Off-target effect of high-dose sildenafil on adenosine 5'- diphosphate and collagen-induced platelet activation through mitogen-activated protein kinase pathway in treated BALB/C mice and in vitro experiments: A preliminary study.

ABSTRACT: Sildenafil, a common over-the-counter pill often self-administered at high doses for erectile dysfunction, has been reported to rarely cause prothrombotic events and sudden cardiac death in a few case reports. Therefore, we investigated the in vitro and in vivo effect of sildenafil treatment and dosage on platelet activation and mitogen-activated protein kinase (MAPK) phosphorylation. BALB/C mice were segregated into four groups, each having four mice each (control, low [3.25 mg/kg], medium [6.5 mg/kg], and high [13 mg/kg] sildenafil), and after the treatment, blood was drawn from each mouse and washed platelets prepared. Washed platelets were incubated with CD41 PE-Cy7 and Phospho-p38 MAPK PE antibodies and analyzed using a flow cytometer for platelet activation and adenosine 5'- diphosphate (ADP)/collagen-induced MAPK phosphorylation. Washed platelets obtained from the venous blood of 18 human volunteers, were incubated with PAC-1 FITC and Phospho-p38 MAPK PE antibodies, and platelet activation (ADP and collagen), followed by flow cytometry analysis. There was a significant increase in both platelet activation as well as MAPK phosphorylation in the presence of collagen in the high-dose (13 mg/kg) sildenafil group (P = 0.000774). Further, increased platelet activation was observed in samples that were treated with high-dose sildenafil as compared to the untreated samples (P < 0.00001). These studies show the risk of prothrombotic episodes in patients on high-dose sildenafil (100 mg), in those with even mild endothelial dysfunction due to ADP, and collagen-induced platelet activation through MAPK phosphorylation, which was not seen in the low-and intermediate-dose cohorts.

Effect of topical sildenafil on wound healing and oxidative stress in rats.

BACKGROUND: In this study, the effects of topical sildenafil applications on oxidative damage levels and antioxidative metabolism and their contribution to wound healing and treatment were investigated. MATERIALS AND METHODS: A total of 24 healthy male rats aged 16-18 weeks, each weighing 200-250 g, were randomly divided into three groups: Group A received a saline solution, Group B received an epithelializing cream, and Group C received sildenafil cream. Following skin preparation and anesthesia, 6 mm diameter punch biopsies created wounds on the rats' backs. The treatment protocol involved daily topical dressing for seven days, after which tissue and blood samples were collected for analysis. Tissue samples underwent histopathological examination, while malondialdehyde (MDA) levels, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase activities in wound tissue and blood samples were measured. RESULTS: The wound surface area created by the punch decreased in all groups by the end of the seventh day; However, the degree of wound healing differed in favor of the sildenafil cream group. Histopathologically, according to Greenhalgh's Modified Wound Healing Scoring System, all findings were graded. In the Anova test, the differences between glutathione peroxidase, catalase, and malondialdehyde levels in the serum and tissue of rats was statistically significant (P < 0.05), whereas superoxide dismutase levels were not statistically significant (P > 0.05). In the Bonferroni test, the serum CAT levels between groups A and C (P = 0.003), between groups B and C (P = 0.035), and the serum MDA levels between groups A and B (P = 0.018) and between groups A and C (P = 0.001) were found to be significant statistically. By the way, the results between tissue CAT levels in the B and C groups (P = 0.020) and between tissue GPx levels (P = 0.001) in all groups were also significant statistically. CONCLUSIONS: The study findings indicated that topical application of sildenafil led to noteworthy alterations in serum and tissue antioxidative metabolism as well as oxidative damage levels among rats with induced wounds. Sildenafil may be useful in wound treatment; it has been concluded that it is capable of directing new studies to be carried out.

Perioperative sildenafil therapy in pulmonary hypertension associated with congenital cardiac disease: An updated meta-analysis.

To provide an updated meta-analysis to evaluate the efficacy and safety of sildenafil on pediatric patients with pulmonary hypertension (PH) associated with congenital heart disease (CHD). To assess the efficacy and safety of sildenafil, five outcomes, time duration of post-operative need for mechanical ventilation, time duration of post-operative ICU stay, length of hospitalization (LOH), the incidence of mortalities and pulmonary arterial pressure to aortic pressure ratio (PAP/AoP) were regarded as primary efficacy outcomes. Standardized mean difference (SMD) was calculated for continuous data. In comparison to the control group (CG), there was a significant decrease in the time duration of ICU stay in the sildenafil group (SG) (SMD = -0.61 [95% CI -1.17, 0.04]; P < 0.01, I2 = 85%). Length of hospitalization was assessed in the sildenafil and control groups (SMD = -0.18 [95% CI -0.67, 0.31] P = 0.05, I2 = 62%). However, there was no significant difference seen in mortality rates between the SG and CG (SMD = 0.53 [ 95% CI 0.13, 2.17] p = 0.61, I2 = 0%), in the time duration of postoperative mechanical ventilation between the SG and CG (SMD = -0.23 [95% CI -0.49, 0.03] p = 0.29, I2 = 19%), or PAP/AoP ratio between the SG and CG (SMD = -0.42 [95% CI -1.35, 0.51] P < 0.01, I2 = 90%). Based on our analysis, sildenafil has little to no effect in reducing postoperative morbidity and mortality due to PH in infants and children with CHD.

Comparison of Different Treatments of Persistent Pulmonary Hypertension of the Newborn: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening disease. Despite being considered the gold standard treatment scheme, inhaled nitric oxide (iNO) is not readily available in settings with limited resources. Therefore, in recent years, research on related drugs is being actively pursued. Herein, we aimed to use random-effects network meta-analysis to evaluate the efficacy and associated mortality of different PPHN therapies. DATA SOURCES: We electronically searched the PubMed, Embase, and Cochrane Library for data up to January 27, 2023. STUDY SELECTION: Randomized controlled trials involving neonates with PPHN assessing efficacy and mortality of various treatments. DATA EXTRACTION: Details of study population, treatments, and outcomes were extracted. DATA SYNTHESIS: Direct pairwise comparisons and a network meta-analysis was performed under random effects. The ranking probability was further assessed based on the surface under the cumulative ranking curve (SUCRA). We analyzed 23 randomized clinical trials involving 902 newborns with PPHN. Sixteen different treatment strategies were compared with each other and conventional therapy (CON). A median concentration of 10-20 parts per million (ppm) iNO (MNO) coupled with sildenafil orally administered at a dose of 1-3 mg/kg/dose every 6-8 hours (OSID) demonstrated the best efficacy (MNO + OSID vs. CON: odds ratio [OR] = 27.53, 95% CI, 2.36-321.75; SUCRA = 0.818, ranking first; moderate quality). OSID combined with milrinone administered IV also performed well in terms of efficacy (OSID + milrinone vs. CON: OR = 25.13, 95% CI = 1.67-377.78; SUCRA = 0.811, ranking second; low quality) and mortality reduction (CON vs. OSID + milrinone: OR = 25.13, 95% CI = 1.67-377.78; SUCRA = 0.786, ranking last; low quality). CONCLUSIONS: MNO + OSID is the most effective PPHN treatment. If iNO is not available, OSID + milrinone is preferred.

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.

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.

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.

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.

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.

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.