orally or through nasogastric tubes 1 week before and 1 week after surgery. Twenty-three patients of comparable medical status were given sildenafil only upon the institution of cardiopulmonary bypass and for 1 week after surgery. Postoperatively, the 15 patients who were given preoperative sildenafil had significantly lower mean pulmonary arterial pressures (25.6 ± 3.1 vs. 30.4 ± 5.7 mmHg; P = 0.005) and pulmonary arterial/aortic pressure ratios (0.35 ± 0.05 vs. 0.42 ± 0.07; P = 0.002) than did the other 23 patients. The preoperative therapy also shortened cardiopulmonary bypass time, mechanical ventilation time, and lengths of intensive care unit and hospital stays. No sildenafil-related hypertensive crises or sequelae occurred. As monotherapy, oral sildenafil in low doses appears to control pulmonary hypertension safely and effectively in children undergoing operations to correct congenital heart defects, particularly when it is given both preoperatively and postoperatively. Further study is warranted.

Topics: Administration, Oral; Antihypertensive Agents; Blood Pressure; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Child, Preschool; Drug Administration Schedule; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Intensive Care Units; Italy; Length of Stay; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Respiration, Artificial; Retrospective Studies; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents

We documented the frequency of large spontaneous portosystemic shunts in patients with moderate or severe portopulmonary hypertension (POPH) and determined the association between large shunts and response to treatment.. We performed a retrospective case-control study of data from patients with mild (mean pulmonary artery pressure [MPAP], 25-35 mm Hg; n = 18), moderate (MPAP, 35-50 mm Hg; n = 45), and severe POPH (MPAP, >50 mm Hg; n = 16). Data were compared with those from controls (normal echocardiography with estimated right ventricular systolic pressure, <35 mm Hg; n = 122). Spontaneous portosystemic shunts greater than 10 mm in diameter, identified by computed tomography or magnetic resonance, were classified as large. Response to treatment at 6 months was defined by right ventricular systolic pressure or MPAP as significant (<35 mm Hg), partial (35-50 mm Hg), or no response (>50 mm Hg).. The frequency of spontaneous shunts did not differ significantly between groups of subjects with severe (n = 14 of 16), moderate (n = 38 of 45), or mild POPH (n = 11 of 18) or normal echocardiograms (controls, n = 86 of 122) (P = .77). Large shunts were associated with severe (14 of 16) and moderate POPH (32 of 45), compared with mild POPH (6 of 18) or controls (30 of 122) (P < .01). In 13 patients with severe POPH, large shunts were associated with lack of response to treatment in 90% (8 of 9) or partial response in 50% (2 of 4). Among 27 patients with moderate POPH, large shunts were associated with no response to treatment in 13 of 19 (68%) and a partial response in 2 of 6 (33%).. Large spontaneous portosystemic shunts are associated significantly with moderate and severe POPH, and with lack of response to treatment.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Case-Control Studies; Child; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Magnetic Resonance Imaging; Male; Mesentery; Middle Aged; Piperazines; Purines; Regional Blood Flow; Renal Veins; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Splenic Vein; Sulfonamides; Sulfones; Tomography, Spiral Computed; Treatment Outcome; Vena Cava, Inferior

In the past 5-10 years, drug treatment of idiopathic pulmonary arterial hypertension has evolved considerably. Experience and results from use of such updated treatment in Norway has not been reported.. 32 patients newly diagnosed with idiopathic pulmonary arterial hypertension, were consecutively assessed with respect to hemodynamics and physical capacity. The results after three months were compared with those after 12 months. Observed survival was compared with estimated survival from the time when only conventional treatment was available.. The patients (78% women) were 42 ± 14 years, had dyspnea in NYHA class 2.9 ± 0.4 and a maximal oxygen uptake of 12.0 ± 3.9 ml/kg/min (37 ± 13% of the expected). Updated treatment led to significantly improved hemodynamics and physical capacity, which persisted during follow-up. During 43 ± 31 months follow-up, seven patients died while two underwent bilateral lung transplantation. Observed transplantation-free survival was 81% after one, two and three years, while that for estimated transplantation-free survival was 70%, 58% and 49% respectively.. Treatment of idiopathic pulmonary arterial hypertension with updated treatment improves hemodynamics and thereby symptoms. Mortality remains high, but is probably lower than it was when only conventional treatment was available.

Topics: Adult; Airway Resistance; Antihypertensive Agents; Bosentan; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Lung Volume Measurements; Male; Middle Aged; Oxygen Consumption; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Aged; Aged, 80 and over; Double-Blind Method; Female; Heart Failure; Humans; Hypertension, Pulmonary; Longitudinal Studies; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prevalence; Purines; Respiratory Function Tests; Sildenafil Citrate; Stroke Volume; Sulfones

Meconium aspiration syndrome causes respiratory failure after birth and in vivo monitoring of pulmonary edema is difficult. The objective of the present study was to assess hemodynamic changes and edema measured by transcardiopulmonary thermodilution in low weight newborn piglets. Additionally, the effect of early administration of sildenafil (2 mg/kg vo, 30 min after meconium aspiration) on this critical parameter was determined in the meconium aspiration syndrome model. Thirty-eight mechanically ventilated anesthetized male piglets (Sus scrofa domestica) aged 12 to 72 h (1660 ± 192 g) received diluted fresh human meconium in the airway in order to evoke pulmonary hypertension (PHT). Extravascular lung water was measured in vivo with a PiCCO monitor and ex vivo by the gravimetric method, resulting in an overestimate of 3.5 ± 2.3 mL compared to the first measurement. A significant PHT of 15 Torr above basal pressure was observed, similar to that of severely affected humans, leading to an increase in ventilatory support. The vascular permeability index increased 57%, suggesting altered alveolocapillary membrane permeability. Histology revealed tissue vessel congestion and nonspecific chemical pneumonitis. A group of animals received sildenafil, which prevented the development of PHT and lung edema, as evaluated by in vivo monitoring. In summary, the transcardiopulmonary thermodilution method is a reliable tool for monitoring critical newborn changes, offering the opportunity to experimentally explore putative therapeutics in vivo. Sildenafil could be employed to prevent PHT and edema if used in the first stages of development of the disease.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Extravascular Lung Water; Humans; Hypertension, Pulmonary; Infant, Newborn; Lung; Male; Meconium Aspiration Syndrome; Piperazines; Purines; Sildenafil Citrate; Sulfones; Sus scrofa; Thermodilution; Time Factors; Vasodilator Agents

A 33-year-old male with severe hereditary pulmonary arterial hypertension had a confirmed diagnosis of occlusive venopathy and microvasculopathy. He remained stable for three and a half years on oral sildenafil, 75 mg t.i.d. (six-minute walked distance of 375 m vs 105 m at baseline), but required addition of bosentan (125 mg b.i.d.), subsequently. Despite the fatal outcome at five years post-diagnosis, the observations suggest a potential usefulness of vasodilators as a bridge for lung transplant in selected cases with significant venous/capillary involvement. The occurrence of veno-occlusive and capillary lesions in the familial form of pulmonary arterial hypertension reinforces the difficulties with the current classification of the disease.

Topics: Adult; Biopsy; Familial Primary Pulmonary Hypertension; Fatal Outcome; Humans; Hypertension, Pulmonary; Lung; Male; Phenotype; Piperazines; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The present study was designed to analyze protein expression in lungs from pulmonary hypertensive rats in order to identify novel signaling pathways. This was achieved by proteomic studies in which proteins from lung homogenates from hypoxic were compared to normoxic rats. The expression of these proteins was then investigated in lungs from hypoxic rats treated with either an activator of soluble guanylyl cyclase, BAY 412272, or an inhibitor of phosphodiesterase type 5, sildenafil. The proteomic study revealed an up-regulation of guanine nucleotide-binding protein β, GST-ω-1, cathepsin D, chloride intracellular channel subunit 5, annexin A4, F-actin capping protein CapZ (CapZα), and the translation factor elongation factor 1 δ in lungs from chronic hypoxic rats with pulmonary hypertension. Immunohistochemistry revealed that CapZα, cathepsin D, and annexin A4 were expressed in the pulmonary vascular wall and immunoblotting showed these proteins correlated to alterations in muscularization. Both drugs inhibited hypoxia-induced increase in right ventricular systolic pressure and pulmonary arterial muscularization, and prevented most of the protein regulations observed after hypoxia. These findings suggest that pulmonary pressure is an important factor for initiating signaling pathways leading to protein expression and muscularization in the pulmonary vasculature.

Topics: Amino Acid Sequence; Animals; Gene Expression Regulation; Guanylate Cyclase; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Molecular Sequence Data; Phosphodiesterase 5 Inhibitors; Piperazines; Proteome; Proteomics; Purines; Pyrazoles; Pyridines; Rats; Rats, Wistar; Signal Transduction; Sildenafil Citrate; Sulfones

Persistent pulmonary hypertension of the newborn (PPHN) is a common problem in the neonates with a high mortality rate. The prevalence ranges from 0.38-0.99 per 1,000 live births at Queen Sirikit National Institute of Child Health. The survival rate has improved after the advent of high-frequency ventilation and inhaled nitric oxide. However, inhaled nitric oxide is expensive and unavailable in most neonatal centers in Thailand. Sildenafil is a phosphodiesterase inhibitor type 5 that selectively reduces pulmonary vascular resistance and hence may play a role in the treatment of PPHN.. To evaluate effectiveness and short-term side effects of oral sildenafil for infants > 36 weeks gestational age who have PPHN.. The present study was conducted between January 2006 and December 2008 in the neonatal intensive care unit (NICU) at Queen Sirikit National Institute of Child Health. All infants > or = 36 weeks gestational age who were diagnosed as PPHN by echocardiogram and had an oxygenation index > or = 20 were included in the study. Oral sildenafil was given as per study protocol with a starting dose of 0.25-0.5 mg/kg/dose. Oxygenation index (OI), oxygen saturations (SpO2), alveolar arterial oxygen gradient (A-aDO2) and mean arterial blood pressure (MAP) were monitored serially.. A total of 40 infants were diagnosed with PPHN during this period. Eleven infants were included in the present study. The initial median OI was 31.95 (24.25-48.25). All infants received standard therapy with mechanical ventilation, sedation and inotropic drugs. OI decreased 4.6% from base line after the first hour of starting oral sildenafil and progressively decreased by 13%, 27%, 37%, 41% and 90% at 2, 4, 6, 12 and 24 hours respectively. Oral sildenafil was discontinued in one infant. It was combined with inhaled iloprost in 2 infants due to systemic hypotension and with inhaled nitric oxide in one infant due to deterioration. One infant died during the present study.. Oral sildenafil may be effective in improving oxygenation in some infants with persistent pulmonary hypertension of the newborn. Systemic hypotension was a cause for concern in the present study. Further studies are needed to assess the pharmacokinetics, efficacy and long-term side effects of this drug.

Topics: Administration, Oral; Blood Pressure; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Oxygen; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Bosentan; Combined Modality Therapy; Drug Therapy, Combination; Eisenmenger Complex; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Iron, Dietary; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Bosentan; Combined Modality Therapy; Drug Therapy, Combination; Extracorporeal Membrane Oxygenation; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Primary ciliary dyskinesia (PCD) is an autosomal recessive heterogeneous group of conditions with variable clinical findings like recurrent respiratory tract infections, bronchiectasis, situs inversus, singly or in various combinations. Development of Pulmonary arterial hypertension can be a late complication of this disease. Here we present a case of PCD with recurrent respiratory tract infections, bronchiectasis and severe PAH, who responded to treatment with Oxygen, IV broad spectrum antibiotics and oral sildenafil.

Topics: Adult; Anti-Bacterial Agents; Bronchiectasis; Cardiotonic Agents; Ciliary Motility Disorders; Digitalis Glycosides; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Male; Oxygen Inhalation Therapy; Piperazines; Purines; Recurrence; Respiratory Tract Infections; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Treatment Outcome; Vasodilator Agents

Chronic phosphodiesterase-5 inhibition improves peak oxygen consumption, ventilatory efficiency (VE/VCO(2) slope) and pulmonary artery pressure (PAP) in heart failure (HF). In 40 male patients, Sildenafil treatment produced a significant (p<0.001) decrease in dyspnea upon exertion (DOE) at maximal exercise. The correlations between the change in systolic PAP and both the change in the VE/VCO(2) slope (r=0.57, p<0.001) and DOE at maximal exercise (r(s)=0.49, p<0.001) were significant. DOE at maximal exercise is significantly reduced and the degree of improvement in PAP is reflected by the degree of improvement in the VE/VCO(2) slope and DOE following Sildenafil therapy.

Topics: Aged; Dyspnea; Exercise Test; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Consumption; Physical Exertion; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents; Work of Breathing

Sildenafil is used to treat pulmonary hypertension in neonatal and pediatric patients. Pharmacokinetic studies in these patients are complicated by the limited sample volume. We present the validation results of an assay method to quantitate sildenafil and desmethylsildenafil simultaneously in 50 microL of plasma. Deuterated sildenafil was used as an internal standard. After liquid-liquid extraction, analytes were separated on an ultra-performance liquid chromatography (UPLC)-column and quantified via tandem mass spectrometry. The calibration range was linear, with acceptable accuracy and a precision of <15% for both compounds. The lower limits of quantification were 1 ng/mL. Matrix effects were present, but inter-plasma batch variability was under 12%. The method was successfully applied to samples from a pharmacokinetic study into sildenafil pharmacokinetics in neonates, making maximum use of the limited number and amount of plasma samples available.

Topics: Bayes Theorem; Calibration; Chromatography, High Pressure Liquid; Female; Humans; Hypertension, Pulmonary; Indicators and Reagents; Infant, Newborn; Phosphodiesterase Inhibitors; Piperazines; Plasma; Purines; Reference Standards; Reproducibility of Results; Sildenafil Citrate; Solvents; Sulfones; Tandem Mass Spectrometry

Bronchopulmonary dysplasia is a common adverse outcome of very premature babies treated with long-lasting ventilation and oxygen therapy. Infants with bronchopulmonary dysplasia may develop pulmonary arterial hypertension. We report on severe bronchopulmonary dysplasia in a preterm infant who developed secondary, symptomatic and progressively severe pulmonary arterial hypertension. He was treated with sildenafil for 12 months, with complete resolution of pulmonary arterial hypertension. Eighteen months after therapy discontinuation, the patient was asymptomatic, and his systolic pulmonary artery pressure was normal. Routine use of sildenafil in preterm infants with bronchopulmonary dysplasia and secondary pulmonary arterial hypertension could be the future; large studies should confirm this report.

Topics: Antihypertensive Agents; Blood Pressure; Bronchopulmonary Dysplasia; Drug Administration Schedule; Gestational Age; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Male; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Ultrasonography; Vasodilator Agents

To describe the pharmacokinetics and exposure of oral sildenafil (SIL) in neonates (2-5 kg) with pulmonary hypertension (PH).. We included 11 neonates (body weight 2-5 kg, postnatal age 2-121 days) who received SIL and extracorporeal membrane oxygenation (ECMO) treatment for PH. SIL capsules were given via a nasogastric tube. Blood samples were collected via a pre-existing arterial line to quantify SIL and metabolite plasma levels (219 samples). Non-linear mixed effects modelling was used to describe SIL and desmethylsildenafil (DMS) pharmacokinetics.. A one-compartment model was suitable for SIL and DMS. Interpatient and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (SIL) and 62% and 26% (DMS). Patient weight, postnatal age and post-ECMO time did not explain variability. Concomitant fluconazole use was associated with a 47% reduction in SIL clearance. The exposure expressed as average plasma concentration area under the curve over 24 h (AUC(24 (SIL+DMS))) ranged from 625 to 13 579 ng/h/ml. An oral dose of 4.2 mg/kg/24 h would lead to a median AUC(24 (SIL+DMS)) of 2650 ng/h/ml equivalent to 20 mg three times a day in adults. Interpatient variability was large, with a simulated AUC(24 (SIL+DMS)) range (10th and 90th percentiles) of 1000-8000 ng/h/ml.. SIL pharmacokinetics are highly variable in post-ECMO neonates and infants. In a median patient, the current dose regimen of 0.5-2.0 mg/kg four times a day leads to an exposure comparable to the recommended adult dose of 20 mg four times a day. Careful dose titration, based on efficacy and the occurrence of hypotension, remains necessary. Follow-up research should include appropriate pharmacodynamic endpoints, with a population pharmacokinetic/pharmacodynamic analysis to assign a suitable exposure window or target concentration.

Topics: Antihypertensive Agents; Area Under Curve; Biological Availability; Birth Weight; Capsules; Extracorporeal Membrane Oxygenation; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Intubation, Gastrointestinal; Off-Label Use; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

The lungs of patients with pulmonary arterial hypertension (PAH) exhibit decreased bioavailability of nitric oxide and downstream signaling through cyclic guanosine monophosphate (cGMP). Therapies that enhance cGMP-mediated vasodilation have shown efficacy in treating PAH. We tested the hypothesis that combination therapy with sildenafil, a cGMP phosphodiesterase type 5 inhibitor, and brain natriuretic peptide (BNP), a receptor-mediated guanosine cyclase stimulator, synergistically attenuates monocrotaline-induced PAH in rats compared with either monotherapy.. Adult male Sprague-Dawley rats were subcutaneously injected with monocrotaline (n = 41, 50 mg/kg). After approximately 4 weeks, the rats were infused intravenously with vehicle solution, sildenafil (42 and 85 microg/kg/min), or BNP (50 and 100 ng/kg/min), alone and in varied combination. The primary endpoint was the relative change in right ventricular systolic pressure (RVSP) and mean arterial systemic pressure (MAP). Secondary endpoints included heart rate and dP/dt.. Vehicle infusions did not alter hemodynamic variables. Sildenafil85 (85 microg/kg/min) alone decreased RVSP (-16.6 +/- 5.6%) and decreased MAP (-4.0 +/- 4.7%). BNP50 (50 ng/kg/min) and BNP100 (100 ng/kg/min) decreased RVSP (-23.3 +/- 5.7% and -27.1 +/- 2.9%, respectively) and MAP (-6.4 +/- 5.8% and -14.3 +/- 4.1%, respectively). Combination therapy with sildenafil42 and BNP50 decreased RVSP (-20.7 +/- 5.6%) and showed a lessened systemic effect (MAP = -11.6 +/- 5.9%). Combination therapy with sildenafil85 and BNP100 decreased RVSP (-27.6 +/- 3.2%, P = NS) and showed increased systemic effect (MAP = -20.7 +/- 3.1%, P < 0.05) in comparison with sildenafil85.. This study suggests that intravenous administration of both sildenafil and BNP monotherapy produces significant improvement in RVSP, making them potentially viable options for the treatment of PAH, whereas combination therapy produces no additional improvement in pulmonary hemodynamics.

Topics: Animals; Drug Therapy, Combination; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; Natriuretic Peptide, Brain; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Time Factors

Common complications after surgery for transposition of the great arteries (TGA) include systemic ventricular dysfunction and arrhythmia after atrial baffle repair (AB) and outflow tract stenosis or regurgitation after the arterial switch (AS). Severe pulmonary hypertension (PHT) is a rarely reported problem after AB and AS. In this study we sought to evaluate the frequency of late onset severe PHT following surgical repair for TGA. We report 3 cases, 2 after AB and 1 after AS, describe the frequency of this complication and treatment response, by comparing the response to pulmonary vasodilators in this group of patients to that of idiopathic or connective tissue disease (CTD) related PHT. We currently follow 85 patients >or=17 years of age with repaired TGA; 77 after AB and 8 after AS. 3.5% of our adult congenital heart disease patients with TGA have developed late severe PHT. None of these patients demonstrated clinical improvement with Bosentan at 6 months, however 2 of 3 were stabilised with the addition of Sildenafil to initial therapy. The third patient died 4 months after the diagnosis of severe PHT, whilst waiting for heart-lung transplantation, despite Bosentan, Sildenafil and inotropic support. By contrast, of 37 patients with idiopathic or CTD related PHT commenced on Bosentan as initial therapy, 32 (86.5%) demonstrated a clinical response at 6 months; the other patients had Sildenafil as added therapy after 6 months. Our data suggest that patients with TGA and late onset PHT are less likely to achieve a clinical response on pulmonary vasodilator monotherapy (P = 0.006). Whilst more investigation is needed, our experience suggests an aggressive clinical course, often requiring combination PHT treatment.

Topics: Adolescent; Adult; Antihypertensive Agents; Cardiac Surgical Procedures; Cardiotonic Agents; Drug Therapy, Combination; Echocardiography, Doppler; Humans; Hypertension, Pulmonary; New South Wales; Piperazines; Postoperative Complications; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Transposition of Great Vessels; Vasodilator Agents

Topics: Diuresis; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventricular Dysfunction, Right

The occurrence of deteriorating renal function test results along with the attempts at diuresis of anasarca has been described but not named, and no solution other than the standard treatment of related medical conditions such as congestive heart failure (CHF) and reducing or stopping diuretics has been offered. Phosphodiesterase type 5 inhibitors (PD5I) are known to reduce pulmonary hypertension (PH). The PD5Is sildenafil and, just recently, tadalafil, have FDA indications in primary pulmonary hypertension (PPH).. In this observational study of CorPRADA patients treated with PD5I, 12 out of 19 cases met criteria for inclusion in statistical analysis. Medication reductions/discontinuations generally were made. Pre- and post-treatment data were analyzed using matched pairs.. There were significant improvements in edema, glomerular filtration rate (GFR), weight, and loop diuretic dosage required, while strong trends were seen in urine output per day and urine output per unit loop diuretic per day.. The identification of CorPRADA and the use of standard treatments for PH plus PD5I medication show promise in achieving successful diuresis of anasarca while stabilizing or improving renal function simultaneously.

Topics: Azotemia; Blood Pressure; Carbolines; Diuresis; Diuretics; Edema; Glomerular Filtration Rate; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Heart Disease; Purines; Sildenafil Citrate; Sulfones; Tadalafil

Pulmonary hypertension is a group of diseases comprising vascular constriction and obstructive changes of the pulmonary vasculature. Phosphodiesterase type 5 inhibitors, for example, sildenafil, can alleviate vascular remodeling in the monocrotaline pulmonary hypertension model in rats. We investigate the mechanisms of sildenafil on the pulmonary vascular remodeling of pulmonary hypertension induced by monocrotaline (MCT) in rats. Thirty Sprague-Dawley rats (weighing 200-220 g) were administered with MCT abdominal cavity injection or equivalent volume of normal saline (NS) (which were treated as C group n = 10) to induce pulmonary hypertension model. Fourteen days later, 20 MCT treated rats were randomly fed with sildenafil (25mg/kg/day) or placebo as S, P group (10 rats for each group), respectively. Another 6 weeks later, mean pulmonary artery pressure (mPAP), index of right ventricular hypertrophy (RV/LV+S) of all animals were measured under general anesthesia. Pulmonary tissue was collected to investigate pathological features of pulmonary arteries and to measure protein expression of ERK(1)/ERK(2) and MKP1. After 6 weeks, there were significant elevated mPAP and RV/LV+S in both P and S groups. The ratio of wall thickness to vessel diameter in pulmonary arteries with diameters <200 microm were increased in both P and S groups. But the ratio of wall thickness to vessel diameter was smaller in S group than that in P group. The phosphorylation level of ERK(1)/ERK(2) were elevated in both P and S groups, but the level of phosphorlation ERK(1)/ERK(2) were lower in S group than that in P group. Intriguingly, the expression level of MKP1 was significantly increased in both S and P groups, while it was higher in S group than that in P group. The sildenafil can decrease mPAP and inhibit the progress of pulmonary vascular remodeling in pulmonary hypertension rats. The ERK-MAP kinase signaling pathway might play a role during this process.

Topics: Actins; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Dual Specificity Phosphatase 1; Fluorescent Antibody Technique; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Monocrotaline; Phosphorylation; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Signal Transduction; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Humans; Hypertension, Pulmonary; Piperazines; Purines; Respiratory Distress Syndrome; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Edema; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

Pulmonary hypertension carries significant maternal and fetal risk during pregnancy and the postpartum period. As maternal mortality is high, specific targeted therapy for pulmonary hypertension may be required during pregnancy.. We describe 2 pregnant patients who presented with severe secondary pulmonary arterial hypertension during their last trimester. They were electively treated in the late antepartum and early postpartum periods with sildenafil and intravenous epoprostenol and successfully delivered healthy infants via cesarean section without postpartum complications.. Although pulmonary hypertension is associated with a risk of maternal mortality and most women are advised against pregnancy, new therapies may improve the outcome of pregnancy in patients with pulmonary hypertension.

Topics: Adult; Cesarean Section; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pregnancy Trimester, Third; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sterilization, Tubal; Sulfones; Vascular Resistance; Vasodilator Agents; Young Adult

Topics: Carbolines; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Meta-Analysis as Topic; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil

Sildenafil, a phosphodiesterase-5 inhibitor, and simvastatin, a cholesterol lowering drug, both have therapeutic effects on PAH; however, the combination of these drugs has not been tested in the treatment of PAH. The purpose of this study was to determine whether the combination of sildenafil and simvastatin is superior to each drug alone in the prevention of MCT-induced PAH. Phosphorylated Smad levels were decreased in lung tissue in MCT-injected rats, whereas ERK protein levels were increased. This indicates a possible role for an increase in mitogenic ERK activity in addition to decreased proapoptotic Smad signaling in the MCT model of PAH. Combination sildenafil and simvastatin treatment prevented the MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH), exerted an anti-proliferative effect on pulmonary artery smooth muscle cells (PASMC). Our results indicate that combination therapy with sildenafil and simvastatin attenuated the development of pulmonary hypertension more than either treatment alone.

Topics: Animals; Anticholesteremic Agents; Disease Models, Animal; Drug Therapy, Combination; Hypertension, Pulmonary; Male; Monocrotaline; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Simvastatin; Sulfones

Sildenafil is a phosphodiesterase type 5 inhibitor used as a therapeutic adjunct in critically ill neonates with persistent pulmonary hypertension. Sildenafil is associated with several ocular complications in adults and is suspected to exacerbate retinopathy of prematurity (ROP). The risk of ocular complication in sildenafil-treated newborns, not otherwise at risk for the development of ROP, is unknown.. Twenty-two neonates with birth gestational age greater than 34 weeks and birth weight over 2,100 g who received oral sildenafil for more than 2 weeks were assessed by a pediatric ophthalmologist for potential ocular complications.. Four patients had ocular findings: 2 had bacterial conjunctivitis; 1 had optic nerve hypoplasia, choroidal coloboma, and nystagmus; 1 had previously suffered from a hypotensive episode and had a documented cortical injury accompanied by bilateral optic disk atrophy and nystagmus. All cases seemed unrelated to sildenafil use and improved despite continued use of the drug.. Our results do not support the need for a routine ophthalmologic examination in term and near-term neonates receiving sildenafil.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Birth Weight; Eye; Female; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Assessment; Sildenafil Citrate; Sulfones

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Europe; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Practice Guidelines as Topic; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes

Topics: Antihypertensive Agents; Child; Endothelium-Dependent Relaxing Factors; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

We hypothesize that sildenafil attenuates pulmonary hypertension through suppressing pulmonary vascular remodeling. Thirty male adult Sprague-Dawley rats were randomized to receive saline injection (Group 1), subcutaneous monocrotaline (MCT) (60 mg/kg) (Group 2), and MCT plus oral sildenafil (30 g/kg per day) (Group 3) 5 days after MCT administration. By Day 35, Western blot showed lower connexin43 and membranous protein kinase C epsilon expressions but higher oxidative stress in right ventricle in Group 2 compared with the other groups. Additionally, pulmonary Smad1/5 was lowest, whereas connexin43 and Smad3 were highest in Group 2. Pulmonary mRNA expressions of tumor necrosis factor-alpha, caspase-3, plasminogen activator inhibitor-1, and transforming growth factor-beta were higher, whereas bone morphogenetic protein Type II receptor, Bcl-2, and endothelial nitric oxide synthase were lower in Group 2 than in the other groups. Similarly, mRNA expressions of tumor necrosis factor-alpha, caspase-3, and beta-myosin heavy chain were increased, whereas Bcl-2, endothelial nitric oxide synthase, and alpha-myosin heavy chain expressions in right ventricle were reduced in Group 2 compared with the other groups. Number of lung arterioles was lowest, whereas number of arterioles with muscularization of the medial layer was highest in Group 2. Right ventricle systolic pressure and weight were elevated in Group 2 compared with the other groups. In conclusion, sildenafil effectively alleviates MCT-induced pulmonary hypertension through suppressing pulmonary vascular remodeling.

Topics: Animals; Arterioles; Blood Vessels; Caspase 3; Connexin 43; Hypertension; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Nitric Oxide Synthase Type III; Piperazines; Purines; Random Allocation; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Tumor Necrosis Factor-alpha; Ventricular Myosins

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Canada; Cost Control; Drug Costs; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes

Pulmonary arterial hypertension (PAH) still cannot be cured, warranting the search for novel treatments. Fasudil (a Rho kinase inhibitor) was compared with bosentan (an endothelin receptor blocker) and sildenafil (a phosphodiesterase 5 inhibitor), with emphasis on right ventricular (RV) function, in a reversal rat model of monocrotaline (MCT)-induced PAH. In addition, the effects of combining bosentan or sildenafil with fasudil were studied. MCT (40 mg·kg body weight(-1)) induced clear PAH in male Wistar rats (n = 9). After 28 days, echocardiography, RV catheterisation and histochemistry showed that cardiac frequency, stroke volume and RV contractility had deteriorated, accompanied by RV dilatation and hypertrophy, and marked pulmonary arterial wall thickening. Mean pulmonary arterial pressure and pulmonary vascular resistance increased significantly compared to healthy rats (n = 9). After 14 days, MCT-treated rats received a 14-day oral treatment with bosentan, sildenafil, fasudil or a combination of fasudil with either bosentan or sildenafil (all n = 9). All treatments preserved cardiac frequency, stroke volume and RV contractility, and reduced pulmonary vascular resistance and RV dilatation. Fasudil lowered RV systolic pressure and mean pulmonary arterial pressure significantly, by reducing pulmonary arterial remodelling, which reduced RV hypertrophy. Combining bosentan or sildenafil with fasudil had no synergistic effect. Fasudil significantly improved PAH, to a greater degree than did bosentan and sildenafil.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Familial Primary Pulmonary Hypertension; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Monocrotaline; Piperazines; Pulmonary Artery; Purines; Rats; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

We report the case of a treatment-naive patient with pulmonary arterial hypertension who presented with decompensated right ventricular failure and cardiogenic shock. Unstable hemodynamics, hypoxia and end-organ hypoperfusion limited up-titration of pharmacotherapy. Mechanical circulatory support with veno-venous extracorporeal membrane oxygenation (VV-ECMO) was initiated to permit dose titration of pulmonary vasodilator therapy. VV-ECMO was weaned after 10 days of support, with successful transition to intravenous epoprostenol and oral sildenafil.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Combined Modality Therapy; Epoprostenol; Extracorporeal Membrane Oxygenation; Female; Humans; Hypertension, Pulmonary; Injections, Intravenous; Piperazines; Purines; Shock, Cardiogenic; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Right

We report a woman with atrial septal defect and severe pulmonary hypertension with 25.0 Wood unit.m(2) of indexed total pulmonary vascular resistance. She underwent successful corrective repair of atrial septal defect after 2 years of treatment with sildenafil, and has been monitored for 4 years after repair. This case supports a "treat and repair" approach using advanced pulmonary vasodilator therapy in selected patients with inoperable severe pulmonary hypertension associated with atrial septal defect.

Topics: Adult; Cardiac Catheterization; Cardiac Surgical Procedures; Echocardiography, Doppler, Color; Eisenmenger Complex; Female; Follow-Up Studies; Heart Septal Defects, Atrial; Humans; Hypertension, Pulmonary; Long-Term Care; Piperazines; Purines; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Sulfones; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Vasodilator Agents

There are only a few reports of pulmonary hypertension (PH) in hypersensitivity pneumonitis (HP) and an approved vasomodulatory therapy for PH does not exist at all for interstitial lung disease (ILD), particularly for HP.. The case of a 53-year-old woman with chronic HP and severe life-threatening PH treated with a combined specific vasomodulatory therapy is reported. Sustained clinical and hemodynamic improvement was achieved.. Further investigation of PH in HP and specific vasomodulatory therapy is necessary.

Topics: Alveolitis, Extrinsic Allergic; Chronic Disease; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Phenylpropionates; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The long-term effects of drugs developed for the control of pulmonary arterial hypertension (PAH) are little known, since multicenter studies usually last 12 to 16 weeks.. To evaluate the two-year outcome of PAH patients receiving monotherapy with sildenafil (a phosphodiesterase-5 inhibitor), with regard to their functional capacity.. Twenty four patients (ages between 8 and 54 years) with idiopathic PAH (IPAH, n = 9) or congenital heart disease-associated PAH (CHD-PAH, n = 15) were treated with sildenafil for two years, with daily oral doses ranging from 60 to 225 mg (tid). Physical capacity was assessed by the distance walked in the 6-minute walk test (DW6M) and by the degree of dyspnea at the end of the walk (Borg scale); peripheral oxygen saturation was also recorded (SpO(2)6M, pulse oximetry).. In the 18 patients who completed the two-year follow-up, there was a progressive and sustained increase in DW6M, both in the IPAH group (from 239 +/- 160 m to 471 +/- 66 m, p = 0.0076) and in the CHD-PAH group (from 361 +/- 144 m to 445 +/- 96 m, p = 0.0031), with improvement of dyspnea at the end of the walk (p<0.05 for both groups). No decrease in SpO(2)6M was observed in the groups; in patients with CHD-PAH, in particular, SpO(2)6M went from 77 +/- 20% to 79 +/- 16% (p = 0.5248). Five deaths occurred (three in the IPAH group) and one patient was lost to follow-up during the study period.. In a two-year follow-up, sildenafil proved useful in the control of the functional status of PAH patients, with significant improvement in both groups considered.

Topics: Adolescent; Adult; Child; Dyspnea; Exercise Test; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Statistics, Nonparametric; Sulfones; Time Factors; Treatment Outcome; Young Adult

Topics: Administration, Inhalation; Contrast Media; Follow-Up Studies; Humans; Hypertension, Pulmonary; Imaging, Three-Dimensional; Male; Middle Aged; Nitric Oxide; Oximetry; Piperazines; Purines; Radiographic Image Enhancement; Radiography, Thoracic; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

Idiopathic pulmonary arterial hypertension (IPAH) is characterized by a progressive increase in pulmonary vascular resistance, which may lead to right ventricular failure and death. Major cardiovascular and pulmonary alterations occur during pregnancy and therefore worsen or increase the complications of pulmonary arterial hypertension (PAH). A patient diagnosed with IPAH after a successful full-term pregnancy and cesarean section with epidural anesthesia is presented. The postoperative course was complicated by progressive dyspnea, and lower limb edema. The outcome of treatment with sildenafil during puerperium was favorable in this patient. The clinical course was complicated by an unexpected spontaneous pregnancy after primary infertility.

Topics: Female; Humans; Hypertension, Pregnancy-Induced; Hypertension, Pulmonary; Piperazines; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Sildenafil is increasingly being used in the management of pulmonary arterial hypertension in the newborn. Its role in patients with congenital cardiac disease is less well defined and as yet has only been reported sporadically.. Present our experience with sildenafil treatment in patients with a failing Fontan circulation.. Retrospective review of 13 symptomatic patients after Fontan palliation who received treatment with sildenafil between January, 2006 and July, 2008.. Three patients suffered from protein-losing enteropathy, four patients presented with bronchial casts, two had severe cyanosis after fenestrated Fontan procedure, two had prolonged chylous effusions, one had a previous failure of Fontan and take-down, and one patient had arrhythmias and end-stage cardiac failure requiring conversion to an extra-cardiac Fontan. Sildenafil was used in the dosage of 1-2 milligrams per kilogram 3-4 times per day. Protein-losing enteropathy and alpha-1-antitrypsin levels improved in all three patients on sildenafil treatment. One of these patients had a concomitant catheter creation of a fenestration, as did two patients presenting with bronchial casts and both patients with persistent chylous effusions. All four patients with bronchial casts and two patients with cyanosis improved significantly on sildenafil treatment. Chylous effusions decreased after sildenafil and stent enlargement of a fenestration. There were no significant side effects requiring sildenafil withdrawal over a treatment period ranging from 2 months to 2 years.. Sildenafil can be used safely and effectively in the treatment of patients with a failing Fontan circulation.

Topics: Child; Child, Preschool; Female; Follow-Up Studies; Fontan Procedure; Heart Failure; Humans; Hypertension, Pulmonary; Male; Piperazines; Postoperative Complications; Protein-Losing Enteropathies; Purines; Retrospective Studies; Shock; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents

Topics: Antihypertensive Agents; Bosentan; Dyspnea; Hemodynamics; Histiocytosis, Langerhans-Cell; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones

To explore treatment patterns and resource utilization and cost for subjects with pulmonary arterial hypertension (PAH).. Retrospective claims database analysis of 706 patients with PAH enrolled in a large, geographically diverse US managed-care organization.. In the final sample of PAH patients treated with bosentan (n=251) or sildenafil (n=455), average age was 57 years, 86% of patients were commercially insured, and 52% of patients were male. Gender distribution varied significantly across subgroups, with a lower proportion of males in the bosentan (30%) subgroup compared with the sildenafil group (64%) (p<0.001). Average baseline Charlson comorbidity score was 2.4. Average numbers of fills per month were 0.8 and 0.4 for bosentan and sildenafil patients, respectively (p<0.001). Over 80% of patients received only one PAH treatment in the first 90 days following the index date, with 28% of bosentan and 13% of sildenafil patients receiving combination therapy (p<0.001). Over one-third of bosentan patients and one-quarter of sildenafil patients experienced a dose increase in the follow-up period (p=0.009). Sixteen percent of sildenafil patients experienced a dose decrease in the follow-up period, while a smaller proportion of patients receiving bosentan (4%) experienced a dose decrease (p<0.001). On average, number of PAH-related per subject per month (PSPM) inpatient stays and emergency department visits and PSPM length of inpatient stays were statistically similar between the subgroups. PAH-related PSPM healthcare costs were high for both subgroups, with average monthly costs of $5,332 and $3,632 among bosentan and sildenafil patients, respectively (p=0.003). Differences in total costs were driven mainly by differences in pharmacy expenditures.. Of the oral agents approved for treating PAH at the time of this study, sildenafil was most commonly prescribed as index therapy and was also associated with the lowest costs, largely due to significantly lower pharmacy costs. This study is characterized by limitations inherent to claims database analyses, such as the potential for coding errors and lack of information on whether a drug was taken as prescribed. Furthermore, PAH severity (WHO functional class) was not assessed.

Topics: Antihypertensive Agents; Bosentan; Female; Health Care Costs; Health Expenditures; Health Services; Humans; Hypertension, Pulmonary; Insurance Claim Review; Male; Managed Care Programs; Middle Aged; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; United States; Vasodilator Agents

Experimental left-to-right shunt-induced pulmonary arterial hypertension (PAH) can be partially prevented by the endothelin-A receptor blocker sitaxsentan or by the phosphodiesterase-5 inhibitor sildenafil. We hypothesized that the combined administration of these drugs would completely prevent shunt-induced PAH, arguing in favor of a major role of endothelial dysfunction in the initiation of the disease. Twenty-four 3-wk-old piglets were randomized to a sham operation or to placebo, sitaxsentan therapy, or sitaxsentan combined with sildenafil after the anastomosis of the left subclavian artery to the pulmonary arterial trunk. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry and quantitative real-time PCR for endothelin-1, angiopoietin-1, and bone morphogenetic protein receptor (BMPR) signaling molecules. Three months of left-to-right shunting induced an increase in pulmonary vascular resistance (PVR) and medial thickness, an overexpression of endothelin-1, and angiopoietin-1 and decreased expressions of BMPR-2 and BMPR-1A. Sitaxsentan partially prevented a shunt-induced increase in PVR, medial thickness, and associated biological disturbances. Sildenafil combined with sitaxsentan normalized PVR, medial thickness, and the expression of endothelin-1. However, the expression of angiopoietin-1 remained increased, and the expressions of BMPR-1A and BMPR-2 were incompletely returned to normal. The coupling of right ventricular end-systolic to arterial elastances was maintained in all circumstances. Sitaxsentan combined with sildenafil prevents shunt-induced PAH more effectively than sitaxsentan alone, suggesting a major role for the targeted signaling pathways in the initiation of the disease. Sitaxsentan alone or combined with sildenafil did not affect right ventricular function.

Topics: Angiopoietin-1; Animals; Bone Morphogenetic Protein Receptors, Type II; Disease Models, Animal; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Isoxazoles; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Circulation; Purines; Sildenafil Citrate; Subclavian Artery; Sulfones; Thiophenes; Treatment Outcome

Selective right pulmonary arteriography and 3-dimensional computed tomography revealed multiple severe stenoses of the peripheral pulmonary artery associated with poststenotic aneurysms in a 65-year-old woman. She was referred to the hospital for evaluation of dry cough, gradually increasing dyspnea and multiple nodular shadows on a chest radiograph. Echocardiography and cardiac catheterization showed severe pulmonary hypertension, though other structural heart diseases or well-characterized congenital syndromes were ruled out. She was diagnosed as isolated peripheral pulmonary artery branch stenosis. Recent advances in CT technology enable a less-invasive assessment of pulmonary artery, and can be useful in the management of pulmonary arterial hypertension.

Topics: Aged; Aneurysm; Arterial Occlusive Diseases; Cardiac Catheterization; Constriction, Pathologic; Cough; Dyspnea; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Imaging, Three-Dimensional; Oxygen Inhalation Therapy; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Ultrasonography; Vasodilator Agents; Warfarin

The present study investigated whether BAY 41-2272(5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine), a novel pyrazolopyridine that activates guanylyl cyclase and sensitizes the enzyme towards nitric oxide (NO), inhibits the development of pulmonary hypertension. BAY 41-2272 (1 or 10 mg/kg/day) was administered intraperitoneally, and sildenafil (25 mg/kg/day), an inhibitor phosphodiesterase type 5, was given in the drinking water to rats kept under chronic hypobaric hypoxia for two weeks. Right ventricular systolic pressure and hypertrophy, degree of muscularization and relaxation of pulmonary arteries were measured, and immunoblotting was performed. Chronic hypoxia increased right ventricular systolic pressure and expression of soluble guanylyl cyclase and phosphorylated vasodilator-stimulated phosphoprotein (VASP-P(ser239)). BAY 41-2272 prevented hypoxia-induced increase in right ventricular systolic pressure and right ventricular hypertrophy to the same extent as sildenafil. Only sildenafil significantly decreased hypoxia-induced muscularization of pulmonary arteries. Expressed relative to soluble guanylyl cyclase expression, VASP-P(ser239) was increased in lungs from rats treated with BAY 41-2272. Acutely BAY 41-2272 caused pulmonary as well as systemic vasodilatation. In the chronic setting systemic blood pressure was not different to baseline at trough after intraperitoneally administered BAY 41-2272. BAY 41-2272 vasorelaxation in isolated pulmonary resistance arteries was inhibited by an inhibitor of guanylyl cyclase, ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxaline-1-one), and of Na(+)-K(+)-ATPase, ouabain. In conclusion, in an adult rat model of chronic hypoxic pulmonary hypertension, BAY 41-2272 to a similar degree as sildenafil prevents pulmonary hypertension. Thus, BAY 41-2272 may provide a novel therapeutic compound for treating chronic hypoxic pulmonary hypertension.

Topics: Animals; Cell Adhesion Molecules; Guanylate Cyclase; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Microfilament Proteins; Phosphoproteins; Piperazines; Pulmonary Artery; Purines; Pyrazoles; Pyridines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Time Factors; Vasodilation; Vasodilator Agents

2-Methoxyestradiol (2ME) is a major nonestrogenic metabolite of estradiol. Our previous studies suggest that 2ME, in several models of cardiac and/or vascular injury, strongly inhibits cardiac and vascular remodeling. Furthermore, our most recent study shows that in male rats, 2ME attenuates the development and retards the progression of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH), and in female rats, 2ME eliminates the exacerbation of PAH and the increased mortality due to ovariectomy. The current standard of care of patients with PAH includes treatment with an endothelin receptor antagonist (eg, bosentan) or a phosphodiesterase5 inhibitor (eg, sildenafil). Moreover, combination therapy is often prescribed. Therefore, in the present study, we compared the efficacy of 2ME (10 μg · kg(-1) · h(-1), 2ME-10) to the effects of bosentan (200 mg/kg; BOS), sildenafil (50 mg/kg; SIL), and their respective combinations with 2ME-10 (2ME + BOS and 2ME + SIL groups, respectively). Treatments were initiated 12 days after administration of MCT (60 mg/kg). Twenty-eight days after MCT administration, right ventricular peak systolic pressure was measured and morphometric analysis was conducted. 2ME exhibited beneficial effects in pulmonary hypertensive animals and had efficacy comparable to that of BOS and SIL. Importantly, combination treatments had favorable effects on survival, vascular remodeling, and inflammatory response, and the 2ME + SIL combination was significantly more efficacious than any other treatment. These results indicate that 2ME is effective in experimental PAH and suggests that 2ME may provide additional therapeutic benefit over existing drugs used for the treatment of pulmonary hypertension.

Topics: 2-Methoxyestradiol; Animals; Antihypertensive Agents; Bosentan; Drug Synergism; Drug Therapy, Combination; Estradiol; Female; Hypertension, Pulmonary; Male; Monocrotaline; Muscle, Smooth, Vascular; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Limited data suggest a benefit following sildenafil treatment in patients with pulmonary hypertension (PH) and interstitial lung disease (ILD). The role of sildenafil in the management of PH in ILD is not clear. We report our experience of ILD patients with PH after 6-month sildenafil therapy.. We reviewed 15 patients (mean age 55 ± 15 years; 8 men) with ILD (mean FVC 52.6 ± 15.4%) and PH (mean right ventricular systolic pressure 73.8 ± 17.8 mm Hg). Median brain natriuretic peptide: 37 (5-452) pmol/L; mean 6MWD: 156 ± 101 m.. Following 6-month treatment with sildenafil, brain natriuretic peptide levels were lower (n = 12, P = 0.03), 6MWD was higher (n = 6, P < 0.05), but no change in right ventricular systolic pressure (n = 11) was demonstrated.. Our observations suggest that sildenafil may be useful in the management of PH in ILD. Controlled trials are warranted before therapeutic recommendations can be made.

Topics: Cohort Studies; Exercise Test; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Middle Aged; Natriuretic Peptide, Brain; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents; Walking

Topics: Comorbidity; Dose-Response Relationship, Drug; Exercise Test; Exercise Tolerance; Hemodynamics; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Vasodilator Agents

A 54-year-old woman with a 20-year history of Raynaud phenomenon was admitted to our hospital complaining of progressive dyspnea on exertion since 5 years previously. Interstitial lung disease was diagnosed, accompanied by pulmonary arterial hypertension (PAH) associated with systemic sclerosis. After oxygen therapy and treatment with sildenafil, her clinical condition and PAH gradually improved. However, she was readmitted due to deterioration of Raynaud phenomenon and progressive dyspnea in March 2009. Right heart catheterization findings demonstrated that her mean pulmonary arterial pressure (PAP) was elevated, at 48 mmHg. Bosentan was therefore added to an increased dose of sildenafil. Consequently, her dyspnea, 6-min walking distance, serum brain natriuretic peptide level, and PAP improved. Combination therapy with bosentan and sildenafil was effective for this case of refractory PAH associated with fibrotic lung in systemic sclerosis.

Topics: Antihypertensive Agents; Bosentan; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Middle Aged; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Topics: Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Patient Selection; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Drug Therapy, Combination; Familial Primary Pulmonary Hypertension; Glucocorticoids; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; POEMS Syndrome; Prednisolone; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

The authors report a case of severe pulmonary arterial hypertension (PAH) in a 75-year-old woman who had received a diagnosis of neurofibromatosis type 1 (NF1) 23 years before. She presented with progressive dyspnoea and recurrent syncope. Even though the patient initially improved after starting supportive and specific treatment for PAH, she then deteriorated and died from respiratory failure 11 months after the diagnosis of PAH. Prompt recognition of such an unusual association between PAH and NF1 and appropriate therapeutic intervention could ameliorate quality of life and prolong survival in this patient population.

Topics: Aged; Anticoagulants; Combined Modality Therapy; Diuretics; Dyspnea; Fatal Outcome; Female; Follow-Up Studies; Furosemide; Humans; Hypertension, Pulmonary; Neurofibromatosis 1; Oxygen Inhalation Therapy; Piperazines; Purines; Recurrence; Sildenafil Citrate; Spironolactone; Sulfones; Syncope; Vasodilator Agents

Sildenafil can cause transient, mild ERG changes in healthy individuals taking large single doses. Although the drug was originally intended for intermittent use in erectile dysfunction, it has now been approved for chronic use in subjects with pulmonary arterial hypertension (PAH). The purpose of our study is to investigate possible ERG changes in subjects using large doses of sildenafil on a chronic daily basis.. We examined five subjects with PAH taking sildenafil daily for 1-4 years. Full-field electroretinogram (ERG), multifocal ERG (mfERG), and color testing were performed. Three of the subjects returned on a later date for challenge off and on the medication.. On chronic daily sildenafil, color vision testing was normal, and ERG and mfERG amplitudes were normal; however, cone implicit times on drug were modestly lengthened. There were no consistent full-field ERG changes when off the drug, but the mfERG showed a small amplitude increase and implicit time decrease, which returned 1 h after re-dosing.. There was a modest lengthening of cone implicit time on chronic daily doses of sildenafil and a hint that some of these changes may be reversible in the short term. It does not appear that chronic sildenafil usage at these dosage levels is seriously toxic or threatening to vision.

Topics: Adult; Color Vision; Dose-Response Relationship, Drug; Drug Administration Schedule; Electroretinography; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Reaction Time; Retinal Cone Photoreceptor Cells; Sildenafil Citrate; Sulfones; Vasodilator Agents; Vision, Ocular

To determine the clinical course and outcomes of infants with chronic lung disease (CLD) and pulmonary hypertension (PH) who received prolonged sildenafil therapy.. We conducted a retrospective review of 25 patients <2 years of age with CLD in whom sildenafil was initiated for the treatment of PH while they were hospitalized from January 2004 to October 2007. Hemodynamic improvement was defined by a 20% decrease in the ratio of pulmonary to systemic systolic arterial pressure or improvement in the degree of ventricular septal flattening with serial echocardiograms.. Chronic sildenafil therapy (dose range, 1.5-8.0 mg/kg/d) was initiated at a median of 171 days of age (range, 14-673 days of age) for a median duration of 241 days (range, 28-950 days). Twenty-two patients (88%) achieved hemodynamic improvement after a median treatment duration of 40 days (range, 6-600 days). Eleven of the 13 patients with interval estimates of systolic pulmonary artery pressure with echocardiogram showed clinically significant reductions in PH. Five patients (20%) died during the follow-up period. Adverse events leading to cessation or interruption of therapy occurred in 2 patients, 1 for recurrent erections, and the other had the medication held briefly because of intestinal pneumatosis.. These data suggest that chronic sildenafil therapy is well-tolerated, safe, and effective for infants with PH and CLD.

Topics: Blood Pressure; Bronchopulmonary Dysplasia; Echocardiography; Female; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Treatment Outcome

A retrospective study of the UK Pulmonary Hypertension Service for Children for the first 5-year period of its existence.. Records of 216 children with idiopathic pulmonary arterial hypertension (IPAH) and associated pulmonary arterial hypertension (APAH) were reviewed. Kaplan-Meier survival curves were constructed for different diagnostic groups and for different therapies.. At cardiac catheterisation only 7.4% of those with IPAH and 6% of those with APAH responded positively to vasodilator testing and so were treated with nifedipine. Others needing treatment were given continuous intravenous epoprostenol, bosentan or sildenafil singly or in combination. For IPAH survival rates were 85.6%, 79.9% and 71.9% at 1, 3 and 5 years, respectively, compared with a survival time of less than a year in historical untreated controls. A combination of intravenous epoprostenol with either bosentan or sildenafil, or both, appeared to achieve the best outcome. Six children underwent lung transplantation. In APAH survival rates were 92.3%, 83.8% and 56.9% at 1, 3 and 5 years, respectively, postoperative congenital heart disease with severe pulmonary hypertension having the worst outcome.. New pulmonary hypertension-specific medicines have improved survival in children as in adults. Outcome in this series compares favourably with international outcome data.

Topics: Adolescent; Bosentan; Case-Control Studies; Child; Child, Preschool; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Kaplan-Meier Estimate; Lung Transplantation; Male; Nifedipine; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; United Kingdom; Vasodilator Agents

Pulmonary arterial hypertension associated with portal hypertension occurs in about 5% of patients being evaluated for liver transplantation. Treatment is required to facilitate safe transplantation, and oral pulmonary vasodilators have yet to be prospectively evaluated for this disease. The objective of this study was to determine the hemodynamic outcome in a consecutive cohort of patients offered sildenafil as first-line treatment for portopulmonary hypertension. We identified consecutive patients at the University of Rochester referred by the liver transplant team. All had catheter-confirmed disease and were treated with sildenafil. Patients were excluded from analysis if they did not have follow-up catheterizations. The change in pulmonary vascular resistance at the time of first follow-up was the primary outcome. Eleven patients began sildenafil, and 9 had follow-up right heart catheterizations during a 3-year period. Pulmonary vascular resistance dropped in each patient; as a group, the mean dropped from 575 to 375 dynes/second/cm(5). Four of 9 patients achieved a mean pulmonary artery pressure

Topics: Adult; Cardiac Catheterization; Cohort Studies; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Liver Transplantation; Male; Middle Aged; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents

Portopulmonary hypertension (POPH), or pulmonary arterial hypertension associated with cirrhosis, carries a high mortality and often precludes liver transplantation. Many POPH patients have preserved or increased cardiac output; therefore, decreasing pulmonary artery pressure rather than improving cardiac output is more important in reducing liver transplant risk, and this makes sildenafil an attractive therapeutic option. We assessed the clinical response of patients with POPH treated with sildenafil monotherapy. We retrospectively reviewed the charts of 10 patients with POPH and sildenafil monotherapy. Eight of 10 patients had hepatitis C virus infection. Patients took 31 +/- 14 mg (mean +/- standard deviation) thrice daily and were followed for 21 +/- 16 months. The World Health Organization functional class improved from 3.0 +/- 0.0 to 2.3 +/- 0.5 at 1 year (P < 0.05). Four of 8 patients increased the 6-minute walk distance at 1 year by 30 m or more. Three patients became transplant-eligible, 1 of whom underwent successful transplantation, and 3 patients have been stable without progression of liver disease or POPH. The remainder were not transplant candidates because of refractory POPH (n = 2) or other comorbidities (n = 2). We conclude that sildenafil may be an effective therapy for POPH that can stabilize or improve hemodynamics in patients with POPH and thereby facilitate liver transplantation.

Topics: Female; Fibrosis; Hemodynamics; Hepacivirus; Hepatitis C; Humans; Hypertension, Pulmonary; Liver Transplantation; Male; Middle Aged; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension (PH) is a common complication of sarcoidosis that is associated with increased mortality. The pathogenesis of PH in sarcoidosis is uncertain, and the role of pulmonary arterial hypertension (PAH)-specific therapies remains to be determined.. We conducted a retrospective study of patients with sarcoidosis and PH at two referral centers. New York Heart Association (NYHA) functional class, exercise capacity, hemodynamic data, pulmonary function tests, and survival were collected and analyzed.. Twenty-two sarcoidosis patients treated with PAH-specific therapies were identified. After a median of 11 months of follow-up, NYHA class was improved in nine subjects. Mean 6-min walk distance (n = 18) increased by 59 m (p = 0.032). Patients with a higher FVC experienced a greater increment in exercise capacity. Among 12 patients with follow-up hemodynamic data, mean pulmonary artery pressure was reduced from 48.5 +/- 4.3 to 39.4 +/- 2.8 mm Hg (p = 0.008). The 1- and 3-year transplant-free survival rates were 90% and 74%, respectively.. PAH-specific therapy may improve functional class, exercise capacity, and hemodynamics in PH associated with sarcoidosis. Prospective, controlled trials of PAH therapies for sarcoidosis are warranted to verify this apparent benefit. Mortality among the study population was high, highlighting the need for urgent evaluation at a lung transplant center.

Topics: Administration, Inhalation; Administration, Oral; Aged; Antihypertensive Agents; Bosentan; Cohort Studies; Drug Therapy, Combination; Epoprostenol; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Piperazines; Probability; Purines; Respiratory Function Tests; Retrospective Studies; Risk Assessment; Sarcoidosis; Severity of Illness Index; Sildenafil Citrate; Statistics, Nonparametric; Sulfonamides; Sulfones; Survival Rate; Treatment Outcome

Inhibition of phosphodiesterase 5 (PDE5) decreases pulmonary pressure and improves symptoms in patients with pulmonary arterial hypertension. It is unclear however, whether inhibition of PDE5 can prevent myocardial remodelling during right-ventricular pressure overload.. Right-ventricular pressure overload was produced in male rats in a pulmonary hypertension model (monocrotaline 60 mg/kg s.c.) or by surgical pulmonary artery banding. PDE5 inhibition using oral sildenafil (50 mg/kg/day in drinking water) or placebo was initiated 14 days after monocrotaline treatment and continued for 14 days until final examination. In the pulmonary artery banding groups, rats were treated with sildenafil (50 mg/kg/day) or placebo for 21 days following surgical pulmonary artery banding. At the final experiments, right-ventricular haemodynamics were measured and remodelling was analysed using histological, biochemical, and gene expression markers. Both monocrotaline and pulmonary artery banding increased right-ventricular systolic pressure to approximately 80 mmHg. In parallel, both interventions induced markers of hypertrophy (upregulation of natriuretic peptides, increase in myocyte diameter) and fibrosis (upregulation of collagen types 1A2 and 3A1) as well as mRNA expression of the tissue inhibitor of matrix metalloproteases 1 and osteopontin in the right ventricle. In monocrotaline model, sildenafil decreased pulmonary pressure, reduced right-ventricular hypertrophy, and prevented fibrosis marker gene upregulation. After pulmonary artery banding, in contrast, sildenafil increased markers of myocardial remodelling and right-ventricular myocyte diameter.. Sildenafil prevents myocardial remodelling in pulmonary hypertension through an indirect action via right-ventricular unloading.

Topics: Administration, Oral; Animals; Blood Pressure; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Fibrillar Collagens; Fibrosis; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Myocardium; Natriuretic Peptides; Osteopontin; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Rats, Wistar; RNA, Messenger; Sildenafil Citrate; Stroke Volume; Sulfones; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Ventricular Pressure; Ventricular Remodeling

Pulmonary arterial hypertension is a rare disorder in childhood, the two most common types being idiopathic pulmonary arterial hypertension and pulmonary hypertension associated with congenital left-to-right shunt lesions, together accounting for almost 90% of cases.. The clinical presentation of idiopathic pulmonary arterial hypertension (familial and non familial) is essentially non-specific and varies with age. Pulmonary vasoreactivity testing identifies responders and non-responders. Responders are treated with calcium channel blockers and have a better prognosis. Non-responders have a very limited survival beyond diagnosis if not treated with more selective pulmonary arterial vasodilators. Prostacyclin, endothelin receptor antagonists and phosphodiesterase-5 inhibitors improve haemodynamics, functional class and exercise tolerance and delay deterioration. Patients with congenital left-to-right shunts and irreversible pulmonary arterial hypertension leading to Eisenmenger's syndrome have multiple organ disease. Despite a very pronounced exercise intolerance, their clinical course is rather stable with survival up to 40-60 years, depending on the complexity of their underlying cardiac defect. Treatment is based on general measures along with the same three types of selective pulmonary vasodilators as in idiopathic pulmonary arterial disease. Improvement in haemodynamics, functional class and exercise tolerance are comparable for both patient groups.. Pulmonary hypertension in children is idiopathic or associated with congenital heart disease in the majority of patients. Treatment with new selective pulmonary vasodilators offers haemodynamic and functional improvement.

Topics: Activin Receptors, Type II; Antigens, CD; Antihypertensive Agents; Bone Morphogenetic Protein Receptors, Type II; Bosentan; Calcium Channel Blockers; Child; Electrocardiography; Endoglin; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Incidence; Piperazines; Point Mutation; Prevalence; Purines; Receptors, Cell Surface; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

It has been widely accepted that development of porto-pulmonary hypertension (POPH) is independent of the cause of portal hypertension. The degree of hepatic damage and liver function do not correlate with predisposition to POPH or its severity. However, portal hypertension has been confirmed as a prerequisite for developing pulmonary hypertension. Transthoracic echocardiography is the best screening test for the presence of POPH, but a diagnosis of POPH can be established only by right heart catheterization. Randomized controlled trials comparing the efficacy and safety of different pharmacologic strategies are lacking in patients with POPH. The general management includes diuretics and oxygen supplementation. Notably, moderate to severe POPH predisposes candidates for orthotopic liver transplantation to a higher risk of perioperative mortality. Vasomodulating pharmacologic agents are used in patients with moderate to severe POPH to decrease pulmonary arterial hypertension, thereby permitting liver transplantation to be performed safely. Epo-prostenol is the best-studied medication, and bosentan appears promising.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Echocardiography; Epoprostenol; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Transplantation; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a rare complication of glycogen storage disease (GSD), and several cases with a poor outcome have been reported. A 17-year-old boy, who was diagnosed with GSD at 1 year of age, complained of shortness of breath on exertion, and was diagnosed with PAH based on the echocardiographic findings. Beraprost sodium (BPS) was started, and his symptoms improved after 3 months of treatment. Eighteen months later, he experienced frequent episodes of syncope. Because increasing the dose of BPS was ineffective, he was admitted to hospital. The echocardiogram showed marked elevation of the right ventricular pressure and low cardiac output, and his symptoms deteriorated despite continuous infusion of olprinone hydrochloride. Because a single dose of sildenafil increased his cardiac output, treatment with 25 mg sildenafil twice daily was started. His symptoms gradually ameliorated, and 3 weeks later he left the hospital. Two months after starting sildenafil, the cardiac index and the serous B-type natriuretic peptide concentration had become normal. Sildenafil may be effective in patients with secondary PAH and in patients who have developed tolerance to BPS.

Topics: Administration, Oral; Adolescent; Antihypertensive Agents; Drug Tolerance; Echocardiography; Electrocardiography; Epoprostenol; Glycogen Storage Disease Type I; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Natriuretic Peptide, Brain; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Syncope; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension (PH) is an important cause of mortality in systemic sclerosis (SSc), where it can be isolated (pulmonary arterial hypertension [PAH]) or associated with interstitial lung disease (ILD). This study was undertaken to characterize determinants of survival among SSc patients with either type of PH who received PAH-specific therapy.. Consecutive SSc patients with PAH or ILD-associated PH confirmed by right heart catheterization were included in the study. Kaplan-Meier and Cox proportional hazards models were used to compare survival between SSc patients with PAH and those with ILD-associated PH and to identify predictors of survival.. Fifty-nine patients (39 with PAH and 20 with ILD-associated PH) were identified. The majority (15 of 20 with ILD-associated PH and 27 of 39 with PAH) received an endothelin receptor antagonist as initial therapy. Median followup time was 4.4 years (range 2.7-7.4 years). Survival was significantly worse in SSc patients with ILD-associated PH than in those with PAH (1-, 2-, and 3-year survival rates 82%, 46%, and 39% versus 87%, 79%, and 64%, respectively; P < 0.01 by log rank test). In a multivariable analysis, ILD-associated PH was associated with a 5-fold increase in risk of death compared with PAH. Pulmonary vascular resistance index was also an independent predictor of mortality in the overall cohort (hazard ratio 1.05, P < 0.01) and was a significant univariable risk factor in each group separately. Type of initial PAH therapy and the use of warfarin were not related to survival.. Survival in SSc complicated by PH remains poor despite currently available treatment options. While therapy may be associated with improved survival in PAH compared with historical controls, the prognosis for patients with ILD-associated PH is particularly grim. Early diagnosis and treatment may improve outcomes since worsening hemodynamic factors were associated with reduced survival.

Topics: Bosentan; Cohort Studies; Comorbidity; Endothelin Receptor Antagonists; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Isoxazoles; Lung Diseases, Interstitial; Male; Maryland; Middle Aged; Piperazines; Prognosis; Proportional Hazards Models; Purines; Receptors, Endothelin; Scleroderma, Diffuse; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; Thiophenes; Vasodilator Agents

Phosphodiesterase-5 (PDE5) inhibitors, which induce relaxation of smooth muscle with some selectivity for the pulmonary vasculature, are used in the treatment of pulmonary hypertension. In some patients, the use of PDE5 inhibitors does not result in the desired magnitude of pulmonary vasodilation. The use of additional vasodilators to further reduce pulmonary vascular resistance is often accompanied by unacceptable reductions in systemic arterial pressure.. In 3 patients with heart failure, pulmonary hypertension and low systemic arterial pressures treated with sildenafil, systemic nitrates were added to reduce pulmonary hypertension further. Hemodynamic measurements were made before and after addition of nitrates. Addition of systemic nitrates to sildenafil led to a reduction in mean pulmonary arterial pressure of 11 mm Hg, from 37 mm Hg to 26 mm Hg (P = .06), whereas mean systemic arterial pressure decreased by only 4 mm Hg, from 77 mm Hg to 73 mm Hg (P = .53). The ratio of pulmonary vascular resistance to systemic vascular resistance was reduced by 45% (P = .1). Treatment with sildenafil and nitrates was continued for two to eight months, with no episodes of marked systemic hypotension, syncope, or lightheadedness.. These results suggest that addition of systemic nitrates to sildenafil results in a potentiation of vasodilation that is relatively selective for the pulmonary vasculature, and that this combination may be safe and effective in the treatment of pulmonary hypertension in patients with low systemic arterial pressures.

Topics: Cyclic GMP; Drug Therapy, Combination; Heart Failure; Humans; Hypertension, Pulmonary; Isosorbide Dinitrate; Male; Middle Aged; Nitro Compounds; Nitroglycerin; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Topics: Administration, Oral; Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Extracellular Matrix Proteins; Fibrosis; Hemodynamics; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Myocardium; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Sildenafil Citrate; Sulfones; Ventricular Remodeling

The aim of our study was to describe the efficacy of addition of intravenous or subscutaneous prostanoids in idiopathic pulmonary arterial hypertension (PAH) patients deteriorating on bosentan or on bosentan-sildenafil.. PAH treatment at our hospital is standardized with first-line oral therapy in New York Heart Association class III patients followed by addition of prostanoids on clinical worsening.. Mean improvement in 6-minute walk distance after 4 months of prostanoids was 86 m (p < 0.01) in the bosentan group versus 41 m (p < 0.05) in the bosentan-sildenafil group, and these improvements persisted at long-term follow-up.. From these results we conclude that addition of subcutaneous or intravenous prostanoids can be efficacious in PAH deteriorating on oral therapy.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Topics: Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Preoperative Care; Pulmonary Disease, Chronic Obstructive; Purines; Sildenafil Citrate; Sulfones

Pulmonary hypertension (PH) is a factor of poor prognosis in the postoperative period of heart transplant (HT) and thus, the study of the degree of reversibility to vasodilators is mandatory during the preoperative assessment.. To evaluate the pulmonary and systemic hemodynamic effects of sildenafil as a vasodilator during the PH reversibility test in patients that are candidates to HT.. Patients awaiting HT were submitted to the measurement of systemic and pulmonary hemodynamic variables before and after the administration of a single sublingual dose of 100 mg of sildenafil during right heart catheterization.. Fourteen patients (age: 47+/-12 years, 71.4% men) with advanced heart failure Ejection Fraction (EF) 25 +/- 7%, Functional Class (FC - NYHA) FC III - 6 and FC IV - 8, were evaluated in this study. The acute administration of sildenafil showed to be effective in decreasing the systolic (62.4 +/- 12.1 vs 51.5 +/- 9.6 mmHg, CI=95%, p<0.05) and mean (40.7 +/- 7.3 vs 33.8 +/- 7.6 mmHg, CI=95%, p <0.05) pressures of the pulmonary artery. There was also a significant decrease in the pulmonary (4.2 +/- 3 vs 2.0 +/- 0.9 uWood, CI=95%, p<0.05) and systemic vascular resistance (22.9 +/- 6.8 vs 18.6 +/- 4.1 Wood, CI=95%, p<0.05), associated to an increase in the cardiac output (3.28 +/- 0.79 vs 4.12 +/-1.12 uWood, CI=95%, p<0.05) without, however, significantly interfering in the systemic arterial pressure (87.8 +/- 8.2 vs 83.6 +/- 9.1 mmHg, CI=95%, p=0.3).. The sublingual administration of sildenafil is an effective and safe alternative as a vasodilator during the PH reversibility test in patients with heart failure and awaiting a HT.

Topics: Administration, Sublingual; Female; Heart Failure; Heart Rate; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is often treated with endothelin (ET) receptor blockade or phosphodiesterase-5 (PDE5) inhibition. Little is known about the specific effects on right ventricular (RV) function and metabolism. We determined the effects of single and combination treatment with Bosentan [an ET type A (ET(A))/type B (ET(B)) receptor blocker] and Sildenafil (a PDE5 inhibitor) on RV function and oxidative metabolism in monocrotaline (MCT)-induced PAH. Fourteen days after MCT injection, male Wistar rats were orally treated for 10 days with Bosentan, Sildenafil, or both. RV catheterization and echocardiography showed that MCT clearly induced PAH. This was evidenced by increased RV systolic pressure, reduced cardiac output, increased pulmonary vascular resistance (PVR), and reduced RV fractional shortening. Quantitative histochemistry showed marked RV hypertrophy and fibrosis. Monotreatment with Bosentan or Sildenafil had no effect on RV systolic pressure or cardiac function, but RV fibrosis was reduced and RV capillarization increased. Combination treatment did not reduce RV systolic pressure, but significantly lowered PVR, and normalized cardiac output, RV fractional shortening, and fibrosis. Only combination treatment increased the mitochondrial capacity of the RV, as reflected by increased succinate dehydrogenase and cytochrome c oxidase activities, associated with an activation of PKG, as indicated by increased VASP phosphorylation. Moreover, significant interactions were found between Bosentan and Sildenafil on PVR, cardiac output, RV contractility, PKG activity, and mitochondrial capacity. These data indicate that the combination of Bosentan and Sildenafil may beneficially contribute to RV adaptation in PAH, not only by reducing PVR but also by acting on the mitochondria in the heart.

Topics: Animals; Body Weight; Bosentan; Capillaries; Cyclic GMP-Dependent Protein Kinases; Diffusion; Endothelin Receptor Antagonists; Fibrosis; Hemodynamics; Hypertension, Pulmonary; In Vitro Techniques; Male; Mitochondria, Heart; Myocardial Contraction; Myocardium; Myocytes, Cardiac; Myoglobin; Organ Size; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfonamides; Sulfones; Ultrasonography

Chest pain is a common complaint in patients with pulmonary arterial hypertension (PAH). Left main coronary artery (LMCA) compression by an enlarged pulmonary artery trunk (PAT) has been associated with angina, but appropriate diagnostic and treatment approaches remain poorly defined. We present two cases of angina caused by LMCA compression from an enlarged pulmonary artery, one of which also presented with new, severe left ventricular systolic dysfunction attributed to myocardial ischemia. Diagnosis of LMCA stenosis was made via coronary angiography followed by computed tomography-gated coronary angiography (CT-CA), which confirmed pulmonary artery enlargement as the source of extrinsic compression. Restoring LMCA patency with percutaneous intervention and/or aggressive treatment of pulmonary hypertension led to significant improvement in angina, cardiac function and quality of life. Given the negative impact on cardiac function, prompt diagnosis and treatment of extrinsic LMCA compression should be considered a priority.

Topics: Adult; Angina Pectoris; Angioplasty, Balloon, Coronary; Coronary Angiography; Coronary Stenosis; Echocardiography; Epoprostenol; Humans; Hypertension, Pulmonary; Male; Middle Aged; Myocardial Ischemia; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Stents; Sulfones; Tomography, X-Ray Computed; Ultrasonography, Interventional; Vasodilator Agents

Topics: Adenoidectomy; Anesthetics, Intravenous; Anticoagulants; Antihypertensive Agents; Bosentan; Child; Down Syndrome; Elective Surgical Procedures; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Intubation, Intratracheal; Piperazines; Piperidines; Propofol; Purines; Remifentanil; Severity of Illness Index; Sildenafil Citrate; Sleep Apnea, Obstructive; Sulfonamides; Sulfones; Tonsillectomy; Treatment Outcome; Vasodilator Agents; Warfarin

A 23-year-old woman with multiple sclerosis developed respiratory symptoms 3 years after introduction of interferon beta-1b. The diagnosis of pulmonary arterial hypertension (PAH) was established. The patient partially responded to sildenafil and bosetan treatment. This is the first report of PAH, associated with interferon beta therapy. As shown in experimental models, interferon treatment can induce PAH by stimulation of thromboxane cascade and secretion of various inflammatory mediators.

Topics: Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Immunologic Factors; Interferon beta-1b; Interferon-beta; Multiple Sclerosis; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Young Adult

Pulmonary arterial hypertension (PAH) is a life-threatening disease of the pulmonary arterioles, which, in the absence of effective therapy, progresses rapidly to right heart failure and death. Opening of a patent foramen ovale (PFO) is common in patients with severe pulmonary hypertension (PH), resulting in resistive hypoxemia. We report the case of a 40-year-old woman with idiopathic pulmonary hypertension (iPAH) in New York Heart Association (NYHA) class III to IV, who was admitted in the intensive care unit with hemodynamic compromise and severe hypoxemia due to right-to-left shunt throughout a PFO. Combination therapy initially with inhaled iloprost and sildenafil, and then addition of an endothelin A receptor-selective antagonist (sitaxsentan), resulted in impressive improvement in oxygenation with reversal of the right-to-left shunt and marked improvement in functional class of the patient.

Topics: Adult; Antihypertensive Agents; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Epoprostenol; Female; Foramen Ovale, Patent; Humans; Hypertension, Pulmonary; Iloprost; Isoxazoles; Piperazines; Purines; Sildenafil Citrate; Sulfones; Thiophenes; Treatment Outcome; Vasodilator Agents

The present authors report the case of an adult with chronic granulomatous disease who developed an unusual lung fibrosis associated with severe pulmonary hypertension. Histological analysis of a lung biopsy showed a diffuse infiltration with pigmented macrophages without granulomas, which particularly involved the pulmonary arterial and venular walls. Clinical and histological findings were suggestive of pulmonary veno-occlusive disease. Such a clinical association has not been previously described in the literature and might be due to the persistent expression of gp91phox at a very low level. In conclusion, the present case report illustrates a novel manifestation of chronic granulomatous disease.

Topics: Adult; Biopsy; Bronchoalveolar Lavage; Bronchoscopy; Diagnosis, Differential; Diuretics; Furosemide; Granulomatous Disease, Chronic; Hemodynamics; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Respiratory Function Tests; Sildenafil Citrate; Smoking; Sulfones; Tomography, X-Ray Computed

In this column, the authors highlight a medication incident that occurred with Revatio (sildenafil), along with the learnings and recommendations from a previously published ISMP Canada Safety Bulletin. It is well-known to health care practitioners that use of nitroglycerin therapy is contraindicated in patients taking sildenafil (commonly known as Viagra). Many health care practitioners may be unaware that sildenafil is also marketed under the brand name Revatio for treatment of primary pulmonary hypertension or pulmonary hypertension secondary to connective tissue disease. The following incident signals the need to heighten the awareness that Revatio is a brand name for sildenafil.

Topics: Canada; Contraindications; Drug Interactions; Female; Humans; Hypertension, Pulmonary; Medication Errors; Medication Systems; Middle Aged; Myocardial Ischemia; Nitroglycerin; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a rare but life-threatening condition that is characterized by progressive elevation of pulmonary artery pressure and pulmonary vascular resistance, leading to right-sided heart failure and frequently death. Orally administered agents used for the treatment of symptomatic, moderate-to-severe PAH include sildenafil and the endothelin (ET) receptor antagonists (ERAs), bosentan and sitaxentan (sitaxsentan). Ambrisentan is a new oral ET(A) receptor-selective ERA, with higher ET receptor affinity than bosentan. Placebo-controlled, randomized clinical trials (RCTs) have demonstrated that ambrisentan (5 or 10 mg/day) is safe and effective. To provide health economic data on the multiple oral PAH therapies currently available, a population-based cost-minimization analysis (CMA) was conducted for Canada.. The primary requirement for a CMA is that all clinical outcomes be equivalent between comparator treatments. To provide such supporting data, a literature search was conducted for RCTs of oral agents used to treat symptomatic PAH. This was followed by application of direct and indirect statistical methods to support the hypothesis of clinical equivalence between the oral agents. Estimates for PAH prevalence, incidence and death rates were then used to build a population-based CMA model. The base-case analysis considered costs for drug therapy, outpatient pharmacy costs, medical consultations and visits, laboratory and diagnostic procedures and other healthcare-related resources. In addition, costs for secondary pharmacotherapy in cases where the primary agent had to be discontinued because of adverse effects were also included. The time horizon for evaluating pharmacotherapy was 3 years, all costs were in 2008 Canadian dollars ($Can) and the costs were discounted at a rate of 3% annually. The study perspective was the Canadian healthcare system.. There were no double-blind RCTs comparing ambrisentan with any of the other oral agents. Therefore, an indirect comparison of placebo-controlled trials of PAH drugs had to be used to support the clinical equivalence. This included a calculation of standardized mean differences (SMD) between agents (vs placebo) and a meta-regression analysis on the primary and secondary trial endpoints. Keeping in mind the caveats associated with indirect trial comparisons, the data suggested similar clinical efficacy over 12-16 weeks between agents, as indicated by the identical magnitude of the SMD between the active agent and placebo and the non-significant differences between drugs as determined by the meta-regression analysis. The population-based model projected that the number of PAH patients clinically suitable for these drugs in Canada would be 931 in the first full-budget year (i.e. 2009) with an increase to 1114 by the third full year. The CMA revealed the following rank order of the least to most costly agent; sildenafil, ambrisentan, sitaxentan and bosentan. Sildenafil was the least costly, primarily because of the lower daily drug-acquisition cost. Of the three ERAs, ambrisentan would be associated with annual cost savings of $Can3.4 and $Can5.6 million when used as an alternative to sitaxentan or bosentan, respectively.. Ambrisentan is less costly than other available ERAs, including bosentan and sitaxentan, but is more costly than sildenafil. In PAH patients in whom an ERA is the preferred agent, ambrisentan may be the drug of choice because of its economic advantages and improved safety profile.

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Canada; Costs and Cost Analysis; Drug Costs; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Piperazines; Placebos; Purines; Pyridazines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Treatment Outcome

Topics: Administration, Inhalation; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventilator Weaning

There are several possible pathophysiological links between the development of pulmonary hypertension and myelofibrosis with myeloid metaplasia. We report a woman with myelofibrosis and myeloid metaplasia who presented with dyspnea and massive, painful splenomegaly. Right heart catheterization evidenced pulmonary hypertension. Her management consisted of splenic irradiation associated to sildenafil. Dyspnea in patients with myelofibrosis and myeloid metaplasia can be secondary to pulmonary hypertension and conversely the differential diagnosis of pulmonary hypertension should include a myeloproliferative syndrome.

Topics: Anticoagulants; Cardiac Catheterization; Diagnosis, Differential; Diuretics; Drug Therapy, Combination; Dyspnea; Echocardiography, Doppler; Electrocardiography; Female; Fibrinolytic Agents; Furosemide; Heparin, Low-Molecular-Weight; Humans; Hypertension, Pulmonary; Middle Aged; Myeloproliferative Disorders; Palliative Care; Phosphodiesterase Inhibitors; Piperazines; Primary Myelofibrosis; Purines; Sildenafil Citrate; Splenic Diseases; Splenomegaly; Sulfones; Vasodilator Agents

The available therapies and prognosis of idiopathic pulmonary fibrosis remain relatively poor, and concurrent pulmonary hypertension further increases the risk of death and complications after lung transplantation. Limited data exist for the treatment of pulmonary hypertension associated with idiopathic pulmonary fibrosis. We describe a case where intravenous treprostinil was used to bridge an elderly patient with idiopathic pulmonary fibrosis with severe pulmonary hypertension to successful single-lung transplantation.

Topics: Aged; Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Lung Transplantation; Piperazines; Purines; Sildenafil Citrate; Spirometry; Sulfones; Tomography, X-Ray Computed; Treatment Outcome; Vasodilator Agents

Topics: Administration, Inhalation; Algorithms; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Lung Transplantation; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary Hypertension is a serious complication of sickle cell disease (SCD), with high morbidity and mortality. Endothelin (ET)-1, a potent vasoconstrictor elevated in SCD, acts through the ET receptors (ETR), ETR-A and ETR-B. Bosentan and ambrisentan are ETR blockers used in primary pulmonary hypertension. We report on the use of ETR blocking agents in a cohort of 14 high-risk SCD adult patients with pulmonary hypertension. Patients underwent right heart catheterization, 6-min walk test, echocardiogram, physical examination and blood work-up before starting ETR blockers. Eight patients received ETR blockers as initial therapy; six patients were already taking sildenafil. Over more than 6 months of therapy, sequential measurements of 6-min walk distance increased significantly (baseline 357 +/- 22 to 398 +/- 18 m at 5-6 months, P < 0.05). Downward trends were observed for amino-terminal brain natriuretic peptide and tricuspid regurgitant velocity. Pulmonary artery mean pressures decreased in three patients that had repeat right heart catheterization (44-38 mmHg). Adverse events were: increased serum alanine aminotransferase (2), peripheral oedema (4), rash (1), headache (3), decreased haemoglobin (2). Therapy was stopped in two patients who were switched then to the other ETR blocker agent. These data suggest preliminary evidence for the benefit of bosentan and ambrisentan in pulmonary hypertension in SCD.

Topics: Adult; Anemia, Sickle Cell; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Drug Evaluation; Drug Therapy, Combination; Endothelin Receptor Antagonists; Exercise Test; Humans; Hypertension, Pulmonary; Middle Aged; Phenylpropionates; Piperazines; Purines; Pyridazines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Statins have been proposed to be a potential treatment for pulmonary arterial hypertension. If introduced into clinical practice, the statin would have to be used in conjunction with established therapy. We investigated the effects of combining simvastatin with a phosphodiesterase type-5 inhibitor, sildenafil, in the rat model of hypoxia-induced pulmonary hypertension. Rats were allocated to either: 1) a prevention protocol, to receive simvastatin 20 mg x kg(-1) x day(-1) by intraperitoneal injection or sildenafil 75 mg x kg(-1) x day(-1) orally or the combination (or vehicle) for 2 weeks beginning at the start of exposure to hypoxia (10% inspired oxygen); or 2) a treatment protocol, where the same agents were administered in the last 2 weeks of a 4-week period of hypoxia. In both protocols, the combination of sildenafil and simvastatin lowered pulmonary artery pressure and produced a significantly greater reduction in right ventricular hypertrophy and pulmonary vascular muscularisation than either drug alone. Moreover, the combination augmented significantly endothelial nitric oxide synthase expression and cGMP levels in the lung and right ventricle above that produced by either drug independently and resulted in greater inhibition of RhoA activity. These data suggest that simvastatin can be usefully combined with sildenafil in the treatment of pulmonary arterial hypertension to achieve greater therapeutic benefit.

Topics: Animals; Cyclic GMP; Disease Models, Animal; Drug Therapy, Combination; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Male; Nitric Oxide Synthase Type III; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Circulation; Purines; Rats; Rats, Sprague-Dawley; rhoA GTP-Binding Protein; Signal Transduction; Sildenafil Citrate; Simvastatin; Sulfones

Topics: Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Respiration, Artificial; Retrospective Studies; Scotland; Sildenafil Citrate; Sulfones; Treatment Outcome

Severe pulmonary hypertension is a progressive disease which leads to limitations of functional status and poor survival. We evaluated efficacy and safety of a short (3 months) and a long term (12 months) sildenafil treatment in patients with severe pulmonary hypertension. We treated 12 patients with pulmonary hypertension with oral sildenafil. Patients were followed at three time points, at baseline, and after 3 and 12 months of treatment. Primary end point was improvement in functional exercise capacity assesed by 6-minute walk test, and secondary end points were changes in right ventricle hemodynamics. We found significant improvement in 6-minute walk test distance from 357 +/- 193 m at baseline to 431 +/- 179 m after three months and further improvement to 501 +/- 159 m after 12 months (p < 0.01); decrease in right ventricule pressure from 107 +/- 42 mmHg at baseline to 87 +/- 32 mmHg after 12 months (p < 0.01); and, decrease in right ventricule diameter from 3.2 +/- 1.1 cm to 2.76 +/- 0.86 cm after twelve months (p < 0.01). Drug-related adverse events were mild and transient in our group of patients. Long-term (12 months) sildenafil treatment is effective and safe in our patients with idiopathic and chronic thrombo-embolic pulmonary hypertension.

Topics: Adult; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Walking

Topics: Bosentan; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged; Piperazines; Pulmonary Edema; Pulmonary Medicine; Pulmonary Veno-Occlusive Disease; Purines; Risk; Sildenafil Citrate; Sulfonamides; Sulfones; Tomography, X-Ray Computed; Treatment Outcome

The aim of this study was to assess the effect of tadalafil (0.5, 2.5, and 10 mg/kg per day) on the progression of pulmonary arterial hypertension (PAH) in early treatment and on the survival rate in late treatment on the monocrotaline (MCT)-induced PAH rat model. Tadalafil was administered once daily to rats for 3 weeks from the day of MCT-injection or 21 days after the injection. With early treatment, tadalafil at 10 mg/kg per day prevented the development of PAH by maintaining mean pulmonary artery pressure within the normal range and attenuated right ventricular hypertrophy. With late treatment, tadalafil tended to increase the partial pressure of oxygen in arterial blood and dose-dependently improved the survival rate by 55%, 60%, and 70% at 0.5, 2.5, and 10 mg/kg per day, respectively, versus 40% in the MCT-control group. Both early and late treatments with tadalafil were associated with elevated lung cyclic guanosine monophosphate (cGMP). These results suggest that tadalafil relaxes pulmonary arteries by elevating cGMP in lungs and extend survival time by improving pulmonary hemodynamics even when treatment occurs in the late phase of PAH. Thus, it is expected that tadalafil may be an effective, once-daily treatment option in humans with PAH.

Topics: Animals; Blood Gas Analysis; Carbolines; Cyclic GMP; Disease Progression; Dose-Response Relationship, Drug; Hemodynamics; Hydrogen-Ion Concentration; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Organ Size; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Poisons; Pulmonary Circulation; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Survival; Tadalafil

Sildenafil, a potent phosphodiesterase type 5 (PDE5) inhibitor, has been proposed as a treatment for pulmonary arterial hypertension (PAH). The mechanism of its anti-proliferative effect on pulmonary artery smooth muscle cells (PASMC) is unclear. Nuclear translocation of nuclear factor of activated T-cells (NFAT) is thought to be involved in PASMC proliferation and PAH. Increase in cytosolic free [Ca2+] ([Ca2+]i) is a prerequisite for NFAT nuclear translocation. Elevated [Ca2+]i in PASMC of PAH patients has been demonstrated through up-regulation of store-operated Ca2+ channels (SOC) which is encoded by the transient receptor potential (TRP) channel protein. Thus we investigated if: 1) up-regulation of TRPC1 channel expression which induces enhancement of SOC-mediated Ca2+ influx and increase in [Ca2+]i is involved in hypoxia-induced PASMC proliferation; 2) hypoxia-induced promotion of [Ca2+]i leads to nuclear translocation of NFAT and regulates PASMC proliferation and TRPC1 expression; 3) the anti-proliferative effect of sildenafil is mediated by inhibition of this SOC/Ca2+/NFAT pathway.. Human PASMC were cultured under hypoxia (3% O2) with or without sildenafil treatment for 72 h. Cell number and cell viability were determined with a hemocytometer and MTT assay respectively. [Ca2+]i was measured with a dynamic digital Ca2+ imaging system by loading PASMC with fura 2-AM. TRPC1 mRNA and protein level were detected by RT-PCR and Western blotting respectively. Nuclear translocation of NFAT was determined by immunofluoresence microscopy.. Hypoxia induced PASMC proliferation with increases in basal [Ca2+]i and Ca2+ entry via SOC (SOCE). These were accompanied by up-regulation of TRPC1 gene and protein expression in PASMC. NFAT nuclear translocation was significantly enhanced by hypoxia, which was dependent on SOCE and sensitive to SOC inhibitor SKF96365 (SKF), as well as cGMP analogue, 8-brom-cGMP. Hypoxia-induced PASMC proliferation and TRPC1 up-regulation were inhibited by SKF and NFAT blocker (VIVIT and Cyclosporin A). Sildenafil treatment ameliorated hypoxia-induced PASMC proliferation and attenuated hypoxia-induced enhancement of basal [Ca2+]i, SOCE, up-regulation of TRPC1 expression, and NFAT nuclear translocation.. The SOC/Ca2+/NFAT pathway is, at least in part, a downstream mediator for the anti-proliferative effect of sildenafil, and may have therapeutic potential for PAH treatment.

Topics: Calcium; Calcium Channels; Cell Proliferation; Cell Survival; Cells, Cultured; Humans; Hypertension, Pulmonary; Hypoxia; Myocytes, Smooth Muscle; NFATC Transcription Factors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; TRPC Cation Channels

Severe pulmonary sarcoidosis is often complicated by pulmonary hypertension (PH) caused by different pathophysiological mechanisms.. To assess the acute vasoresponsiveness in patients with sarcoidosis and PH and the relation to the therapeutic effect of sildenafil.. A retrospective chart review of 25 patients with recalcitrant pulmonary sarcoidosis being evaluated for lung transplantation at our centre. Haemodynamics were evaluated by right heart catheterisation in 24 patients of whom 19 had PH. Eight of the 19 patients received vasodilator challenge with inhaled nitric oxide (iNO).. The study group of eight patients (seven men) had a median age of 51 years (range 38 years-58 years). During iNO we observed a reduction in all patients' mean pulmonary arterial pressure (MPAP) of median 9 mmHg (range 1 mmHg-20 mmHg) (P = 0.01) and in all patients' pulmonary vascular resistance of median 2.0 Wood Units (0.7 Wood Units-5.8 Wood Units) (P = 0.01). Acute vasoresponsiveness defined as reduction in MPAP of >or=10 mmHg to a MPAP of

Topics: Administration, Inhalation; Administration, Oral; Adult; Bronchodilator Agents; Chi-Square Distribution; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Piperazines; Purines; Respiratory Function Tests; Retrospective Studies; Sarcoidosis; Sildenafil Citrate; Statistics, Nonparametric; Sulfones; Treatment Outcome; Vasodilator Agents

Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression.. We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34+, CD34+/AC133+, CD34+/KDR+, and CD34+/AC133+/KDR+ progenitor cells was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies.. Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.

Topics: AC133 Antigen; Aged; Antigens, CD; Antigens, CD34; Arginine; Cells, Cultured; Cyclic GMP; Down Syndrome; Eisenmenger Complex; Endothelium, Vascular; Exercise; Female; Flow Cytometry; Glycoproteins; Hematopoietic Stem Cells; Humans; Hypertension, Pulmonary; Inflammation Mediators; Male; Middle Aged; Natriuretic Peptide, Brain; Peptides; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Stem Cells; Sulfones; Vascular Endothelial Growth Factor Receptor-2; Vasodilator Agents

Chronic lung disease (CLD) is often complicated by chronic pulmonary vascular changes and pulmonary hypertension (PH) in young children. Current therapies for severe PH in such patients, including oxygen, inhaled nitric oxide, and parenteral prostacyclin, are often suboptimal, cumbersome, and expensive. Recently, oral endothelin receptor blockers and phosphodiesterase-5 inhibitors have been used successfully to control and reverse pulmonary vascular disease in idiopathic PH, but the use and efficacy of these agents in pediatric CLD have not been previously reported. We report a series of six children with CLD and severe PH treated with bosentan (six of six) and sildenafil (four of six). Vascular reactivity was assessed by cardiac catheterization prior to and after 6 months of therapy. Serial echocardiography was also used to assess response. Patients have been treated for 2.1-2.9 years (mean, 2.53 years). Response to therapy has included improvement in oxygenation, symptoms, echocardiographic parameters, and hemodynamics by cardiac catheterization. Transiently elevated liver enzymes were noted associated with viral respiratory infections in two subjects; no other adverse effects were noted. Three patients with large cardiac right-to-left shunts prior to therapy had subsequent shunt reversal, two of whom underwent shunt closure later. Oral therapy with bosentan alone or in combination with sildenafil improves PH in patients with CLD over a period of 3-4 years.

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Bronchopulmonary Dysplasia; Cardiac Catheterization; Child; Child, Preschool; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Topics: Chronic Disease; Endarterectomy; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Embolism; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil) are selective pulmonary vasodilators in patients with pulmonary arterial hypertension. The mechanism(s) underlying this specificity remains unclear, but studies in genetically modified animals suggest it might be dependent on natriuretic peptide bioactivity.. We explored the interaction between PDE5 inhibitors and the natriuretic peptide system to elucidate the (patho)physiological relationship between these two cyclic GMP (cGMP)-regulating systems and potential of a combination therapy exploiting these cooperative pathways.. Pharmacological evaluation of vascular reactivity was conducted in rat isolated conduit and resistance vessels from the pulmonary and systemic circulation in vitro, and in anesthetized mice in vivo. Parallel studies were undertaken in an animal model of hypoxia-induced pulmonary hypertension (PH).. Sildenafil augments vasodilatation to nitric oxide (NO) in pulmonary and systemic conduit and resistance arteries, whereas identical vasorelaxant responses to atrial natriuretic peptide (ANP) are enhanced only in pulmonary vessels. This differential activity is mirrored in vivo where sildenafil increases the hypotensive actions of ANP in the pulmonary, but not systemic, vasculature. In hypoxia-induced PH, combination of sildenafil plus the neutral endopeptidase (NEP) inhibitor ecadotril (which increases endogenous natriuretic peptide levels) acts synergistically, in a cGMP-dependent manner, to reduce many indices of disease severity without significantly affecting systemic blood pressure.. These data demonstrate that PDE5 is a key regulator of cGMP-mediated vasodilation by ANP in the pulmonary, but not systemic, vasculature, thereby explaining the pulmonary selectivity of PDE5 inhibitors. Exploitation of this mechanism (i.e., PDE5 and neutral endopeptidase inhibition) represents a novel, orally active combination therapy for pulmonary arterial hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Hypertension, Pulmonary; Male; Neprilysin; Piperazines; Protease Inhibitors; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Thiorphan; Treatment Outcome; Vascular Resistance; Vasodilation; Vasodilator Agents

Acute pulmonary embolism produces acute pulmonary hypertension, which can be counteracted by activating the nitric oxide-cyclic guanosine 3',5'-monophosphate (cGMP) pathway. While previous studies have shown that sildenafil (an inhibitor of cGMP-specific phosphodiesterase type 5) or nitrite (a storage molecule for nitric oxide) produces beneficial effects during acute pulmonary embolism, no previous study has examined whether the combination of these drugs can produce additive effects. Here, we expand previous findings and examine whether sildenafil enhances the beneficial haemodynamic effects produced by a low-dose infusion of nitrite in a dog model of acute pulmonary embolism. Haemodynamic and arterial blood gas evaluations were performed in non-embolized dogs treated with saline (n = 4), and in embolized dogs (intravenous injections of microspheres) that received nitrite (6.75 micromol/kg intravenously over 15 min. followed by 0.28 micromol/kg/min.) and sildenafil (0.25 mg/kg over 30 min.; n = 8), or nitrite followed by saline (n = 8), or saline followed by sildenafil (n = 7), or only saline (n = 8). Plasma thiobarbituric acid-reactive substances (TBARS) concentrations were determined using a fluorometric method. Acute pulmonary embolism increased pulmonary artery pressure by approximately 24 mmHg. While the infusion of nitrite or sildenafil infusions reversed this increase by approximately 42% (both P < 0.05), the combined infusion of both drugs reversed this increase by approximately 58% (P < 0.05). Similar effects were seen on the pulmonary vascular resistance index. Nitrite or sildenafil alone produced no significant hypotension. However, the combined infusion of both drugs caused transient hypotension (P < 0.05). Both drugs, either alone or combined, blunted the increase in TBARS concentrations caused by acute pulmonary embolism (all P < 0.05). These results suggest that sildenafil improves the beneficial haemodynamic effects of nitrite during acute pulmonary embolism.

Topics: Acute Disease; Animals; Blood Pressure; Disease Models, Animal; Dogs; Drug Synergism; Drug Therapy, Combination; Female; Hemodynamics; Hypertension, Pulmonary; Infusions, Intravenous; Lipid Peroxides; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Respiration; Sildenafil Citrate; Sodium Nitrite; Sulfones; Vascular Resistance

Procedures using cardiopulmonary bypass (CPB) and aortic cross-clamping are associated with a variable degree of ischemia/reperfusion of the lungs, leading to acute pulmonary hypertension (PHT). The purpose of this study was to compare the effects of the sildenafil analog (UK343-664), a phosphodiesterase type V(PDEV) inhibitor, with milrinone, a PDE type III inhibitor, in a porcine model of acute PHT following CPB. After the pigs were anesthetized, pressure-tipped catheters were placed in the right ventricle and carotid and pulmonary arteries. Cardiac output was measured with an ultrasound probe on the ascending aorta. After heparinization and placement of aortic and right atrial cannulae, non-pulsatile CPB was instituted and cardioplegia administered following aortic cross-clamping. After 30 minutes, the clamp was removed and the animals re-warmed and separated from CPB in sinus rhythm. The animals were randomized to 3 groups, and 16 animals were studied to completion: milrinone (n=5) 50 microg/kg; sildenafil-analog (n=5) 500 microg/kg; and normal saline (NS) (n=6). Hemodynamic data were collected at baseline pre-CPB and, following termination of CPB, at baseline, 5, 10 and 30 minutes after administration of the drug. Pulmonary hypertension was present in all groups following CPB. After administration of the drugs, mean pulmonary artery pressure decreased in all 3 groups; however, only in the sildenafil-analog group did pulmonary vascular resistance(PVR) decrease by 35%, from 820 to 433 dynes . cm . sec(-5) at 5 minutes (p<0.05), and continued to be decreased at 10 minutes by 26% (P<0.05). Pulmonary selectivity was demonstrated with sildenafil-analog, because there were no similar changes in systemic vascular resistance(SVR) and no significant changes in systemic hemodynamics. Sildenafil-analog, a PDEV inhibitor, shows a promising role for managing the PVR increases that occur following CPB.

Topics: Acute Disease; Animals; Blood Pressure; Cardiopulmonary Bypass; Hypertension, Pulmonary; Milrinone; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidinones; Reperfusion Injury; Sildenafil Citrate; Sulfones; Sus scrofa; Vascular Resistance

Increased pulmonary vascular resistance causing pulmonary artery hypertension is a major problem in the treatment of congenital diaphragmatic hernia with a strong association to mortality. We here report a patient with intractable pulmonary hypertension at 4 weeks of age unresponsive to conventional treatment. After administration of the platelet-derived growth factor (PDGF) receptor antagonist imatinib, pulmonary artery pressure gradually decreased to acceptable levels and the patient's clinical condition gradually improved.

Topics: Benzamides; Bosentan; Combined Modality Therapy; Continuous Positive Airway Pressure; Diuretics; Enteral Nutrition; Extracorporeal Membrane Oxygenation; Heart Failure; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Hypoxia; Iloprost; Imatinib Mesylate; Infant, Newborn; Male; Nitric Oxide; Piperazines; Protein Kinase Inhibitors; Purines; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Sildenafil Citrate; Sulfonamides; Sulfones

Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Double-Blind Method; Drug Therapy, Combination; Dyspepsia; Epoprostenol; Female; Headache; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Intravenous; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Walking

Sustained pressure overload of the right ventricle (RV) causes RV hypertrophy and failure. Cyclic-GMP has previously been shown to modulate left ventricular hypertrophy.. To evaluate the effects of sildenafil, a phosphodiesterase-5 (PDE5) inhibitor elevating c-GMP, on myocardial hypertrophy and function in rats with RV hypertrophy.. Rats were pulmonary trunk banded (PTB) and randomized to receive sildenafil (SIL) or vehicle (VEC) for three (n=14) and nine weeks (n=18). In addition, rats with established RV hypertrophy were randomized to SIL or VEC (n=17) three weeks after PTB. Right ventricular function was evaluated by echocardiography and RV hypertrophy by histology and RV weight.. Sildenafil failed to inhibit the development of RV hypertrophy when given for both 3 and 9 weeks. On the contrary, sildenafil increased RV hypertrophy after 3 weeks (RV/bodyweight: SIL 0.099+/-0.016 vs. VEC 0.081+/-0.011; p<0.05) and total heart weight after 9 weeks (SIL 1.05+/-0.10 vs. VEC 0.93+/-0.08 g; p<0.05). Sildenafil also failed to reverse established RV hypertrophy, but significantly improved RV myocardial function as measured by Tricuspid Annular Plane Systolic Excursion (TAPSE: SIL 1.85+/-0.027 vs. VEC 1.39+/-0.037 mm; p<0.05).. PDE5 inhibition by sildenafil failed to prevent or reverse RV hypertrophy in rats operated by pulmonary trunk banding. It actually increased RV hypertrophy and improved RV contractile function when given to rats with established RV hypertrophy.

Topics: Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Echocardiography; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Ventricular Function, Right

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE-5). Its chronic administration has been shown to improve exercise capacity, World Health Organization functional class, and haemodynamics in patients with symptomatic pulmonary arterial hypertension (PAH). There is however, no data describing the clinical consequences of sudden cessation of sildenafil treatment. In this series, 9 patients with NYHA Class II-IV PAH who were stable on 2 months of sildenafil monotherapy, had their sildenafil ceased to accommodate a 2-week washout period, required for enrollment in research involving an endothelin receptor antagonist. Six minute walk distance (SMWD) and clinical assessments were performed before cessation of sildenafil, and again 2 weeks later. Over the course of this 2-week washout period, 6 of the 9 patients reported increased breathlessness and fatigue, 1 of these was hospitalized with worsening right heart failure. The SMWD fell in 6 patients, with falls of greater than 100 m recorded in 4 patients. This was accompanied by a worsening of NYHA Class from 2.5 +/- 0.2 to 3.1 +/- 0.1 (mean +/- SEM, p = 0.01). These data indicate that sudden cessation of sildenafil monotherapy, in patients with PAH, carries with it a significant and unpredictable risk of rapid clinical deterioration. We recommend that if sildenafil needs to be ceased, it would be more prudent to consider concurrent vasodilator therapy before the gradual cessation of sildenafil.

Topics: Adult; Disease Progression; Drug Administration Schedule; Exercise Tolerance; Fatigue; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Respiration; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents; Withholding Treatment

Topics: Heart Transplantation; Heart Ventricles; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Preoperative Care; Purines; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Right; Ventricular Function

Topics: Adolescent; Adult; Aged; Carbolines; Exercise Tolerance; Female; Half-Life; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil

Sildenafil has been shown to be effective in the treatment of pulmonary hypertension, and has favourable effects on endothelial function. Our hypothesis is that a part of the beneficial effects of sildenafil in patients with pulmonary hypertension is due to the improvement of the endothelial function.. Nine patients (seven females, age 67+/-9 years) with thromboembolic pulmonary hypertension were treated with sildenafil, at a mean dose of 150+/-75 mg/die. At baseline and after 6 months all patients underwent: right-heart catheterization, 6-min walking distance, and a study of endothelial function, including the measure of the flow-mediated vasodilation of the brachial artery, and the dosage of plasma levels of endothelin-1 and von Willebrand factor.. During follow-up we found a significant reduction of mean pulmonary artery pressure and arteriolar resistances. Accordingly, the functional capacity improved (an average of+37 m). Sildenafil improved endothelial-dependent vasodilation and reduced plasma concentrations of endothelin-1 (from 4.5+/-0.6 to 3.1+/-0.7 pg/mL; p<0.0001) and von Willebrand factor (from 183.1+/-10.1 to 149.1+/-17.6 mU/mL; p<0.0001).. Improvement of the endothelial function may represents one of the mechanisms able to explain the favourable effects sildenafil has shown in patients with pulmonary hypertension.

Topics: Aged; Brachial Artery; Chronic Disease; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilation

The availability of inhibitors of cGMP-specific phosphodiesterase 5 (PDE 5), such as sildenafil, has revolutionized the treatment of pulmonary hypertension (PH). Sildenafil may exert its protective effects in a mechanism-based fashion by targeting a pathophysiologically attenuated NO-cGMP signaling pathway. To elucidate this, we analyzed changes in the pulmonary expression and activity of key enzymes of NO-cGMP signaling as well as the functional pulmonary responses to sildenafil in the 5 or 21 day hypoxia mouse model of PH. Surprisingly, we found doubled NO synthase (NOS) II and III levels, no evidence for attenuated NO bioavailability as evidenced by the nitrosative/oxidative stress marker protein nitro tyrosine, and no changes in the expression and activity of the NO receptor, soluble guanylyl cyclase (sGC). PDE 5 was either unchanged at day 5 or, after 21 days of hypoxia, even significantly decreased along with unchanged activity. Biochemically, these changes were mirrored by increased cGMP spillover into the lung perfusate and cGMP-dependent phosphorylation of the vasodilator-stimulated phosphoprotein, VASP. Sildenafil further augmented cGMP and phospho-VASP levels in lungs of mice exposed for 5 or 21 days and decreased pulmonary arterial pressure in mice after 5 days but not 21 days of hypoxia. In conclusion, NO-cGMP signaling is compensatorily up-regulated in the hypoxic mouse model of PH, and sildenafil further augments this pathway to functionally alleviate pulmonary vasoconstriction.

Topics: Animals; Cyclic GMP; Hypertension, Pulmonary; Hypoxia; Lung; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphorylation; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Up-Regulation

Pulmonary hypertension frequently complicates interstitial lung disease, where it is associated with a high mortality. Patients with this dual diagnosis often fare worse than those with pulmonary arterial hypertension (PAH) alone and respond poorly to standard PAH therapy, often dying of right ventricular (RV) failure. We hypothesize that nitric oxide synthase (NOS) uncoupling is important in the pathogenesis of interstitial lung disease-associated pulmonary hypertension, and this process can be abrogated by phosphodiesterase type 5 (PDE5) inhibition to improve pulmonary vascular remodeling and right ventricular function. Intratracheal bleomycin (4 U/kg) or saline control was administered to C57/BL6 mice after anesthesia. After recovery, animals were fed a diet of sildenafil (100 mg.kg(-1).day(-1)) or vehicle for 2 wk when they underwent hemodynamic measurements, and tissues were harvested. Survival was reduced in animals treated with bleomycin compared with controls and was improved with sildenafil (100.0 vs. 73.7 vs. 84.2%, P < 0.05). RV/LV+S ratio was higher in bleomycin-alone mice with improvement in ratio when sildenafil was administered (33.00 +/- 0.01% vs. 20.98 +/- 0.01% P < 0.05). Histology showed less pulmonary vascular and RV fibrosis in the group cotreated with sildenafil. Bleomycin was associated with a marked increase in superoxide generation by DHE histological staining and luminol activity in both heart and lung. Treatment with sildenafil resulted in a concomitant reduction in superoxide levels in both heart and lung. These data demonstrate that PDE5 inhibition ameliorates RV hypertrophy and pulmonary fibrosis associated with intratracheal bleomycin in a manner that is associated with improved NOS coupling and a reduction in reactive oxygen species signaling.

Topics: Animals; Bleomycin; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Activation; Hypertension, Pulmonary; Male; Mice; Mice, Inbred C57BL; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Fibrosis; Purines; Reactive Oxygen Species; rho-Associated Kinases; rhoA GTP-Binding Protein; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Right

Complex pulmonary atresia (CPA) i.e. pulmonary atresia with ventricular septal defect and major aorto-pulmonary collaterals (MAPCAs) or Tetralogy of Fallot with MAPCAs frequently have a clinical course complicated by development of pulmonary arterial (PA) hypertension.. A cross-sectional retrospective review of patients >16 years with CPA or Tetralogy of Fallot with MAPCAs and PA hypertension treated with sildenafil was conducted. Case notes were reviewed for baseline and follow-up (after sildenafil) characteristics.. Five patients, 4 female, median age 28 (range 18 to 47) years, were identified. All patients experienced symptomatic improvement: 2 of 4 wheelchair bound patients responded dramatically and walked 345 and 157 m respectively in 6 min following sildenafil therapy. One of the 4 with marked PA arborization abnormalities and severe ventricular dysfunction had initial symptomatic improvement. Another patient improved from walking less 100 m to climbing 2 flights of stairs. Arterial saturations improved in 2 cases from 70 and 60% to 87 and 84% respectively, whilst arterial saturations remained static in 1 case despite embolization of a classical Blalock-Taussig shunt. One patient with PA arborization/diminished PA bed was unable to tolerate sildenafil.. Sildenafil is well tolerated and leads to symptomatic improvement and better saturations in the majority of patients with CPA with PA hypertension when used in isolation or as an adjunct to percutaneous PA angioplasty.

Topics: Adolescent; Adult; Aortopulmonary Septal Defect; Cross-Sectional Studies; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Atresia; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Tetralogy of Fallot; Young Adult

Perinatal exposure to chronic hypoxia induces sustained hypertension and structural and functional changes in the pulmonary vascular bed. We hypothesized that highland newborn lambs (HLNB, 3600 m) have a higher pulmonary arterial pressure (PAP) due in part to a higher activity/expression of phosphodiesterase 5 (PDE5). We administered sildenafil, a PDE5 inhibitor, during basal and hypoxic conditions in the pulmonary hypertensive HLNB and compared them to lowland newborn lambs (LLNB, 580 m). Additionally, we compared the vasodilator responses to sildenafil in isolated small pulmonary arteries and the PDE5 mRNA expression and evaluated the vascular remodeling by histomorphometric analysis in these newborn lambs. Under basal conditions, HLNB had a higher PAP and cardiac output compared with LLNB. Sildenafil decreased the PAP during basal conditions and completely prevented the PAP increase during hypoxia in both groups. HLNB showed a greater contractile capacity and a higher maximal dilation to sildenafil. PDE5 mRNA expression did not show significant differences between HLNB and LLNB. The distal pulmonary arteries showed an increased wall thickness in HLNB. Our results showed that HLNB are more sensitive to sildenafil and therefore could be useful for treatment of pulmonary hypertension in high-altitude neonates.

Topics: Animals; Animals, Newborn; Dose-Response Relationship, Drug; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Models, Biological; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; RNA, Messenger; Sheep; Sheep, Domestic; Sildenafil Citrate; Sulfones; Vasodilator Agents

We describe a 44-year-old male patient with human immunodeficiency virus (HIV) infection and pulmonary arterial hypertension who was treated with several protease inhibitors and with sildenafil. In order to guide treatment with sildenafil, the pharmacokinetics and dynamics of sildenafil were monitored at various time points. In comparison with healthy subjects, the maximal concentration in plasma (Cmax), area under the curve (AUC), and elimination half-life of sildenafil were approximately doubled in the patient. After increasing the sildenafil dose to ensure therapeutic drug levels over 24 hours, the pulmonary arterial hypertension and physical performance of the patient improved significantly. We conclude that the elimination of sildenafil is impaired in patients treated with protease inhibitors, but to a lesser extent than predicted from single-dose studies reported in the literature. Patients treated concomitantly with protease inhibitors and sildenafil need close monitoring of plasma levels, pharmacodynamics, and toxicity of sildenafil in order to be treated optimally.

Topics: Adult; Area Under Curve; Drug Interactions; Half-Life; HIV Infections; HIV Protease Inhibitors; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Reference Values; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil has been widely used as an orphan drug for several years, mostly at a dose of 50mg tid. Since a recent randomized study showed no dose-response relationship, the target dose in future will be 20mg tid. This might, however, have a negative effect on patients being already on 50mg tid. During the past years we usually up-titrated the sildenafil dosage in monthly intervals from 12.5 to 25mg, and then finally to 50mg tid. Therefore, we wondered if a dose-response relationship could be found in a group of 23 patients, in whom we had measured a 6-min walking distance (6-MWD) at all time points. The 6-MWD was virtually unchanged during the treatment with sildenafil 12.5 and 25mg tid, respectively. However, there was a significant improvement by 34+/-63 and 26+/-47m in the 6-MWD after increasing the sildenafil dose to 50mg tid compared with baseline (p=0.015) and 25mg tid (p=0.014), respectively. In conclusion, these data suggest that sildenafil has a clinically relevant dose-response relationship with a significant improvement in 6-MWD only at a dose of 50mg tid.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Bosentan; Dose-Response Relationship, Drug; Exercise; Female; Heart Rate; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase Inhibitors; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents; Walking

Long-term follow-up after transition to oral agents from parenteral prostanoid therapy has not been well characterized.. We reviewed our long-term experience after oral transitioning in patients with pulmonary hypertension. Patients were weaned off parenteral therapy based on a pre-determined outpatient protocol. Data were collected retrospectively after transition had taken place.. Twenty-one transitioned patients were identified. Fifteen patients (71.4%) were successfully transitioned (ST): 7 to bosentan, 5 to bosentan and sildenafil, and 3 to sildenafil. Six patients failed transition (FT). None of the patients in the FT group received sildenafil. Prior to transition attempt, patients in the ST group were treated with parenteral agents for a mean of 26 months vs. 16 months in the FT group (p=0.12). Maximal epoprostenol dose was low in both groups (ST 17.8 ng/kg/min vs. FT 14.5 ng/kg/min). Mean duration of oral therapy prior to transition was 11 months. After a mean follow-up of 24 months, most patients on both groups were able to maintain stable 6 min walk distance and hemodynamics. FT was not associated with short- or long-term adverse events.. Oral transition from parenteral prostanoid agents can be safely done in a selected group of patients. Most patients are able to maintain stable functional class and hemodynamics at long follow up regardless of success of transition attempt. Combination therapy with sildenafil appears to be associated with higher likelihood of successful transitioning.

Topics: Administration, Oral; Adult; Aged; Antihypertensive Agents; Bosentan; Chi-Square Distribution; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Parenteral; Male; Middle Aged; Piperazines; Prostaglandins; Purines; Retrospective Studies; Sildenafil Citrate; Statistics, Nonparametric; Sulfonamides; Sulfones; Treatment Outcome

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild-to-moderate disease severity characterized by a mean pulmonary artery pressure (mPAP < 35 mm Hg). Patients with severe disease (mPAP > 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second(-1) cm(-5). The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long-term consequences.

Topics: Adult; Blood Pressure; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Diseases; Liver Transplantation; Male; Piperazines; Pulmonary Artery; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Embolism, Amniotic Fluid; Female; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The objectives of this study were to assess the frequency and severity of pulmonary hypertension (PH) and the effect of sildenafil treatment in patients with recalcitrant pulmonary sarcoidosis.. This investigation was a single-center, retrospective study of all patients (n = 25) with end-stage pulmonary sarcoidosis referred for lung transplantation. Hemodynamic measurements were evaluated by right-side cardiac catheterization in 24 of 25 patients. Sildenafil treatment for patients with sarcoidosis-associated PH was introduced in April 2004.. The study group of 24 patients (16 men, 8 women) had a median age of 45 (range 35 to 58) years, and duration of sarcoidosis of 11 (range 2 to 38) years. Mean pulmonary arterial pressure (MPAP) was median 36 (range 18 to 73) mm Hg. PH (MPAP >25 mm Hg) was present in 19 of 24 patients (79%). Sildenafil was administered to 12 of 13 patients at a dose of 150 (range 75 to 225) mg/day for 4 (range 1 to 12) months. Sildenafil treatment was associated with reductions in MPAP of -8 mm Hg (CI -1 to -15 mm Hg), and PVR -4.9 Wood units (CI -7.2 to -2.6 Wood units). Cardiac output and cardiac index also increased during treatment (p = 0.01, respectively). There were no consistent changes in 6-minute walk distance.. Patients with severe pulmonary sarcoidosis have a high prevalence of PH. Sildenafil treatment was associated with significant improvements in hemodynamic parameters.

Topics: Adult; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Prevalence; Purines; Retrospective Studies; Sarcoidosis, Pulmonary; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

We present a case of scleroderma complicated by severe pulmonary hypertension. The use of a three-drug (bosentan, iloprost, and sildenafil) approach contributed to significant improvement of both the clinical conditions and the pulmonary hemodynamics. Combining three pulmonary vasodilators with different mechanisms of action could benefit patients with severe pulmonary hypertension resistant to conventional therapy.

Topics: Bosentan; Drug Therapy, Combination; Electrocardiography; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Evans syndrome is a rare cause of hemolysis in pediatric patients. The authors describe two severely affected patients who had previously been heavily treated, and who subsequently developed severe pulmonary hypertension. Both patients were successfully managed by a combination of immunosuppression and anti-pulmonary hypertension treatment. The first patient to present, case A, received an allogeneic bone marrow transplant with subsequent cure of both Evans syndrome and pulmonary hypertension and is now on a weaning dose of sildenafil. Case B is being worked up for allogeneic bone marrow transplantation. The authors speculate that the pulmonary hypertension was caused by the underlying immune dysregulation and hemolysis and that Evans syndrome joins the list of other hemolytic anemias that cause pulmonary hypertension, such as sickle cell disease, thalassemia, and paroxysmal nocturnal hemoglobinuria. However, they suggest a vasculitic process as the main cause.

Topics: Anemia, Hemolytic, Autoimmune; Bone Marrow Transplantation; Child; Child, Preschool; Female; Hemolysis; Humans; Hypertension, Pulmonary; Infant; Piperazines; Purines; Purpura, Thrombocytopenic, Idiopathic; Sildenafil Citrate; Sulfones; Syndrome; Transplantation, Homologous; Vasodilator Agents

Topics: Anesthesia, General; Animals; Humans; Hypertension, Pulmonary; Infant, Newborn; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

A rare case of childhood pulmonary haemosiderosis with juvenile idiopathic arthritis is discussed, with particular reference to treatment with hydroxychloroquine and sildenafil for pulmonary hypertension which occurs secondary to this disease.

Topics: Adolescent; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Juvenile; Female; Hemosiderosis; Humans; Hydroxychloroquine; Hypertension, Pulmonary; Malaysia; Piperazines; Prednisolone; Purines; Sildenafil Citrate; Spironolactone; Sulfones; Vasodilator Agents

There is increasing evidence for beneficial effects of the type 5 phosphodiesterase inhibitor, sildenafil, in idiopathic pulmonary arterial hypertension (PAH). The effects of sildenafil in severe PAH associated with an atrial septal defect (ASD) have not been clearly delineated.. This extended case series reviews our experience with sildenafil treatment in three patients with severe PAH and Eisenmenger syndrome associated with an ASD. Case notes were reviewed for baseline and follow-up anatomic, clinical and haemodynamic characteristics.. Of three patients identified, median age 44.3 years (range, 28 to 59 years), two had large secundum ASDs and the other a sinus venous defect. All patients had severe PAH and were desaturated at rest and/or during exercise. Sildenafil was started because of progressive and severe effort intolerance. All patients experienced symptomatic improvement, had higher arterial saturations (range 8-19%) and improvement in effort tolerance (88 m and 56 m improvement in 6-min walk test distance (MWTD) in two patients). Right ventricular (RV) function and Doppler derived RV systolic pressure improved in two patients. Pulmonary arterial pressures decreased in two patients who had cardiac catheterization (range 4 to 14 mm Hg). Pulmonary vascular resistance decreased from 7.58 to 3.8 Wood's units in one patient who is now awaiting surgery. Another patient developed significant pulmonary vasoreactivity (8.3 to 6.2 Wood's units with 100% oxygen) after 16 months of sildenafil therapy.. Sildenafil not only relieves symptoms associated with severe PAH in patients with large ASDs, but also improves pulmonary arterial hemodynamics and RV function.

Topics: Adult; Female; Heart Septal Defects, Atrial; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Treatment Outcome

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase-5 inhibitor, has shown promising results as a novel oral monotherapy in the treatment of pulmonary arterial hypertension (PAH). We conducted a cross-sectional survey of 19 consecutive PAH patients, aged 16-75 years, with WHO functional class II or worse over 3 months of oral sildenafil. Improvement in exercise capacity was achieved in 15/19 (79%) patients. 6-minute walk test distance increased from 299+/-118 m to 360+/-127 m, p=0.016, and WHO functional class decreased significantly. Both PASP and CI showed a non-significant trend toward improvement. Patients also reported significant improvement in physical (p=0.002) and social (p<0.001) functioning, and general health (p=0.01) of Rand SF-36 questionnaire. There was improvement in domains of role limitation due to physical health (p=0.16), emotion (p=0.14), and energy level (p=0.4). Our study suggests that oral sildenafil monotherapy is effective in improving exercise capacity and health-related quality of life amongst PAH patients.

Topics: Adult; Cross-Sectional Studies; Exercise Tolerance; Health Status; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfones

Combination therapy has been recommended for the treatment of pulmonary arterial hypertension (PAH). However, there is scant information on combination therapy after failure of monotherapy, particularly in patients with scleroderma-associated PAH (PAH-SSD). From a group of 82 consecutive patients with PAH who received initial bosentan monotherapy, a total of 13 idiopathic PAH (IPAH) and 12 PAH-SSD patients requiring additional therapy with sildenafil were studied. Sildenafil was added for clinical deterioration based upon symptoms, New York Heart Association (NYHA) classification or 6-min walk distance (6MWD). Clinical data and haemodynamics were collected at baseline. Assessments were made at 1-3-month intervals. At baseline, there were no differences in demographics, NYHA classification, haemodynamics or 6MWD between the two groups. After initiation of bosentan, both groups experienced clinical improvement but ultimately deteriorated (median time to monotherapy failure 792 versus 458 days for IPAH and PAH-SSD patients, respectively). After addition of sildenafil, more IPAH patients tended to improve in NYHA class (five out of 13 versus two out of 12) and walked further (mean difference in 6MWD 47+/-77 m versus -7+/-40 m) compared with PAH-SSD patients. In conclusion, addition of sildenafil after bosentan monotherapy failure improved New York Heart Association class and 6-min walk distance in idiopathic pulmonary arterial hypertension patients but failed to improve either parameter in scleroderma-associated pulmonary arterial hypertension patients. Additional studies are needed to assess the tolerability and efficacy of this combination in patients with scleroderma-associated pulmonary arterial hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Exercise Test; Female; Humans; Hypertension, Pulmonary; Lung Volume Measurements; Male; Middle Aged; Piperazines; Pulmonary Wedge Pressure; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Sildenafil (phosphodiesterase type 5 inhibitor) has been shown to be effective in pulmonary arterial hypertension (PAH). We evaluated the efficacy and safety of oral sildenafil in patients of severe PAH with special emphasis on dose response relationship, time of onset of clinical response and its effects on different haemodynamic parameters.. Forty-four patients of severe PAH of either idiopathic pulmonary arterial hypertension [23 (51.7%)] or Eisenmenger syndrome [21 (48.3%)] were studied. All patients underwent six-minute walk test (SMWT) and echocardiography, while some also underwent cardiac catheterization. Sildenafil was started after a test dose and was gradually increased up to a target dose of 300 mg/day. Patients were followed-up 2 weekly for 10 weeks and monthly thereafter for functional class assessment and SMWT. Echocardiography and cardiac catheterization were repeated after at least 1 month of achieving maximal sildenafil dose (target dose or maximally tolerated dose). Drug safety and tolerability were assessed by monitoring patients for adverse effects including fundus examination.. Mean follow-up duration was 18.7+/-8.8 months (range 7-30 months). Mean maximum dose achieved was 276.1+/-62.2 mg/day (range 75-300 mg/day). A significant improvement in NYHA class (2.54+/-0.5 vs. 1.31+/-0.4, p=0.0001) and in SMWT distance (247.4+/-74.7 vs. 366.3+/-93.8 m, p=0.0001) was noted. All patients reported "feeling better" within 2 weeks of starting 12.5 mg thrice a day sildenafil. Marked improvement was noticed at 150 mg/day dose. Some minor additional benefit was noticed with further increase in the dose up to 225 mg/day. No further benefit was noted in improvement of NYHA class and SMWT distance by further increasing the dose of sildenafil. Haemoptysis as well as chest pain, if present, were also improved. On follow-up cardiac catheterization, a significant reduction in mean pulmonary arterial pressure (from 67.0+/-10.2 to 56.9+/-9.5 mm Hg, p=0.001), PVRI (from 19.5+/-7.0 to 11.1+/-6.9 WU m2, p=0.0001) and PVR/SVR ratio (0.6+/-0.3 vs. 0.4+/-0.2, p=0.013) with increase in cardiac index (2.9+/-1.1 l/min vs. 3.7+/-1.1 l/min, p=0.008) was noted. Systemic as well as pulmonary arterial oxygen saturations also improved significantly. Sildenafil was generally well tolerated, except for rhinorrhoea in 2, bodyache in 1 and headache in 1 patient. No visual symptom or change in fundus examination was noted.. Oral sildenafil improves functional capacity, haemodynamic parameters and is safe in patients with severe PAH. Benefits start as early as 2 weeks. The effects are dose related. A target dose of 150 mg/day appears to be optimal. Being very effective, widely available, relatively inexpensive, and very easy to use and very well tolerated without any major side effect, sildenafil may qualify as a first line medication for these patients.

Topics: Administration, Oral; Adolescent; Adult; Cardiac Catheterization; Chest Pain; Child; Dose-Response Relationship, Drug; Echocardiography; Eisenmenger Complex; Exercise Test; Female; Follow-Up Studies; Hemoptysis; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Pulmonary arterial hypertension, both primary and secondary, continues to pose a therapeutic problem. In this study, we evaluate the efficacy and safety of a low-dose of oral sildenafil in 10 patients with pulmonary arterial hypertension.. We administered a single daily dose of 0.5 milligrams per kilogram of sildenafil for 3 months to 10 patients with pulmonary arterial hypertension. Their average age was 26.8 years. Diagnoses were primary pulmonary arterial hypertension in 3 patients, and secondary pulmonary arterial hypertension due to congenital cardiac disease in the remaining 7 patients. Outcome measures included the clinical state, the mean pulmonary arterial pressure, and the indexed pulmonary vascular resistance; the latter two assessed at the beginning and at the end of the treatment period by cardiac catheterization. We also analysed the cost of the treatment.. Oral treatment was well tolerated, and resulted in an improvement of the functional capacity in 9 of the 10 patients. Pulmonary arterial pressure decreased from 70 to 60 millimetres of mercury (p equal to 0.05), and indexed pulmonary vascular resistance decreased from 21.8 to 15.8 Wood units per square metre (p equal to 0.006). The mean cost per patient for 3 months on oral treatment with sildenafil was 120.99 American dollars.. A low dose of 0.5 milligrams per kilogram per day of oral sildenafil, instead of 1 to 4 milligrams per kilogram per day, provided early clinical and haemodynamic improvements, and proved less expensive. Additional experience is now required to define more reliably the true long-term benefits of this therapy.

Topics: Administration, Oral; Adolescent; Adult; Child; Drug Costs; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary artery hypertension can complicate the early postoperative care of patients with left ventricular assist devices (LVADs). Inhaled nitric oxide (INO) is frequently used to manipulate pulmonary resistance after LVADs have been placed. We evaluated the effect of oral sildenafil therapy on pulmonary artery pressure, systemic pressure, and nitric oxide utilization.. After Institutional Review Board approval, the records of 10 consecutive adult patients with LVADs and pulmonary hypertension who received sildenafil were reviewed. Demographics, surgical history, INO use, inotrope requirements, and hemodynamic response to oral sildenafil at multiple intervals were collected. Hemodynamic data were analyzed with a two-way analysis of variance of repeated measures with correction for multiple comparisons.. There were 8 men and 2 women with 6 Heartmate XVE LVADs and 4 Thoratec LVADs (both, Thoratec, Pleasanton, California). When weaning was attempted, 8 patients who received INO demonstrated rebound pulmonary hypertension or increased right heart dysfunction. All patients were on inotropic therapy with dobutamine and milrinone. Sildenafil produced a significant reduction in pulmonary artery systolic pressure within 90 minutes of oral administration (p = 0.042). Significant changes in systolic blood pressure, mean arterial pressure, systemic vascular resistance, and heart rate were not observed. All 8 patients receiving INO were weaned within 12 hours without recurrent pulmonary hypertension. All 10 patients were weaned from inotropic support within 72 hours. No patient suffered right-side heart failure requiring intervention.. Oral sildenafil represents a useful adjunctive therapy for patients with LVADs. In our series, it provided additional reduction of pulmonary artery pressure, and facilitated weaning from INO and inotropes without deleterious hemodynamic consequences.

Topics: Administration, Inhalation; Adult; Aged; Blood Pressure; Female; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones

We report a case of a seven-yr-old girl with a PAH treated with continuation therapy of bosentan and sildenafil. The combination therapy revealed safety and efficacy in long-term follow up.

Topics: Antihypertensive Agents; Bosentan; Child; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Lung Transplantation; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

During the past 18 years, sildenafil has evolved from a potential anti-angina drug to an on-demand treatment for erectile dysfunction and more recently to a new orally active treatment for pulmonary hypertension. Recent studies suggest that the drug has powerful cardioprotective effect against ischemia/reperfusion injury, doxorubicin-induced cardiomyopathy and anti-hypertensive effect induced by chronic inhibition of nitric oxide synthase in animals. Based on several recent basic and clinical studies, it is clear that sildenafil and other clinically approved type-5 phosphodiesterase-5 inhibitors including vardenafil and tadalafil will eventually be developed for several cardiovascular indications including essential hypertension, endothelial dysfunction, ischemia/reperfusion injury, myocardial infarction, ventricular remodeling and heart failure.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antihypertensive Agents; Carbolines; Cardiomyopathies; Cardiovascular Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Doxorubicin; Endothelium, Vascular; Enzyme Inhibitors; Erectile Dysfunction; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents; Ventricular Remodeling

Topics: Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antihypertensive Agents; Bosentan; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension is a common problem in patients with congenital diaphragmatic hernia (CDH). In a subset of these patients, pulmonary hypertension persists despite optimized ventilatory management and supportive care. Sildenafil, a phosphodiestrase V inhibitor, has been used in the treatment of pulmonary hypertension in adults and children. Cardiovascular effects of sildenafil in patients with CDH and pulmonary hypertension are not known.. To describe the changes in cardiovascular and respiratory parameters in newborn infants with CDH and persistent pulmonary hypertension refractory to inhaled nitric oxide (iNO) during the first 2 weeks of sildenafil administration.. Retrospective data analysis of seven patients with CDH (birth weight = 2,573 +/- 1,019 g; gestational age = 35.6 +/- 4.3 weeks) receiving oral sildenafil for pulmonary hypertension refractory to iNO. Findings of serial echocardiograms and data on cardiovascular and respiratory status were assessed.. Right cardiac output increased and left cardiac output tended to increase 1.5-4 h after initiation of sildenafil and the increase was sustained throughout the study. Echocardiographic indices of pulmonary hypertension showed an apparent reduction in abnormally high pulmonary vascular resistance. Systemic blood pressure tended to decrease. Shortening fraction did not change. Ventilatory index and the need for iNO tended to decrease in the five surviving infants.. These preliminary findings suggest that sildenafil may improve cardiac output by reducing pulmonary hypertension refractory to iNO in patients with CDH.

Topics: Administration, Oral; Blood Flow Velocity; Blood Pressure; Cardiac Output; Electrocardiography; Hernia, Diaphragmatic; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Topics: Cardiac Catheterization; Follow-Up Studies; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Prognosis; Pulmonary Diffusing Capacity; Pulmonary Fibrosis; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Survival Rate

Primary pulmonary hypertension is a rare disease with an ominous prognosis for which new therapeutic options are being developed. Recently, there have been case reports indicating that sildenafil may be of benefit in short- to midterm follow-up. However, long-term clinical data of sildenafil in primary pulmonary hypertensive patients is lacking. We report a patient with primary pulmonary hypertension treated with sildenafil 200 mg/day for 50 months with a sustained clinical response.

Topics: Adult; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfones; Time Factors

Topics: Administration, Intranasal; Administration, Oral; Animals; Bosentan; Drug Evaluation, Preclinical; Endothelin A Receptor Antagonists; Epoprostenol; Forecasting; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Isoxazoles; Life Expectancy; Lung Transplantation; Monocrotaline; Piperazines; Platelet-Derived Growth Factor; Purines; Randomized Controlled Trials as Topic; Rats; Sheep; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Vasodilator Agents

Epoprostenol significantly improves function and survival in patients with pulmonary arterial hypertension (PAH) but is associated with many risks and side effects. Furthermore, effective oral therapy is now available. We report our long-term experience with 13 patients from among 118 treated with epoprostenol who were able to be weaned to oral therapy, including 6 with persistently abnormal hemodynamics (mean pulmonary artery pressure > or = 35 mm Hg).. Oral therapy with bosentan (n = 11) or sildenafil (n =2) was started before weaning epoprostenol in all but 1 patient. Right heart catheterization was performed when patients reached a dose of 2 ng/kg/min, and epoprostenol was discontinued with hemodynamic monitoring. Functional class and 6-minute walk test were assessed at regular intervals. Repeat right heart catheterization was performed 1 year after discontinuation of epoprostenol.. Nine patients remained on oral therapy alone for up to 46 months. Four patients deteriorated in functional class, and 2 of them resumed epoprostenol therapy. Inhaled iloprost was started in another patient. One additional patient died, unrelated to PAH. Twelve patients underwent right heart catheterization at the time of epoprostenol discontinuation. Hemodynamic evaluation 13.2 +/- 0.9 months later showed that the 5 patients with normal or nearly normal hemodynamics at the time of discontinuation of epoprostenol had no deterioration, whereas 4 of the 7 patients with abnormal hemodynamics had worsened. The 6-minute walk test at last follow-up was not significantly changed from maximal distance on epoprostenol (420 +/- 94 vs 412 +/- 95 meters).. Weaning from epoprostenol to sildenafil or bosentan with sustained clinical improvement is possible, even with persistent pulmonary hypertension; however, patients with persistently abnormal hemodynamics are at risk for hemodynamic and clinical deterioration and require close follow-up.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Antihypertensive Agents; Blood Pressure; Bosentan; Cardiac Catheterization; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Male; Middle Aged; Piperazines; Purines; Retreatment; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance; Vasodilator Agents

Sildenafil (Viagra, Pfizer) is being increasingly used to treat pulmonary hypertension in children. However, there are limited data available to suggest dosage regimens. The purpose of this study was to determine the effects of escalating doses of sildenafil on hemodynamics and gas exchange in children with pulmonary hypertension because of congenital cardiac defects.. Prospective, observational study.. Pediatric intensive care unit in a tertiary care children's hospital.. Ten children with pulmonary hypertension because of congenital cardiac defects who were in the intensive care unit and on nitric oxide after cardiac surgery.. Patients received sildenafil every 4 hours via a gastric tube in incremental doses of 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, and 2.0 mg/kg along with nitric oxide during their stay in the intensive care unit until they were extubated. Hemodynamic and arterial blood gas measurements were taken before (baseline) and 60 minutes after the administration of sildenafil.. All doses of sildenafil caused significant reduction in pulmonary artery pressure with no significant effect on systemic arterial and central venous pressures. Arterial partial pressure of oxygen was decreased after a 2.0 mg/kg dose of sildenafil but not significantly. No significant differences were found among the 4 doses.. For the treatment of pulmonary hypertension in children with congenital cardiac defects, a 0.5 mg/kg dose of sildenafil every 4 hours is therapeutically as effective as a 2.0 mg/kg dose every 4 hours. However, a large dose-ranging and pharmacokinetic study of sildenafil in children with pulmonary hypertension because of congenital cardiac defects is needed to validate the safety and efficacy of the dose-range and dosing interval suggested by this study.

Topics: Analysis of Variance; Blood Gas Analysis; Bronchodilator Agents; Cardiac Surgical Procedures; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Heart Defects, Congenital; Heart Rate; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Purines; Research Design; Sildenafil Citrate; Sulfones; Treatment Outcome; United Kingdom; Vasodilator Agents

Topics: Anti-Anxiety Agents; Attention Deficit and Disruptive Behavior Disorders; Child; Comorbidity; Diagnosis, Differential; Dose-Response Relationship, Drug; Down Syndrome; Heart Defects, Congenital; Hospitalization; Humans; Hypertension, Pulmonary; Lorazepam; Male; Oxygen Inhalation Therapy; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Decision Making; Eisenmenger Complex; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Purines; Safety; Sildenafil Citrate; Sulfones

To assess the efficacy of treatment with sildenafil monotherapy in patients with pulmonary hypertension.. An observational study was undertaken in 11 patients with pulmonary hypertension in functional class II or III who received treatment with sildenafil (150 mg/day). Seven of the patients had inoperable chronic thromboembolic pulmonary hypertension and 4 had pulmonary arterial hypertension. To assess treatment response, the following parameters were assessed during follow-up at 3, 6, and 12 months: exercise tolerance in the 6-minute walk test, change in functional class, and systolic pulmonary arterial pressure measured by echocardiography.. We observed a significant improvement in exercise tolerance, as shown by increased 6-minute walk distance after 3, 6, and 12 months of treatment (increases of 20, 67, and 95 m, respectively). All patients showed an improvement in functional class. The results of echocardiography did not reveal statistically significant differences in systolic pulmonary arterial pressure between baseline and 6 or 12 months of treatment. No significant adverse effects were observed, although sildenafil treatment was suspended in 1 patient due to persistent headache.. The results of this study confirm that sildenafil is an effective drug for the management of pulmonary arterial hypertension and inoperable chronic thromboembolic pulmonary hypertension both in the short term and medium to long term, and that the drug is well tolerated and shows few side effects.

Topics: Adolescent; Adult; Aged; Child; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Embolism; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension carries a poor prognosis in both adult and pediatric patients. Current understanding of the mechanisms underlying pulmonary arterial hypertension has enabled the rapid development of appropriate drugs, such as endothelin receptor antagonists and 5-phosphodieste-rase inhibitors, that can be administered orally and which are generally well tolerated. The aims of the present study were to evaluate functional class and exercise capacity following long-term treatment with sildenafil or bosentan in patients with idiopathic pulmonary arterial hypertension and Eisenmenger's syndrome and to compare results in the two groups.. Seven patients were included in the pulmonary arterial hypertension study, and diagnoses of idiopathic pulmonary arterial hypertension were confirmed. Five patients were treated with sildenafil, while two received bosentan. The five patients with a non-restrictive ventricular septal defect and pulmonary arterial hypertension were treated with sildenafil. In one patient, bosentan was added to the sildenafil.. Both sildenafil and bosentan significantly improved exercise capacity in patients with idiopathic pulmonary arterial hypertension. The treatment effect was less in those with Eisenmenger physiology. Although the improvement in World Health Organization functional class was greater in patients with idiopathic pulmonary arterial hypertension, it was significant in both groups.. Long-term treatment with sildenafil and bosentan improved both exercise capacity and functional class in patients with idiopathic pulmonary arterial hypertension and in those with hypertension due to congenital heart disease. The changes were more marked in patients with idiopathic pulmonary arterial hypertension.

Topics: Adolescent; Adult; Antihypertensive Agents; Bosentan; Child; Eisenmenger Complex; Female; Humans; Hypertension, Pulmonary; Infant; Male; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Increased platelet activation is recognized in patients with sickle cell disease (SCD), but its pathogenesis and clinical relevance remain uncertain. Pulmonary arterial hypertension (PAH), an important complication of SCD, is characterized by a proliferative pulmonary vasculopathy, in situ thrombosis, and vascular dysfunction related to scavenging of nitric oxide (NO) by hemoglobin released into blood plasma during intravascular hemolysis. We investigated links between platelet activation, PAH and NO scavenging in patients with SCD. Platelet activation marked by activated fibrinogen receptor correlated to the severity of PAH (r = 0.58, P < .001) and to laboratory markers of intravascular hemolysis, such as reticulocyte count (r = 0.44, P = .02). In vitro exposure of platelets to pathologically relevant concentrations of cell-free hemoglobin promoted basal- and agonist-stimulated activation and blocked the inhibitory effects on platelet activation by an NO donor. In patients with SCD, administration of sildenafil, a phosphodiesterase-5 inhibitor that potentiates NO-dependent signaling, reduced platelet activation (P = .01). These findings suggest a possible interaction between hemolysis, decreased NO bioavailability, and pathologic platelet activation that might contribute to thrombosis and pulmonary hypertension in SCD, and potentially other disorders of intravascular hemolysis. This supports a role for NO-based therapeutics for SCD vasculopathy. This trial was registered at www.clinicaltrials.gov as no. NCT00352430.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Anemia, Sickle Cell; Female; Flow Cytometry; Hemoglobins; Hemolysis; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Platelet Activation; Purines; Sildenafil Citrate; Sulfones; Thrombosis

We report a 16-year-old man with severe heart failure due to idiopathic pulmonary arterial hypertension (IPAH). The patient was initially treated with a combination of beraprost, a prostacyclin analog, and sarpogrelate, a serotonin receptor inhibitor. However, he was unresponsive to the treatment. We then changed the treatment to sildenafil, and his condition dramatically improved. Sildenafil has an immediate pulmonary vasodilator effect in patients already receiving vasodilators for IPAH.

Topics: Adolescent; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Serotonin Antagonists; Sildenafil Citrate; Succinates; Sulfones; Treatment Outcome; Vasodilator Agents

Sudden, intraoperative cardiovascular deterioration as a result of pulmonary embolization of bone marrow fat is a potentially fatal complication during total hip and knee arthroplasty, intramedullary nailing, and spine surgery. Anesthetic management is challenging in the presence of increased right ventricular afterload due to pulmonary hypertension. Selective pulmonary vasodilation may be an appropriate prophylactic or therapeutic measure. The effect of sildenafil (phosphodiesterase inhibitor) on cardiovascular deterioration after bone marrow fat embolization was therefore investigated.. Bone cement (polymethylmethacrylate) was injected into three lumbar vertebrae in 12 sheep. Invasive blood pressures and heart rate were recorded continuously until 60 min after the last injection. Cardiac output and arterial and mixed venous blood gas variables were measured at selected time points. Before the first cement injection, 6 animals received a bolus injection (0.7 mg/kg) of sildenafil, with continuous infusion (0.2 mg . kg . h) thereafter. Postmortem lung and kidney biopsies were taken for semiquantitative analysis of intravascular fat.. Fat embolism was associated with a transient increase (21 +/- 7mmHg) in pulmonary arterial pressure. A transient decrease in arterial blood pressure and temporary increases in central venous pressure and dead space were also observed. No significant changes in any cardiovascular variable were observed after fat embolism in the sildenafil group. There was significantly (P < 0.05) less intravascular fat in the lungs of the sildenafil (median count of 5 emboli per microscopic view) compared with the control group (median count of 1).. Administration of sildenafil prevented the acute cardiovascular complications after bone marrow fat embolism in sheep.

Topics: Animals; Blood Gas Analysis; Blood Pressure; Bone Cements; Bone Marrow; Cardiac Output; Embolism, Fat; Female; Heart Rate; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Polymethyl Methacrylate; Pulmonary Circulation; Purines; Sheep; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is commonly associated with CREST (Calcinosis, Raynaud phenomenon, Esophageal motility disorders, Sclerodactyly, and Telangiectasia) syndrome. Sildenafil, an oral phosphodiesterase type-5 inhibitor, may offer benefits in the pharmacological management of PAH. However, little is known about the long-term hemodynamic effects of sildenafil, and the potential role of sildenafil in long-term combination with beraprost, an oral prostacyclin analogue, remains unclear. We therefore examined the hemodynamic effect of oral sildenafil alone and when coadministered with beraprost in a patient with PAH associated with CREST syndrome. Traces of the acute hemodynamic effects of beraprost (20 microg) disappeared after 2 hours. In contrast, the acute hemodynamic effects of sildenafil (50 mg) produced a greater reduction in PAP (31%) and PVR (40%), and these effects also disappeared after 5 hours. After 1 month of combination therapy of sildenafil (25 mg) twice daily and beraprost (20 microg) 3 times daily, the fall in pulmonary artery pressure and pulmonary vascular resistance was sustained (31% in both). Furthermore, the patient had significantly improved her 3-minute walk test and NYHA function class without significant adverse effects at the reported doses. The findings indicate that oral sildenafil is a potent pulmonary vasodilator that appears to act synergistically with oral beraprost to cause sustained pulmonary vasodilatation in a patient with PAH associated with CREST syndrome.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; CREST Syndrome; Cryoprotective Agents; Drug Therapy, Combination; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Administration, Oral; Female; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Intraoperative Period; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones

This report describes a case of bleeding as a complication of circumcision in a 2-week-old infant being treated with sildenafil for persistent pulmonary hypertension of the newborn. The vasodilatory effects of sildenafil on the penile vasculature may have contributed to the postoperative bleeding in this patient.

Topics: Circumcision, Male; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Piperazines; Postoperative Hemorrhage; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Chronic alveolar hypoxia induces pulmonary hypertension, evident from elevated pulmonary artery pressure (PAP), pulmonary vascular resistance, right ventricular hypertrophy (RVH), and increased muscularization of the pulmonary vasculature. Additionally, the vasoconstrictor response to acute hypoxia (HPV) may be reduced in the remodeled vasculature. However, no direct comparison of different treatments on the various parameters characterizing pulmonary hypertension has been performed yet. Against this background, we compared the effects of inhaled NO, infused iloprost, a stable prostacyclin analogue, and oral sildenafil, a phosphodiesterase 5 inhibitor, on hypoxia-induced pulmonary hypertension.. Exposure of rabbits to chronic hypoxia (FiO(2)=0.10) for 42 days. Treatment with infused iloprost, oral sildenafil, and inhaled nitric oxide.. We quantified PAP, pulmonary vascular resistance, RVH, vascular remodeling, vasoreactivity, and the strength of HPV. Chronic hypoxia resulted in an increase in (a) the right ventricle/(left ventricle+septum) ratio from 0.26+/-0.01 to 0.44+/-0.01, (b) PAP, and (c) the degree of muscularization from 14.0+/-4.0% to 43.5+/-5.3%. Treatment with iloprost and sildenafil, but not with NO, prevented the increase in muscularization. In contrast, RVH was strongly inhibited by sildenafil, whereas NO had some minor, and iloprost had no effect. Only iloprost reduced PAP compared to NO and sildenafil. The downregulation of HPV was abrogated only by NO.. We demonstrated (a) that the parameters characterizing hypoxia-induced pulmonary hypertension are not functionally linked, (b) that the downregulation of HPV under chronic hypoxia can be prevented by inhaled NO but not by sildenafil and iloprost, and (c) that iloprost is particularly effective in preventing vascular remodeling and sildenafil in preventing RVH.

Topics: Analysis of Variance; Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hypertension, Pulmonary; Hypoxia; Iloprost; Nitric Oxide; Piperazines; Purines; Rabbits; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

The endothelin system plays an important role in the development of pulmonary hypertension. Several studies have suggested that interfering with the function of the endothelin system will be helpful in pulmonary hypertension treatment. In the present study, we investigated the preventive and therapeutic effects of sildenafil on pulmonary hypertension in monocrotaline-treated rats. In the preventive study, the level of mean pulmonary arterial pressure, right ventricular divide, left ventricular and septum, small pulmonary arterial morphologic and elastic fiber changes were highly improved in the treated group (P<0.05). The expressions of endothelin-1 A type receptors on small pulmonary arterial hypertension were significantly reduced in the sildenafil-treated group (P<0.05). The ET-1 level in plasma was increased in the sildenafil-treated group, but did not reach significance. Emphysema, interstitial pneumonia were significantly improved in the sildenafil-treated group. The same findings were also observed in the therapeutic study. The present results suggest that sildenafil can prevent and reverse the development of pulmonary hypertension in monocrotaline-treated rats by improving the function of endothelin system in pulmonary arteries.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Lung Diseases, Interstitial; Male; Monocrotaline; Piperazines; Pulmonary Artery; Pulmonary Emphysema; Purines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents

The treatment of pulmonary arterial hypertension (PAH) in pregnancy is reviewed.. PAH is a disease characterized by narrowing of the pulmonary arteries and increased vascular resistance. Women with PAH should avoid becoming pregnant, as the physiological, cardiovascular, and pulmonary changes that occur during pregnancy can exacerbate the condition. However, several viable treatment options are available to improve the outcomes in this patient population, including inhaled nitric oxide, calcium-channel blockers, targeted pulmonary vasodilators, and sildenafil. Epoprostenol, a naturally occurring prostaglandin and vasodilator, is a pregnancy category B drug. Reproductive studies in rats and rabbits have found no impaired fertility or fetal harm at 2.5-4.8 times the recommended human dosage of epoprostenol. Most of the published case reports describe initiating epoprostenol 2-4 ng/kg/min i.v. several weeks before or near the time of delivery. Iloprost is a pregnancy category C drug but has demonstrated benefit in pregnant patients with PAH, with no congenital abnormalities and no postpartum maternal or infant mortality reported. Sildenafil causes vasodilation of the pulmonary vascular bed and vasodilation in the systemic circulation. Two case reports have described the successful treatment with sildenafil, a pregnancy category B drug, of pregnant patients with PAH. Patients with idiopathic PAH or chronic thromboembolic PAH should receive full-dose subcutaneous low-molecular-weight heparin therapy instead of warfarin for bleeding prophylaxis during pregnancy.. Targeted pulmonary vasodilators are viable treatment options for pregnant patients with PAH. Early recognition and management of worsening symptoms are essential to improve outcomes for both the mother and infant.

Topics: Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Purines; Sildenafil Citrate; Sulfones; Thromboembolism; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Phosphodiesterase Inhibitors; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Sildenafil and bosentan were added recently to the treatment with great expectations, effectiveness for the acute exacerbation of pulmonary arterial hypertension (PAH) is not fully examined. Two cases of acutely exacerbated PAH associated with collagen vascular diseases were treated first with sildenafil for six months followed by bosentan for another six months and the characteristics of this treatment modality were examined. Sildenafil showed an immediate effect which started in as early as approximately 30 min and was maximized in 60-90 min after oral ingestion. Continuous use of sildenafil for six months lowered pulmonary arterial pressure, pulmonary vascular resistance and the levels of brain natriuretic peptides along with an increased distance in 6-minute-walk, and replacement of it to with bosentan kept these effects. We think it as a treatment choice to use sildenafil first as a reliever and replace it with a controller bosentan, considering the immediate effects of sildenafil.

Topics: Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Mixed Connective Tissue Disease; Natriuretic Peptide, Brain; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

A 7-month-old male Papillon was presented to us with mild dyspnea, cyanosis and a diastolic murmur detected by cardiac auscultation. Echocardiography revealed severe pulmonary arterial hypertension (PH), and administration of 1 mg/kg of oral sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, twice daily was initiated. Exercise capacity, cyanosis, dyspnea and cardiac murmur were improved after therapy for 4 weeks. PCV was remarkably high (74%) after therapy for 3 years, however, increasing the dose of sildenafil decreased this value (60%). Follow-up after therapy for 4 years revealed that treatment with oral sildenafil only continued to provide the dog with an excellent quality of life, without any side effects.

Topics: Animals; Dog Diseases; Dogs; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Follow-Up Studies; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Altitude Sickness; Erectile Dysfunction; Heart Diseases; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Raynaud Disease; Sildenafil Citrate; Stroke; Sulfones; Vasodilator Agents

Topics: Exercise Test; Humans; Hypertension, Pulmonary; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfones; Survival Analysis; Vasodilator Agents

We describe the case of a 30-year-old female patient with chronic thromboembolic pulmonary hypertension that has an excellent functional capacity under treatment with sildenafil. She did an exercise stress echocardiography that revealed marked right ventricular dilatation during exercise. This information was used for clinical decision and the authors discuss the potential utility of this echocardiographyc sign.

Topics: Adult; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Dilatation, Pathologic; Echocardiography, Doppler; Exercise Test; Female; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thromboembolism; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Right

We describe successful use of enteral sildenafil following surgery for congenital heart disease in three cases. One infant after repair of ventricular septal defect and aortic coarctation had pulmonary hypertension non-responsive to nitric oxide, another infant and 3.5 year child following palliative surgery for congenital heart disease with univentricular physiology were treated with inhaled nitric oxide and had severe systemic desaturations associated with endotracheal suctioning. Therapy with sildenafil reduced pulmonary arterial pressure, prevented episodes of arterial desaturations and allowed weaning from nitric oxide (Ref. 7). Full Text (Free, PDF) www.bmj.sk

Topics: Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Phosphodiesterase Inhibitors; Piperazines; Postoperative Complications; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

We describe two systemic sclerosis (SSc) patients with isolated pulmonary arterial hypertension (PAH) who were given treatment with 50 mg oral sildenafil per day. We evaluated the efficacy of oral sildenafil for isolated PAH in SSc patients by direct assessment with cardiac catheterization before and 6 months after the initiation of sildenafil. Right-heart catheterization demonstrated decreased mean pulmonary artery pressure, decreased pulmonary vascular resistance, and increased cardiac output after treatment with sildenafil. Brain natriuretic peptide levels were gradually decreased. The 6-min walking distance was greatly extended. Moreover, the physical conditions of both patients were much improved. We recognized no adverse events. We propose that oral sildenafil may be beneficial as a selective pulmonary vasodilator and as long-term treatment in SSc patients with isolated PAH.

Topics: Female; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged; Natriuretic Peptide, Brain; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfones; Vasodilator Agents

Perioperative pulmonary hypertension is a challenging clinical problem with numerous etiologies including hypoxia, adrenergic stimulation, and local inflammation. New oral phosphodiesterase-5 (PDE-5) inhibitors used for the treatment of erectile dysfunction may have beneficial effects on the pulmonary vasculature owing to the abundance of PDE-5 receptors in the lung. The purpose of this study was to compare the efficacy of sildenafil, vardenafil, and tadalafil in preventing acute hypoxic pulmonary vasoconstriction and hypoxia-induced pulmonary artery tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1beta) expression.. Isolated rat pulmonary arteries suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), sildenafil, vardenafil, or tadalafil to assess (1) pulmonary artery relaxation; (2) inhibition of phenylephrine-induced pulmonary artery contraction; (3) inhibition of hypoxic pulmonary vasoconstriction (pO2 = 30-35 mm Hg); and (4) hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression (reverse transcriptase-polymerase chain reaction).. Sildenafil, vardenafil, and tadalafil resulted in dose-dependent pulmonary artery relaxation and inhibited phenylephrine-induced pulmonary artery contraction, but only tadalafil significantly inhibited hypoxic pulmonary vasoconstriction (52.08% +/- 7.65% tadalafil versus 88.63% +/- 8.96% vehicle; 98.61% +/- 10.04% sildenafil; 68.46% +/- 15.84% vardenafil). Hypoxia-induced upregulation of TNF-alpha and IL-1beta mRNA in pulmonary artery was significantly decreased by tadalafil, but not sildenafil or vardenafil pretreatment.. We conclude that sildenafil, vardenafil, and tadalafil were equally efficacious in causing pulmonary artery relaxation, but only tadalafil inhibited hypoxic pulmonary vasoconstriction and attenuated hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Evaluation, Preclinical; Gene Expression Regulation; Hypertension, Pulmonary; Hypoxia; Imidazoles; Interleukin-1; Isometric Contraction; Male; Phenylephrine; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Tumor Necrosis Factor-alpha; Vardenafil Dihydrochloride; Vasoconstriction

The stability of sildenafil citrate 2.5 mg/mL in two extemporaneously prepared oral suspensions stored at 4 and 25 degrees C was studied.. Thirty 25-mg tablets of sildenafil citrate were ground to powder, and the powder was combined with a 1:1 mixture of Ora-Sweet and Ora-Plus or a 1:1 mixture of methylcellulose 1% and Simple Syrup, NF, to produce two 2.5-mg/mL suspensions. Five plastic bottles of each suspension were stored in amber plastic prescription bottles at 4 or 25 degrees C. Samples were collected on days 0, 7, 14, 28, 42, 56, 70, and 91 for analysis of sildenafil content by high-performance liquid chromatography; pH was also measured. Samples were visually observed against black and white backgrounds.. The mean concentration of sildenafil citrate exceeded 98% of the initial concentration in all samples at both temperatures throughout the 91-day study period. No changes in pH, odor, or physical appearance were observed.. Sildenafil citrate 2.5 mg/mL in two extemporaneously compounded oral suspensions was stable for 91 days in plastic prescription bottles at 4 and 25 degrees C.

Topics: Child; Drug Stability; Drug Storage; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Suspensions; Temperature; Vasodilator Agents

Topics: Adult; Female; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

To evaluate the effects of phosphodiesterase type III and V (PDEIII and PDEV) inhibition on pulmonary and systemic haemodynamics in a porcine model of acute pulmonary hypertension.. Twenty-four adult swine were anaesthetized with 1 MAC isoflurane and mechanically ventilated with an FI(O(2)) of 100%. Micromanometer-tipped catheters were placed in the ascending aorta, pulmonary artery and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue, U46619. The animals were then randomized to four groups: Group 1 (n=6) received 50 mg of sildenafil (PDEV inhibitor) diluted in water via an orogastric tube; Group 2 (n=6) received 50 microg kg(-1) of i.v. milrinone (PDEIII inhibitor); Group 3 (n=6) received sildenafil followed by milrinone; and Group 4 (n=6) received placebo via an orogastric tube.. Pulmonary hypertension was achieved in all animals. Calculated pulmonary vascular resistance decreased by an average of 36% after sildenafil (P<0.05), 41% after milrinone (P<0.05), and 61% with both drugs combined (P<0.05). Systemic vascular resistance decreased by 37% (P<0.05) with milrinone alone, and 36% (P<0.05) with milrinone and sildenafil combined but it was preserved in the sildenafil group. Cardiac output and right ventricular dP/dT were significantly improved after milrinone or both drugs combined, but not with sildenafil.. Milrinone and sildenafil are effective pulmonary vasodilators, with independent action and additive effect. Both drugs combined achieved a better haemodynamic profile, with greater pulmonary vasodilatation and increased contractility but without additional systemic vasodilatation. The systemic haemodynamic profile (systemic vasodilation, cardiac output, right ventricular dP/dT) is improved with milrinone but not with sildenafil.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-AMP Phosphodiesterases; Acute Disease; Animals; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Disease Models, Animal; Drug Evaluation; Drug Therapy, Combination; Hemodynamics; Hypertension, Pulmonary; Milrinone; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

Oral sildenafil has been demonstrated to be an effective treatment for pulmonary hypertension, and is increasingly used in children. We report an infant with pulmonary hypertension, stable on regular treatment with oral sildenafil, who presented in acute respiratory failure after aspiration, requiring ventilation and intensive care. The course of the stay in intensive care was difficult, with recurrent pulmonary hypertensive crises despite use of oral sildenafil, use of 100% oxygen, high frequency oscillatory ventilation, and inhaled nitric oxide. In view of his instability, and the presumed inability to absorb the sildenafil orally due to gastrointestinal malabsorption, sildenafil was administered as a continuous intravenous infusion. With this therapy, it proved possible to wean from oxygen, nitric oxide, and ventilatory support. Intravenous sildenafil, therefore, might be an effective alternative for children with pulmonary hypertension during episodes of acute deterioration and malabsorption, preventing life-threatening pulmonary hypertensive crises. Its pharmacokinetics, efficacy, and safety, nonetheless, need to be validated in randomized controlled trials.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infant; Infusions, Intravenous; Malabsorption Syndromes; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Brain natriuretic peptide (BNP) blunts hypoxic pulmonary hypertension in animal models, but its acute hemodynamic effects in patients with pulmonary arterial hypertension (PAH) are not known. The aim of this study was to determine if human B-type natriuretic peptide is a safe and efficacious pulmonary vasodilator in patients with PAH and if the pulmonary hemodynamic effects are potentiated by phosphodiesterase inhibition.. Open-label study.. Medical ICUs of three tertiary care hospitals in New England.. Thirteen consecutive adult patients undergoing right-heart catheterization and a pulmonary vasodilator trial for the initial evaluation of PAH.. Patients were administered inhaled nitric oxide (iNO), i.v. epoprostenol, and a 3-h infusion of BNP alone and 1 h after an oral dose of the phosphodiesterase-5 inhibitor sildenafil.. iNO and sildenafil alone decreased mean pulmonary artery pressure (mPAP) without a significant fall in pulmonary vascular resistance (PVR). Epoprostenol decreased both mPAP and PVR. BNP alone had no significant effect on pulmonary hemodynamics, but the combination of sildenafil plus BNP decreased mPAP and PVR for up to 6 h after stopping BNP. The decrease in mPAP with sildenafil plus BNP (+/- SE) was greater than after 1 h of sildenafil alone (44.6 +/- 3.8 to 40.6 +/- 3.9 mm Hg, p = 0.027). An acute vasodilator response, defined as a decrease in mPAP > 10 mm Hg and end mPAP < 40 mm Hg, was seen in 0 of 8 patients with iNO, 1 of 13 patients with epoprostenol, 0 of 13 patients with BNP, and 4 of 12 patients with sildenafil plus BNP. BNP decreased mean systemic arterial pressure (5.6 +/- 2.8 mm Hg) but had no effect on cardiac output or systemic vascular resistance.. A 3-h BNP infusion does not significantly improve pulmonary hemodynamics in most patients with PAH but is well tolerated and augments the acute pulmonary vasodilator effect of sildenafil.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Aged, 80 and over; Blood Pressure; Drug Synergism; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Natriuretic Peptide, Brain; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Cystic fibrosis (CF) patients with advanced lung disease are at risk for developing pulmonary vascular disease and pulmonary hypertension, characterized by progressive exercise intolerance beyond the exercise-limiting effects of airways disease in CF. We report on a patient with severe CF lung disease who experienced clinically significant improvements in exercise tolerance and pulmonary hypertension without changing lung function during sildenafil therapy.

Topics: Adult; Cystic Fibrosis; Exercise Tolerance; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

In Europe intravenous (IV) iloprost, an alternative to epoprostenol, is an accepted treatment option for severely compromised patients with idiopathic pulmonary arterial hypertension (IPAH). Once initiated, this therapy usually has to be continued lifelong or as bridging to transplantation. In our paper we describe two patients with IPAH in World Health Organisation (WHO) functional classes II and III while on treatment with continuous IV iloprost monotherapy or combination therapy with continuous IV iloprost plus oral bosentan, respectively. The duration of IV iloprost therapy was 4.5 and 2.5 years, respectively. Because of life-threatening or recurring catheter-related complications during long-term IV iloprost therapy, these patients were switched to non-invasive combination therapy consisting of oral bosentan plus aerosolized iloprost (patient 1) and oral bosentan plus aerosolized iloprost plus oral sildenafil (patient 2), respectively. After four weeks of additional bosentan therapy, stepwise reduction and discontinuation of IV iloprost were performed within eight hours in the patient in WHO class II, and within five days in the patient in WHO class III. Simultaneously, therapy with aerosolized iloprost was started in the first patient and with aerosolized iloprost plus sildenafil in the second patient. Both patients were safely switched from IV iloprost to non-invasive combination therapy while WHO classification of functional status remained unchanged for at least 12 and 14 months, respectively. These data suggest that selected patients with complications due to IV iloprost treatment can be safely switched to non-IV combination therapies.

Topics: Antihypertensive Agents; Bosentan; Drug Administration Schedule; Drug Combinations; Female; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Middle Aged; Patient Selection; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

To study systemic and pulmonary effects of low-dose sildenafil with surfactant in newborn piglets with pulmonary hypertension (PHT) induced by thromboxane A(2) analog (U46619).. Piglets (1-3 days, 1.7-2.5 kg) were mechanically ventilated and prepared for the continuous measurement of mean systemic and pulmonary arterial pressures (MAP and PAP, respectively), heart rate and pulmonary artery flow (as cardiac output). Following stabilization, PHT was induced by intravenous U46619 infusion (0.2-0.8 microg/kg/min) for 120 min. Piglets were randomized for intratracheal administration of surfactant (BLES, 4 ml/kg) with saline (n=6) or sildenafil (0.05 mg/kg, n=6) given after 60 min of U46619 treatment. Temporal changes of hemodynamic measurements were analyzed by two-way ANOVA.. There was progressive PHT induced by U46619 (161% of baseline), with increased PAP and pulmonary vascular resistance and decreased cardiac output. Surfactant and sildenafil combined improved PAP along with reduced pulmonary vascular resistance. Cardiac output was higher with surfactant and sildenafil combined than surfactant alone. No significant changes in heart rate, stroke volume, MAP and systemic vascular resistance were observed. Ratio of PAP:MAP was lowered with surfactant and sildenafil combined. Systemic oxygen consumption was not different between groups but the oxygen extraction ratio was higher than baseline in surfactant alone (P<0.05).. Adding low-dose sildenafil to surfactant is effective in alleviating the progressive PHT developed in newborn piglets induced by thromboxane A(2). Intratracheal sildenafil may be a useful therapeutic adjunct to critically ill neonates with PHT.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Blood Pressure; Drug Therapy, Combination; Hypertension, Pulmonary; Intubation, Intratracheal; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Surface-Active Agents; Swine; Vascular Resistance; Vasoconstrictor Agents

This report describes a patients with PPH with atrial septal aneurysm and a severe right to left shunt through the patent foramen ovale who showed a dramatic decrease in the pulmonary artery systolic pressure and interatrial shunt disappeared after sildenafil treatment.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Blood Pressure; Echocardiography, Transesophageal; Female; Heart Aneurysm; Heart Septal Defects, Atrial; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Artery; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Human Immunodeficiency Virus (HIV)-related pulmonary hypertension is a relatively rare disease that can affect HIV sufferers. This is almost always associated with a poor outcome and death. An 18 month-old girl, probably the youngest on record, was diagnosed to have pulmonary hypertension (PHT) and retrospectively found to have HIV infection. Sildenafil was used to control her PHT and she remains alive even after 2 years.

Topics: Cardiomegaly; Enzyme-Linked Immunosorbent Assay; Female; HIV Infections; Humans; Hypertension, Pulmonary; Infant; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Humans; Hypertension, Pulmonary; Patient Selection; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Sildenafil Citrate; Sulfones

Topics: Cardiac Output, Low; Heart; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension can complicate the early clinical course in newborn infants with congenital diaphragmatic hernia. We report the successful use of combination therapy with enteral sildenafil and intravenous prostaglandin E1 in a preterm infant with severe pulmonary hypertension and right heart failure early after congenital diaphragmatic hernia repair.

Topics: Alprostadil; Drug Therapy, Combination; Heart Failure; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Piperazines; Postoperative Care; Premature Birth; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Administration, Inhalation; Epoprostenol; Fatal Outcome; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Pneumothorax; Purines; Sildenafil Citrate; Sulfones

Sildenafil, tezosentan, and prostacyclin reduce pulmonary vascular pressures in pulmonary hypertension, but have potential to vasodilate the systemic circulation. Nebulized vasodilators allow targeted drug delivery, high local drug concentrations, less systemic hypotension, and better matching of the lung's ventilation and perfusion. We aimed to estimate pulmonary deposition of these drugs from commonly employed nebulizers using in vitro techniques and to create a mathematical model to predict inspired mass of aerosol.. Lung deposition was estimated by characterization of drug output and particle size distribution (PSD) of nebulizers using helium-neon laser diffraction techniques. A mathematical model for each device was created to estimate pulmonary deposition using patients' breathing patterns and was verified with a mechanical-breathing model.. Total output and PSD were similar for the Hudson Updraft II and Whisperjet nebulizers, consisting of half the nebulizer's charge, with (1/4) of particles < or = 5 microm, in the respirable fraction (RF). Drug output increased with inspiratory flow for the Pari LC Star. Differences were noted in device performance, depending on the drug tested. Estimated pulmonary deposition (mean, 95% CI) was 8.1 (7.2, 9.0)% of the initial drug charge for the Hudson Updraft II, 6.4 (5.8, 7.0)% for the Whisperjet, and 33.0 (28.3, 37.9)% for the Pari LC Star. A mechanical model was consistent with our mathematical model.. All drugs could be nebulized, but expected pulmonary deposition varied depending on the nebulizer and drug.

Topics: Adolescent; Antihypertensive Agents; Child; Epoprostenol; Humans; Hypertension, Pulmonary; Models, Theoretical; Nebulizers and Vaporizers; Piperazines; Purines; Pyridines; Sildenafil Citrate; Sulfones; Tetrazoles; Vasodilator Agents

Endothelial dysfunction is likely to contribute to the pathogenesis of idiopathic Pulmonary Arterial Hypertension (iPAH). We hypothesize that there are different patterns of endothelial cell function, which we studied in 17 children with iPAH.. Pulmonary flow reserve was determined by acetylcholine infusion into segmental pulmonary arteries utilizing quantitative angiography and intra-arterial Doppler flow wire. Depending on the reactivity of the pulmonary to systemic arterial pressure ratio to short-term oxygen and intravenous epoprostenol or aerosolized iloprost responders and nonresponders were classified. In 7 responders to oxygen-prostanoid administration the pressure ratio decreased from 0.9 +/- 0.2 to 0.31 +/- 0.11 (p = 0.01), the mean pulmonary flow reserve showed an excessive increase to 3.6 +/- 2.0 (p = 0.01) after infusion of acetylcholine. In 10 non-responders the pressure ratios remained unchanged during oxygen-prostanoid testing. 4 of 5 patients without any effect to acetylcholine died despite long-term epoprostenol treatment. The other 5 nonresponders to oxygen-prostanoid showed an impaired but significant increase of the pulmonary flow reserve of 1.6 +/- 1.1 (p = 0.01). 2 of these patients did not only improve clinically, but regained vascular reactivity by additional therapy with sildenafil.. Endothelial reactivity in iPAH is either extensive, impaired or absent. Acetylcholine infusion casts a light on the pathogenesis and has implications for therapy.

Topics: Acetylcholine; Adolescent; Blood Pressure; Child; Child, Preschool; Endothelial Cells; Epoprostenol; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infant; Lung; Piperazines; Purines; Regional Blood Flow; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil, an oral phosphodiesterase Type 5 inhibitor, has vasodilatory effects through a cGMP-dependent mechanism. We previously showed that aortic banding could result in left ventricular overloading and pulmonary hypertension (PH). In this study, we investigated whether early administration of sildenafil, either immediately after or 2 weeks after aortic banding, could ameliorate the development of PH and alter gene expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS), and alter the levels of cGMP in rats undergoing an ascending aortic banding. Rats (n = 32) were divided into sham-operated and banding groups with or without treatment. The banded rats were further divided into three groups: (i) receiving saline on Days 1-28 (AOB28; n = 8), (ii) receiving saline on Days 1-14 followed by treatment with 50 mg/kg/day sildenafil on Days 15-28 (AOB28/Sil(15-28); n = 8), and (iii) receiving 50 mg/kg/day sildenafil on days 1-28 (AOB28/Sil(1-28); n = 8). The sham-operated rats were administrated saline on Days 1-28 (n = 8). Four weeks after banding, there was a significant development of PH with pulmonary vascular remodeling. Although both sildenafil-treatment groups had significant increases in cGMP and had reductions in the thickening in the medial layer of pulmonary arteriole, notable attenuation of PH occurred only in the AOB28/Sil(1-28) group. PreproET-1 and eNOS messenger RNA (mRNA) expressions were measured by competitive reverse transcription polymerase chain reaction, and eNOS protein was determined by Western blotting. Sildenafil did not alter the elevated ET-1 or preproET-1 mRNA in banded rats. Interestingly, pulmonary eNOS increased in the AOB28/Sil(1-28) group. In conclusion, early treatment with sildenafil inhibited the rise in pulmonary arterial pressure and pulmonary vascular remodeling in PH secondary to heart failure, and cGMP, but not ET-1, might be involved. Clinically, early repeated administration of sildenafil may offer an alternative in protecting against PH in heart failure.

Topics: Animals; Cyclic GMP; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Male; Nitric Oxide Synthase Type III; Phosphodiesterase Inhibitors; Piperazines; Purines; Random Allocation; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones

The dual endothelin receptor antagonist, bosentan, and the phosphodiesterase inhibitor, sildenafil, are efficacious in experimental and clinical pulmonary hypertension (PHT). The effects of bosentan, sildenafil, and their combination were evaluated in rats with monocrotaline (MCT)-induced PHT. A first group consisted of control rats with no MCT injection. Four other groups of rats received MCT subcutaneously and were assigned to receive no treatment, 300 mg/kg/day bosentan as food admix, 100 mg/kg/day sildenafil in drinking water, or their combination for 4 weeks. The doses of bosentan and sildenafil were the maximally effective doses based on a dose-range-finding study. Mortality was 0%, 53%, 11%, 11%, and 0%, respectively, in the five different groups. Bosentan and sildenafil significantly attenuated the increase in mean pulmonary arterial pressure, and the combination had an additional effect. Similarly, bosentan, sildenafil, and, to a greater extent, their combination significantly reduced right ventricular (RV) hypertrophy. Bosentan, but not sildenafil, decreased norepinephrine and BNP plasma concentrations, reduced kidney weight, and normalized systemic hemodynamics. In conclusion, bosentan and sildenafil are efficacious in rats with chronic PHT, and their combination shows an additional effect for decreasing pulmonary arterial pressure, reducing plasma catecholamines, maintaining body weight, and reducing mortality.

Topics: Animals; Bosentan; Disease Models, Animal; Drug Therapy, Combination; Endothelin Receptor Antagonists; Hypertension, Pulmonary; Male; Monocrotaline; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfonamides; Sulfones

Sildenafil has been shown to be an effective treatment of pulmonary arterial hypertension and is believed to present with pulmonary selectivity. This study was designed to determine the site of action of sildenafil compared with inhaled nitric oxide (NO) and intravenous sodium nitroprusside (SNP), known as selective and nonselective pulmonary vasodilators, respectively. Inhaled NO (40 ppm), and maximum tolerated doses of intravenous SNP and sildenafil, (5 microg x kg(-1) x min(-1) and 0.1 mg x kg(-1) x h(-1)), respectively, were administered to eight dogs ventilated in hypoxia. Pulmonary vascular resistance (PVR) was evaluated by pulmonary arterial pressure (Ppa) minus left atrial pressure (Pla) vs. flow curves, and partitioned into arterial and venous segments by the occlusion method. Right ventricular hydraulic load was defined by pulmonary arterial characteristic impedance (Zc) and elastance (Ea) calculations. Right ventricular arterial coupling was estimated by the ratio of end-systolic elastance (Ees) to Ea. Decreasing the inspired oxygen fraction from 0.4 to 0.1 increased Ppa - Pla at a standardized flow of 3 l x min(-1) x m(-2) from 6 +/- 1 to 18 +/- 1 mmHg (mean +/- SE). Ppa - Pla was decreased to 9 +/- 1 by inhaled NO, 14 +/- 1 by SNP, and 14 +/- 1 mmHg by sildenafil. The partition of PVR, Zc, Ea, and Ees/Ea was not affected by the three interventions. Inhaled NO did not affect systemic arterial pressure, which was similarly decreased by sildenafil and SNP, from 115 +/- 4 to 101 +/- 4 and 98 +/- 5 mmHg, respectively. We conclude that inhaled NO inhibits hypoxic pulmonary vasoconstriction more effectively than sildenafil or SNP, and sildenafil shows no more selectivity for the pulmonary circulation than SNP.

Topics: Administration, Inhalation; Anesthetics, Intravenous; Animals; Blood Pressure; Chloralose; Dogs; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hypertension, Pulmonary; Hypoxia; Injections, Intravenous; Nitric Oxide; Nitroprusside; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

In neonates with acute pulmonary hypertension (PHT), the dose-response effect of sildenafil citrate, a selective phosphodiesterase-5 inhibitor that can alleviate PHT, has not been detailedly examined. We tested the hypothesis that the treatment of hypoxia-induced acute PHT with sildenafil would dose-dependently reduce the elevated pulmonary and systemic arterial pressures (PAP and SAP, respectively) with no effect on the oxygenation in newborn animals. We also examined the regional hemodynamic responses. Using a randomized controlled design, piglets (age range, 1-3 days; weight range, 1.5-2.1 kg) were anesthetized and acutely instrumented to measure cardiac index, left common carotid, superior mesenteric and left renal arterial flow indexes, SAP, and PAP. After stabilization, hypoxia was induced with fractional inspired oxygen concentration at 0.15 and, subsequently, piglets were randomized to receive i.v. sildenafil at 0.06, 0.2, or 2.0 mg/kg per hour or normal saline (controls) for 90 min (n = 6 each). Within 30 min of hypoxia (PaO2, 31 +/- 5 mmHg), the piglets developed PHT (PAP, 33 +/- 5 vs. 26 +/- 4 mmHg at baseline; P < 0.05. Sildenafil dose-dependently reduced the hypoxia-induced PHT (PAP at 90 min: 33 +/- 6, 29 +/- 6, and 26 +/- 6 mmHg of 0.06, 0.2, and 2.0 mg/kg per hour, respectively, vs. 44 +/- 8 mmHg of controls; P < 0.05. Sildenafil at 2.0 mg/kg per hour had the greatest decrease in SAP (P < 0.05) with no significant change at 0.06 and 0.2 mg/kg per hour. Pulmonary selectivity (PAP:SAP ratio) was best in the group treated with 0.2 mg/kg per hour dosage of sildenafil (P < 0.05). There were no differences in cardiac index and regional flow indexes between groups. Although hypoxia decreased oxygen delivery and increased oxygen extraction with no significant effect on oxygen consumption, the administration of sildenafil did not affect the oxygen metabolism (vs. controls). In neonatal piglets, i.v. sildenafil dose-dependently alleviates the hypoxia-induced acute PHT, with the best pulmonary selectivity at 0.2 mg/kg per hour, and shows no significant effect on regional circulation and oxygen metabolism.

Topics: Animals; Animals, Newborn; Blood Flow Velocity; Blood Pressure; Dose-Response Relationship, Drug; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Kidney; Oxygen Consumption; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine; Vasodilator Agents

Portopulmonary hypertension is a recognized but uncommon complication of cirrhosis. Liver transplantation may be contraindicated in patients with severe portopulmonary hypertension. In order to decrease the pulmonary arterial pressure, intravenous administration of epoprostenol has been shown to provide substantial beneficial results in these patients. Additionally, a recent case report demonstrated that long-term oral administration of sildenafil decreased pulmonary arterial pressure, but its effects on splanchnic hemodynamics were not measured. We report on a patient with cirrhosis and portopulmonary hypertension and the changes in the hemodynamic status after an oral administration of sildenafil. This case report clearly delineates that sildenafil decreases pulmonary arterial pressure but may exacerbate portal hypertension and hyperdynamic circulation in patients with cirrhosis and portopulmonary hypertension.

Topics: Adult; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Antihypertensive Agents; Bosentan; Disease Management; Drug Interactions; Endothelin Receptor Antagonists; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Isoxazoles; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Vasodilator Agents; Walking

Skeletal manifestations are the hallmark of the osteogenesis imperfecta group of disorders. Extraskeletal involvement may, however, contribute significantly to morbidity. Structural cardiovascular anomalies reported in osteogenesis imperfecta include aortic root dilatation and aortic and mitral valve dysfunction. Herein is reported the first case of involvement of the right side of the heart in osteogenesis imperfecta.

Topics: Endothelium-Dependent Relaxing Factors; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Infant, Newborn; Length of Stay; Nitric Oxide; Osteogenesis Imperfecta; Patient Discharge; Piperazines; Purines; Radiography, Thoracic; Sildenafil Citrate; Sulfones; Treatment Outcome; Tricuspid Valve; Ultrasonography; Vasodilator Agents

New oral substances such as beraprost, bosentan and sildenafil have proven effective in different forms of pulmonary arterial hypertension (PAH), both alone and in combination with standard treatment such as intravenous and inhaled prostacyclins. However, there are few reports so far on the effect of a combination of exclusively oral substances. In this paper, we present our initial findings of treatment using a combination of these oral substances in a heterogeneous group of patients with different forms of PAH.. Eleven patients with a median age of 12.9 years (5.5-54.7 years) with both idiopathic PAH and forms associated with congenital cardiac defects (PAH-CHD) with a mean pulmonary arterial pressure > 25 mmHg were enrolled in an observational, open-label, prospective, single-centre study. Either combination treatment with bosentan and sildenafil was started initially, or an existing bosentan treatment was complemented with sildenafil given as an add-on therapy. Mean doses given were 2.3 +/- 0.6 mg kg(-1) for bosentan and 2.1 +/- 0.9 mg kg(-1) for sildenafil. Clinical status, exercise capacity, and haemodynamics were assessed at baseline and at the end of the observation period after a mean follow-up time of 1.1 years (0.5-2.5 years).. No major side effects regarding liver function and blood pressure regulation were noted. One patient died of sudden death elsewhere. Most patients were in New York Heart Association (NYHA) functional class III. Clinical improvement was about one NYHA class (mean 2.8 +/- 0.4-1.6 +/- 0.8, P = 0.001), which was associated with an increase of transcutaneous oxygen saturation (89.9 +/- 9.9-92.3 +/- 7.1%; P = 0.037), maximum oxygen uptake (18.1 +/- 6.8-22.8 +/- 10.4 mL kg(-1) x min; P = 0.043), and 6-minute walking distance (351 +/- 58-451 +/- 119 m; P = 0.039). Mean pulmonary arterial pressure measured invasively decreased (62 +/- 12-46 +/- 18 mmHg; P = 0.041).. In our patient group, a combination of oral bosentan and sildenafil proved to be safe and effective. Clearly, randomized, double-blind, placebo-controlled studies are warranted to define the role and type of combination therapies in PAH.

Topics: Administration, Oral; Adolescent; Adult; Antihypertensive Agents; Bosentan; Child; Child, Preschool; Drug Therapy, Combination; Endothelin Receptor Antagonists; Exercise Test; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Idiopathic pulmonary arterial hypertension (IPAH) is an uncommon and devastating disease which, if untreated, progresses rapidly and leads to right heart failure and death. The course of the disease has been altered by advances in medical therapies. However, the effects of long-term alternative therapies and responses to each treatment protocols are not definite. We want to define an IPAH case, which had long-term temporary responses to the conventional therapy plus calcium channel blockers treatment and moreover compared the long-term clinical and physiologic effects of oral sildenafil mono therapy and additional inhaled iloprost therapy. Patients with IPAH may have response to a short-term vasodilatation therapy but they have to follow for the long-term results and may be of benefit from combination treatments.

Topics: Administration, Inhalation; Adult; Diagnosis, Differential; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Iloprost; Male; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Vasodilator Agents

Idiopathic pulmonary arterial hypertension is a disease involving small muscular pulmonary arteries and arterioles. Treatment with prostacyclin analogs and endothelin receptor antagonists is the cornerstone of therapy in these patients. Recent evidence suggests that phosphodiesterase-5 inhibitors such as sildenafil may improve functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Despite these advances, pulmonary arterial hypertension remains a deadly and progressive disease and it has been suggested that combination therapy aimed at multiple targets may produce a greater improvement while minimizing adverse effects. We report three patients who declined after initial improvement on bosentan and subsequently showed an improvement in their functional capacity and brain natriuretic peptide (BNP) with the addition of sildenafil. This benefit has been sustained over a mean follow-up period of 19 (range 12-24) months.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Time Factors

Persistent pulmonary hypertension of the newborn (PPHN) was described in 1969 by Gersomy and co-workers as persistent foetal circulation. Supra - systemic pulmonary artery pressures result in right to left shunting of blood through the ductus arteriosus and/or foramen ovale. This results from failure of the normal adaptation to extra uterine life of the foetal heart/lung system. The incidence is estimated at about 0.1-0.2% of live born infants, majority being term or post term. There is no race or gender related predisposition. Management was always difficult before the advent of nitric oxide (and now sildenafil). We report two newborn infants born at The Mater Hospital with perinatal asphyxia resulting inpersistent pulmonary hypertension that were successfully managed with sildenafil.

Topics: Asphyxia Neonatorum; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Hypoxia; Infant, Newborn; Pharmacy Service, Hospital; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

We describe four cases of chronic pulmonary hypertension in infants and children with chronic lung disease and pulmonary hypoplasia due to severe congenital diaphragmatic hernia (CDH) or congenital cystic adenomatoid malformation (CCAM). We report data from cardiac catheterization under various conditions: baseline respiratory support and room air, hyperoxic and inhaled nitric oxide challenge. We further report cardiac catheterization measures after chronic pulmonary vasodilator therapy with sildenafil alone or a combination of sildenafil and inhaled nitric oxide (three patients).. Case series.. Tertiary academic center.. Infants and children ages 0-11 yrs with CDH (n = 3) or CCAM (n = 1) with evidence of chronic pulmonary hypertension by echocardiogram and cor pulmonale (n = 3).. Catheterization and pulmonary vasodilator therapy.. Pulmonary vascular resistance, pulmonary arterial pressure, and changes in these measures were assessed. A 20% change in pulmonary vascular resistance was considered a clinically significant response. Ten catheterizations were performed in four patients. All patients had elevated pulmonary vascular resistance and pulmonary arterial pressures at initial catheterizations and significant vasodilation during inhaled nitric oxide.. Chronic lung disease following pulmonary hypoplasia from CDH and CCAM is associated with abnormal pulmonary vascular tone in infants and children with evidence of chronic pulmonary hypertension. Chronic pulmonary vasodilator therapy may improve pulmonary vascular function and enhance lung growth in infants and children who are treated during their period of potential for rapid lung growth.

Topics: Cardiac Catheterization; Child; Child, Preschool; Chronic Disease; Cystic Adenomatoid Malformation of Lung, Congenital; Female; Free Radical Scavengers; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Lung; Lung Diseases; Male; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension is a serious disorder, difficult to treat especially in the severe forms. The treatment consists mainly of calcium channel blockers, anti-coagulation, intravenous epoprostenol, inhaled nitric oxide and recent agents as bosentan and sildenafil. Sildenafil, a phosphodiesterase 5 specific inhibitor, has been largely evaluated in primary pulmonary hypertension, and in some cases of secondary pulmonary hypertension including parenchymal and thromboembolic diseases; it has not yet been evaluated in severe pulmonary hypertension with elevated pre-capillary resistance in operated mitral stenosis. We report the cases of two patients operated from mitral valve replacement for severe mitral stenosis with elevated pre-capillary resistance, where oral sildenafil, introduced empirically immediately after the surgical procedure at the dose of 50 mg/d, permitted a significant decrease in pulmonary pressures and resistances, allowing a rapid withdrawal of nitric oxide and reducing therefore hospitalization time in the intensive care unit. We think that this simple treatment, with or without association to nitric oxide, should be generalized to persistent pulmonary hypertension following cardiac surgery.

Topics: Capillaries; Female; Humans; Hypertension, Pulmonary; Middle Aged; Mitral Valve Stenosis; Phosphodiesterase Inhibitors; Piperazines; Postoperative Care; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones

Severe pulmonary hypertension with no response to vasodilators on an acute hemodynamic study is a contraindication to cardiac transplantation. The development of oral pulmonary vasodilators improves the prognosis in these patients. We present the case of a patient whose admission to the waiting list for cardiac transplantation was possible after 6 months of combination therapy with Sildenafil and Bosentan.. The patient was a 50-year-old man with severe dilated alcohol-induced cardiomyopathy. A pretransplantation study, including a right hemodynamic analysis, revealed irreversible pulmonary hypertension, with 59 mm Hg mean pulmonary artery pressure and 6.4 Wood IU pulmonary vascular resistance, with no response to acute vasodilators with nitric oxide or prostacyclin. Initially, heart transplantation was not possible and the patient started treatment with oral Sildenafil. After 6 months there was no improvement in echocardiographic or hemodynamic parameters, and combination therapy with Bosentan was started. With the combination therapy, the patient progressively improved clinically and hemodynamically, the pressures becoming normal at the sixth month, at which time he was included on the waiting list for a heart transplantation. Eight months later he received a graft with a good posttransplantation course, no right ventricular failure in the acute phase, and absence of pulmonary hypertension on echocardiogrphic and invasive studies.. Combinations of an oral pulmonary vasodilator with diverse action mechanisms may represent an alternative for patients with irreversible pulmonary hypertension who do not respond to monotherapy.

Topics: Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents; Waiting Lists

Topics: Female; Humans; Hypertension, Pulmonary; Male; Natriuretic Peptide, Brain; Peptide Fragments; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventricular Remodeling

A 70-year-old man with a past history of lung resection for early stage lung cancer was admitted to our hospital because of worsening exertional dyspnea. Right heart catheterization revealed severe pulmonary arterial hypertension (PAH) with pulmonary vascular resistance of 1671.64 dyne.sec.cm(-5). The patient was treated with sildenafil added to an oral prostacyclin analog, beraprost, and long term oxygen therapy. His exertional dyspnea continued to improve until his sudden death following nasal bleeding. Autopsy revealed marked thickening of pulmonary arteriolar walls, but no recurrence of lung cancer, significant pulmonary embolism or pulmonary parenchymal disease. His PAH could not be explained by the mild airway obstruction or sleep apnea syndrome, and unrelated pulmonary vascular disease was suspected.

Topics: Aged; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Neoplasms; Male; Oxygen Inhalation Therapy; Phosphodiesterase Inhibitors; Piperazines; Pneumonectomy; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance

Topics: Female; Humans; Hypertension, Pulmonary; Middle Aged; Piperazines; Pulmonary Artery; Pulmonary Edema; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Myocardin gene has been identified as a master regulator of smooth muscle cell differentiation. Smooth muscle cells play a critical role in the pathogenesis of hypoxia-induced pulmonary hypertension (PH) and pulmonary vascular remodelling (PVR). The purpose of this study was to investigate the change of myocardin gene expression in the pulmonary vessels of hypoxia-induced PH affected by Sildenafil treatment and the involvement of endothelial cells transdifferentiation into smooth muscle cells in the process of hypoxia-induced PH and PVR. Myocardin and relative markers were investigated in animal models and cultured endothelial cells. Mean pulmonary artery pressure (mPAP) was measured. Immunohistochemistry and immunofluorescence were used to show the expression of smooth muscle alpha-actin (SMA), in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT-PCR) were performed respectively to detect the myocardin and SMA expression at mRNA levels. Small interfering RNA (siRNA) induced suppression of myocardin in cultured cells. We confirmed that hypoxia induced the PH and PVR in rats. Sildenafil could attenuate the hypoxia-induced PH. We found that myocardin mRNA expression is upregulated significantly in the hypoxic pulmonary vessels and cultured cells but downregulated in PH with Sildenafil treatment. The porcine pulmonary artery endothelial cells (PAECs) transdifferentiate into smooth muscle-like cells in hypoxic culture while the transdifferentiation did not occur when SiRNA of myocardin was applied. Our results suggest that myocardin gene, as a marker of smooth muscle cell differentiation, was expressed in the pulmonary vessels in hypoxia-induced PH rats, which could be downregulated by Sildenafil treatment, as well as in hypoxic cultured endothelial cells. Hypoxia induced the transdifferentiation of endothelial cells of vessels into smooth muscle-like cells which was regulated by myocardin.

Topics: Actins; Animals; Arterioles; Biomarkers; Cell Differentiation; Cells, Cultured; Endothelial Cells; Gene Expression Regulation; Hypertension, Pulmonary; Hypoxia; Immunohistochemistry; Male; Models, Animal; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nuclear Proteins; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sildenafil Citrate; Sulfones; Trans-Activators; Vasodilator Agents

We report our experience of using sildenafil in treatment on primary arterial pulmonary hypertension.. This case concern a 38 years old senegalese woman. She was hospitalised for global cardiac failure with right signs predominance and grade IV dyspnea related to pulmonary hypertension.. No evident cause of the pulmonary hypertension had been found after explorations. Adding sildénafil to her symptomatic treatment provided fast favourable evolution quantified by clinical test and Doppler-ultrasound heart examination. However the patient died three month later by cerebral hemorrhage due to overdose of antivitamine K.. We suggest using sildenafil in the treatment of primary arterial pulmonary hypertension on the way going to cardio-pulmonary transplantation.

Topics: Adult; Female; Humans; Hypertension, Pulmonary; Piperazines; Purines; Senegal; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Humans; Hypertension, Pulmonary; Infant, Newborn; Piperazines; Purines; Retinopathy of Prematurity; Sildenafil Citrate; Sulfones; Vasodilator Agents

We investigated the pulmonary vascular effects of prophylactic use of sildenafil, a specific phosphodiesterase-5 inhibitor, in late-gestation fetal lambs with chronic pulmonary hypertension. Fetal lambs were operated on at 129 +/- 1 days gestation (term = 147 days). Ductus arteriosus (DA) was compressed for 8 days to cause chronic pulmonary hypertension. Fetuses were treated with sildenafil (24 mg/day) or saline. Pulmonary vascular responses to increase in shear stress and in fetal PaO2 were studied at, respectively, day 4 and 6. Percent wall thickness of small pulmonary arteries (%WT) and the right ventricle-to-left ventricle plus septum ratio (RVH) were measured after completion of the study. In the control group, DA compression increased PA pressure (48 +/- 5 to 72 +/- 8 mmHg, P < 0.01) and pulmonary vascular resistance (PVR) (0.62 +/- 0.08 to 1.15 +/- 0.11 mmHg x ml(-1) x min(-1), P < 0.05). Similar increase in PAP was observed in the sildenafil group, but PVR did not change significantly (0.54 +/- 0.06 to 0.64 +/- 0.09 mmHg x ml(-1) x min(-1)). Acute DA compression, after brief decompression, elevated PVR 25% in controls and decreased PVR 35% in the sildenafil group. Increased fetal PaO2 did not change PVR in controls but decreased PVR 60% in the sildenafil group. %WT and RVH were not different between groups. Prophylactic sildenafil treatment prevents the rise in pulmonary vascular tone and altered vasoreactivity caused by DA compression in fetal lambs. These results support the hypothesis that elevated PDE5 activity is involved in the consequences of chronic pulmonary hypertension in the perinatal lung.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Chronic Disease; Ductus Arteriosus; Fetus; Hemodynamics; Hypertension, Pulmonary; Lung; Oxygen; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Circulation; Purines; Sheep; Sildenafil Citrate; Stress, Mechanical; Sulfones; Vascular Resistance; Vasodilation

Selective pulmonary vasodilators attenuate acute pulmonary embolism (APE)-induced pulmonary hypertension. We examined the effects of intravenous sildenafil on the hemodynamic and respiratory changes caused by APE in anesthetized dogs. Sham operated animals (n=3) received only saline infusions. APE was induced by intravenous injections of microspheres in amounts adjusted to increase mean pulmonary artery pressures (MPAP) by 20 mmHg. Hemodynamic evaluation was performed and arterial blood samples were drawn for blood gas analysis at baseline, 15 and 30 min after APE was induced, and then 15, 30, and 45 min after the sildenafil infusion (1 mg kg(-1) infused intravenously in 15 min followed by 0.3 mg kg(-1) h(-1) for 30 min) started in the Sildenafil group (n=7), or saline infusion started in the control group (n=8). APE induced sustained pulmonary hypertension and 325% increase in pulmonary vascular resistance index (PVRI) without significant changes in the other hemodynamic parameters. While the animals in the control group showed no further changes in MPAP and PVRI, a significant decrease in MPAP and PVRI (-25 and -45%, respectively; P<0.05 both) was observed with sildenafil. No significant changes in the other hemodynamic parameters were observed in both groups. APE decreased PaO2, whereas sildenafil attenuated the decrease in PaO2 (P<0.05). We conclude that intravenous sildenafil can selectively attenuate the increases in MPAP and PVRI after APE.

Topics: Animals; Dogs; Female; Heart Rate; Hypertension, Pulmonary; Infusions, Intravenous; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Embolism; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance

Sildenafil, a phosphodiesterase type-5 inhibitor, offers potential to treat pulmonary hypertension associated with a variety of conditions. We assessed the early impact of sildenafil on a cohort of patients referred to our unit who had severe pulmonary hypertension secondary to chronic thromboembolic disease which was not amenable to pulmonary thromboendarterectomy and who also had coexisting left ventricular dysfunction. Six patients were studied. Diagnosis of pulmonary embolic disease was made by ventilation perfusion scanning and/or CT pulmonary angiography. All patients were anticoagulated with oral coumarin derivatives and none were considered suitable for pulmonary thromboendarterectomy. Pulmonary hypertension was diagnosed by right heart catheterisation and each patient had Medical Research Council (MRC) dyspnoea score and New York Heart Association (NYHA) class noted and 2D echocardiography prior to commencement of sildenafil 50 mg three times a day. After 6 weeks of sildenafil therapy, right heart catheterisation and 2D echocardiography were repeated, and MRC dyspnoea score, NYHA class and exercise capacity were recorded. All patients demonstrated an improvement in mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, MRC dyspnoea score, NYHA class and gas transfer. No adverse effects of sildenafil were noted. Our data suggests that sildenafil is an effective and well-tolerated therapy for patients with severe pulmonary hypertension associated with pulmonary thromboembolic disease and impaired left ventricular function, producing beneficial effects as early as 6 weeks.

Topics: Adult; Aged; Cardiac Output; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Left

The present study addressed whether combined treatment with a phosphodiesterase type 5 inhibitor, sildenafil, and a nitric oxide donor, molsidomine, prevents development of pulmonary hypertension in chronic hypoxic rats. Two weeks of hypoxia increased right ventricular systolic pressure, and right ventricular and lung weight. Treatment with either sildenafil (10 mg/kg/day) or molsidomine (15 mg/kg/day) in drinking water reduced right ventricular systolic pressure and weight, while lung weight was unchanged. Combining sildenafil and molsidomine did not have additional effects compared to molsidomine alone. The number of muscularized pulmonary arteries with diameters below 50 microm was increased in vehicle and sildenafil-treated, but not in molsidomine-treated hypoxic rats. Acetylcholine relaxation was blunted in arteries from vehicle and molsidomine-treated, but not in sildenafil-treated rats. In conclusion, both sildenafil and molsidomine blunts pulmonary hypertension and right ventricular hypertrophy in chronic hypoxic rats, but no synergistic effects were observed.

Topics: Acetylcholine; Actins; Animals; Atrial Natriuretic Factor; Body Weight; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Guanylate Cyclase; Heart Ventricles; Hypertension, Pulmonary; Hypoxia; Lung; Male; Molsidomine; Muscle, Smooth; Oxadiazoles; Piperazines; Pulmonary Artery; Purines; Quinoxalines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Systole; Vasodilation; Vasodilator Agents

We report the case of a male patient who underwent orthotopic cardiac transplantation. A marginal donor was used, because the recipient's clinical condition was critical. He experienced cardiogenic shock due to right ventricular dysfunction secondary to pulmonary hypertension associated with vasoplegia. After the introduction of sildenafil, the patient recovered hemodynamically, his pulmonary vascular resistance decreased, the vasoactive drugs were withdrawn, and his right ventricular function improved.

Topics: Adult; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Function, Right

Use of inhaled nitric oxide for treatment of pulmonary hypertension in adult critical illness is limited by its mode of delivery and high costs, prompting evaluation of alternative therapies. We report the use of oral sildenafil in a patient with severe secondary pulmonary hypertension and right ventricular dysfunction. Following reduction in mean pulmonary artery pressure and pulmonary vascular resistance with inhaled nitric oxide, crossover to sildenafil therapy maintained control of pulmonary hypertension, facilitating discontinuation of respiratory and cardiovascular organ support. The relative pulmonary vascular specificity of oral sildenafil, and its low cost, makes it an attractive therapeutic alternative to inhaled nitric oxide, and warrants further study.

Topics: Administration, Oral; Aged; Critical Care; Female; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Although sildenafil, an oral phosphodiesterase type-5 inhibitor, may offer benefits in the pharmacological management of pulmonary hypertension (PH), safety and effectiveness have not been studied during coadministration with beraprost, an oral prostacyclin analogue. To address this issue, we administered oral beraprost (40 microg) on day 1 and beraprost (40 microg) plus sildenafil (25 mg) on days 2 to 6 patients with moderate to severe PH. Although sildenafil plus beraprost produced transient flushing in 2 of 6 patients, systemic hemodynamics and arterial and venous gas analyses were similar in comparisons between the 2 treatment groups. In contrast, sildenafil plus beraprost therapy resulted in a 2.2-fold greater reduction in mean pulmonary arterial pressure and a 1.6-fold greater reduction in pulmonary vascular resistance compared with beraprost alone, and reductions in these parameters persisted longer with combination therapy than with beraprost alone. Addition of oral sildenafil to beraprost appears to represent a safe and effective therapeutic option, at least in the acute phase, for patients with pulmonary hypertension.

Topics: Administration, Oral; Aged; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones

We hypothesized that chronic oral administration of the phosphodiesterase-5 inhibitor sildenafil could improve the exercise capacity and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH) on the basis of previous short-term studies. We tested this hypothesis in 14 subjects with PAH, including seven patients with the idiopathic form and seven patients with atrial septal defects, but no other congenital heart abnormalities. Patients were subjected to a 6-min walk test and dyspnea was graded according to the Borg scale. Pulmonary flow and pressures were measured by Doppler echocardiography. Patients were given sildenafil, 75 mg orally three times a day, and followed up for 1 year. Sildenafil therapy resulted in the following changes: increase in the 6-min walk distance from a median value of 387 m (range 0 to 484 m) to 462 m (range 408 to 588 m; P < 0.01), improvement of the Borg dyspnea score from 4.0 (median value) to 3.0 (P < 0.01), and increased pulmonary flow (velocity-time integral) from a median value of 0.12 (range 0.08 to 0.25) to 0.23 (range 0.11 to 0.40; P < 0.01) with no changes in pulmonary pressures. In one patient with pulmonary veno-occlusive disease diagnosed by a lung biopsy, sildenafil had a better effect on the pulmonary wedge pressure than inhaled nitric oxide (15 and 29 mmHg, respectively, acute test). He walked 112 m at baseline and 408 m at one year. One patient died at 11 months of treatment. No other relevant events occurred. Thus, chronic administration of sildenafil improves the physical capacity of PAH patients and may be beneficial in selected cases of veno-occlusive disease.

Topics: Adolescent; Adult; Echocardiography, Doppler; Exercise Tolerance; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

Portopulmonary hypertension is a poorly understood and uncommon complication of advanced chronic liver disease. Current therapy is based largely on treatment options proven in idiopathic pulmonary hypertension. The severity of the portopulmonary hypertension should best be attenuated medically before attempting combined liver and lung transplantation to avoid increased peri-operative mortality. This case report describes the successful use of sildenafil to decrease the pulmonary vascular resistance in a patient with hepatitis-C cirrhosis who was preparing for liver transplantation.

Topics: Female; Follow-Up Studies; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilation; Vasodilator Agents

Phosphodiesterase Type 5 (PDE5) inhibition represents a novel strategy for the treatment of pulmonary hypertension.. Our aim was to establish the distribution of PDE5 in the pulmonary vasculature and effects of PDE5 inhibition on pulmonary artery smooth muscle cells (PASMCs).. PDE5 expression was examined by immunohistochemistry and Western blotting, in both normal and hypertensive lung tissues. DNA synthesis, proliferation, PDE activity, and apoptosis were measured in distal human PASMCs treated with soluble guanylyl cyclase activators (nitric oxide donors and BAY41-2272) and sildenafil.. Cells containing PDE5 and alpha-smooth muscle actin occurred throughout the pulmonary vasculature, including obstructive intimal lesions. Three molecular forms of PDE5 were identified and protein expression was greater in hypertensive than control lung tissue. Most cyclic guanosine monophosphate hydrolysis (about 80%) in cultured cells was attributed to PDE5. Sildenafil induced a greater elevation of intracellular cyclic guanosine monophosphate levels compared with nitric oxide donors and BAY41-2272 (about 10-fold versus about 2-fold) and cotreatment had a synergistic effect, increasing cyclic nucleotide levels up to 50-fold. Dual stimulation of soluble guanylyl cyclase and inhibition of PDE5 activities also had significant downstream effects, increasing phosphorylation of vasodilator-stimulated phosphoprotein, reducing DNA synthesis and cell proliferation, and stimulating apoptosis, and these effects were mimicked by cyclic guanosine monophosphate analogs.. Phosphodiesterase Type 5 is the main factor regulating cyclic guanosine monophosphate hydrolysis and downstream signaling in human PASMCs. The antiproliferative effects of this signaling pathway may be significant in the chronic treatment of pulmonary hypertension with PDE5 inhibitors such as sildenafil.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Blotting, Western; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Hydrolysis; Hypertension, Pulmonary; Immunohistochemistry; Myocytes, Smooth Muscle; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones

Topics: Hemoglobinopathies; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adult; Hemoglobinopathies; Humans; Hypertension, Pulmonary; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

During the last decade new approaches to the treatment of pulmonary arterial hypertension (PH) have increased symptomatic relief and prolonged survival. PH is a common sequel of the hemoglobinopathies, thalassemia and sickle cell anemia, but the use of standard oral treatment options, such as calcium channel blockers, endothelin receptor antagonists, and long-term anticoagulation therapy, is limited because of toxicity and poor effectiveness. Sildenafil citrate is a selective and potent inhibitor of cGMP-specific phosphodiesterase-5 (PDE5) which promotes selective smooth muscle relaxation in lung vasculature and has been utilized successfully in the treatment of PH. The primary objective of this study was to evaluate the efficacy of sildenafil treatment in the control of PH in patients with hemoglobinopathies.. In this study patients with hemoglobinopathies (thalassemia intermedia n=4; thalassemia major n=2; sickle thalassemia n=1) suffering from severe PH were treated with sildenafil citrate (50 mg b.i.d.) for periods ranging from 4 to 48 months.. A significant decrease in pulmonary pressure and improvement in exercise capacity and functional class were observed in all patients. No significant adverse events were reported.. These data, in a small group of patients, indicate that sildenafil citrate is effective in the treatment of PH in hemoglobinopathies that cannot be treated with alternative oral drugs and is well tolerated long-term at a daily dose of 100 mg, though studies including more patients may uncover toxicities and limitations of efficacy.

Topics: Administration, Oral; Adult; Blood Transfusion; Clinical Trials as Topic; Dose-Response Relationship, Drug; Echocardiography, Doppler; Female; Hemoglobinopathies; Humans; Hypertension, Pulmonary; Male; Piperazines; Priapism; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Vasodilator Agents

Heart transplantation is contraindicated in patients with acute irreversible pulmonary hypertension (PH), but new drugs are opening up therapeutic possibilities. Sildenafil citrate is a nonselective pulmonary vasodilator that is being used in our hospital to treat several patients with PH and which has allowed the inclusion of 1 patient on the waiting list for heart transplantation. A 20-year-old man with Becker muscular dystrophy was diagnosed at the age of 19 years with dilated cardiomyopathy with severe pulmonary artery systolic pressure (PH = 60 mm Hg). A pretransplantation study, including a right hemodynamic analysis with an acute vasodilator test using intravenous epoprostenol, revealed the irreversible character of the PH. Inasmuch as the administration of dobutamine did not achieve an adequate reduction of PH, oral sildenafil was started (25 mg every 12 hours) as salvage therapy. An echocardiogram obtained 2 months after starting sildenafil therapy showed normal right cavities, previously dilated, as well as minimal protosystolic tricuspid regurgitation without PH. A new right hemodynamic study performed after 4 months showed a reduction in pulmonary vascular resistance, from 8 U to 3.5 U Woods. As a result, the patient has now been included on the waiting list for heart transplantation. The promising example of this patient confirms the necessity to carry out controlled trials to establish definitively the indications for the use of sildenafil in patients with irreversible PH.

Topics: Administration, Oral; Adult; Blood Pressure; Cardiac Output; Cardiomyopathy, Dilated; Echocardiography; Heart Rate; Heart Transplantation; Humans; Hypertension, Pulmonary; Male; Patient Selection; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

We report the use of oral sildenafil in a 5-month-old preterm infant with severe bronchopulmonary dysplasia and pulmonary arterial hypertension refractory to inhaled nitric oxide treatment, maximal ventilatory support and conventional vasodilator therapy. Sildenafil was prepared as a liquid suspension by the method of trituration and administered via an orogastric tube to the patient. Forty-eight hours after sildenafil treatment, echocardiography revealed that the tricuspid incompetence was substantially diminished and the contractility of both ventricles improved, indicating a marked reduction in pulmonary arterial pressure. Oral sildenafil treatment was continued for 6 months until complete resolution of pulmonary arterial hypertension, and oxygen supplement was weaned off. There was no adverse effect during the treatment period. Oral sildenafil may be useful in reducing pulmonary vascular resistance and can be considered for treatment of severe pulmonary arterial hypertension secondary to bronchopulmonary dysplasia.

Topics: Administration, Oral; Bronchopulmonary Dysplasia; Female; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications.

Topics: Administration, Oral; Animals; Animals, Newborn; Chronic Disease; Cyclic GMP; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Infant, Newborn; Infant, Newborn, Diseases; Lung; Piperazines; Pulmonary Artery; Purines; Reference Values; Sildenafil Citrate; Sulfones; Swine; Treatment Outcome; Vasodilator Agents

Topics: Activities of Daily Living; Aged; Disease Progression; Dyspnea; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

In patients with pulmonary hypertension (PH) secondary to congestive heart failure, inhaled nitric oxide (NO) increases pulmonary vascular smooth-muscle intracellular cyclic guanosine monophosphate (cGMP) concentration, thereby decreasing pulmonary vascular resistance (PVR) and increasing cardiac index (CI). However, these beneficial effects of inhaled NO are limited in magnitude and duration, at least in part due to cGMP hydrolysis by the type 5 isoform of phosphodiesterase (PDE5). The goal of this study was to determine the acute pulmonary and systemic hemodynamic effects of the selective PDE5 inhibitor, sildenafil, administered alone or in combination with inhaled NO in patients with congestive heart failure and PH.. Single center, case series, pharmacohemodynamic study.. Cardiac catheterization laboratory of a tertiary care academic teaching hospital.. We studied 11 patients with left ventricular systolic dysfunction due to coronary artery disease or idiopathic dilated cardiomyopathy who had PH.. We administered oral sildenafil (50 mg), inhaled NO (80 ppm), and the combination of sildenafil and inhaled NO during right-heart and micromanometer left-heart catheterization.. Sildenafil administered alone decreased mean pulmonary artery pressure by 12 +/- 5%, PVR by 12 +/- 5%, systemic vascular resistance (SVR) by 13 +/- 6%, and pulmonary capillary wedge pressure by 12 +/- 7%, and increased CI by 14 +/- 5% (all p < 0.05) [+/- SEM]. The combination of inhaled NO and sildenafil decreased PVR by 50 +/- 4%, decreased SVR by 24 +/- 3%, and increased CI by 30 +/- 4% (all p < 0.01). These effects were greater than those observed with either agent alone (p < 0.05). In addition, sildenafil prolonged the pulmonary vasodilator effect of inhaled NO. Administration of sildenafil alone or in combination with inhaled NO did not change systemic arterial pressure or indexes of myocardial systolic or diastolic function.. PDE5 inhibition with sildenafil improves cardiac output by balanced pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled NO in patients with chronic congestive heart failure and PH.

Topics: Adult; Bronchodilator Agents; Cardiac Output; Drug Therapy, Combination; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

There are few reports of pulmonary hypertension in Gaucher disease. We report a patient who showed significant clinical improvement after treatment with sildenafil.

Topics: Adult; Echocardiography; Female; Gaucher Disease; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Antihypertensive Agents; Bosentan; Drug Evaluation; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Bronchopulmonary dysplasia (BPD), the chronic lung disease of preterm infants, and pulmonary emphysema, both significant global health problems, are characterized by an arrest in alveolar growth/loss of alveoli structures. Mechanisms that inhibit distal lung growth are poorly understood, but recent studies suggest that impaired vascular endothelial growth factor signaling and reduced nitric oxide (NO) production decreases alveolar and vessel growth in the developing lung, features observed in experimental oxygen-induced BPD. NO exerts its biological activity by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production.. Because cGMP is inactivated by phosphodiesterase (PDE) enzymes, we hypothesized that the cGMP-specific PDE5 inhibitor sildenafil would promote angiogenesis and attenuate oxygen-induced lung injury in newborn rats. METHODS, MEASUREMENTS, AND MAIN RESULTS: In vitro, sildenafil (10(-4) M) increased endothelial capillary network formation of human pulmonary endothelial cells exposed to hyperoxia. In vivo, rat pups were randomly exposed from birth to normoxia, hyperoxia (95% O(2), BPD model), and hyperoxia+sildenafil (100 mg/kg/day subcutaneously). Rat pups exposed to hyperoxia showed fewer and enlarged air spaces as well as decreased capillary density, mimicking pathologic features seen in human BPD. These structural anomalies were associated with echographic (decreased pulmonary acceleration time) and structural (right ventricular hypertrophy and increased medial wall thickness) signs of pulmonary hypertension. Sildenafil preserved alveolar growth and lung angiogenesis, and decreased pulmonary vascular resistance, right ventricular hypertrophy and medial wall thickness.. Our findings suggest a role for the NO/cGMP pathway during alveolar development. Sildenafil may have therapeutic potential in diseases associated with impaired alveolar structures.

Topics: Animals; Animals, Newborn; Cells, Cultured; Cyclic GMP; Humans; Hypertension, Pulmonary; Lung; Lung Diseases; Neovascularization, Physiologic; Oxygen; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Alveoli; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Ultrasonography, Doppler

Topics: Adult; Anti-Inflammatory Agents; Cyclophosphamide; Drug Therapy, Combination; Dyspnea; Female; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Methylprednisolone; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Failure; Vasodilator Agents

To determine whether bosentan decreases the plasma concentration of sildenafil in patients with pulmonary arterial hypertension.. Ten patients (aged 39-77 years) with pulmonary arterial hypertension in WHO functional class III received bosentan 62.5 mg twice daily for 1 month, then 125 mg twice daily for a second month. Sildenafil 100 mg was given as a single dose before starting bosentan (visit 1) and at the end of each month of bosentan treatment (visits 2 and 3). Sildenafil and its primary metabolite, desmethylsildenafil, were measured in plasma at 0 h and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 h using liquid chromatography-tandem mass spectrometry. Statistical analysis was by repeated measures anova, using log transformed data where appropriate.. Treatment with bosentan 62.5 mg twice daily for 4 weeks was associated with a two-fold increase in sildenafil clearance/F and a 50% decrease in the AUC (P < 0.001). Increasing the dose of bosentan to 125 mg twice daily led to a further increase in sildenafil oral clearance and decrease in the AUC (P < 0.001 vs. 62.5 mg bosentan). The ratio of AUC on bosentan treatment relative to that of visit 1 was 0.47 [95% confidence interval (CI) 0.36, 0.61] for visit 2 and 0.31 (95% CI 0.23, 0.41) for visit 3 (P < 0.001). Sildenafil C(max) fell from 759 ng ml(-1) on visit 1 to 333 ng ml(-1) on visit 3 (P < 0.01) and there was a significant decrease in the plasma half-life of sildenafil on the higher bosentan dose (P < 0.05). The AUC and plasma half-life of desmethylsildenafil was also decreased by bosentan in a dose-dependent manner (P < 0.01).. Bosentan significantly decreases the plasma concentration of sildenafil when coadministered to patients with pulmonary hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Area Under Curve; Bosentan; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones

Persistent pulmonary hypertension of the newborn (PPHN) is partly due to impaired nitric oxide (NO)-cGMP signaling. BAY 41-2272 is a novel direct activator of soluble guanylate cyclase, but whether this drug may be an effective therapy for PPHN is unknown. We hypothesized that BAY 41-2272 would cause pulmonary vasodilation in a model of severe PPHN. To test this hypothesis, we compared the hemodynamic response of BAY 41-2272 to acetylcholine, an endothelium-dependent vasodilator, and sildenafil, a selective inhibitor of PDE5 in chronically instrumented fetal lambs at 1 and 5 days after partial ligation of the ductus arteriosus. After 9 days, we delivered the animals by cesarean section to measure their hemodynamic responses to inhaled NO (iNO), sildenafil, and BAY 41-2272 alone or combined with iNO. BAY 41-2272 caused marked pulmonary vasodilation, as characterized by a twofold increase in blood flow and a nearly 60% fall in PVR at day 1. Effectiveness of BAY 41-2272-induced pulmonary vasodilation increased during the development of pulmonary hypertension. Despite a similar effect at day 1, the pulmonary vasodilator response to BAY 41-2272 was greater than sildenafil at day 5. At birth, BAY 41-2272 dramatically reduced PVR and augmented the pulmonary vasodilation induced by iNO. We concluded that BAY 41-2272 causes potent pulmonary vasodilation in fetal and neonatal sheep with severe pulmonary hypertension. We speculate that BAY 41-2272 may provide a novel treatment for severe PPHN, especially in newborns with partial response to iNO therapy.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acetylcholine; Animals; Animals, Newborn; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Enzyme Activation; Female; Fetus; Guanylate Cyclase; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Pregnancy; Pulmonary Circulation; Purines; Pyrazoles; Pyridines; Sheep; Signal Transduction; Sildenafil Citrate; Sulfones; Vasodilation

Acute pulmonary embolism (APE) is a major cause of pulmonary hypertension and death. We examined the effects of sildenafil on the hemodynamic changes caused by APE in anesthetized dogs. Sham-operated dogs (n = 3) received only saline. APE was induced by stepwise IV injections of 300 mum microspheres in amounts adjusted to increase mean pulmonary artery pressures by 20 mm Hg. Hemodynamic evaluation was performed at baseline, after APE was induced, and then after sildenafil 0.25 mg/kg (n = 8), or sildenafil 1 mg/kg + 0.3 mg . kg(-1) . h(-1) (n = 8) or saline (n = 9) infusions were started. Similar experiments were conducted to examine the effects of sildenafil in rat isolated perfused lung preparation. Plasma thiobarbituric acid reactive species were also determined in both studies to measure oxidative stress. Both doses of sildenafil reduced mean pulmonary artery pressures in dogs by approximately 8 to 16 mm Hg (both P < 0.05) and attenuated the increase in oxidative stress after APE. Mean arterial blood pressure remained unaltered after both doses of sildenafil. Sildenafil produced similar effects after APE in rat isolated perfused lung preparation. These findings indicate that IV sildenafil can selectively attenuate the increases in mean pulmonary artery pressures after APE, possibly through antioxidant mechanisms.

Topics: Acute Disease; Animals; Blood Pressure; Dogs; Female; Hemodynamics; Hypertension, Pulmonary; Male; Malondialdehyde; Oxidative Stress; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Thiobarbituric Acid Reactive Substances; Vasodilator Agents

Topics: Adult; Bosentan; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Assessment; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

We present the case of a full term neonate with severe persistent pulmonary hypertension of the newborn (PPHN) after birth asphyxia cared for at the St. Elizabeth Hospital in Curacao, Netherlands Antilles. Although the child was ventilated with high pressures and was given high doses of cardiovascular pressors, the arterial oxygen levels remained low with an alveolar-arterial O2 gradient of 651 mmHg. As a last resort, sildenafil (1.5 mg/kg) was given via a nasogastric tube. This resulted in an immediate and sustained elevation of arterial oxygenation and subsequent complete recovery. After administration of sildenafil there was a transient hypotension which was corrected by a single bolus of saline.. We discuss the current treatment modalities of persistent pulmonary hypertension of the newborn and the potential use of phosphodiesterase 5 inhibitors such as sildenafil in a situation where the standard of practice with inhaled nitric oxide and extracorporeal membrane oxygenation is not available.

Topics: Bronchodilator Agents; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Resource Allocation; Sildenafil Citrate; Sulfones

Topics: Adult; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Hypertension, Pulmonary; Methylprednisolone; Mixed Connective Tissue Disease; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Primary pulmonary arterial hypertension (PPH) is a rare disease of undetermined origin and fatal prognosis. A better prognosis is associated with at least 20% reduction of either pulmonary artery pressure or pulmonary vascular resistance ("responders") in acute vasodilatory trials. Prostacycline (PGI2) or nitric oxide (NO) administration promises valuable results. NO is one of the most powerful vasodilating agents, endogenously produced by endothelial cells. It migrates from these cells to smooth muscle cells and stimulates production of cGMP, that induces smooth muscle relaxation. cGMP is hydrolyzed by 5-phopshodiesterase (PDE-5). Several papers documenting hypotensive effect in pulmonary circulation of specific PDE5 inhibitor--sildenafil (Viagra--Pfizer) have been published recently. We present a case report of a 26 year old female patient with PPH--"nonresponder" in a trial with NO--and NO responder after sildenafil administration. Initial values were: mean pulmonary artery pressure (mPAP) was 58 mmHg, pulmonary vascular resistance was 10.9 Wood's units. mPAP and PVR during NO inhalation (40 ppm) decrease from 62 to 54 mmHg and from 11.4 to 10.3 Wood's units, respectively. Measurements performed 60 minutes after 50 mg of sildenafil orally disclosed a 19% reduction of mPAP and 21% reduction of PVR. NO inhalation caused further decrease of both parameters: mPAP was decreased for additional 28% and PVR for additional 36% in comparison to initial results. Neither peripheral hypotension nor other side effects were observed. A month-long administration of sildenafil in a dose 2 x 25 mg daily reduced mPAP and PVR to values reported for the acute trial. Physical capability improved also. It was assessed as increased distance in a six-minute-walk test (280 vs. 400 m in the first week of treatment, and 330 m in a fourth week of treatment). Echocardiography showed moderate decrease of right ventricle and right atrium diameters, along with decrease of the degree of relative tricuspid regurgitation with unchanged maximal velocity of regurgitant wave. Specific PDE-5 inhibitors might be an attractive alternative in the treatment of pulmonary hypertension in case the above noted observations are confirmed.

Topics: Electrocardiography; Female; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Interferon alpha2 is widely used in hepatitis and high-risk melanoma. Interferon-induced pulmonary arterial hypertension as a side effect is rare.. We describe a melanoma patient who developed severe pulmonary arterial hypertension 30 months after initiation of adjuvant interferon alpha2b therapy. Discontinuation of interferon did not improve pulmonary arterial hypertension. This patient could be treated successfully with phosphodiesterase-5 inhibitor therapy.. This is only the 5th case of interferon-induced pulmonary arterial hypertension and the first documented case where pulmonary arterial hypertension was not reversible after termination of interferon alpha2 therapy. If interferon alpha2 treated patients develop respiratory symptoms, pulmonary arterial hypertension should be considered in the differential diagnosis. For these patients phosphodiesterase-5 inhibitors, e.g. sildenafil or vardenafil, could be an effective therapeutic approach.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Humans; Hypertension, Pulmonary; Imidazoles; Interferon-alpha; Melanoma; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

Topics: Cardiac Surgical Procedures; Critical Care; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Inhibition of the type 5 phosphodiesterase and inhibition of Rho kinase are both effective in reducing pulmonary hypertension (PH). Here we investigate whether Rho kinase inhibition is involved in the beneficial effect of the type 5 phosphodiesterase inhibitor sildenafil on PH. Chronic hypoxia-induced PH in rats is associated with an increase in RhoA activity in pulmonary artery that was maximal after 2 days (10.7+/-0.9-fold increase, n=6, P<0.001). The activity of Rho kinase assessed by measuring the level of myosin phosphatase target subunit 1 (MYPT1) phosphorylation was also increased (5.7+/-0.8-fold over control, n=8). Chronic fasudil (30 mg kg(-1) day(-1); 14 days) and sildenafil (25 mg kg(-1) day(-1); 14 days) treatments reduced PH and pulmonary cardiovascular remodelling, and inhibited the MYPT1 phosphorylation in pulmonary artery from hypoxic rats by 82.3+/-3% (n=4) and by 76.6+/-2% (n=4), respectively. The inhibitory effect of sildenafil (10 microM) on MYPT1 phosphorylation was demonstrated by the loss of actin stress fibres in vascular smooth muscle cells. However, in vitro kinase assays indicated that sildenafil had no direct inhibitory action on Rho kinase activity. Sildenafil treatment induced increased RhoA phosphorylation and association to its cytosolic inhibitory protein, guanine dissociation inhibitor (GDI) in pulmonary artery.We propose that sildenafil inhibits RhoA/Rho kinase-dependent functions in pulmonary artery through enhanced RhoA phosphorylation and cytosolic sequestration by GDI. The inhibition of intracellular events downstream of RhoA thus participates in the beneficial effect of sildenafil on PH.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Actins; Animals; Carrier Proteins; Chronic Disease; Cytoskeleton; Guanine Nucleotide Dissociation Inhibitors; Hypertension, Pulmonary; Hypoxia; Male; Phosphodiesterase Inhibitors; Phosphoprotein Phosphatases; Phosphorylation; Piperazines; Protein Phosphatase 1; Purines; Rats; Rats, Wistar; rhoA GTP-Binding Protein; Sildenafil Citrate; Sulfones

For patients with pulmonary arterial hypertension (PAH) two first line therapies - iloprost inhalation (Ventavis) and bosentan (Tracleer) -- are available in Germany. A third substance, sildenafil, is already approved in the US and will be approved for this indication in the European Union soon. Patients with PAH can be stabilized or improved with a specific mono-therapy for a limited period of time only. Therefore, the question arises when and how to initiate treatment escalation. The available data from controlled clinical trials are insufficient to give a definite answer to these questions. Moreover, it is still unclear which combination of the above mentioned substances may be superior in the treatment of PAH. On the other hand, combination therapy is already reality in clinical practice. Based on this background experts from specialized centers dealing with PAH discussed the scientific basis of the role of combination therapy in PAH patients during a workshop held on April 22/23. 2005 in Wiesbaden. The goal of this workshop was to formulate a common position with regard to combination therapy of PAH on the basis of the available scientific data and clinical experience.

Topics: Administration, Inhalation; Antihypertensive Agents; Bosentan; Controlled Clinical Trials as Topic; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones

We report a case of severe pulmonary hypertension in a neonate associated with impaired alveolarisation and plexiform pulmonary arteriopathy. Treatment with oral sildenafil in addition to inhaled nitric oxide (NO) resulted in recovery from the pulmonary hypertensive crisis. Long term sildenafil therapy was associated with complete resolution of the pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Lung Diseases; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Alveoli; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Drug Combinations; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Sildenafil attenuates acute pulmonary embolism-induced pulmonary hypertension. However, the hemodynamic effects of sildenafil in combination with other vasodilators during acute pulmonary embolism have not been examined yet. In the present study, we examined the hemodynamic effects of combined sildenafil (0.25 mg/kg, i.v.) and L-arginine (100, 200, 500, and 1000 mg/kg/h, i.v.) in an anesthetized dog model of acute pulmonary embolism. Plasma nitrite/nitrate (NO(x)) and cGMP concentrations were determined using an ozone-based chemiluminescence assay and a commercial enzyme immunoassay, respectively. We found that L-arginine alone did not attenuate acute pulmonary embolism-induced pulmonary hypertension. However, significant decreases in mean pulmonary artery pressure were observed 30, 45, 60, and 75 min after the administration of sildenafil alone or after the combined administration of sildenafil and L-arginine (all P < 0.05). No significant differences among groups were observed in the respiratory parameters. While L-arginine significantly increased NO(x) concentrations, cGMP concentrations increased only when sildenafil was administered (all P < 0.05). These results suggest that while sildenafil attenuates acute pulmonary embolism-induced pulmonary hypertension, L-arginine does not enhance the beneficial hemodynamic effects of sildenafil. In addition, these findings suggest that stimulation of NO synthesis with L-arginine during acute pulmonary embolism does not produce beneficial effects.

Topics: Acute Disease; Analysis of Variance; Animals; Arginine; Blood Pressure; Cyclic GMP; Dogs; Female; Heart Rate; Hypertension, Pulmonary; Infusions, Intravenous; Male; Nitrates; Nitrites; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Respiration; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents

Topics: Child; Clinical Trials, Phase III as Topic; Humans; Hypertension, Pulmonary; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Vasodilator Agents

To evaluate the clinical effects of treatment with oral sildenafil on severe pulmonary hypertension after cardiac surgery.. From September 2002 to January 2005, oral sildenafil was added to the treatment regime in 27 cases of severe pulmonary hypertension after cardiac surgery. All these cases were given general treatments including intravenous prostaglandin E1 and inhalation of nitric oxide before the use of sildenafil, which did not show obvious effects on decreasing pulmonary pressure. Then a combined treatment [general treatment plus oral sildenafil (1-2 mg/kg, q8h; Pfizer Ltd)] was instituted. Pulmonary artery pressure, systolic pulmonary artery pressure/systolic systemic blood pressure (Pp/Ps) were measured before and every hour after adding sildenafil.. One hour after adding sildenafil, the patients' pulmonary artery pressure decreased remarkably (P < 0.01) with no adverse effects on systematic artery pressure. SO(2) and PaO(2) of all cases improved respectively (P < 0.05). One or two days later, the patients' hemodynamics were stable and some patients stopped inhaling nitric oxide and the dosage of prostaglandin E1 decreased. 25 cases stopped use of ventilator and were discharged safely. 2 cases died of multiple organ dysfunction.. Sildenafil is a highly selective and effective pulmonary hypertension vasodilator, which can be given for the treatment of pulmonary hypertension after cardiac surgery.

Topics: Adolescent; Adult; Cardiac Surgical Procedures; Child; Child, Preschool; Female; Humans; Hypertension, Pulmonary; Infant; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Young Adult

A 3-month-old boy with coarctation of the aorta (CoA), ventricular septal defect (VSD), atrial septal defect, and severe pulmonary hypertension (PH) underwent one-stage repair consisting of patch closure of VSD and coarctation repair. Inhalation of nitric oxide (iNO) was commenced to treat residual severe PH on the day of the operation. Oral sildenafil citrate was commenced on the day 1 and iNO was gradually weaned off on the day 3. There was no "rebound", severe increase in pulmonary artery pressure, which commonly occurs after discontinuation of iNO. Then the patient was extubated without any difficulties or recurrent PH. The oral sildenafil citrate therapy was ceased on the day 8. Prophylactic use of oral sildenafil citrate for PH might be an useful alternative to shorten the duration of iNO therapy and intensive care unit (ICU) stay in the selected patients after congenital open heart surgery.

Topics: Administration, Inhalation; Administration, Oral; Aortic Coarctation; Bronchodilator Agents; Cardiac Surgical Procedures; Child, Preschool; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Piperazines; Postoperative Period; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Blood Pressure; Hemodynamics; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Topics: Adult; Arginine; Chronic Disease; Citrulline; Cyclic GMP; Endothelium, Vascular; Erectile Dysfunction; Humans; Hypertension, Pulmonary; Infant; Male; Marketing; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

We report the rare subchronic clinical course of a giant, dissecting pulmonary artery aneurysm in an oligosymptomatic middle-aged woman who had idiopathic pulmonary hypertension. Diagnosis was simple with the use of echocardiography and multislice computed tomography. Conversely, deciding on the treatment was difficult, because prominent surgeons declined to perform surgical repair of the aneurysm and recommended heart-lung transplantation. Therefore, we were forced to treat our patient medically. She survived for 1 year, including 8 months of treatment with sildenafil, and then died suddenly while awaiting transplantation. Our patient, who had a dissecting, high-pressure pulmonary artery aneurysm, had an unexpectedly stable and uneventful clinical course for 1 year, which, under more favorable circumstances, might have provided enough time for heart-lung transplantation to be performed.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Aortic Dissection; Echocardiography; Fatal Outcome; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Artery; Pulmonary Wedge Pressure; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Vasodilator Agents

Sildenafil, a phosphodiesterase 5 inhibitor, is currently under investigation for therapy of pulmonary hypertension. This study was designed to investigate chronic effects of sildenafil in monocrotaline (MCT)-induced pulmonary hypertension in rats. Four weeks after a single subcutaneous injection of MCT, the animals displayed nearly threefold elevated pulmonary artery pressure and vascular resistance values, with a concomitant decline in central venous oxygen saturation and arterial oxygenation. Marked right heart hypertrophy was evident, and massive thickening of the precapillary artery smooth muscle layer was histologically apparent. Further deterioration of pulmonary hypertension occurred 6 weeks after MCT injection, with some animals dying during this period because of right heart failure. When chronically administered from Days 14-28, sildenafil significantly increased plasma cyclic guanosine monophosphate and inhibited the development of pulmonary hypertension and right heart hypertrophy, with preservation of gas exchange and systemic arterial pressure. A corresponding efficacy profile was also noted for long-term feeding with sildenafil from Days 28-42. Moreover, the death rate significantly decreased in those animals treated with sildenafil. We conclude that sildenafil attenuates MCT-induced pulmonary hypertension and cor pulmonale in rats.

Topics: Administration, Oral; Animals; Biopsy, Needle; Disease Models, Animal; Drug Administration Schedule; Drug Interactions; Hemodynamics; Hypertension, Pulmonary; Immunohistochemistry; Male; Monocrotaline; Phosphodiesterase Inhibitors; Piperazines; Probability; Pulmonary Heart Disease; Purines; Random Allocation; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Sildenafil Citrate; Sulfones; Survival Rate; Time Factors

Sildenafil, an oral phosphodiesterase type-5 inhibitor, has vasodilatory effects through a cyclic guanosine 3', 5'-monophosphate-dependent mechanism, whereas beraprost, an oral prostacyclin analog, induces vasorelaxation through a cAMP-dependent mechanism. We investigated whether the combination of oral sildenafil and beraprost is superior to each drug alone in the treatment of pulmonary hypertension. Rats were randomized to receive repeated administration of saline, sildenafil, beraprost, or both of these drugs twice a day for 3 weeks. Three weeks after monocrotaline (MCT) injection, there was significant development of pulmonary hypertension. The increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight were significantly attenuated in the Sildenafil and Beraprost groups. Combination therapy with sildenafil and beraprost had additive effects on increases in plasma cAMP and cyclic guanosine 3', 5'-monophosphate levels, resulting in further improvement in pulmonary hemodynamics compared with treatment with each drug alone. Unlike MCT rats given saline, sildenafil, or beraprost alone, all rats treated with both drugs remained alive during 6-week follow-up. These results suggest that combination therapy with oral sildenafil and beraprost attenuates the development of MCT-induced pulmonary hypertension compared with treatment with each drug alone.

Topics: Administration, Oral; Analysis of Variance; Animals; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Male; Piperazines; Probability; Purines; Random Allocation; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Survival Rate; Vascular Patency; Vasodilator Agents

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Epoprostenol; Hypertension, Pulmonary; Male; Piperazines; Purines; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Sildenafil Citrate; Sulfones; Treatment Outcome

Topics: Animals; Disease Models, Animal; Hypertension, Pulmonary; Lung; Male; Piperazines; Purines; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Sensitivity and Specificity; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil (Pfizer Pharmaceuticals, Sandwich, Kent, UK) has been associated with pulmonary vasorelaxation. A more potent Sildenafil analogue (UK 343-664 [Pfizer Pharmaceuticals]) has been developed, but its effects in vivo have not been studied. This study evaluated the effects of UK 343-664 (Pfizer) during acute pulmonary hypertension.. Fourteen adult swine were anesthetized with 1 minimum alveolar concentration isoflurane and were mechanically ventilated with an FIO(2) of 50%. End tidal CO(2) was maintained between 32 and 36 mm Hg. Micromanometer tipped catheters were placed in the ascending aorta, pulmonary artery, and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound.. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue U46619. Animals were randomized into two groups. Group 1 (n = 9) received 500 microg of UK 343-664 (Pfizer) intravenously for more than 2 minutes. Group 2 (n = 5) served as the control group. Data were recorded continuously for 60 minutes. Statistical analyses were performed with the analysis of variance and t tests. A p less than 0.05 was considered significant.Pulmonary hypertension was achieved in all animals. The administration of UK 343-664 (Pfizer) was associated with a significant decrease in pulmonary artery pressure (30.3%; p < 0.05) and pulmonary vascular resistance (42%; p < 0.05) with mild systemic vasodilatation. These effects were partially maintained at 30 minutes (a 17.3% and 39% decrease, respectively; p < 0.05).. The administration of UK 343-664 (Pfizer) was associated with predominant pulmonary vasodilatation without systemic hypotension. This may represent a significant advance in the treatment of acute pulmonary hypertension. Potential clinical implications for this new phosphodiesterase enzyme type V (PDEV) inhibitor merit further study.

Topics: Acute Disease; Animals; Disease Models, Animal; Hypertension, Pulmonary; Piperazines; Purines; Pyrimidinones; Random Allocation; Sildenafil Citrate; Sulfones; Swine; Vasodilator Agents

Topics: Epoprostenol; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Here we report the experience obtained from a combined treatment with intravenous (i.v) prostacyclin and oral sildenafil in patients with severe pulmonary hypertension (PHT) who had a poor response to prior treatment with prostacyclin alone.. Sildenafil was added to the treatment in four patients with PHT (primary in two patients and secondary to collagenosis in the other two) with no adequate response to i.v. prostacyclin treatment. The clinical course, 6minutes walking test and echocardiogram were evaluated.. Initial sildenafil dose was 12.5 mg three times daily, which was increased up to 50 mg three times daily in one patient and up to 50 mg four times daily in the other three. The symptoms of right heart failure were controlled in all cases. Before the start of sildenafil administration, two patients had class III dyspnea and two patients had class IV dyspnea. Two patients converted to class I (previously class III and IV), and the other two converted to class II. The distance walked within 6 minutes increased (average increase 55%) and systolic pulmonary artery pressure decreased in all patients (average reduction 27%). Effects of sildenafil were substained. The only side effect seen was mild headache.. Our experience supports the value of sildenafil in the treatment of PHT and suggests that combined treatment is useful for rescuing patients who fail to respond to initial treatment with i.v. prostacyclin.

Topics: Adult; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Male; Piperazines; Purines; Respiratory Distress Syndrome, Newborn; Retinopathy of Prematurity; Sildenafil Citrate; Sulfones; Vasodilator Agents

Different vasodilators and different routes of application are used for the treatment of primary pulmonary hypertension (PPH). Recently, sildenafil, a phosphodiesterase-V inhibitor, has been shown to have beneficial hemodynamic effects in PPH. However, the hemodynamic effects of sildenafil have not been characterized and compared to other vasodilators such as inhaled nitric oxide (iNO) or iloprost in PPH in the same group of patients.. We investigated prospectively 10 consecutive patients with PPH using iNO, iloprost aerosol, and oral sildenafil to test acute hemodynamic response during right-heart catheterization.. iNO, iloprost aerosol, and sildenafil caused a significant fall of mean pulmonary artery pressure and pulmonary vascular resistance (PVR) [p < 0.05]. Correspondingly, cardiac output and mixed venous saturation increased slightly in all groups. Systemic arterial pressure and vascular resistance were mainly unaltered. Using a PVR reduction of > or =20% to define a significant response, 7 of 10 patients were responders to iloprost aerosol, whereas 4 of 10 patients responded to iNO and oral sildenafil. Improvement of oxygenation as indicated by an increase of arterial oxygen tension was observed with iloprost aerosol (p < 0.01).. All of the three substances, iNO, iloprost aerosol, and oral sildenafil, significantly improved pulmonary hemodynamics in patients with PPH. The most prominent hemodynamic effects and improvement of oxygenation were observed with iloprost aerosol.

Topics: Administration, Inhalation; Administration, Oral; Adult; Cardiac Catheterization; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitric Oxide; Piperazines; Prospective Studies; Purines; Risk Assessment; Sampling Studies; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Epoprostenol therapy has improved survival in primary pulmonary hypertension; however, only two thirds of patients are alive 3 years after starting treatment. Combined therapy with sildenafil, a phosphodiesterase 5 inhibitor, may provide additional benefit. The authors prospectively evaluated the acute hemodynamic and biochemical effects of sildenafil and inhaled nitric oxide, alone and in combination, in 8 patients with primary pulmonary hypertension receiving chronic epoprostenol. Average duration of epoprostenol therapy was 2.9 +/- 1.6 years (mean +/- SD) and mean dose was 25.7 +/- 10.8 ng/kg/min. A single 50 mg dose of sildenafil decreased mean pulmonary arterial pressure 10% (P<.05), increased cardiac output 8%, and decreased pulmonary vascular resistance 24% (P<.005). Although nitric oxide led to a similar decrease in mean pulmonary arterial pressure of 10% (P<.05), cardiac output was unchanged, resulting in a decrease in pulmonary vascular resistance of only 13%, which was not statistically different from baseline. These results suggest that sildenafil has greater acute hemodynamic effects than nitric oxide and that it can further reduce pulmonary vascular resistance in patients already demonstrating a benefit from chronic epoprostenol.

Topics: Adult; Blood Pressure; Cardiac Output; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Piperazines; Pulmonary Artery; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance

We describe a case of chronic pulmonary hypertension in a 7-wk-old infant with congenital diaphragmatic hernia and an oral teratoma. Our patient was dependent on low-dose inhaled nitric oxide and was still very unstable with systemic right ventricular pressures leading to frequent oxygen desaturations. We administered sildenafil therapy to stabilize the infant with discontinuation of inhaled nitric oxide. We describe successful discontinuation of the inhaled therapy as well as a period of stabilization and improvement with continued sildenafil administration.. Case report.. Intensive care nursery in tertiary academic center.. A 7-wk-old infant with congenital diaphragmatic hernia who was mechanically ventilated from birth.. Oral sildenafil 0.3 mg/kg/dose every 12 hrs.. Right ventricular pressure (from tricuspid valve regurgitant flow) to systemic systolic arterial pressure was measured by echocardiogram. Right ventricular to systemic pressure ratio was marginally improved with the initiation of sildenafil therapy. Inhaled nitric oxide was successfully discontinued, and the patient clinically stabilized temporarily, but he ultimately succumbed to his pulmonary hypertension.. Sildenafil may be a useful therapy for chronic pulmonary hypertension in congenital diaphragmatic hernia, but further studies of safety and efficacy need to be performed.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Echocardiography; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones

The treatment of patients with pulmonary arterial hypertension remains a challenge. We set out to investigate the use of sildenafil, a selective inhibitor of phosphodiesterase type 5, in patients with this disease.. Ten patients (8 females, mean age 34.5+/-3.3 years) with pulmonary hypertension underwent right heart catheterisation with vasodilator testing using incremental doses of intravenous sildenafil without adverse events. All patients were subsequently commenced on oral sildenafil 50 mg t.d.s. Nine patients had repeat right heart catheterisation 3 months after the commencement of oral therapy. There was a significant reduction in mean pulmonary artery pressure (from 55.8+/-5.9 to 50.4+/-6.1 mmHg, p=0.038 ) and pulmonary vascular resistance (from 10.1+/-1.7 to 8.6+/-1.5 Wood units, p=0.009 ), and an increase in cardiac output (from 4.7+/-0.3 to 5.0+/-0.4 l/min, p=0.15 ). Furthermore, there was a significant increase in the 6-minute walk test, a mean of 112 m. In response to a quality-of-life questionnaire, patients indicated marked clinical improvement on sildenafil. Sildenafil was discontinued in 1 patient due to a transient visual disturbance. The only patient previously awaiting transplantation was removed from the active transplantation list.. Sildenafil is well tolerated in its intravenous and oral forms and appears to improve both pulmonary haemodynamics and the clinical status of patients with pulmonary hypertension after 3 months of oral therapy.

Topics: Administration, Oral; Adult; Blood Pressure; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance

Topics: Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones

Eisenmenger syndrome in pregnancy may be a life-threatening disease despite recent additions to the treatment options.. We present a woman with severe pulmonary hypertension due to Eisenmenger syndrome treated during pregnancy and delivery and postpartum with L-arginine and sildenafil to enhance the nitric oxide pathway. This combination was associated with significant improvement in the mother's clinical and hemodynamic condition and fetal well-being.. The concomitant use of sildenafil and L-arginine for the management of pulmonary hypertension in pregnancy, combined with multidisciplinary care, permitted a good outcome for the mother and her infant.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Arginine; Drug Therapy, Combination; Eisenmenger Complex; Female; Humans; Hypertension, Pulmonary; Patient Care Team; Phosphodiesterase Inhibitors; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Purines; Sildenafil Citrate; Sulfones

Sildenafil, a potent type 5 nucleotide-dependent phosphodiesterase (PDE) inhibitor, has been recently proposed as a therapeutic tool to treat or prevent pulmonary artery hypertension (PAHT). We thus studied the effect of sildenafil on both the calcium signaling of isolated pulmonary artery smooth muscle cells (PASMCs) and the reactivity of pulmonary artery (PA) obtained from chronic hypoxia (CH)-induced pulmonary hypertensive rats compared with control (normoxic) rats. CH rats were maintained in an hypobaric chamber (50.5 kPa) for 3 wk leading to full development of PAHT. Intracellular calcium concentration ([Ca2+]i) was measured in PASMCs loaded with the calcium fluorophore indo 1. Unlike in control rats, sildenafil (10-100 nM) decreased the resting [Ca2+]i value in PASMCs obtained from CH rats. In PASMCs from both control and CH rats, sildenafil concentration dependently inhibited the [Ca2+]i response induced by G-coupled membrane receptor agonists such as angiotensin II and phenylephrine but had no effect on the amplitude of the [Ca2+]i response induced by caffeine. Sildenafil (0.1 nM-1 microM) concentration dependently reduced basal PA tone that is present in CH rats and relaxed PA rings precontracted with phenylephrine in both control and CH rats. These data show that sildenafil is a potent pulmonary artery relaxant in CH rats and that it normalizes CH-induced increases in resting [Ca2+]i and basal tone. Consequently, pharmacological inhibition of sildenafil-sensitive PDE5 downregulates the Ca2+ signaling pathway involved in this model of pulmonary hypertension.

Topics: Angiotensin II; Animals; Caffeine; Calcium; Calcium Signaling; Chronic Disease; Disease Models, Animal; Hypertension, Pulmonary; Hypoxia; Male; Muscle, Smooth, Vascular; Phenylephrine; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Vasoconstriction; Vasoconstrictor Agents

Topics: Animals; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Aged; Cardiac Surgical Procedures; Humans; Hypertension, Pulmonary; Male; Middle Aged; Perioperative Care; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventricular Dysfunction, Right