sildenafil-citrate and Pulmonary-Arterial-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

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

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

The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial.

Topics: Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Guanosine Monophosphate; Guanylate Cyclase; Heart Failure; Humans; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Retrospective Studies; Sildenafil Citrate; Soluble Guanylyl Cyclase; Tadalafil; 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

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

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

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

Sildenafil, approved two decades ago, is the inhibitor of phosphodiesterase 5 (PDE5). First of all, it was designated for angina pectoris, but soon it showed a wonderful efficacy in erectile dysfunction (ED) and then pulmonary arterial hypertension (PAH). Due to the distribution of phosphodiesterase (PDE) in almost all organs, maybe it effects other diseases. Hence, a great number of investigations began to understand the role of PDEi in different organs. Preliminary research on sildenafil in cell culture and animal models has yielded promising results. Soon, a greater number of animal researches and clinical trials joined them. The results disclosed sildenafil can have beneficial effects in each organ such as heart, liver, kidney, brain, and intestines. Furthermore, it has significantly improved the prognosis of organ ischemia in various animal models. Clinical trials in several diseases, such as recurrent spontaneous miscarriage, fatty liver disease, bronchopulmonary dysplasia (BPD), heart failure, and premature ejaculation (PE) brought promising results. Although some clinical trials are available on the effects of sildenafil on various diseases, further studies on humans are needed to consolidate the ultimate effects of sildenafil. The aim of this review was to describe the effects of sildenafil on each organ and explain its mechanisms of action. Further, other PDE inhibitors such as tadalafil and vardenafil have been briefly discussed in parts of this review.

Topics: Erectile Dysfunction; Heart; Humans; Lung; Male; Pulmonary Arterial Hypertension; Sildenafil Citrate

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

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

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

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

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

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

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

Pulmonary hypertension (PH) is often caused by left heart disease (LHD) such as heart failure (HF) or valvular heart disease. Historically, few randomized controlled trials have evaluated the off-label use of medications for treating pulmonary arterial hypertension (PAH) in patients with PH-LHD. However, multiple randomized controlled trials have been published over the last decade that investigated their use in patients with PH-LHD. In addition, recent updates in the classification and definitions of PH have led to an improved recognition of PH-LHD phenotypes, notably combined post-capillary and pre-capillary PH and isolated post-capillary PH. In this systematic review, we show that PAH medications should not be recommended in two distinct HF populations: patients with HF without definitive PH diagnosis and patients with isolated post-capillary PH due to HF. In addition, the use of bosentan or macitentan is not recommended in patients with combined post-capillary and pre-capillary PH due to HF, but sildenafil may be considered to improve pulmonary hemodynamics and exercise capacity in patients with combined post-capillary and pre-capillary PH due to HF. Riociguat 2 mg 3 times daily may also be considered to improve pulmonary hemodynamics in patients with combined post-capillary and pre-capillary PH due to heart failure with reduced ejection fraction but not heart failure with preserved ejection fraction. The postoperative use of sildenafil in the setting of PH after valvular heart disease intervention was evaluated. Limited clinical data and safety concern warrants caution with the postoperative use of sildenafil in patients with PH due to valvular heart disease. Despite recent advances in the understanding of PAH medications for patients with PH-LHD, uncertainty remains about their utility in distinct subgroups. Nonetheless, PAH pharmacotherapy should generally be avoided for most patients with PH-LHD.

Topics: Bosentan; Endothelin Receptor Antagonists; Heart Diseases; Hemodynamics; Humans; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines; Sildenafil Citrate; Sulfonamides

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

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

Sildenafil (REVATIO

Topics: Adult; Clinical Trials as Topic; Computer Simulation; Confounding Factors, Epidemiologic; Female; Humans; Male; Models, Biological; Pulmonary Arterial Hypertension; Risk Factors; Sildenafil Citrate; Survival Analysis; Time Factors; Treatment Outcome; Young Adult

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

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

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

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

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

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

Despite the growing evidence of efficacy, scarce information exists regarding the cost of tadalafil to improve the functional classes of pediatric patients with pulmonary arterial hypertension. This study aims to determine the cost-utility of tadalafil compared sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia.. A Markov model was developed to compare expected costs, outcomes, and quality-adjusted life-years of sildenafil and tadalafil in pediatric patients with pulmonary arterial hypertension. The model was analyzed probabilistically, and a value of information analysis was conducted to inform the value of conducting further research to reduce current uncertainties in the evidence base. Cost-effectiveness was evaluated at a willingness-to-pay value of US $5180.. The mean incremental cost of tadalafil versus sildenafil is US $15 270. The 95% credible interval for the incremental cost ranges from US $28 033.65 to US $5940.86. The mean incremental benefit of tadalafil versus sildenafil is 1.00 quality-adjusted life-years (QALY). The 95% credible interval for the incremental benefit ranges from 1.88 to 0.31 QALY. The expected incremental cost per QALY is estimated at US $15 286. There is a probability less than 1% that tadalafil is more cost-effective than sildenafil at a threshold of US $5180 per QALY. Form the value of information analysis, the theoretical upper bound on the value of further research was US $9.298 for Colombia.. Our economic evaluation shows that tadalafil 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; Humans; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Sildenafil Citrate; Tadalafil

Topics: Administration, Inhalation; Administration, Oral; Animals; Collagen; Disease Models, Animal; Epoprostenol; Heart; Hemodynamics; Hypoxia; Indoles; Male; Myocardium; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Artery; Pyrroles; Rats, Sprague-Dawley; Sildenafil Citrate; Vascular Remodeling; Vasodilator Agents

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

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

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

BACKGROUND To explore the efficacy of beraprost sodium combined with sildenafil and its effects on the vascular endothelial function and inflammation in left heart failure patients complicated with pulmonary arterial hypertension. MATERIAL AND METHODS A total of 80 patients with left heart failure complicated with pulmonary arterial hypertension was enrolled as the subjects of this study and assigned into an observation group (n=40) and a control group (n=40) using a random number table. The changes in pulmonary arterial hypertension-associated indicators at 3 months after treatment and the alterations in the levels of cardiac function-associated biochemical indicator brain natriuretic peptide (BNP), inflammatory factor tumor necrosis factor alpha (TNF-alpha), and mean pulmonary arterial pressure during treatment were compared between the 2 groups. RESULTS At 3 months after treatment, the pulmonary arterial hypertension-associated indicators human urotensin II and calcitonin gene-related peptide in the observation group were lower and higher, respectively, than those in control group. Moreover, the observation group had significantly lower BNP and TNF-alpha levels and mean pulmonary arterial pressure than the control group. After intervention, the echocardiographic parameters left ventricular ejection fraction (LVEF), cardiac output (CO), and stroke volume (SV) in both groups were significantly higher than those before intervention, and the observation group had significantly higher LVEF, SV, and CO than the control group after intervention. CONCLUSIONS Beraprost sodium combined with sildenafil for left heart failure complicated with pulmonary arterial hypertension can effectively improve pulmonary arterial hypertension, alleviate left heart failure, and reduce inflammatory responses, thereby achieving better clinical efficacy in patients.

Topics: Aged; Aged, 80 and over; Echocardiography; Endothelial Cells; Epoprostenol; Exercise Tolerance; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Pulmonary Arterial Hypertension; Pulmonary Artery; Sildenafil Citrate; Stroke Volume; Treatment Outcome; Ventricular Function, Left; Ventricular Function, Right

Pulmonary arterial hypertension (PAH) is an incurable disease, although symptoms are treated with a range of dilator drugs. Despite their clinical benefits, these drugs are limited by systemic side-effects. It is, therefore, increasingly recognised that using controlled drug-release nanoformulation, with future modifications for targeted drug delivery, may overcome these limitations. This study presents the first evaluation of a promising nanoformulation (highly porous iron-based metal-organic framework (MOF); nanoMIL-89) as a carrier for the PAH-drug sildenafil, which we have previously shown to be relatively non-toxic in vitro and well-tolerated in vivo. In this study, nanoMIL-89 was prepared and charged with a payload of sildenafil (generating Sil@nanoMIL-89). Sildenafil release was measured by Enzyme-Linked Immunosorbent Assay (ELISA), and its effect on cell viability and dilator function in mouse aorta were assessed. Results showed that Sil@nanoMIL-89 released sildenafil over 6 h, followed by a more sustained release over 72 h. Sil@nanoMIL-89 showed no significant toxicity in human blood outgrowth endothelial cells for concentrations up to100µg/ml; however, it reduced the viability of the human pulmonary artery smooth muscle cells (HPASMCs) at concentrations > 3 µg/ml without inducing cellular cytotoxicity. Finally, Sil@nanoMIL-89 induced vasodilation of mouse aorta after a lag phase of 2-4 h. To our knowledge, this study represents the first demonstration of a novel nanoformulation displaying delayed drug release corresponding to vasodilator activity. Further pharmacological assessment of our nanoformulation, including in PAH models, is required and constitutes the subject of ongoing investigations.

Topics: Animals; Aorta; Cell Survival; Drug Liberation; Humans; Kinetics; Metal-Organic Frameworks; Mice; Myocytes, Smooth Muscle; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Sildenafil Citrate; Spectrum Analysis; Theranostic Nanomedicine; Vasodilator Agents

Xinmai 'an tablet has been used to improve myocardial blood supply. Recently, some compounds from its formula have shown that they can treat pulmonary arterial hypertension (PAH).. This study investigates the effects of Xinmai 'an extract (XMA) on PAH and further tests the co-therapeutic enhancement with sildenafil (SIL).. XMA could improve SIL's efficacy in the treatment of PAH by decreasing cell viability more effectively at non-cytotoxic concentrations (250 μg/mL) and reducing Right Ventricular Systolic Pressure (RVSP) in PAH rat. Potential mechanisms might at least in part be through activating the MAPK signalling pathway.. The combination of XMA and SIL can improve the efficacy of pulmonary hypertension and reduce the dosage of SIL.

Topics: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Drug Synergism; Drugs, Chinese Herbal; Enzyme Inhibitors; Male; MAP Kinase Signaling System; Myocytes, Smooth Muscle; Plant Extracts; Pulmonary Arterial Hypertension; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

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

Portopulmonary hypertension (PoPH) is a clinical condition associated with end-stage liver disease, described by the coexistence of pulmonary arterial hypertension (PAH) and portal hypertension. In PoPH patients, there is a right ventricle (RV) remodeling to compensate for the increased resistance in the lung circulation. There are no studies on the effects of the PAH-targeted pharmacological treatment on the RV dimension and function. The present study summarizes our experience in patients with PoPH treated with sildenafil in a period of 6 years (from 2013 to 2019). We enrolled 64 consecutive patients identified as PoPH, all treated with sildenafil (57.6% in monotherapy; in the other cases in association with macitentan; in 19.0% with initial combination therapy). A hemodynamic invasive cardiopulmonary study was performed at baseline and after 6 months of sildenafil treatment. In our population we showed a significative improvement in RV performance, with a significant increase in RV stroke volume (+33%), RV ejection fraction (+31%) and RV stroke work index (+17.5%). We registered the reduction of the RV cavity dimension over time in all patients treated with sildenafil (RV end diastolic diameter decreased by 15% after 6 months of follow-up). Regarding diastolic function, we highlighted a very significant reduction in RV end-diastolic pressure (-50% concerning baseline). Sildenafil was effective both when used as monotherapy and in combination with macitentan. In conclusion, Sildenafil had a positive impact on RV systolic and diastolic function in patients with PoPH and was able to conditionate the reverse remodeling of the RV.

Topics: Humans; Hypertension; Pulmonary Arterial Hypertension; Sildenafil Citrate; Stroke Volume; Ventricular Dysfunction, Right; Ventricular Remodeling

Anticentriole autoantibodies-positive systemic sclerosis (SSc) has been reported to develop pulmonary arterial hypertension (PAH) at a high rate. In this report, we describe two patients with anticentriole antibodies-positive SSc-PAH who were treated with pulmonary vasodilators. Both cases were elderly women with poor physical conditions and clinical findings of SSc. Case 1 was resistant to combination therapy with pulmonary vasodilators; in Case 2, hemodynamic improvement was obtained by upfront combination therapy at an early stage. Because anticentriole antibodies-positive SSc-PAH rapidly deteriorates, careful hemodynamic observation and timely aggressive use of pulmonary vasodilators should be considered.

Topics: Aged; Aged, 80 and over; Antibodies, Antinuclear; Autoantibodies; Bosentan; Cardiac Catheterization; Centrioles; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Female; Forced Expiratory Volume; Humans; Imatinib Mesylate; Protein Kinase Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Diffusing Capacity; Pyrimidines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Tadalafil; Tomography, X-Ray Computed; Vasodilator Agents

NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A. PAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar-Kyoto rats. Animals were assigned into groups: 1. 'No MCT'; 2. 'MCT Only'; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT.. From haemodynamic assessments, NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals.. These findings suggest that NTP42 and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.

Topics: Acetamides; Animals; Antihypertensive Agents; Disease Models, Animal; Heart Ventricles; Hemodynamics; Humans; Hypertrophy, Right Ventricular; Male; Monocrotaline; Pulmonary Arterial Hypertension; Pulmonary Artery; Pyrazines; Rats; Rats, Inbred WKY; Receptors, Thromboxane; Sildenafil Citrate; Vascular Remodeling

We here report the successful recovery from coronavirus disease-19 (COVID-19) pneumonia in a patient with β-thalassemia major (β-TM) and severe pulmonary arterial hypertension (PAH), focusing on the patient's comorbidities, therapeutic course and drug interaction.

Topics: Angiotensin Receptor Antagonists; beta-Thalassemia; Betacoronavirus; Comorbidity; Coronavirus Infections; COVID-19; Drug Interactions; Humans; Pandemics; Phosphodiesterase 5 Inhibitors; Pneumonia, Viral; Pulmonary Arterial Hypertension; SARS-CoV-2; Sildenafil Citrate; Treatment Outcome

Topics: Acetamides; Adolescent; Antihypertensive Agents; Asymptomatic Diseases; Bone Morphogenetic Protein Receptors, Type II; Cardiac Catheterization; Disease Progression; Dyspnea; Echocardiography; Exercise Tolerance; Female; Genetic Testing; Heterozygote; Humans; Male; Phenylpropionates; Pulmonary Arterial Hypertension; Pyrazines; Pyridazines; Sildenafil Citrate; Syncope; Vasodilator Agents

Sildenafil is a potent selective inhibitor of phosphosdiesterase-5 previously used in erectile dysfunction and subsequently approved in 2005 for pulmonary arterial hypertension treatment. Since oral administration of sildenafil shows pharmacokinetic problems with mean absolute bioavailability of 41%, the goal of this work was to develop a novel sildenafil self-emulsifying drug delivery system (SEDDS) for oral absorption improvement and management of dosage. One pharmaceutical solution and four SEDDS containing sildenafil were successfully obtained and SEDDS formed O/W nanoemulsion with droplet size less than 300 nm. The stability studies evidenced that the SEDDS containing 3.3% w/w of sildenafil yielded the best results. The safety of 2-pyrrolidone/isobutanol in oral formulations was assessed in mice and no lethality was achieved in the placebo groups with LD50 of 490 mg/Kg for SEDDS II-3.3, suggesting it as a safe excipient for humans. Therewithal, in silico studies using PBPK models provided the pharmacokinetic profile of sildenafil SEDDS. Subsequently, in silico evaluation indicated that the sildenafil SEDDS droplet size influenced its bioavailability, enhancing absorption, assuring a good pharmacokinetic profile. These findings suggest that the formulations developed here presented the potential to enhance drug oral absorption with the possibility to control drug dosage as they are liquid pharmaceutical formulations.

Topics: Animals; Chemistry, Pharmaceutical; Drug Delivery Systems; Emulsions; Humans; Mice; Pulmonary Arterial Hypertension; Sildenafil Citrate

Assessment of health-related quality of life (HRQoL) are often measured as an important patient-reported outcome (PRO) in clinical studies. Pulmonary arterial hypertension (PAH) is a common complication of atrial septal defect (ASD). This study aimed to compare the HRQoL of PAH related uncorrected secundum ASD at pre and post therapy with oral sildenafil therapy.. We conducted quasi experimental study at Sardjito General Hospital Yogyakarta since April 2016 to August 2017. Adults with PAH related uncorrected secundum ASD, listed on Congenital Heart Disease and Pulmonary Hypertension (COHARD-PH) registry, and met the inclusion and exclusion criteria were recruited as subject. Interview was done at pre and 12 weeks post oral sildenafil therapy 3 × 20 mg using the EQ-5D-3L questionnaire. Statistical analysis was done using Wilcoxon test and paired T-test to determine the differences of EQ-5D utility and EQ-VAS score at pre and post therapy.. A total of 18 adult patients with PAH related to uncorrected secundum ASD were enrolled in this study (83.33% female; mean age 38.72 ± 10.81 years old). The most frequent reported problems pre therapy were pain/discomfort (83%) and anxiety/depression (78%). Wilcoxon test showed the median of EQ-5D utility score were increased after sildenafil therapy (before = 0.604, after = 0.664; Z = - 2703; p:0.007), respectively. Meanwhile, the paired T-test results showed an increase of EQ-VAS mean difference 6.67 ± 8.75 (p:0.005; 95% CI 2.32-11.02) after sildenafil therapy.. The administration of oral sildenafil therapy 3 × 20 mg during 12 weeks in adult patients with PAH related uncorrected secundum ASD gives better HRQoL.

Topics: Administration, Oral; Adult; Female; Heart Septal Defects, Atrial; Humans; Male; Middle Aged; Non-Randomized Controlled Trials as Topic; Pulmonary Arterial Hypertension; Quality of Life; Registries; Sildenafil Citrate; Surveys and Questionnaires

Topics: Angiogenesis Inhibitors; Animals; Drug Therapy, Combination; Hypoxia; Indoles; Male; Pulmonary Arterial Hypertension; Pyrroles; Rats; Rats, Wistar; Receptors, Thromboxane A2, Prostaglandin H2; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Topics: Acetamides; Antihypertensive Agents; Drug Substitution; Drug Therapy, Combination; Epoprostenol; Female; Humans; Infusion Pumps; Middle Aged; Phenylpropionates; Pulmonary Arterial Hypertension; Pyrazines; Pyridazines; Sildenafil Citrate; Tadalafil; 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

Congenital extrahepatic portocaval shunt (CEPS), also known as Abernethy malformation, is an extremely rare anomaly of the splanchnic venous system, especially when accompanied by pulmonary arterial hypertension.. We report a case of a 15-year-old female who was diagnosed with CEPS (Abernethy type Ib) accompanied by pulmonary arterial hypertension. This case was incidentally identified during abdominal ultrasound examination and confirmed by mesenteric and splenic arteriography. During more than 4 years of follow-up, after receiving sildenafil (80 mg/day), the patient's condition improved in the first year after discharge. However, one year later, the patient's conditions start to deteriorate.. This article presents a rare case of Abernethy malformation accompanied by pulmonary arterial hypertension, which can be diagnosed by using abdominal ultrasonography, portal vein computed tomography angiography or mesenteric and splenic arteriography. This malformation had limited treatment and poor prognosis.

Topics: Adolescent; Antihypertensive Agents; Arterial Pressure; Disease Progression; Female; Humans; Incidental Findings; Portal Vein; Pulmonary Arterial Hypertension; Pulmonary Artery; Sildenafil Citrate; Treatment Outcome; Vascular Malformations; Vasodilator Agents; Vena Cava, Inferior

Pulmonary arterial hypertension (PAH) is a progressive disease associated with high morbidity and mortality, despite advances in medical therapy. We compared the effects of infigratinib (NVP-BGJ398), a new FGF receptor-1 inhibitor, with or without the PDE-5 inhibitor sildenafil, on vascular function and remodelling as well as on gene expression of signal transducers for receptors of TGF-β (Smads-1/2/4) and transcription factor of endothelial-mesenchymal transition (Twist-1) in established experimental PAH. Types I and III pro-collagen and TGF-β expressions in lung fibroblasts were analysed in vitro after the different treatments.. PAH was induced in male Wistar rats with monocrotaline. 14 days later, treatments [sildenafil (SIL), infigratinib (INF) or their combination (SIL+INF)] were given for another 14 days. On Day 28, echocardiography and haemodynamic assays were performed, and lungs and pulmonary vessels were removed for analysis by histology, immunohistochemistry and RT-PCR. Fibroblasts prepared from PAH lungs were also analysed for TGF-β and pro-collagen.. Only the combination of infigratinib and sildenafil significantly improved right ventricular systolic pressure and vascular remodelling parameters (right ventricular hypertrophy, smooth muscle α-actin, vessel wall thickness, and vascular collagen content). Infigratinib may act by reducing gene expression of Smads-1/4 and Twist-1 in lung tissue, as well as TGF-β and types I and III pro-collagen in lung fibroblasts.. In this model of monocrotaline-induced PAH, the combination of the new inhibitor of FGF receptor-1, infigratinib, and sildenafil effectively improved haemodynamics and decreased vascular remodelling.

Topics: Animals; Antihypertensive Agents; Injections, Intraperitoneal; Male; Monocrotaline; Phenylurea Compounds; Pulmonary Arterial Hypertension; Pyrimidines; Rats; Rats, Wistar; Receptor, Fibroblast Growth Factor, Type 1; Sildenafil Citrate

Topics: Activin Receptors, Type II; Female; Humans; Hypertension, Pulmonary; Middle Aged; Mutation, Missense; Pedigree; Pulmonary Arterial Hypertension; Sildenafil Citrate; Telangiectasis; Treatment Outcome; Vasodilator Agents