Study UNICO: Perception of Urologists and Andrologists, in Spain, about the Use of Sildenafil Oral Suspension in Patients with Erectile Dysfunction

Objective: To describe the profile of patients with erectile dysfunction (ED), attending to consultation and satisfaction using sildenafil oral suspension, from the specialist’s perception. Materials and methods: This is a nationwide multicenter, epidemiological, descriptive and observational study, with the studied population as the unit of study. Thirty urologists and/or andrologists completed a questionnaire with questions about ED patients’ profile attending to their practice, sildenafil oral suspension perception of effectiveness and safeness, and their opinion about patients’ satisfaction after sildenafil oral suspension treatment. Aggregate data were collected for the last 6 patients treated or on treatment with sildenafil oral suspension. Results: Overall, 40.9% and 24.9% of patients had moderate or severe ED, respectively. Among the patients, 73.6% were older than 50 years. The disease progression was approximately one year (11.8 months). ED etiology was mostly organic (38.1%) and mixed (31.8%). Cardiovascular comorbidities were present in 57.4%, mental health problems in 16.4% and hormonal disorders in 10.2% of the patients. The main reason for choosing sildenafil oral suspension was the ease of dose adjustment. The specialists considered that 73.4% of the patients responded satisfactorily to treatment. They also rated the perceived effectiveness and safeness of the product as very good or good. Conclusions: Urologists and andrologists consider that most patients with ED achieve a high degree of satisfaction with sildenafil oral suspension. The main advantage of the treatment is the possibility of adjusting the dose according to patient’s needs and circumstances (AU)

Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial.

BACKGROUND: SARS-CoV-2 seems to affect the regulation of pulmonary perfusion. Hypoperfusion in areas of well-aerated lung parenchyma results in a ventilation-perfusion mismatch that can be characterized using subtraction computed tomography angiography (sCTA). This study aims to evaluate the efficacy of oral sildenafil in treating COVID-19 inpatients showing perfusion abnormalities in sCTA. METHODS: Triple-blinded, randomized, placebo-controlled trial was conducted in Chile in a tertiary-care hospital able to provide on-site sCTA scans and ventilatory support when needed between August 2020 and March 2021. In total, 82 eligible adults were admitted to the ED with RT-PCR-confirmed or highly probable SARS-COV-2 infection and sCTA performed within 24 h of admission showing perfusion abnormalities in areas of well-aerated lung parenchyma; 42 were excluded and 40 participants were enrolled and randomized (1:1 ratio) once hospitalized. The active intervention group received sildenafil (25 mg orally three times a day for seven days), and the control group received identical placebo capsules in the same way. Primary outcomes were differences in oxygenation parameters measured daily during follow-up (PaO2/FiO2 ratio and A-a gradient). Secondary outcomes included admission to the ICU, requirement of non-invasive ventilation, invasive mechanical ventilation (IMV), and mortality rates. Analysis was performed on an intention-to-treat basis. RESULTS: Totally, 40 participants were enrolled (20 in the placebo group and 20 in the sildenafil group); 33 [82.5%] were male; and median age was 57 [IQR 41-68] years. No significant differences in mean PaO2/FiO2 ratios and A-a gradients were found between groups (repeated-measures ANOVA p = 0.67 and p = 0.69). IMV was required in 4 patients who received placebo and none in the sildenafil arm (logrank p = 0.04). Patients in the sildenafil arm showed a significantly shorter median length of hospital stay than the placebo group (9 IQR 7-12 days vs. 12 IQR 9-21 days, p = 0.04). CONCLUSIONS: No statistically significant differences were found in the oxygenation parameters. Sildenafil treatment could have a potential therapeutic role regarding the need for IMV in COVID-19 patients with specific perfusion patterns in sCTA. A large-scale study is needed to confirm these results. TRIAL REGISTRATION: Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial, NCT04489446, Registered 28 July 2020, https://clinicaltrials.gov/ct2/show/NCT04489446 .

Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia.

OBJECTIVE: To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH). BACKGROUND: Although antenatal sildenafil administration rescues vascular abnormalities in lungs of fetal rabbits with CDH, it only partially improves airway morphometry. We hypothesized that we could additionally stimulate lung growth by combining this medical treatment with fetal TO. METHODS: CDH was created on gestational day (GD)23 (n=54). Does were randomized to receive either sildenafil 10 mg/kg/d or placebo by subcutaneous injection from GD24 to GD30. On GD28, fetuses were randomly assigned to TO or sham neck dissection. At term (GD30) fetuses were delivered, ventilated, and finally harvested for histological and molecular analyses. Unoperated littermates served as controls. RESULTS: The lung-to-body-weight ratio was significantly reduced in sham-CDH fetuses either (1.2 ±â€Š0.3% vs 2.3 ±â€Š0.3% in controls, P=0.0003). Sildenafil had no effect on this parameter, while CDH fetuses undergoing TO had a lung-to-body-weight ratio comparable to that of controls (2.5 ±â€Š0.8%, P<0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ±â€Š0.8 br/mm2 vs 3.5 ±â€Š0.9 br/mm2, P=0.043) and lung mechanics (static elastance 61 ±â€Š36 cmH2O /mL vs 113 ±â€Š40 cmH2O/mL, P=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ±â€Š0.8 br/mm2, P=0.001 and 31 ±â€Š9 cmH2O/mL, P<0.0001 respectively). Both CDH-sham and CDH-TO fetuses treated with placebo had an increased medial wall thickness of peripheral pulmonary vessels (41.9 ±â€Š2.9% and 41.8 ±â€Š3.2%, vs 24.0 ±â€Š2.9% in controls, P<0.0001). CDH fetuses treated with sildenafil, either with or without TO, had a medial thickness in the normal range (29.4% ±â€Š2.6%). Finally, TO reduced gene expression of vascular endothelial growth factor and surfactant protein A and B, but this effect was counteracted by sildenafil. CONCLUSION: In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.

Effects of sildenafil and tadalafil on skin flap viability.

Vascular complication is one of the causes of skin flap healing failure. Sildenafil and tadalafil, a type-5 phosphodiesterase inhibitor, can improve flap viability, however, the action mechanisms involved in this process are still unclear. To assess the effects of orally administered sildenafil and tadalafil on the healing kinetics and skin flap viability, sixty-two Wistar rats were divided into three groups: control (n = 22), sildenafil (n = 20), and tadalafil (n = 20). The solutions were administered orally (dose: 10 mg/kg) immediately after the surgical procedure and then every 24 h. At postoperative days 7 and 14, the skin flap samples were collected, submitted to histological processing and evaluated under optical microscopy. In experimental groups (sildenafil and tadalafil), we found an increased vascularization (p < 0.05) on the 7th and 14th day associated with the ulcer size decrease on the 14th day, although it was not significant. There was a higher influx of neutrophils and a decrease of mononuclear population on the 7th day (p < 0.05). On the 14th day, these differences were observed only in the tadalafil group (p < 0.05). This study suggested positive results with the use of sildenafil and tadalafil as adjuvant drugs in skin flap viability.

Treprostinil palmitil inhibits the hemodynamic and histopathological changes in the pulmonary vasculature and heart in an animal model of pulmonary arterial hypertension.

Treprostinil palmitil (TP) is a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE). In this study, TP was delivered by inhalation (treprostinil palmitil inhalation suspension, TPIS) in a rat Sugen 5416 (Su)/hypoxia (Hx) model of pulmonary arterial hypertension (PAH) to evaluate its effects on hemodynamics, pulmonary vascular remodeling, and cardiac performance and histopathology. Male Sprague-Dawley rats received Su (20 mg/kg, s.c), three weeks of Hx (10% O2) and 5 or 10 weeks of normoxia (Nx). TPIS was given during the 5-10 week Nx period after the Su/Hx challenge. Su/Hx increased the mean pulmonary arterial blood pressure (mPAP) and right heart size (Fulton index), reduced cardiac output (CO), stroke volume (SV) and heart rate (HR), and increased the thickness and muscularization of the pulmonary arteries along with obliteration of small pulmonary vessels. In both the 8- and 13-week experiments, TPIS at inhaled doses ranging from 39.6 to 134.1 µg/kg, QD, dose-dependently improved pulmonary vascular hemodynamics, reduced the increase in right heart size, enhanced cardiac performance, and attenuated most of the histological changes induced by the Su/Hx challenge. The PDE5 inhibitor sildenafil, administered at an oral dose of 50 mg/kg, BID for 10 weeks, was not as effective as TPIS. These results in Su/Hx challenged rats demonstrate that inhaled TPIS may have superior effects to oral sildenafil. We speculate that the improvement of the pathobiology in this PAH model induced by TPIS involves effects on pulmonary vascular remodeling due to the local effects of TRE in the lungs.

A 24-Year-Old Woman With Dyspnea, Chest Pain, and Dry Cough.

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

Sildenafil citrate-loaded targeted nanostructured lipid carrier enhances receptivity potential of endometrial cells via LIF and VEGF upregulation.

The main objective of this research is to prepare sildenafil citrate (SC)-loaded arginyl-glycyl-aspartic acid (RGD)-containing nanostructured lipid carrier (SC-loaded NLC-RGD) and evaluate their effects on the receptivity potential of endometrial cells. Hot homogenization method was used to prepare SC-loaded NLC-RGD. Then, size, drug encapsulation, and morphology of prepared nanoparticles were studied by photon correlation spectroscopy technic, ultrafiltration method, and scanning electron microscopy, respectively. Subsequently, the influence of SC-loaded NLC-RGD on endometrial receptivity was evaluated by in vitro implantation assay. Finally, expression of vascular endothelial growth factor (VEGF), leukemia inhibitory factor (LIF), and integrin beta 3 (as endometrial receptivity markers) was assessed in SC-loaded NLC-RGD-treated endometrial cells by reverse transcription polymerase chain reaction (RT-PCR). Particles with a nano-size diameter (92.7 nm), appropriate polydispersity index (0.21), spherical morphology, and acceptable loading efficiency were prepared. In vitro implantation assay showed that SC, SC-loaded NLC, and SC-loaded NLC-RGD improve the rate of endometrial attachment potential by 1.6 ± 0.4, 1.7 ± 0.3, and 2.3 ± 0.3 times, respectively. Analysis of RT-PCR results showed the enhancing mRNA of LIF and VEGF in SC-treated endometrial cells. Results also confirmed the higher influence of SC-loaded NLC-RGD on gene expression patterns in comparison to SC. Using NLC-RGD as a carrier to deliver SC to endometrial cells is an effective approach to improve endometrial receptivity. Upregulation of LIF and VEGF is the probable mechanism by which SC enhances the endometrial receptivity potential.

Effect of sildenafil added to antifibrotic treatment in idiopathic pulmonary fibrosis.

Sildenafil is a phosphodiesterase-5 inhibitor used to treat idiopathic pulmonary arterial hypertension; however, its benefits are unclear in patients with advanced idiopathic pulmonary fibrosis (IPF). We aimed to evaluate its effect as an add-on to antifibrotic agents on clinical outcomes of real-world IPF patients. Among a total of 607 IPF patients treated with antifibrotic agent, 66 concurrently received sildenafil. Propensity score matching was performed to adjust for differences in age, sex, body mass index, forced vital capacity (FVC), and diffusing capacity (DLCO) between the sildenafil and no-sildenafil groups. The outcomes of these groups in terms of FVC decline rate, all-cause mortality, hospitalization, and acute exacerbation were compared. Propensity score matching identified 51 matched pairs. The mean age of the patients was 69.5 years and 80.4% were male. Mean FVC and DLCO were 51.7% and 29.5% of the predicted values, respectively. The FVC decline rates did not differ significantly (p = 0.714) between the sildenafil (- 101 mL/year) and no-sildenafil (- 117 mL/year) groups. In multivariable analyses adjusted for comorbidities and presence of pulmonary hypertension, sildenafil had no significant impact on all-cause mortality, hospitalization, or acute exacerbation. Sildenafil add-on to antifibrotic treatment had no significant effects on the clinical outcomes of IPF patients.

Pharmacokinetics and pharmacodynamics of sildenafil in fetal lambs on extracorporeal support.

BACKGROUND: Maternal transplacental administration of sildenafil is being considered for a variety of fetal conditions. Clinical translation also requires evaluation of fetal safety in a higher species, such as the fetal lamb. Experiments with the pregnant ewe are curtailed by minimal transplacental transfer as well as limited access to the fetus. The EXTra-uterine Environment for Neonatal Development (EXTEND) model renders the isolated fetal lamb readily accessible and allows for direct fetal administration of sildenafil. METHODS: Five fetal lambs were placed on extracorporeal support in the EXTEND device and received continuous intravenous (IV) sildenafil (0.3-0.5-0.7 mg/kg/24hr) for a duration of one to seven days. Plasma sildenafil concentrations were sampled at regular intervals to establish the pharmacokinetic profile using population pharmacokinetic modeling. Serial Doppler ultrasound examination, continuous non-invasive hemodynamic monitoring and blood gas analysis were done to evaluate the pharmacodynamic effects and fetal response. FINDINGS: The target concentration range (47-500 ng/mL) was attained with all doses. Sildenafil induced an immediate and temporary reduction of pulmonary vascular resistance, mean arterial pressure and circuit flow, without change in fetal lactate levels and acid-base status. The duration of the systemic effects increased with the dose. INTERPRETATION: Immediate temporary pulmonary vascular and systemic hemodynamic changes induced by sildenafil were biochemically well tolerated by fetal lambs on extracorporeal support, with the 0.5 mg/kg/24 h dose balancing rapid attainment of target concentrations with short-lived systemic effects. RESEARCH IN CONTEXT: None. SEARCH STRATEGY BEFORE UNDERTAKING THE STUDY: A literature review was conducted searching online databases (Medline, Embase and Cochrane), using search terms: fetal OR prenatal OR antenatal AND sildenafil, without time-limit and excluding human studies. Where relevant, investigators were contacted in order to avoid duplication of work. EVIDENCE BEFORE THIS STUDY: Prenatal therapy with sildenafil, a phosphodiesterase-5 inhibitor with vasodilatory and anti-remodeling effects on vascular smooth muscle cells, has been considered for a variety of fetal conditions. One multicenter clinical trial investigating the benefit of sildenafil in severe intrauterine growth restriction (the STRIDER-trial) was halted early due to excess mortality in the sildenafil-exposed arm at one treatment site. Such findings demonstrate the importance of extensive preclinical safety assessment in relevant animal models. Transplacentally administered sildenafil leads to decreased pulmonary arterial muscularization, preventing or reducing the occurrence of pulmonary hypertension in rat and rabbit fetuses with diaphragmatic hernia (DH). Validation of these results in a higher and relevant animal model, e.g. fetal lambs, is the next step to advance clinical translation. We recently demonstrated that, in contrast to humans, transplacental transfer of sildenafil in sheep is minimal, precluding the in vivo study of fetal effects at target concentrations using the conventional pregnant ewe model. ADDED VALUE OF THIS STUDY: We therefore used the extracorporeal support model for fetal lambs, referred to as the EXTra-uterine Environment for Neonatal Development (EXTEND) system, bypassing placental and maternal metabolism, to investigate at what dose the target concentrations are reached, and what the fetal hemodynamic impact and response are. Fetal hemodynamic and metabolic tolerance to sildenafil are a crucial missing element on the road to clinical translation. This is therefore the first study investigating the pharmacokinetics, hemodynamic and biochemical effects of clinical-range concentrations of sildenafil in fetal lambs, free from placental and maternal interference. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: We demonstrated self-limiting pulmonary vasodilation, a decrease of both systemic arterial pressures and circuit flows, induced by clinical range concentrations of sildenafil, without the development of fetal acidosis. This paves the way for further investigation of prenatal sildenafil in fetal lambs on extracorporeal support. A dose of 0.5 mg/kg/24 h offered the best trade-off between rapid achievement of target concentrations and shortest duration of systemic effects. This is also the first study using the EXTEND as a model for pharmacotherapy during pregnancy.

Method development and validation of sildenafil, N-desmethylsildenafil and N1,N4-desmethylsildenafil by LC-MS/MS and its application.

This study aimed to develop an LC-MS/MS method for determining sildenafil and its metabolites N-desmethylsildenafil and N1,N4-desmethylsildenafil in human plasma and applying it to a pharmacokinetic study of sildenafil in healthy volunteers. Sildenafil-d8 was used as the internal standard. Plasma samples were pretreated via protein precipitation with acetonitrile. The extractives were then separated on an ACQUITY UPLC BEH C18 (50-mm × 2.1-mm, 1.7-µm) column using gradient elution. The aqueous and organic mobile phases were ammonium formate 2 mM supplemented with 0.1% formic acid in water and acetonitrile, respectively, and the flow rate was 0.3 mL/min. An electrospray ionization source was applied, and multiple reaction monitoring was operated in the positive mode with selective channels at m/z 475.30 â†’ 100.10, 461.20 â†’ 283.30, 483.30 â†’ 108.10, and 449.00 â†’ 283.00 for sildenafil, sildenafil-d8, N-desmethylsildenafil, and N1,N4-desmethylsildenafil, respectively. The linear calibration curves of sildenafil and its metabolites spanned 1.0-1000 ng/mL. The lower limit of quantification was 1.0 ng/mL. The extractive recovery of analytes from the biological matrix was more than 90% and the matrix effect complied with relevant provisions. The intra- and inter-day precisions of sildenafil and its metabolite were <10%. The intra- and inter-day accuracy of sildenafil, N-desmethylsildenafil, and N1,N4-desmethylsildenafil was more than 99%. The method is highly sensitive and selective, and it was successfully applied to the bioequivalence studies of 100-mg sildenafil citrate tablets in 40 healthy Chinese volunteers.

Influencing Factors for Erectile Dysfunction of Young Adults with No Response to PDE5i.

Erectile dysfunction (ED) is a common male disorder. Although orally-administered phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are now recognized as the primary pharmacological treatment method for ED, 20%-30% of the patients treated with PDE5 inhibitors exhibit no significant effects. This study aims to investigate the influencing factors of ED in young adults with no response to PDE5 inhibitors. ED patients who would take PDE5 inhibitors were included and investigated with a questionnaire. Patients with no response to PDE5 inhibitors (tadalafil and sildenafil) served as study group, and those with response to PDE5 inhibitors as control group. Then Chi square test and logistic regression analysis were applied to find the potential influencing factors. In total, 378 ED patients were included. Ninety-three (24.6%) cases were non-responsive to PDE5 inhibitors, and the remaining 285 (75.4%) responded to PDE5 inhibitors. In multiple logistic regression analysis, we found that history of drinking (OR=3.152; 95%CI 1.672-6.975), spousal noncooperation (OR=2.994; 95%CI 1.589-5.638), number of fixed sex partners (OR=0.358; 95%CI 0.132-0.651), duration of ED (OR=3.356; 95%CI 1.352-8.333), and depression (OR=3.689; 95%CI 1.579-8.979) could be the influencing factors for ED patients' non-response to PDE5 inhibitors. In conclusion, history of drinking, spousal noncooperation, number of fixed sex partner, long duration of ED, and depression could be the influencing factors for ED patients' non-response to PDE5 inhibitors. Patients and doctors should pay attention to these factors.

Xinmai 'an extract enhances the efficacy of sildenafil in the treatment of pulmonary arterial hypertension via inhibiting MAPK signalling pathway.

CONTEXT: 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). OBJECTIVE: This study investigates the effects of Xinmai 'an extract (XMA) on PAH and further tests the co-therapeutic enhancement with sildenafil (SIL). MATERIALS AND METHODS: Pulmonary artery smooth muscle cells were subjected to stimulation with SIL (12.5 µM) and XMA (250 µg/mL) for 48 h. Sprague-Dawley rats were randomly grouped into eight groups (n = 8 per group): (I) control group received saline; (II) MCT group received MCT (60 mg/kg); (III) SIL-Low group received MCT + SIL at 10 mg/kg/day; (IV) SIL-high group received MCT + SIL at 30 mg/kg/day; (V) XMA-High group received MCT + XMA at 251.6 mg/kg/day; (VI) SIL (Low)+XMA (Low) group received SIL (10 mg/kg) + XMA at 62.9 mg/kg/day; (VII) SIL (Low)+XMA (Medium) group received SIL (10 mg/kg) + XMA at 125.8 mg/kg/day; (VIII) SIL (Low)+XMA (High) group received SIL (10 mg/kg) + XMA at 251.6 mg/kg/day. Both XMA and SIL were given by gavage and were maintained daily for 2 weeks. RESULTS: 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. DISCUSSION AND CONCLUSIONS: The combination of XMA and SIL can improve the efficacy of pulmonary hypertension and reduce the dosage of SIL.

Adicionado a sildenafilo más bosentán, comparado con sildenafilo más bosentán, en pacientes adultos con hipertensión arterial pulmonar, clase funcional OMS II, III Y IV, con fracaso a sildenafilo más bosentán / Added to sildenafil plus bosentan, compared with sildenafil plus bosentan, in adult patients with pulmonary arterial hypertension, WHO functional class II, III, and IV, with failure to sildenafil plus bosentan

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de selexipag o iloprost en adición a sildenafilo más bosentán, comparado con el esquema sildenafilo más bosentán, en pacientes adultos con hipertensión arterial pulmonar clase funcional de la Organización Mundial de la Salud (OMS) II, III y IV, con fracaso a la administración conjunta de sildenafilo más bosentán. La hipertensión arterial pulmonar (HAP) es una enfermedad rara caracterizada por la presencia de hipertensión pulmonar precapilar en ausencia de otras causas. En el Perú, no se conoce la prevalencia de HAP. En EsSalud se dispone de sildenafilo para el tratamiento de pacientes con HAP y bosentán para el tratamiento de pacientes sin un adecuado control de la enfermedad con sildenafilo. Asimismo, se dispone de iloprost inhalatorio para el tratamiento de pacientes con HAP durante el perioperatorio de operación cardíaca y en gestantes. No obstante, existen pacientes que no logran un control adecuado de la HAP, a pesar de recibir de forma concomitante sildenafilo más bosentán. Por ello, los médicos especialistas señalan que el control de la HAP, podría lograrse con la adición de un tercer fármaco a la combinación de sildenafilo más bosentán. METODOLOGÍA: Se realizó una búsqueda bibliográfica de literatura científica con el objetivo de identificar evidencia sobre la eficacia y seguridad de selexipag o iloprost adicionado a sildenafilo más bosentán, comparado con sildenafilo más bosentán, en pacientes adultos con hipertensión arterial pulmonar clase funcional OMS II, III y IV, con fracaso a sildenafilo más bosentán. Para identificar documentos de interés para la presente evaluación, se buscó evidencia disponible en las siguientes bases de datos bibliográficas: PubMed, The Cochrane Library y LILACS. Además, se realizó una búsqueda en sitios web pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias y guías de práctica clínica, incluyendo The Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), The National Institute for Health and Care Excellence (NICE), Institute for Quality and Efficiency in Health Care (IQWiG), Haute Authorité de Santé (HAS), Institute for Clinical and Economic Review (ICER), el portal BRISA (Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas), y sitios web de organizaciones internacionales en cardiología como European Respiratory Society (ERS) y European Society of Cardiology (ESC). Se llevó a cabo una búsqueda manual en el portal ClinicalTrials.gov del National Institutes of Health (https://clinicaltrials.gov/) e International Clinical Trials Registry Platform de la Organización Mundial de la Salud (http://apps.who.int/trialsearch/) para la identificación de estudios que emplearan las tecnologías de interés. Finalmente, se revisaron protocolos para RS que pudieran contemplar el uso de la tecnología de interés en el portal PROSPERO del Centre for Reviews and Dissemination de la University of York (https://www.crd.york.ac.uk/PROSPERO/) y en el Systematic Review Register del Joanna Briggs Institute Centre (https://joannabriggs.org/resources/systematic_review_register). RESULTADOS: Se presenta la evidencia incluida siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En el presente documento, se evaluó la mejor evidencia científica disponible hasta la actualidad sobre la eficacia y seguridad de selexipag o iloprost adicionado a sildenafilo más bosentán, comparado con sildenafilo más bosentán, en pacientes adultos con HAP clase funcional OMS II, III y IV con fracaso a sildenafilo más bosentán. Se identificaron dos GPC elaboradas por la ERS/ESC y CHEST que emitieron recomendaciones para el tratamiento de pacientes con HAP y respuesta no favorable a dos clases de fármacos específicos para la HAP, cinco ETS elaboradas por SMC, CADTH, IQWiG, COPTES y CONITEC que evaluaron el uso de selexipag, un ECA que evaluó selexipag y dos ECA que evaluaron iloprost en pacientes con HAP. No se identificaron ETS que evalúen iloprost ni ECA que evalúen la eficacia y seguridad de selexipag o iloprost adicionado a sildenafilo más bosentán pacientes adultos con HAP clase funcional OMS II, III y IV con fracaso a sildenafilo más bosentán. Las dos GPC (ERS/ESC y CHEST) recomiendan agregar una tercera clase de fármaco al tratamiento de pacientes con HAP y respuesta no favorable a dos clases de fármacos específicos para la HAP. La ERS/ESC recomienda agregar selexipag al esquema de sildenafilo más bosentán; mientras que CHEST no establece una recomendación sobre el empleo de selexipag o iloprost. De las cinco ETS que evaluaron selexipag, SMC y CADTH recomendaron el empleo de selexipag en pacientes con HAP; siempre que estos accedan a programas que reduzcan el costo de selexipag para que su uso sea costo-efectivo. Las tres ETS restantes no recomiendan el empleo de selexipag en pacientes con HAP: IQWiG porque no se dispone de datos para evaluar el beneficio de selexipag a largo plazo, COPTES porque selexipag ofrece escaso beneficio clínico y un impacto negativo desde las perspectivas presupuestarias, de equidad y salud pública y CONITEC porque, comparado con placebo, selexipag no reduce la mortalidad, pero si presenta más eventos adversos. El ECA GRIPHON evaluó selexipag en pacientes con HAP con o sin tratamiento previo y sin estar definido el fracaso a la terapia con sildenafilo más bosentán. Esta población es más amplia que la población de interés del presente dictamen y además no reportó comparó los esquemas selexipag más sildenafilo más bosentán versus sildenafilo más bosentán. Por lo tanto, estos resultados no responden directamente a la pregunta PICO del presente dictamen. En el ECA GRIPHON, aunque selexipag (comparado con placebo) redujo el riesgo del desenlace compuesto: muerte por cualquier causa y complicaciones por HAP en la población total del estudio y en el subgrupo de pacientes que ingresaron al estudio con un esquema terapéutico de ARE más iFDE5, el grupo selexipag presentó mayor número de muertes al final del periodo de tratamiento (diferencia no estadísticamente significativa). Además, el grupo de selexipag mostró mayor descontinuación por eventos adversos. Los ECA de McLaughlin et al., y Hoeper et al. evaluaron la adición de iloprost a un esquema de base de bosentán. Por lo tanto, los resultados de estos ECA tampoco responden directamente a la pregunta PICO del presente dictamen. El ECA de McLaughlin et al. encontró que, para la semana 12, el incremento promedio de la 6MWD fue de 30 m con iloprost y 4 m con placebo. Además, hubo mejora en una clase funcional NYHA en el 34 % de los pacientes con iloprost; frente al 6 % de los pacientes con placebo. Los resultados de este estudio fase II deben ser confirmados con un ECA fase III. El ECA de Hoeper et al. fue suspendido por futilidad porque los resultados del análisis interino hacían poco probable el alcanzar el desenlace primario propuesto. Dentro del Petitorio de EsSalud existe vacío terapéutico frente a un paciente con HAP clase funcional OMS II, III y IV en fracaso a la terapia con sildenafilo más bosentán. Agregar un fármaco (con distinto mecanismo de acción) al esquema de sildenafilo más bosentán es una alternativa terapéutica para esta población; tal como recomiendan las GPC para los pacientes con HAP y cuyo esquema doble no produce beneficio. Esta opinión es compartida por el médico especialista de la institución, quien señala que el uso de un fármaco adicionado al esquema de sildenafilo más bosentán puede ser considerado una alternativa terapéutica para esta población, siendo además que en EsSalud se tiene experiencia con el uso de iloprost. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI no aprueba el uso de selexipag más sildenafilo más bosentán en pacientes adultos con hipertensión arterial pulmonar clase funcional OMS II, III y IV, con fracaso a sildenafilo más bosentán y aprueba el uso de iloprost en pacientes adultos con HAP clase funcional OMS II, III y IV, con fracaso a sildenafilo más bosentán.

An Integrative Approach for Improved Assessment of Cardiovascular Safety Data.

Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores codependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide, and pimobendan in Han-Wistar rats. All data were modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h-1, relative standard error (%RSE) within parentheses] were 9.45 (15), 30.7 (7.8), 3.8 (13), and 0.115 (1.7) for QT, HR, total peripheral resistance, and SV, respectively. Potencies (nM, %RSE within parentheses) were IC 50 = 475 (11), IC 50 = 4.01 (5.4), EC 50 = 50.6 (93), and IC 50 = 47.8 (16), and efficacies (%RSE within parentheses) were I max = 0.944 (1.7), Imax = 1.00 (1.3), E max = 0.195 (9.9), and Imax = 0.745 (4.6) for ivabradine, sildenafil, dofetilide, and pimobendan. Hill parameters were estimated with good precision and below unity, indicating a shallow concentration-response relationship. An equilibrium concentration-biomarker response relationship was predicted and displayed graphically. This analysis demonstrates the utility of a model-based approach integrating data from different studies and compounds for refined preclinical safety margin assessment. SIGNIFICANCE STATEMENT: A model-based approach was proposed utilizing biomarker data on heart rate, blood pressure, and QT-interval. A pharmacodynamic model was developed to improve assessment of high-resolution telemetric cardiovascular safety data driven by different drugs (ivabradine, sildenafil, dofetilide, and pimobondan), wherein system- (turnover rates) and drug-specific parameters (e.g., potencies and efficacies) were sought. The model-predicted equilibrium concentration-biomarker response relationships and was used for safety assessment (predictions of 20% effective concentration, for example) of heart rate, blood pressure, and QT-interval.

Studies on metal-organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension.

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.

Persistent Pulmonary Hypertension in Corrected Valvular Heart Disease: Hemodynamic Insights and Long-Term Survival.

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

Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: a double-blind, randomised, placebo-controlled, phase 2b trial.

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

The utility of CYP3A activity endogenous markers for evaluating drug-drug interaction between sildenafil and CYP3A inhibitors in healthy subjects.

Cytochrome P450 (CYP) 3A-related drug-drug interaction (DDI) studies are needed during drug development to determine clinical interaction effects. We aimed to evaluate DDI between sildenafil and two CYP3A inhibitors, clarithromycin and itraconazole, regarding the changes in pharmacokinetics and endogenous markers. An open-label, one-sequence, one-period, two-treatment parallel study was conducted in 32 healthy Korean subjects. Each of 16 subjects were randomly assigned to the clarithromycin and itraconazole groups. Both groups received a single dose of sildenafil 25 mg as a control, and either clarithromycin 250 mg or itraconazole 100 mg was administered four times to inhibit CYP3A activity. Pharmacokinetics of sildenafil showed the similar magnitude of inhibitory effects of the two inhibitors on total CYP3A activity; both inhibitors similarly increased systemic exposure of sildenafil by 2-fold. Urinary 6ß-OH-cortisone/cortisone and plasma 4ß-OH-cholesterol were significantly decreased after clarithromycin administration but not after itraconazole. A significant correlation between sildenafil CL/F and metabolic markers of CYP3A activity was observed after clarithromycin administration. We confirmed that sildenafil has moderate pharmacokinetic interaction with clarithromycin and itraconazole. Endogenous markers well reflected the CYP3A inhibition of clarithromycin, suggesting possible utility in DDI study with moderate to strong CYP3A inhibition; however, there are limitations in predicting intestinal CYP3A mediated DDI.