sildenafil-citrate and Familial-Primary-Pulmonary-Hypertension

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

Oral sildenafil (SDF) is used to treat pulmonary arterial hypertension (PAH), and its bioavailability is approximately 40%. Several formulations of nano and microparticles (for pulmonary delivery) are being developed because it is possible to improve characteristics such as release time, bioavailability, dose, frequency, and even directly target the drug to the lungs. This review summarizes the latest SDF drug delivery systems for PAH and explains challenges related to the development, the preclinical, and the clinical studies. A scoping review was conducted by searching electronic databases including PubMed, Scopus, and Web of Science to identify studies published between 2001 and 2021. From 300 articles found, 31 met the inclusion criteria. This review identified colloidal formulations such as polymeric, lipid, and metal-organic framework nanoparticles. Strategies were determined to reach the deep airways such as polymeric microparticles, large porous microparticles, nanocomposites, and nano in microparticles. Finally, aspects related to toxicological, pharmacokinetics, and gaps in information for potential use in humans were discussed. SDF formulations are significant candidates for the treatment of PAH by inhalation. In summation, future preclinical studies are still required in large animals, as there is no particular formulation yet submitted to clinical studies.

Topics: Administration, Inhalation; Animals; Familial Primary Pulmonary Hypertension; Humans; Lipids; Lung; Metal-Organic Frameworks; Nanotechnology; Pulmonary Arterial Hypertension; Sildenafil Citrate

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

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

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

Pulmonary hypertension is a medical condition characterized by elevated pulmonary arterial pressure and secondary right heart failure. Pulmonary arterial hypertension is a subset of pulmonary hypertension, which is characterized by an underlying disorder of the pulmonary arterial vasculature. Pulmonary hypertension can also occur secondarily to structural cardiac disease, autoimmune disorders, and toxic exposures. Although pregnancies affected by pulmonary hypertension and pulmonary arterial hypertension are rare, the pathophysiology exacerbated by pregnancy confers both high maternal and fetal mortality and morbidity. In light of new treatment modalities and the use of a multidisciplinary approach to care, maternal outcomes may be improving.

Topics: Anesthesia, Obstetrical; Bosentan; Carbolines; Directive Counseling; Epoprostenol; Extracorporeal Membrane Oxygenation; Familial Primary Pulmonary Hypertension; Female; Humans; Iloprost; Infant, Newborn; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pregnancy, High-Risk; Prognosis; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfonamides; Tadalafil

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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: Familial Primary Pulmonary Hypertension; Humans; Pulmonary Arterial Hypertension; Sildenafil Citrate; Vasodilator Agents; Vitamin D Deficiency

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

Pulmonary delivery of vasodilators is a promising alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). The aim of this study was to design and evaluate hydrogel microparticles as a carrier for sustained pulmonary delivery of sildenafil citrate. Spray dried hydrogel microparticles containing biodegradable sodium carboxymethyl cellulose, sodium alginate, and sodium hyaluronate polymers at variable concentrations were prepared. A design of experiment using the "Extreme Vertices Mixture" design was executed. The design was used to study the influence of polymer concentration and their interactions on the physicochemical properties of the formulations in terms of particle size, particle size distribution, product yield, entrapment efficiency, and in-vitro drug release. Selected formulations were also evaluated for swelling, biodegradation, moisture content, in-vitro aerodynamic performance, and cytotoxicity. In addition, a lung deposition and pharmacokinetic study was conducted in rats to study drug accumulation in lungs and blood after intratracheal administration of the spray dried inhalable hydrogel microparticles in comparison to orally administered Viagra®. The results demonstrated that formulated microparticles had a mean geometric particle size between 2 and 5 μm, entrapment efficiency of >80%, and yield ranging between 47 and 66% w/w. The in-vitro drug release profiles showed a sustained drug release of sildenafil citrate for over 24 h. The statistical design showed a significant influence of the microparticulate composition on the physicochemical properties. Furthermore, selected formulations were evaluated for their aerodynamic properties. The aerodynamic properties included fine particle fraction ranging between 24 and 30%, dose recovery percent of 68-8 5%, and average mass median aerodynamic diameter of 4.6-4.8 μm. The in-vivo pharmacokinetic study showed that inhaled spray dried hydrogel microparticles (M6) formulation had significantly higher lung/blood C

Topics: Administration, Inhalation; Administration, Oral; Alginates; Animals; Carboxymethylcellulose Sodium; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Drug Liberation; Dry Powder Inhalers; Familial Primary Pulmonary Hypertension; Humans; Hyaluronic Acid; Hydrogels; Lung; Male; Mice; Microspheres; Particle Size; Powders; Pulmonary Arterial Hypertension; Rats; RAW 264.7 Cells; Sildenafil Citrate; Surface Properties; Tissue Distribution

Systemic artery to pulmonary artery fistulas (SA-PAFs), are extremely rare in people without congenital heart disease. In this group of patients pulmonary arterial hypertension was reported in the single case. Then, we describe a case of multiple SA-PAFs, which were the cause of severe nonreversible arterial pulmonary hypertension in a patient who had a right-sided pneumothorax 35 years earlier.. 52-year-old male Caucasian patient with echocardiographically confirmed pulmonary hypertension (PH) was admitted to cardiology department due to exertional dyspnea and signs of right ventricle failure. Routine screening for causes of secondary PH was negative. Right heart catheterization (RHC) confirmed a high degree arterial PH [mean pulmonary artery pressure (mPAP); 50,6 mmHg, pulmonary wedge pressure (PWP); 11,3 mmHg, pulmonary vascular resistance (PVR); 11,9 Wood's units (WU)] irreversible in the test with inhaled nitric oxide. Oxygen saturation (SaO. Non-congenital SA-PAFs are extremely rare, however, they should be excluded in patients with pulmonary arterial hypertension and history of inflammatory or infectious disease of the lung and pleura, pneumothorax, cancer or Takayashu's disease and after chest trauma.

Topics: Arterio-Arterial Fistula; Cardiac Catheterization; Computed Tomography Angiography; Familial Primary Pulmonary Hypertension; Fatal Outcome; Heart Failure; Humans; Iloprost; Lung; Male; Middle Aged; Pneumothorax; Pulmonary Artery; Pulmonary Wedge Pressure; Sildenafil Citrate; Vascular Resistance

Methylmalonic acidemia or aciduria (MMA) is an inborn error of metabolism that results in the accumulation of methylmalonic acid in blood with an increased excretion in urine. MMA usually presents in early infancy and its effects vary from mild to life-threatening. The clinical symptoms mainly include vomiting, dehydration, hypotonia, developmental delay, and failure to thrive. An association between pulmonary arterial hypertension (PAH) and MMA has been rarely reported. In the present work, the authors report a 16-month boy, who was admitted to the Pediatric Department for cyanosis and fever. He had a family history of primary pulmonary hypertension in a sister. The echocardiography showed a mild pericardial effusion and PAH. The metabolic screening led to the diagnosis of MMA. The condition of the baby worsened rapidly- and he died a few days later. Physicians should be aware about this atypical presentation of the disease, which can be fatal if not diagnosed and managed promptly.

Topics: Amino Acid Metabolism, Inborn Errors; Cyanosis; Familial Primary Pulmonary Hypertension; Fatal Outcome; Fever; Humans; Infant; Male; Methylmalonic Acid; Renal Insufficiency; Sildenafil Citrate; Tachycardia; Vasodilator Agents

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

Chest pain and shortness of breath are chief complaints frequently evaluated in the emergency department. ACS, pulmonary embolism, and disorders involving the lung parenchyma are some of the disease processes commonly screened for. Occasionally, patients presenting with histories and clinical exams consistent with these common illnesses may end up having more rare pathology. We present the case of a young patient who presented with chest pain and dyspnea with ECG changes and history concerning for pulmonary embolism who was ultimately diagnosed with idiopathic primary pulmonary hypertension. The importance of a prompt diagnosis of this condition along with emergency department management of complications related to the disease is discussed in this report.

Topics: Adult; Chest Pain; Computed Tomography Angiography; Diagnosis, Differential; Dyspnea; Electrocardiography; Emergency Service, Hospital; Familial Primary Pulmonary Hypertension; Furosemide; Humans; Male; Sildenafil Citrate; Spironolactone

To evaluate the influence of riociguat on World Health Organization functional class (WHO FC), 6-min walk distance (6MWD), right heart remodeling, and right ventricular-pulmonary arterial (RV-PA) coupling in patients with idiopathic pulmonary arterial hypertension (IPAH) who are treatment-naïve or who have failed to achieve treatment goals with sildenafil therapy.. Twenty patients with IPAH were enrolled: 12 had not previously received PAH-targeted therapy (treatment-naïve subgroup) and 8 had been receiving sildenafil therapy but failed to achieve treatment goals; on entering this pilot study these 8 patients were switched from sildenafil to riociguat therapy (treatment-switch subgroup). Patients received riociguat individually dose-adjusted up to a maximum of 2.5 mg three times daily. After 12 weeks, patients were assessed for WHO FC, 6MWD, right heart remodeling, and RV-PA coupling.. Riociguat significantly improved WHO FC in treatment-naïve patients (from 0/4/8/0 patients in WHO I/II/III/IV at baseline to 1/6/5/0 at week 12) and in treatment-switch patients (from 0/4/4/0 patients in WHO I/II/III/IV at baseline to 1/4/3/0 at week 12). Additionally, treatment-naïve and treatment-switch patients showed significant improvements at week 12 versus baseline in 6MWD (increases of + 76.8 m and + 71.6 m, respectively), RV systolic function, and RV-PA coupling.. These results support the proven efficacy of riociguat in patients with IPAH, including treatment-naïve patients and those switching to riociguat following failure to achieve treatment goals with sildenafil, and suggest that it may be possible to delay disease progression in this patient group.

Topics: Adult; Atrial Remodeling; Drug Substitution; Echocardiography; Enzyme Activators; Familial Primary Pulmonary Hypertension; Female; Heart Atria; Heart Ventricles; Humans; Male; Middle Aged; Pilot Projects; Pulmonary Artery; Pyrazoles; Pyrimidines; Sildenafil Citrate; Ventricular Remodeling; Walk Test

A heavily pregnant woman was treated with Revatio(®) (Sildenafil) against idiopathic pulmonary arterial hypertension, prior to and after her accouchement. To investigate the transfer of sildenafil into breast milk and its metabolism shortly before breastfeeding to the neonatal, a new analytical method was developed and validated, using liquid chromatography tandem mass spectrometry. Additionally, while using linear ion trap scan mode experiments, further metabolites could be identified. Sample preparation was carried out, using solid-phase extraction. For quantification of sildenafil and its major metabolite N-desmethylsildenafil, sildenafil-d8 was used as an internal standard. Within a time frame of 17h covering two Revatio(®) intakes and three breast milk samplings, a concentration range from 1.64 to 4.49ng/ml (sildenafil) and from 1.18 to 1.82ng/ml (N-desmethylsildenafil) could be observed. The current method proved to be accurate and precise in a very low concentration range and establishes the first reported determination of sildenafil and N-desmethylsildenafil in human breast milk.

Topics: Chromatography, Liquid; Familial Primary Pulmonary Hypertension; Female; Humans; Lactation; Milk, Human; Pregnancy; Sildenafil Citrate; Tandem Mass Spectrometry

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

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of the pulmonary artery resulting from currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Phosphodiesterase type 5 (PDE5) inhibitors have been clinically used in the treatment of IPAH. Recently, we have shown that Ca(2+)-sensing receptor (CaSR) antagonists, or calcilytics, inhibit excessive cell proliferation of pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients. In this study, the additive or synergistic effect of calcilytics on antiproliferation following PDE5 inhibition was examined in IPAH-PASMCs by MTT assay. Treatment with sildenafil blocked the excessive cell proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC50 value of 16.9μM. However, sildenafil (0.03-100μM) did not affect the cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). Co-treatment with 0.3μM NPS2143, a calcilytic, additively enhanced the antiproliferative effect induced by sildenafil (3 or 30μM) in IPAH-PASMCs. Additionally, the inhibitory effect of calcilytics, NPS2143 or Calhex 231 (1 or 10μM), on excessive cell proliferation of IPAH-PASMCs was synergistic increased in the presence of 1μM sildenafil. Similar results were obtained by BrdU incorporation assay. These findings reveal that calcilytics additively/synergistically enhance the antiproliferative activity mediated by PDE5 inhibition, suggesting that a combination therapy of a PDE5 inhibitor with a calcilytic may be useful as a novel therapeutic approach for IPAH.

Topics: Benzamides; Cell Line; Cell Proliferation; Cyclohexylamines; Drug Synergism; Familial Primary Pulmonary Hypertension; Humans; Myocytes, Smooth Muscle; Naphthalenes; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Receptors, Calcium-Sensing; Sildenafil Citrate

We present here the case of a patient with pulmonary arterial hypertension and NYHA Class II symptoms who transitioned from PDE-5i therapy to riociguat. No protocol currently exists for transitioning between these PAH medications.. A 59-year old male with a history of anorexigen use initially presented in 2008 and was felt to have non-operable small vessel disease. His care was transitioned to our center after insurance would not cover high-dose sildenafil in addition to ERA therapy.. This case demonstrates a safe and successful transition from higher dose PDE-5is to riociguat with no interruption in therapy.

Topics: Familial Primary Pulmonary Hypertension; Humans; Insurance Coverage; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyrimidines; Sildenafil Citrate; Transitional Care

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

The vasoreactivity test is usually performed to identify pulmonary arterial hypertension (PAH) patients who may benefit from long-term calcium channel blocker (CCB). The first and most commonly used agent is intravenous epoprostenol. A few other agents such as intravenous adenosine and inhaled nitric oxide are also used. In Thailand, epoprostenol is not available and the others are costly. Therefore, inhaled iloprost or oral sildenafil may be alternatives to test vasoreactivity.. To evaluate the hemodynamic effect and response rate of inhaled iloprost and oral sildenafil during acute vasoreactivity test in PAH patients.. In this retrospective descriptive study, the authors recruited patients with idiopathic PAH (IPAH) or PAHassociated with connective tissue disease (PAH-CNT) seen at the Medicine department Siriraj Hospital between January 2005 and December 2011 for whom acute vasoreactivity test was indicated. All patients used 20 microgram of inhaled iloprost via Delphinus® nebulizer for the test. Hemodynamic parameters were recorded before and after iloprost administration. Eight of those patients subsequently had a repeated test using 100 mg of oral sildenafil.. Fifteen patients had acute vasoreactivity testing. Eleven patients were IPAH and four were PAH-CNT Using ESC/ERS guidelines criteria for responsiveness to vasoreactivity test, the response rate was 13% (2 out of 15 patients) using inhaled iloprost. Hemodynamic change was seen as early as five minutes after the inhalation and the effect lasted up to 35 minutes. The response rate was 25% (2 out of 8 patients) using oral sildenafil. Hemodynamic change was seen as early as 30 minutes after sildenafil ingestion and lasted up to 480 minutes.. Inhaled iloprost can be used for acute vasoreactivity test in Thailand. The hemodynamic parameters should be recorded immediately after iloprost inhalation. Oral sildenafil, however, is not a suitable agent for acute vasoreactivity test due to its extended effect.

Topics: Administration, Inhalation; Administration, Oral; Adult; Blood Pressure; Calcium Channel Blockers; Familial Primary Pulmonary Hypertension; Female; Humans; Iloprost; Male; Middle Aged; Piperazines; Pulmonary Artery; Purines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Thailand; Vasodilator Agents

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

Topics: Antihypertensive Agents; Bosentan; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

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

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

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

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

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

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

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

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

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: 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

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

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

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

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

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

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

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 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

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

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

  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

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

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

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

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

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

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

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

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