Eficacia y seguridad de treprostinil o selexipag adicionado a sildenafilo más bosentán, en pacientes adultos con hipertensión arterial pulmonar, clase funcional OMS III, con fracaso a sildenafilo más bosentán / Efficacy and safety of treprostinil or selexipag added to sildenafil plus bosentan, in adult patients with pulmonary arterial hypertension, WHO functional class III, with failure to sildenafil plus bosentan

ANTECEDENTES> En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021 y ampliada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD2022, se ha elaborado el presente dictamen, el que expone la evaluación de la eficacia y seguridad de treprostinil o selexipag en adición a sildenafil más bosentán, comparado con el esquema sildenafil más bosentán, en pacientes adultos con hipertensión arterial pulmonar, clase funcional de la Organización Mundial de la Salud (OMS) III, con fracaso a la administración conjunta de sildenafil más bosentán. Así, Oscar Nelson Aguirre Zurita, médico cardiólogo del Servicio de Cardiología del Instituto Nacional Cardiovascular - INCOR envió al IETSI la solicitud de autorización de uso del producto farmacéutico treprostinil no incluido en el Petitorio Farmacológico de EsSalud siguiendo la Directiva N° 003-IETSI-ESSALUD-2016. ASPECTOS GENERALES: Los aspectos generales de la hipertensión arterial pulmonar (HAP) se han descrito previamente en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N.° 012- DETS-IETSI-2021 (IETSI-EsSalud 2021). Brevemente, la HAP es una enfermedad compleja y progresiva caracterizada por un aumento de la presión en la arteria pulmonar. Los pacientes comúnmente experimentan dificultad para respirar, hinchazón de tobillos y piernas, mareos o desmayos. En promedio, los pacientes viven entre cinco y siete años después del diagnóstico. La enfermedad afecta más comúnmente a personas entre 20 y 40 años de edad, y es más común en mujeres que en hombres. La Organización Mundial de la Salud (OMS) ha desarrollado un sistema de clasificación de HAP basado en el nivel de función y los síntomas. Los pacientes pueden tener Clase Funcional (CF) I a IV, con números crecientes que reflejan una mayor gravedad (CADTH 2015a). La HAP es rara, con una incidencia estimada de hasta 7.6 casos por millón de adultos y una prevalencia de hasta 26-100 por millón de adultos. La morbilidad y la mortalidad siguen siendo significativas y el diagnóstico y tratamiento tempranos son esenciales (Hirani et al. 2020). METODOLOGÍA: Se realizó una búsqueda sistemática utilizando las bases de datos PubMed, Cochrane Library, y LILACS. Además, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo el Scottish Medicines Consortium (SMC), el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institute for Quality and Efficiency in Health Care (IQWiG), el Instituto de Evaluación Tecnológica en Salud de Colombia (IETS), la Comissáo Nacional de Incorporagáo de Tecnologias no Sistema Único de Saúde (CONITEC), entre otros. Asimismo, se revisó la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en hipertensión pulmonar, tales como: American College of Chest Physicians (CHEST), European Society of Cardiology (ESC) y la European Respiratory Society (ERS). Se realizaron búsquedas manuales complementarias en las listas de referencias de los textos completos evaluados. RESULTADOS: La búsqueda de literatura permitió identificar siete publicaciones: dos GPC realizadas por CHEST (Klinger et al. 2019) y ESC-ERS (Humbert et al. 2022); dos ETS elaboradas por HAS (HAS 2011) y CADTH (CADTH 2006); dos ECA (Simonneau et al. 2002; McLaughlin et al. 2003); y un estudio observacional (Barst et al. 2006). CONCLUSIÓN: Por todo lo expuesto, el IETSI no aprueba el uso de treprostinil o selexipag adicionado a sildenafilo más bosentán, en pacientes adultos con hipertensión arterial pulmonar, clase funcional OMS III, con fracaso a sildenafilo más bosentán.

Early maturation of corpus luteum in rabbits - effect of sildenafil citrate on luteolytic capacity in the early luteal period

Background: Prostaglandin F2 alpha (PGF2 α) binds to the specific receptor (PTGFR) on the corpus luteum (CL) in mammals, inducing regression of the CL structure (luteolysis) and initiating a new cycle. While PGF2 α is effective only on mature CL, the immature CL structure (early luteal phase) resists PGF2 α. In this study, sildenafil citrate, which is used to increase blood flow in the genital organs for treating specific pregnancy issues in women, was administered during the early luteal phase in a rabbit model to test the hypothesis of enhancing blood flow to the CL, thereby promoting earlier maturation and enabling a response to PGF2 α. Materials, Methods & Results: The study was conducted in 2 sub-studies: clinical and molecular. A large number of rabbits were initially included in the sub-studies to ensure a sufficient number of pseudo-pregnant rabbits. Ovulation in rabbits was induced with buserelin acetate and was considered as day 0 of the study. The sub-studies were continued with rabbits whose pseudo-pregnancies were confirmed according to progesterone (P4 ) results. As a result, the studies were continued with a total of 41 pseudo-pregnant New Zealand female rabbits, 21 of which were included in the clinical sub-study and 20 in the molecular sub-study. In both sub-studies, on day 3 of the luteal period, rabbits in the treatment group received 5 mg/kg sildenafil citrate and all rabbits received a single dose of exogenous PGF2 α on day 4 to induce luteolysis. In the clinical sub-study, echotexture and intraovarian blood flow changes in the ovaries were determined by ultrasonography (USG) examination. In the molecular sub-study, the expression changes of Hypoxia Inducible Factor 1 Alpha (HIF1A) and Vascular Endothelial Growth Factor (VEGF) related to angiogenesis, Steroidogenic Acute Regulatory Protein (StAR) related to P4 metabolism, Prostaglandin-Endoperoxide Synthase 2 (PTGS2) related to prostaglandin (PG) mechanism and 15-Hydroxyprostaglandin Dehydrogenase (HPGD) genes at mRNA level were determined using Real Time Polymerase Chain Reaction (RT-PCR) in CL tissues obtained with ovariohysterectomy (OVH) at 1 and 12 h after PGF2 α injection. In addition, blood samples were collected for determine P4 levels from all rabbits. In the clinical sub-study; there was no difference between the groups in mean gray values (MGV), whereas there was a significant decrease in both pulsatile index (PI) and resistance index (RI) values at 40 min after PGF2 α injection (P < 0.05). In the molecular sub-study, it was determined that sildenafil citrate had no significant effect (P > 0.05) on the expression levels 1 and 12 h after PGF2 α injection. According to the results of the molecular sub-study, no significant effect of sildenafil citrate on the mRNA expression levels in the investigated genes was detected (P > 0.05). However, within each group, differences were found according to OVH time after PGF2 α injection. It was observed that PTGS2 and HPGD mRNA expressions decreased at the 12th h compared to the 1st h, while HIF1A expression increased (P < 0.05). Discussion: According to the results obtained from clinical and molecular sub-studies, it was determined that a single dose of sildenafil citrate (5 mg/kg) applied on the 3rd day of the luteal period did not contribute to the maturation process of the CL, did not increase blood flow, and was insufficient to break the resistance of the CL against PGF2 α applied on the 4th day of the luteal period. However, a significant decrease in the PI value at the 40th min after PGF2 α injection suggests that sildenafil citrate has a supportive effect, and that this decrease is also seen in the RI value, suggesting that its effect is insufficient against the vasoconstrictive effect of PGF2 α.

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 .

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.

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.

Effects of the FGF receptor-1 inhibitor, infigratinib, with or without sildenafil, in experimental pulmonary arterial hypertension.

BACKGROUND AND PURPOSE: 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-ß (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-ß expressions in lung fibroblasts were analysed in vitro after the different treatments. EXPERIMENTAL APPROACH: 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-ß and pro-collagen. KEY RESULTS: 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-ß and types I and III pro-collagen in lung fibroblasts. CONCLUSIONS AND IMPLICATIONS: 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.

Chronic administration of sildenafil improves endothelial function in spontaneously hypertensive rats by decreasing COX-2 expression and oxidative stress.

AIMS: Spontaneously hypertensive rats (SHR) exhibit impaired endothelial vasodilation and enhanced vasoconstriction. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (Sild) potentiates the nitric oxide (NO)-mediated effects exerting antioxidative and anti-inflammatory actions. In the present study, we hypothesized that Sild could improve endothelial function in SHR. MATERIALS AND METHODS: Male rats were treated daily for 60 days by oral gavage with Sild (45 mg/kg) before the onset of the hypertensive state (pre-hypertensive protocol). The aortic relaxation to acetylcholine (ACh), sodium nitroprusside (SNP) and the phenylephrine (Phe)-induced contraction was evaluated in SHR. Protein expression of eNOS, p-eNOS, caveolin, COX-1, COX-2, ERK and p-ERK was measured by Western blot. KEY FINDINGS: Resting blood pressure was not modified by Sild administration. Treatment with Sild did not alter the relaxation response to SNP but improved the ACh-induced relaxation and reduced Phe-induced contraction in aortic rings from SHR. This protective effect of Sild could be attributed to reduced superoxide anions (O2-) generation, cyclooxygenase type 2 (COX-2) protein downregulation and increased NO bioavailability. SIGNIFICANCE: Sild improves endothelial function in SHR aorta without affecting resting blood pressure values. These results indicate that PDE5 inhibition has a potential role in the improvement of vascular function and could be an adjuvant in the treatment of essential hypertension.

Phosphodiesterase type 5 inhibitors improve microvascular dysfunction markers in pulmonary arterial hypertension associated with congenital heart disease.

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

Sildenafil Use in Children with Pulmonary Hypertension.

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

Comparative Bioavailability of Sildenafil 50-mg Film-Coated Tablets and 50-mg Orally Disintegrating Films in Healthy Mexican Subjects: Results From a Randomized, Open-Label, Crossover Study.

An orally disintegrating film formulation of sildenafil 50 mg (CL Pharm Co, Ltd) was used in this study and compared to the market-available product film coated tablets (Viagra® , Pfizer, Mexico). The objective was to compare the pharmacokinetic properties of these products after a single-dose administration to 47 healthy male volunteers (aged 19-48 years) in a randomized, open-label, 2-way crossover study. Each subject received a single oral dose of 50 mg of sildenafil test or reference product administered under fasting conditions at each of the 2 study periods according to a crossover design. There was a 3-day washout period between drug administrations. Blood samples for pharmacokinetic analysis were collected predose and at different times postdosing. The maximum plasma concentration and area under the curve from administration to last observed concentration time of test and reference products were compared. Pharmacokinetic parameters shown to be within the confidence interval 80% to 125% for log-transformed data and Shuirmann and Anderson Hauck tests showed a high probability that area under the curve values for the test product were within 80% to 125% (P < .05). Adverse events occurred at similar rates for the 2 formulations (8 for each product), headache being the most prevalent. The results suggest that the 2 sildenafil formulations, orally disintegrating films and film-coated tablets, are similar in terms of bioavailability, making the test product a good alternative to treat erectile dysfunction and improving dosing convenience.

Sildenafil and Retinopathy of Prematurity in Preterm Infants with Bronchopulmonary Dysplasia.

OBJECTIVE: To assess whether sildenafil is associated with worsening retinopathy of prematurity (ROP) in very low birth weight (VLBW) infants (≤1500 g) with bronchopulmonary dysplasia (BPD). STUDY DESIGN: This retrospective case-control study included VLBW infants admitted to the neonatal intensive care unit between January 1, 2006, and December 31, 2012. Each infant treated with sildenafil was assigned 3 unexposed controls matched for gestational age, birth weight, and BPD diagnosis. Severe ROP was defined as stage ≥3 ROP. Worsening ROP was defined as increased stage of ROP within 8 weeks + 4 days after initiation of sildenafil or matched postmenstrual age. RESULTS: Twenty-three exposed infants and 69 matched controls met the inclusion criteria for the study (mean birth weight, 715 ± 210 g; mean gestational age, 25 ± 1 weeks). The mean postmenstrual age at sildenafil treatment was 42 ± 8 weeks. Exposed infants had more days of respiratory support (mean, 208 ± 101 days vs 102 ± 33 days; P < .001). Exposed infants had a higher prevalence of severe ROP (26% [6 of 23] vs 7% [5 of 69]; OR, 6.4; 95% CI, 1.2-32.9; P = .026). Five exposed infants and 2 unexposed infants had severe ROP before starting sildenafil and were excluded from the analysis for worsening ROP. The rate of worsening ROP did not differ significantly between exposed infants and unexposed infants ((41% [7 of 17] vs 24% [12 of 51]; OR, 8.4; 95% CI, 0.9-78.6; P = .061). CONCLUSION: Although sildenafil treatment was not statistically significantly associated with worsening of ROP, the raw difference in ROP rate is concerning. Larger studies are warranted to confirm this finding.

Preoperative subcutaneous sildenafil injection increases random flap survival in rats.

PURPOSE: To investigate the effect of subcutaneous sildenafil on random flap survival. METHODS: Fourteen Wistar rats, which were divided in to two groups, were used for this experimental study. Rats in the sildenafil group received subcutaneous sildenafil injections daily for seven days before flap elevation. At the end of the treatment period, 9x3 cm dorsal skin flaps were elevated and reinserted back into their place in all of the animals. Necrotic and whole flaps areas were recorded on graph papers. Seven days after the flap elevation samples for histological examination were taken and angiographies were performed to visualize the flap vascularization. RESULTS: The calculated average percentage of necrotic flap areas were 18.29% and 42.26% in the sildenafil and control group respectively.(p=0.0233). In selected angiography images, vessels were found to be more prominent in the sildenafil group. The average number of capillary formations under light microscopy was higher in the sildenafil group (p= 0.0286). CONCLUSION: The subdermal high dose sildenafil has a positive effect on flap survival.

Preoperative subcutaneous sildenafil injection increases random flap survival in rats

Abstract Purpose: To investigate the effect of subcutaneous sildenafil on random flap survival. Methods: Fourteen Wistar rats, which were divided in to two groups, were used for this experimental study. Rats in the sildenafil group received subcutaneous sildenafil injections daily for seven days before flap elevation. At the end of the treatment period, 9x3 cm dorsal skin flaps were elevated and reinserted back into their place in all of the animals. Necrotic and whole flaps areas were recorded on graph papers. Seven days after the flap elevation samples for histological examination were taken and angiographies were performed to visualize the flap vascularization. Results: The calculated average percentage of necrotic flap areas were 18.29% and 42.26% in the sildenafil and control group respectively.(p=0.0233). In selected angiography images, vessels were found to be more prominent in the sildenafil group. The average number of capillary formations under light microscopy was higher in the sildenafil group (p= 0.0286). Conclusion: The subdermal high dose sildenafil has a positive effect on flap survival.

Sexual habits of men with ED who take phosphodiesterase 5 inhibitors: a survey conducted in 7 countries.

INTRODUCTION: Western cultural perceptions that favour spontaneous sex may create unrealistic expectations for erectile dysfunction (ED) treatment. Little is known about how users of phosphodiesterase type 5 inhibitors (PDE5Is) plan sexual activity and timing of their preactivity PDE5I ingestion. Because various PDE5Is vary in their duration of action and dosage regimen, this may be an important consideration in selecting the optimal agent for the ED patient. AIM: To better understand the sexual habits of PDE5I users. METHODS: Men from 7 countries (Brazil, China, Italy, Japan, Russia, Taiwan, Turkey) were screened online for age, self-reported comorbidities and ED medication use in the prior 3 months. After screening, eligible participants were asked to complete a 7-question, self-administered online survey containing questions regarding sexual habits and behaviours. MAIN OUTCOME MEASURES: Survey questions focused primarily on advanced planning of sexual intercourse and timing of PDE5I ingestion but also addressed the frequency of sexual intercourse and ED medication use. RESULTS: Of the 1458 respondents (response rate: 48%; median age: 48 years [interquartile range (IQR), 44-55]), 83% always/sometimes planned a specific time for intercourse in advance; 72% planned a specific time for sexual intercourse up to several hours in advance. Of respondents who planned in advance, more than half planned specific days of the week (55%) and times of the day (60%) for sexual intercourse. The time to sexual intercourse after dosing was ≤1 hour for 70% and ≤4 hours for 96% of men. The median frequency of sexual intercourse was 6 times/month (IQR, 4-10), with ED medication taken a median of 5 times/month (IQR, 3-8). CONCLUSIONS: Sexual activity is usually planned by ED medication users several hours in advance, and the vast majority are attempting activity within a short time after ingestion of the agent. These data should aid clinicians in the selection of the optimal PDE5I.

Penile microvascular endothelial function in hypertensive patients: effects of acute type 5 phosphodiesterase inhibition.

The primary aim of this study was to evaluate penile endothelial microvascular function in patients with primary arterial hypertension and age-matched normotensive subjects using laser speckle contrast imaging (LSCI). Additionally, we analyzed the acute penile microvascular effects induced by oral phosphodiesterase type 5 inhibitor (sildenafil; SIL) administration. Endothelium-dependent microvascular reactivity was evaluated in the penises and forearms of hypertensive patients (aged 58.8±6.6 years, n=34) and age-matched healthy volunteers (n=33) at rest and 60 min following oral SIL (100 mg) administration. LSCI was coupled with cutaneous acetylcholine (ACh) iontophoresis using increasing anodal currents. Basal penile cutaneous vascular conductance (CVC) values were not significantly different between control subjects and hypertensive individuals. Penile CVC values increased significantly after SIL administration in control (P<0.0001) and hypertensive (P<0.0001) subjects. Peak CVC values were not different between the two groups during penile ACh iontophoresis before SIL administration (P=0.2052). Peak CVC values were higher in control subjects than in hypertensive subjects after SIL administration (P=0.0427). Penile endothelium-dependent microvascular function is, to some extent, preserved in patients presenting with primary arterial hypertension under effective anti-hypertensive treatment. LSCI may be a valuable non-invasive tool for the evaluation of penile vascular responses to phosphodiesterase type 5 inhibitor.

Penile microvascular endothelial function in hypertensive patients: effects of acute type 5 phosphodiesterase inhibition

The primary aim of this study was to evaluate penile endothelial microvascular function in patients with primary arterial hypertension and age-matched normotensive subjects using laser speckle contrast imaging (LSCI). Additionally, we analyzed the acute penile microvascular effects induced by oral phosphodiesterase type 5 inhibitor (sildenafil; SIL) administration. Endothelium-dependent microvascular reactivity was evaluated in the penises and forearms of hypertensive patients (aged 58.8±6.6 years, n=34) and age-matched healthy volunteers (n=33) at rest and 60 min following oral SIL (100 mg) administration. LSCI was coupled with cutaneous acetylcholine (ACh) iontophoresis using increasing anodal currents. Basal penile cutaneous vascular conductance (CVC) values were not significantly different between control subjects and hypertensive individuals. Penile CVC values increased significantly after SIL administration in control (P<0.0001) and hypertensive (P<0.0001) subjects. Peak CVC values were not different between the two groups during penile ACh iontophoresis before SIL administration (P=0.2052). Peak CVC values were higher in control subjects than in hypertensive subjects after SIL administration (P=0.0427). Penile endothelium-dependent microvascular function is, to some extent, preserved in patients presenting with primary arterial hypertension under effective anti-hypertensive treatment. LSCI may be a valuable non-invasive tool for the evaluation of penile vascular responses to phosphodiesterase type 5 inhibitor.

Pharmacokinetics of sildenafil in children with pulmonary arterial hypertension.

BACKGROUND: Recently, sildenafil was introduced to treat pulmonary arterial hypertension (PAH); however, there are currently few studies on the pharmacokinetics of sildenalfil in children. Therefore, we aimed to carry out a pharmacokinetic study of sildenafil in children with PAH using a single dose. METHODS: Twelve children diagnosed with PAH, consisting of with ten males and two females, were recruited for the study after obtaining written consent from their parents or guardians. Blood samples were obtained predose and at 0.25, 0.5, 1, 2, 4, 8 and 12 hours after the oral administration of 1 mg/kg of sildenafil using an extemporal pediatric formulation developed in our laboratory. The samples were analyzed using a previously validated high performance liquid chromatography method. RESULTS: A pharmacokinetic analysis using the WinNonlin 3.1 program that considered the Akaike information criterion (AIC) for selecting a more adjustable model was performed. The following pharmacokinetic parameters were obtained: maximal concentration (Cmax): 366±179 ng/mL, time to maximal concentration: 0.92±0.30 hours, elimination half-life (t1/2): 2.41±1.18 hours, total clearance (CLtot/F): 5.85±2.81 L/hour, volume of distribution (Vd/F): 20.13±14.5 L, absorption rate constants (Ka): 0.343 hour-1, elimination rate (Ke): 0.35 hour-1, area under curve from zero to infinity: 2061±618 ng/mL/hour. The data of all patients adjusted to the model of one compartment were corroborated using AIC. CONCLUSIONS: The parameters Ka, Ke and t1/2 were found to be similar to those reported in adults; however, the values of Cmax and Vd/F were significantly higher. Based on these findings, we propose that treatment regimen of sildenafil be adjusted in children with PAH.