Randomized, Multicenter Study to Assess the Effects of Different Doses of Sildenafil on Mortality in Adults With Pulmonary Arterial Hypertension.

BACKGROUND: Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH. METHODS: This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population. RESULTS: The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P<0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P<0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P=0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil. CONCLUSIONS: Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487.

Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

Differential inhibition of sildenafil and macitentan on saxagliptin metabolism.

The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.

Sildenafil citrate induces prostatic hyperplasia in BPH model rats and aged rats.

Erectile dysfunction (ED), a prevalent disease among middle-aged and elderly males, significantly impacts both patient and partner quality of life. Phosphodiesterase type 5 inhibitor (PDE5i) represents an effective therapeutic method for ED. Given their widespread global utilization, concerns arise regarding potential reproduction-related problems arising from clinical use. During the extensive development of PDE5i, we speculated that the potential of these inhibitors to variably induce prostatic hyperplasia, but this field remains unexplored. In order to verify the male reproductive toxicity of PDE5i, sildenafil citrate at doses of 5, 10 and 20 mg/kg was administered in BPH model rats and aged rats. Anatomical and pathological analyses indicate a compelling association between sildenafil citrate administration and the promotion of prostatic hyperplasia in both BPH model rats and aged rats. Serum analysis showed that serum prostate-binding protein (PBP) exhibited a non-significant but increasing trend following administration of sildenafil citrate to BPH model rats. Furthermore, significant increase in serum levels of E2 and T, as well as T in dorsal lobe prostate tissue of aged rats, were observed compared to the model control group. These results confirm the hypothesis that sildenafil citrate has reproductive toxicity in males.

SIRT1/SREBPs-mediated regulation of lipid metabolism.

Sirtuins, also called silent information regulator 2, are enzymes that rely on nicotinamide adenine dinucleotide (NAD+) to function as histone deacetylases. Further investigation is warranted to explore the advantageous impacts of Sirtuin 1 (SIRT1), a constituent of the sirtuin group, on lipid metabolism, in addition to its well-researched involvement in extending lifespan. The regulation of gene expression has been extensively linked to SIRT1. Sterol regulatory element-binding protein (SREBP) is a substrate of SIRT1 that has attracted significant interest due to its role in multiple cellular processes including cell cycle regulation, DNA damage repair, and metabolic functions. Hence, the objective of this analysis was to investigate and elucidate the correlation between SIRT1 and SREBPs, as well as assess the contribution of SIRT1/SREBPs in mitigating lipid metabolism dysfunction. The objective of this research was to investigate whether SIRT1 and SREBPs could be utilized as viable targets for therapeutic intervention in managing complications associated with diabetes.

Safety of topical sildenafil cream, 3.6% in a randomized, placebo-controlled trial for the treatment of female sexual arousal disorder.

BACKGROUND: There are currently no Food and Drug Administration-approved treatments for female sexual arousal disorder (FSAD), which is physiologically analogous to male erectile dysfunction. AIMS: The study sought to test the systemic and local genital safety of topical sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD and their sexual partners over a 12-week treatment period. METHODS: This was a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream among healthy premenopausal women with FSAD. Safety was assessed by the frequency and incidence of treatment-emergent adverse events (TEAEs) among participants and their sexual partners. Participants recorded the incidence of TEAEs in a daily eDiary (electronic diary). Sexual partners were contacted within 72 hours of each sexual event in which investigational product was used. All participants used placebo cream for 1 month, during a single-blind run-in period, and then if eligible, were randomized 1:1 to sildenafil cream or placebo cream. Participants used their assigned investigational product over a 12-week double-blind dosing period. They attended monthly follow-up visits, in which their eDiary TEAE data were reviewed by the study staff and graded for severity and relationship to study product. OUTCOMES: The frequency and incidence of TEAEs among participants and their sexual partners. RESULTS: During the 12-week double-blind dosing period, there were 78 TEAEs reported by 29 of 99 sildenafil-assigned participants and 65 TEAEs reported by 28 of 94 placebo-assigned participants (P = .76). All TEAEs were mild or moderate in severity. The most common treatment-related TEAE among active and placebo-assigned participants was application site discomfort. There were no differences in the number of treatment-related TEAEs among sildenafil cream vs placebo cream users (P > .99). Four sildenafil cream participants and 3 placebo cream participants discontinued the study due to TEAEs involving application site discomfort (P > .99). There were 9 TEAEs reported by 7 of 91 sexual partners exposed to sildenafil cream vs 4 TEAEs reported by 4 of 84 sexual partners exposed to placebo cream (P = .54). CLINICAL IMPLICATIONS: These data support further clinical development of topical sildenafil cream for the treatment of FSAD. STRENGTHS AND LIMITATIONS: Safety was assessed among participants and their sexual partners after 1357 and 1160 sexual experiences in which sildenafil cream or placebo cream were used, respectively. The phase 2b study was powered for the primary objectives of efficacy, rather than safety. CONCLUSION: These data demonstrate that topically applied sildenafil cream was safe and well tolerated by exposed users and their sexual partners.

Comparisons and correlations of 1-month recall vs 24-hour recall in patient-reported outcomes of an exploratory, phase 2b, randomized, double-blind, placebo-controlled clinical trial of sildenafil cream, 3.6% for the treatment of female sexual arousal disorder.

BACKGROUND: Efficacy assessments in clinical trials of treatments for female sexual arousal disorder (FSAD) and other female sexual dysfunction (FSD) diagnoses rely on various patient-reported outcomes (PROs). AIMS: We sought to compare 1-month recall PRO measures among participants enrolled in a clinical trial who provided these data without (test population) vs with (control population) use of an at-home, 24-hour recall electronic diary (eDiary), capturing similar data. METHODS: Preplanned subset analysis as performed during a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD. Preliminary product efficacy was assessed via 1-month recall and 24-hour recall questionnaires. A subset of the participants, the Evaluation of Recall Subset [ERS] provided PROs via the 1-month recall instruments but did not provide data via the 24-hour recall eDiary. OUTCOMES: Responses to the 1-month recall instruments were compared among ERS (test) vs non-ERS (control) participants. Among the non-ERS population, correlations between 1-month and 24-hour recall endpoints were calculated. RESULTS: There were no significant differences in the study co-primary 1-month recall efficacy endpoints, the Arousal Sensation (AS) domain of the 28-item Sexual Function Questionnaire (SFQ28) and the Female Sexual Distress Scale - Desire, Arousal, Orgasm question 14, among ERS vs non-ERS participants during the initial 1-month no-drug run-in period or the 1-month single-blind placebo run-in period (P values > .47). Scores on these 1-month recall PROs continued to be similar after randomization for sildenafil cream (P values > .30) and placebo cream (P values > .20) assigned ERS and non-ERS participants during the 3-month double-blind dosing period. There were strong correlations between the SFQ28 AS and eDiary AS scores during the no-drug run-in (R = 0.79, P < .01) and the single-blind run-in (R = 0.73 P < .001). During the double-blind dosing period, the SFQ28 AS score continued to be highly correlated with the eDiary AS score among sildenafil cream users (R = 0.83; P < .001) and placebo cream users (R = 0.8; 2 P < .001). CLINICAL IMPLICATIONS: There was no evidence that 1-month recall PRO instruments introduce recall bias; assessing arousal sensations with 24-hour vs 1-month PRO instruments is similar and either method could be used to assess efficacy depending on study objectives. STRENGTHS AND LIMITATIONS: This preplanned subset analysis compared efficacy of PROs based on recall duration. While the subset was preplanned, the study was powered to detect significant differences in the primary efficacy objectives, not among this subset analyses. CONCLUSION: These data will be used in planning future efficacy assessments of sildenafil cream for FSAD. CLINICAL TRIAL REGISTRATION: This clinical trial was registered with ClinicalTrials.gov, NCT04948151.

A novel strategy to induce penile erection during penile doppler ultrasound: oral sildenafil administration plus alprostadil injection.

OBJECTIVES: To evaluate the efficacy of a novel approach to achieve the optimal penile erection during the penile doppler ultrasound (PDU) examination, which was oral sildenafil combined alprostadil injection. MATERIALS AND METHODS: A total of 60 ED patients were enrolled in our prospective study, and they were randomly assigned to two group with different PDU order. The approaches assisted the PDU included two models, mode A meaning injection of 15 µg alprostadil and model B meaning oral sildenafil 100 mg plus injection of 15 µg alprostadil. The PDU parameters were measured continuously before induced erection, and 5, 10, 15, 20, 25 min. RESULTS: Each group included 30 ED patients with similar clinical characteristics. After pooling the results together, the PSV, EDV, and RI were all improved significantly, when adding the oral sildenafil administration to assist PDU. Also, the clinical response of oral sildenafil administration plus alprostadil injection was better than that in alprostadil injection alone (p = 0.016). The arterial ED were decreased from 31.67% to 15.00% with the P value 0.031, and the mixed ED was also decreased statistically (23.33% vs 8.33%, p = 0.024). CONCLUSION: Oral sildenafil administration plus alprostadil injection could improve the diagnostic accuracy of PDU.

Neurodevelopmental outcomes at 2 years in children who received sildenafil therapy in utero: The STRIDER randomised controlled trial.

OBJECTIVE: Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes. DESIGN: Superiority, double-blind randomised controlled trial. SETTING: A total of 20 UK fetal medicine units. POPULATION: Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22+0 and 29+6 weeks of gestation. METHODS: Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation. MAIN OUTCOME MEASURES: All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85. RESULTS: In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm). CONCLUSIONS: Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition.

Multimodal action of phosphodiesterase 5 inhibitors against neurodegenerative disorders: An update review.

Phosphodiesterase type 5 (PDE5) is an enzyme primarily found in the smooth muscle of the corpus cavernosum and also highly expressed in the substantia nigra, cerebellum, caudate, hippocampal regions and cerebellar purkinje cells, responsible for selectively breaking down cyclic guanosine monophosphate (cGMP) into 5'-GMP and regulate intracellular cGMP levels. As a second messenger, cyclic GMP enhances signals at postsynaptic receptors and triggers downstream effector molecules, leading to changes in gene expression and neuronal responses. Additionally, cGMP signaling transduction cascade, present in the brain, is also essential for learning and memory processes. Mechanistically, PDE5 inhibitors share structural similarities with cGMP, competitively binding to PDE5 and inhibiting cGMP hydrolysis. This action enhances the effects of nitric oxide, resulting in anti-inflammatory and neuroprotective effects. Neurodegenerative disorders entail the progressive loss of neuron structure, culminating in neuronal cell death, with currently available drugs providing only limited symptomatic relief, rendering neurodegeneration considered incurable. PDE5 inhibitors have recently emerged as a potential therapeutic approach for neurodegeneration, neuroinflammation, and diseases involving cognitive impairment. This review elucidates the principal roles of 3',5'-cyclic adenosine monophosphate (cAMP) and cGMP signaling pathways in neuronal functions, believed to play pivotal roles in the pathogenesis of various neurodegenerative disorders. It provides an updated assessment of PDE5 inhibitors as disease-modifying agents for conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, Huntington's disease, and neuroinflammation. The paper aims to review the current understanding of PDE5 inhibitors, which concurrently regulate both cAMP and cGMP signaling pathways, positing that they may exert complementary and synergistic effects in modifying neurodegeneration, thus presenting a novel direction in therapeutic discovery. Moreover, the review provides critical about biological functions, therapeutic potentials, limitations, challenges, and emerging applications of selective PDE5 inhibitors. This comprehensive overview aims to guide future academic and industrial endeavors in this field.

Oral phosphodiesterase type 5 inhibitors and priapism: A VigiBase analysis.

PURPOSE: To explore the differences of priapism events among a diverse cohort taking erectogenic medicines (i.e., phosphodiesterase type 5 inhibitors [PDE5i] and intracavernousal drugs). METHODS: We queried the World Health Organization global database of individual case safety reports (VigiBase) for records of the adverse drug reactions (ADR) with sildenafil, tadalafil, avanafil, vardenafil, papaverine, and alprostadil. Disproportionality analyses (case/non-case approach) were performed to assess the reporting odds ratio (ROR) of priapism reporting in PDE5i consumers compared to intracavernousal drug recipients. RESULTS: From a total of 133 819 ADR events for erectogenic medications, 632 were priapism (PDE5is: n = 550, 0.41%; intracavernousal drugs: n = 82, 9.92%). Priapism disproportionality signals from intracavernousal drugs were 25 times stronger than PDE5is (ROR = 34.7; confidence interval [CI] 95%: 27.12-43.94 vs. ROR = 1.38; 95% CI: 1.24-1.54). For all PDE5i agents, the 12-17 years age group had the highest ROR (9.49, 95% CI: 3.76-19.93) followed by 2-11 years (4.31, 95% CI: 1.57-9.4). Disproportionality signals for consumers under 18 for both all PDE5is as a whole (ROR = 4.57, 95% CI: 2.48-7.73) and sildenafil (ROR = 4.89, 95% CI: 2.51-8.62) were stronger than individuals 18 or older (ROR = 1.06, 95% CI: 0.93-1.21 and ROR = 1.08, 95% CI: 0.91-1.26, respectively). CONCLUSIONS: PDE5i use shows disproportionate priapism signals which are higher in young patients.

Sildenafil-induced priapism in a dog : an unusual case report.

BACKGROUND: Priapism is defined as erection that lasts for more than 4 h without sexual stimulation. There are various causes of priapism, but there are no reports of sildenafil-induced priapism in dogs. In human medicine, there were no pre-marketing reports of priapism caused by sildenafil, but post-marketing surveillance has shown that it is rare. In cases of pulmonary hypertension in dogs, sildenafil is the first-line drug of choice for symptomatic relief. CASE PRESENTATION: An 11-year-old neutered male Maltese dog that presented with tachypnea and cough was diagnosed with myxomatous mitral valve disease, American College of Veterinary Internal Medicine (ACVIM) stage C, and was treated medically. Eighteen months after the diagnosis, severe pulmonary hypertension occurred due to left heart disease. At 20 months postdiagnosis, pleural effusion occurred, and sildenafil (2 mg/kg twice daily) was added to the existing treatment. Two weeks later, the dyspnea recurred, confirming pleural fluid recurrence, and sildenafil was increased to 2 mg/kg thrice daily. One day later, the patient developed persistent erections and penile pain. Penile amputation and urethrostomy were recommended but were refused; therefore, analgesia and palliative care were provided. The patient died of acute dyspnea 22 months after the first presentation, with no specific priapism recurrence at the time of death. CONCLUSION: To the best of our knowledge, this is the first report of sildenafil-induced priapism in a dog with pulmonary hypertension.

The clinical efficacy of cGMP-specific sildenafil on mitochondrial biogenesis induction and renal damage in cats with acute on chronic kidney disease.

BACKGROUND: Mitochondrial biogenesis (MB) induction has recently emerged as potential therapeutic approaches in kidney pathology and the mitochondria-targeted therapies should be investigated to improve treatment of animals with kidney diseases. This study aimed to investigate the effects of MB induction with sildenafil citrate on the cGMP/NO pathway, glomerular filtration, and reduction of kidney damage and fibrosis (TGF-ß/SMAD pathway) in cats with acute on chronic kidney disease (ACKD). Thirty-three cats were divided into the non-azotemic (healthy) group (n:8) and the ACKD group (n:25), comprising different breeds, sexes, and ages. Sildenafil citrate was administered to the non-azotemic and ACKD groups (2.5 mg/kg, PO, q12 hours) for 30 days. Serum and urine NO, MDA, NGAL, KIM-1, TGF-ß1, IL-18, FGF 23, PGC-1α and cGMP concentrations were measured. RESULTS: Serum cGMP concentrations increased (P < 0.05) in the non-azotemic group during the 2nd (median 475.99 pmol/mL) and 3rd (median 405.01 pmol/mL) weeks of the study, whereas serum cGMP concentrations decreased in the ACKD group during the 4th(median 188.52 pmol/mL) week compared to the non-azotemic group (P < 0.05). No difference was observed in serum biomarker concentrations except NO, which increased in the 4th week (P < 0.05). The urinary concentrations of NO, MDA, PGC-1α, TGF-ß1, NGAL, KIM-1, IL-18, and FGF 23 in the ACKD group were found to be higher compared to those in the non-azotemic group from the 1st to the 4th week (P < 0.05). In the ACKD group, the urine PGC-1α concentration in the 2nd (median 6.10 ng/mL) week was lower compared to that in the 0 and 1st (median 7.65 and 7.21 ng/mL, respectively) week, and the NO concentration in the 3rd (median 28.94 µmol/mL) week was lower than that in the 0th (median 37.43 µmol/mL) week (P < 0.05). CONCLUSIONS: While sildenafil citrate has been determined to induce a low level of MB and to have a beneficial effect on glomerular filtration, it is observed to be ineffective in mitigating renal damage and fibrosis via the TGF-ß/SMAD pathway in cats with ACKD.

Safety and efficacy of phosphodiesterase-5 (PDE-5) inhibitors in fetal growth restriction: a systematic literature review and meta-analysis.

Introduction: Fetal growth restriction (FGR) is associated with a higher risk of perinatal morbidity and mortality, as well as long-term health issues in newborns. Currently, there is no effective medicine for FGR. Phosphodiesterase-5 (PDE-5) inhibitors have been shown in pre-clinical studies to improve FGR. This study aimed to evaluate the latest evidence about the clinical outcomes and safety of PDE-5 inhibitors for the management of FGR. Methods: Eight databases (PubMed, Embase, Medline, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Database and WangFang Database) were searched for English and Chinese articles published from the database inception to December 2023. Randomized controlled trials (RCTs) reporting the use of PDE-5 inhibitors in FGR were included. The quality of the RCTs was assessed using the Cochrane Risk of Bias Tool. Odds ratio and mean difference (MD) (95% confidence intervals) were pooled for meta-analysis. Results: From 253 retrieved publications, 16 studies involving 1,492 pregnant women met the inclusion criteria. Only sildenafil (15 RCTs) and tadalafil (1 RCT) were studied for FGR. Compared with the control group (placebo, no treatment, or other medication therapies), sildenafil increased birth weight, pregnancy prolongation and umbilical artery pulsatility indices. However, it also increased the risk of pulmonary hypertension in newborns, as well as headache and flushing/rash in mothers. There were no significant differences in gestation age, perinatal mortality or major neonatal morbidity, stillbirth, neonate death, infants admitted to neonatal intensive care unit, intraventricular hemorrhage and necrotizing enterocolitis in infants, as well as pregnancy hypertension and gastrointestinal side effects in mothers between the treatment and the control groups. Discussion: Sildenafil was the most investigated PDE-5 inhibitors for FGR. Current evidence suggests that sildenafil can improve birth weight and duration of pregnancy but at the same time increase the risk of neonatal pulmonary hypertension. It remains uncertain whether the benefits of sildenafil in FGR outweigh the risks and further high-quality RCTs are warranted. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=325909.

Effect of off-label targeted drugs on long-term survival in chronic thromboembolic pulmonary hypertension: Insights from a national multicentre prospective registry.

BACKGROUND AND OBJECTIVE: Off-label pulmonary arterial hypertension (PAH)-targeted drugs are commonly prescribed for non-operated chronic thromboembolic pulmonary hypertension (CTEPH), but their effect on the long-term prognosis of CTEPH remains unknown. This study investigated the effect of off-label PAH-targeted drugs on the long-term survival of CTEPH patients. METHODS: CTEPH patients were enrolled from a prospective multicentre national registry. Except for licensed riociguat and treprostinil, other PAH-targeted drugs were off-label. In the original and propensity score-matched (PSM) samples, five-year survival was compared in two groups: (a) patients not receiving off-label PAH-targeted drugs (control) versus (b) patients receiving off-label PAH-targeted drugs (treatment). The latter group was investigated for the effect of started off-label PAH-targeted drugs at baselines (initial) or during follow-up (subsequent). RESULTS: Of 347 enrolled patients, 212 were treated with off-label PAH-targeted drugs initially (n = 173) or subsequently (n = 39), and 135 were untreated. The 1-, 2-, 3- and 5-year survival of the treatment group was significantly higher than that of the control group (97.1% vs. 89.4%, 92.3% vs. 82.1%, 83.2% vs. 75.1% and 71.1% vs. 55.3%, respectively, log-rank test, p = 0.005). Initial treatment was correlated with better 5-year survival after excluding patients with subsequent treatment to reduce the immortal-time bias (hazard ratio: 0.611; 95% CI: 0.397-0.940; p = 0.025). In PSM samples, patients given initial treatment showed significantly better 5-year survival than untreated patients (68.9% vs. 49.3%, log-rank test, p = 0.008). CONCLUSION: Off-label targeted drugs contributed to improved long-term survival in CTEPH patients receiving pharmacotherapies.

Phosphodiesterase-5 inhibitors use and the risk of alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: The management of Alzheimer's disease (AD) poses considerable challenges, necessitating the pursuit of innovative therapeutic approaches. Recent research has spotlighted the promising role of phosphodiesterase type 5 inhibitors (PDE5Is) in reducing the prevalence of AD, utilizing their vasodilatory properties to suggest a potential neuroprotective effect. This meta-analysis and systematic review aims to assess the relationship between the use of PDE5Is and the risk of AD. METHODS: A detailed examination was carried out across several electronic databases till March 2024, including PubMed, Web of Science, Scopus, CENTRAL, and Embase. The focus was on identifying studies that compare the occurrence of AD among PDE5I users vs non-users. Through a random-effects model, pooled hazard ratios (HRs) were calculated, in alignment with guidelines from the Cochrane Handbook for Systematic Reviews and Meta-Analysis and the PRISMA standards. RESULTS: This analysis included six studies, cumulating a participant count of 8,337,313, involving individuals treated with sildenafil, tadalafil, and vardenafil, against a control group undergoing other or no treatments. The cumulative HR for AD risk among PDE5I users versus the control group was 0.53 (95% CI: 0.32-0.86, p = 0.008), signaling a markedly reduced likelihood of AD development in the PDE5I group. Particularly, sildenafil usage showed a significant risk reduction (HR: 0.46, 95% CI: 0.31-0.70, p < 0.001), while findings for tadalafil and vardenafil were not significant. Test of subgroup differences found no difference between male and female participants in the risk of AD. CONCLUSIONS: Our findings suggest that the use of PDE5Is is associated with a reduced risk of AD, highlighting its potential as a protective agent against neurodegenerative diseases. Given the very low quality of evidence and the heterogeneity among the included studies, further high-quality research is warranted to confirm these findings and elucidate the underlying mechanisms. Register number PROSPERO 2024: CRD42024522197.

Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial.

BACKGROUND: Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21-24 mmHg). METHODS: The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks. DISCUSSION: The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04797286.

Efficient administration of a combination of nifedipine and sildenafil citrate versus only nifedipine on clinical outcomes in women with threatened preterm labor: a systematic review and meta-analysis.

BACKGROUND: Preterm labor (PTL) is a common and serious pregnancy disorder that can cause long-term neurological issues in the infant. There are conflicting studies concerning whether sildenafil citrate (SC) reduces preterm labor complications. Therefore, the meta-analysis aimed to examine the clinical outcomes in women with threatened PTL who received nifedipine plus SC therapy versus only nifedipine. METHODS: For the original articles, six databases were searched using relevant keywords without restriction on time or language until January 13, 2024. The Cochrane risk-of-bias tool for randomized trials (RoB) and the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) were both used to assess the risk of bias in randomized and non-randomized studies, and GRADE determined the quality of our evidence. Meta-analysis of all data was carried out using Review Manager (RevMan) version 5.1. RESULTS: Seven studies with mixed quality were included in the meta-analysis. The study found that combining nifedipine and SC resulted in more prolongation of pregnancy (MD = 6.99, 95% CI: 5.32, 8.65, p < 0.00001), a lower rate of delivery in the 1st to 3rd days after hospitalization (RR = 0.62, 95% CI: 0.50, 0.76, p < 0.00001), a higher birth weight (252.48 g vs. nifedipine alone, p = 0.02), and the risk ratio of admission to the neonatal intensive care unit (NICU) was significantly lower (RR = 0.62, 95% CI: 0.50, 0.76, p < 0.00001) compared to nifidepine alone. The evidence was high for prolongation of pregnancy, delivery rate 24-72 h after admission, and NICU admission, but low for newborn birth weight. CONCLUSIONS: Given the effectiveness of SC plus nifedipine in increased prolongation of pregnancy and birth weight, lower delivery in the 1st to 3rd days after hospitalization, and NICU admission, Gynecologists and obstetricians are suggested to consider this strategy for PTL management, although additional article rigor is required to improve the quality of the evidence.

Oral sildenafil versus bosentan for treatment of persistent pulmonary hypertension of the newborn: a randomized controlled trial.

BACKGROUND: Access to inhaled nitric oxide (iNO) is limited in low resource settings due to non-availability and high cost. There is a need for research on low-cost alternative therapies for management of persistent pulmonary hypertension of the newborn (PPHN). We aimed to compare oral sildenafil and bosentan as monotherapy in the treatment of neonates with PPHN. STUDY DESIGN: In this single-centre open-label randomized controlled trial (RCT), term and late preterm neonates with PPHN, defined as pulmonary arterial systolic pressure (PASP) > 35 mmHg and requiring fraction of inspired oxygen (FiO2) > 0.21, were randomized to receive oral sildenafil and bosentan. The primary outcome was reduction of PASP by 25% within 48 h after start of drug. RESULTS: Thirty-six neonates were analyzed (18 in each group). Initial PASPs were similar in both groups. The median (IQR) time for the primary outcome (PASP to reduce by 25% within 48 h) was 36 (24-48) h and 96 (48-120) h in sildenafil and bosentan groups respectively (p = 0.008). There was also a higher need to add other pulmonary vasodilators in bosentan group as compared to sildenafil group (p = 0.006). CONCLUSION: Sildenafil was associated with quicker reduction of PASP and FiO2 in neonates with PPHN, as compared to bosentan. Large multicentre blinded trials to assess efficacy and safety of bosentan in comparison with other pulmonary vasodilators would help to get a clearer understanding of its role in the management of PPHN, particularly for use in resource-limited settings that lack iNO. CLINICAL TRIAL REGISTRATION: https://ctri.nic.in/Clinicaltrials/rmaindet.php? trialid=63997&EncHid=39716.16132&modid=1&compid=19[CTRI/2022/06/043328].

Prophylactic sildenafil to prevent bronchopulmonary dysplasia: A systematic review and meta-analysis.

BACKGROUND: Bronchopulmonary dysplasia (BPD) persists as one of the foremost factors contributing to mortality and morbidity in extremely preterm infants. The effectiveness of administering sildenafil early on to prevent BPD remains uncertain. The aim of this study was to investigate the efficacy and safety of prophylactically administered sildenafil during the early life stages of preterm infants to prevent mortality and BPD. METHODS: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, and Ichushi were searched. Published randomized controlled trials (RCTs), non-RCTs, interrupted time series, cohort studies, case-control studies, and controlled before-and-after studies were included. Two reviewers independently screened the title, abstract, and full text, extracted data, assessed the risk of bias, and evaluated the certainty of evidence (CoE) following the Grading of Recommendations Assessment and Development and Evaluation approach. The random-effects model was used for a meta-analysis of RCTs. RESULTS: This review included three RCTs (162 infants). There were no significant differences between the prophylactic sildenafil and placebo groups in mortality (risk ratio [RR]: 1.32; 95% confidence interval [CI]: 0.16-10.75; very low CoE), BPD (RR: 1.20; 95% CI: 0.79-1.83; very low CoE), and all other outcome assessed (all with very low CoE). The sample sizes were less than the optimal sizes for all outcomes assessed, indicating the need for further trials. CONCLUSIONS: The prophylactic use of sildenafil in individuals at risk of BPD did not indicate any advantageous effects in terms of mortality, BPD, and other outcomes, or increased side effects.