Early Addition of Selexipag to Double Therapy for Pulmonary Arterial Hypertension.

Importance: A subgroup analysis of a randomized clinical trial established the efficacy of selexipag plus background therapy (monotherapy or double oral therapy [DOT]) vs placebo plus background therapy and found that the addition of selexipag within 6 months had an added benefit. However, the timing of selexipag addition to DOT and the incremental benefit in clinical practice is not well studied. Objective: To compare triple oral therapy (TOT) consisting of selexipag, endothelin receptor antagonist (ERA), and phosphodiesterase type 5 inhibitor (PDE5i) vs DOT consisting of ERA and PDE5i. Design, Setting, and Participants: This comparative effectiveness study was conducted using data from the US Komodo claims database to emulate a randomized trial. Patients aged 18 years or older with pulmonary arterial hypertension (PAH) treated with ERA plus PDE5i with records from July 2015 through June 2022 were duplicated to TOT and DOT and artificially censored when observed treatment deviated from assigned treatment. Hypothetical randomization was emulated using inverse probability of treatment weighting, and the study accounted for censoring-induced selection bias using inverse probability of censoring weighting. A pooled logistic model estimated the per-protocol difference between treatment groups. Data were analyzed from November 2022 through July 2023. Interventions: TOT (addition of selexipag within 3, 6, and 12 months of initiating DOT) vs DOT. Main Outcomes and Measures: Adjusted risk of all-cause hospitalization, PAH-related hospitalization, and PAH-related disease progression over a 2-year follow-up. Results: A total of 2966 patients with PAH (mean [SD] age, 54.3 [14.0] years; 2125 female [71.6%]) met eligibility criteria. Adding selexipag within 6 months of ongoing DOT was associated with a reduction in risk for all-cause hospitalization (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94), PAH-related hospitalization (aHR, 0.81; 95% CI, 0.70-0.95), and PAH-related progression (aHR, 0.82; 95% CI, 0.70-0.95) vs DOT alone. There were no associations if selexipag was initiated within 12 months for all-cause hospitalization, PAH-related hospitalization, or PAH-related disease progression. The association remained with a greater decrease in risk for disease progression vs DOT for selexipag initiation within 3 months (aHR, 0.74; 95% CI, 0.61-0.90). Conclusions and Relevance: This study found that early selexipag addition to ERA plus PDE5i was associated with a reduction in risk of hospitalization and disease progression. These findings suggest that delays in selexipag initiation likely contribute to suboptimal patient and health system outcomes.

Prospective, randomized, placebo-controlled, two-arm study to evaluate the efficacy of coadministration of garlic as a hydrogen sulfide donor and tadalafil in patients with erectile dysfunction not responding to tadalafil alone - A pilot study.

OBJECTIVE: The objective is to evaluate the efficacy of coadministration of garlic (as a hydrogen sulfide [H2S] donor) and tadalafil for patients with ED using a placebo-controlled, prospective, randomized, two-arm pilot study in patients responding poorly to tadalafil alone. MATERIALS AND METHODS: The patients with complaints of ED (with normal penile Doppler) who failed to maintain sustained improvement in erectile function with tadalafil were recruited after excluding those with comorbidities. The study sample was randomized into two groups. Group A received garlic 5 g twice a day orally and Group B received a placebo twice daily orally for 4 weeks. Both groups continued tadalafil 5 mg in the night for 4 weeks. Their erectile function was assessed at the beginning and at the end of 4 weeks using the International Index of Erectile Function (IIEF-EF), erectile function domain and compared. A value of P ≤ 0.05 was considered statistically significant. RESULTS: Nineteen patients in Group A (mean age 37.5 ± 10.6 years) and 16 patients in Group B (mean age 39.6 ± 9.6 years) participated in the pilot study conducted from May 2022 to August 2022. The participants treated with garlic (as an H2S donor) as a coadministrant had statistically significant improvement in IIEF-EF score (P ≤ 0.0001) at the end of 4 weeks compared to placebo. CONCLUSIONS: Garlic (as an H2S donor) as adjunctive therapy was beneficial in our study participants responding poorly to tadalafil alone.

Sildenafil's effectiveness in the primary coronary slow flow phenomenon: a pilot randomised controlled clinical trial.

BACKGROUND: On the one hand, the primary coronary slow flow phenomenon (CSFP) can cause recurrence of chest pain, prompting medical examinations and further healthcare costs, while on the other hand, it can lead to myocardial infarction, ventricular arrhythmia and sudden cardiac death. Nevertheless, there is not any agreement on the optimal treatment for primary CSFP, so we decided to examine the effectiveness of sildenafil in this context. METHODS: This pilot study is a 12-week, triple-blind, randomised, placebo-controlled trial for receiving either 50 mg daily oral sildenafil or placebo. Twenty eligible patients aged 30-70 years from a tertiary hospital in Yazd were randomly allocated in a 1:1 ratio to two groups. The primary outcomes were the alterations in functional capacity (metabolic equivalents, METs), Duke treadmill score (DTS) and angina severity (Canadian Cardiovascular Society (CCS) class). The study protocol registration code is IRCT20220223054103N1. RESULTS: The angina severity in the Sildenafil group improved, with all receivers achieving a state of being asymptomatic during regular physical activity (CCS I). Whereas just 40% of the recipients in the placebo group achieved the same level of improvement (p=0.011). Mean METs at baseline were 9.9 (SD: 3.1) and at week 12 were 13.1 (SD: 3.3) for sildenafil and 9.56 (SD: 2.1) and 9.63 (SD: 2.4) for placebo (difference favouring sildenafil with a median increase of 3.1 (IQR: 1.1 to 4.1, p=0.008)). Median DTS scores at baseline were 3 (IQR: 0 to 9) and at week 12 were 9.5 (IQR: 7.75 to 15) for sildenafil and 7 (IQR: -1.5 to 9.25) and 8 (IQR: 1.5 to 11.25) for placebo (difference favouring sildenafil with a median increase of 5.5 (IQR: 1 to 9.2, p=0.01)). CONCLUSIONS: We suggest that a daily low dose of sildenafil could be a valuable therapeutic option for primary CSFP. TRIAL REGISTRATION NUMBER: IRCT20220223054103N1.

The Antidepressant- and Anxiolytic-Like Effects of the Phosphodiesterase Type-5 Inhibitor Tadalafil are Associated with the Modulation of the Gut-Brain Axis During CNS Autoimmunity.

Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.

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.

Safety assessment of sildenafil use in neonates: a real-world data analysis based on the FDA adverse event reporting system (FAERS).

BACKGROUND: The safety of neonatal sildenafil use remains uncertain. This study aimed to investigate adverse events (AEs) associated with sildenafil use in neonates. RESEARCH DESIGN AND METHODS: We collected data on AEs associated with sildenafil use in neonates from the US Food and Drug Administration Adverse Event Reporting System database, spanning from its inception of the database in 2004 to 2023. Disproportionality measures were employed to analyze the correlation between AEs and sildenafil. RESULTS: Sildenafil was identified as the primary suspect drug in 75 AE reports, involving 214 AEs. Three system organ classes, namely, eye disorders, hepatobiliary disorders, and vascular disorders were associated with sildenafil use. Six preferred terms, namely, flushing, retinopathy of prematurity, hyperbilirubinemia, pulmonary hemorrhage, hypotension, and diarrhea were associated with sildenafil use. Notably, hyperbilirubinemia and pulmonary hemorrhage were previously unreported AEs associated with sildenafil use. CONCLUSION: The results highlight the ongoing uncertainty surrounding the safety of neonatal sildenafil use and provide vital support for risk monitoring and identification in neonates receiving sildenafil. Additionally, the study underscores the need for continuous safety surveillance in neonates treated with sildenafil and suggests further exploration of the precise causal relationships between AEs and sildenafil.

Preliminary Efficacy of Topical Sildenafil Cream for the Treatment of Female Sexual Arousal Disorder: A Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy of topical sildenafil cream, 3.6% among healthy premenopausal women with female sexual arousal disorder. METHODS: We conducted a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream. Coprimary efficacy endpoints were the change from baseline to week 12 in the Arousal Sensation domain of the SFQ28 (Sexual Function Questionnaire) and question 14 of the FSDS-DAO (Female Sexual Distress Scale-Desire, Arousal, Orgasm). RESULTS: Two hundred women with female sexual arousal disorder were randomized to sildenafil cream (n=101) or placebo cream (n=99). A total of 174 participants completed the study (sildenafil 90, placebo 84). Among the intention-to-treat (ITT) population, which included women with only female sexual arousal disorder and those with female sexual arousal disorder with concomitant sexual dysfunction diagnoses or genital pain, although the sildenafil cream group demonstrated greater improvement in the SFQ28 Arousal Sensation domain scores, there were no statistically significant differences between sildenafil and placebo cream users in the coprimary and secondary efficacy endpoints. An exploratory post hoc subset of the ITT population with an enrollment diagnosis of female sexual arousal disorder with or without concomitant decreased desire randomized to sildenafil cream reported significant increases in their SFQ28 Arousal Sensation domain score (least squares mean 2.03 [SE 0.62]) compared with placebo cream (least squares mean 0.08 [SE 0.71], P =.04). This subset achieved a larger mean improvement in the SFQ28 Desire and Orgasm domain scores. This subset population also had significantly reduced sexual distress and interpersonal difficulties with sildenafil cream use as measured by FSDS-DAO questions 3, 5, and 10 (all P ≤.04). CONCLUSION: Topical sildenafil cream improved outcomes among women with female sexual arousal disorder, most significantly in those who did not have concomitant orgasmic dysfunction. In particular, in an exploratory analysis of a subset of women with female sexual arousal disorder with or without concomitant decreased desire, topical sildenafil cream increased sexual arousal sensation, desire, and orgasm and reduced sexual distress. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04948151.

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.

Spontaneous erectile function recovery among young men with erectile dysfunction taking tadalafil 5 mg once a day.

BACKGROUND: Daily (once a day [OaD]) tadalafil intake is a valuable option for men favoring spontaneous over scheduled sexual intercourse. AIM: The study sought to assess the rate of and the clinical factors associated with spontaneous, medication-free erectile function (EF) recovery after discontinuation of tadalafil 5 mg OaD in a cohort of young men seeking first medical help for psychogenic erectile dysfunction (ED) as their primary complaint. METHODS: Data from 96 consecutive patients <50 years of age seeking first medical help for ED and prescribed tadalafil 5 mg OaD were analyzed. Patients completed the International Index of Erectile Function (IIEF) and underwent baseline penile color Doppler ultrasound. Follow-up involved clinical assessments or phone interviews. Spontaneous medication-free EF recovery was defined as IIEF EF domain score >22 after tadalafil discontinuation, prompting cessation of follow-up. Descriptive statistics compared tadalafil OaD responders and nonresponders. Cox regression hazard models explored the association between baseline characteristics and EF recovery risk post-drug discontinuation. Kaplan-Meier analyses estimated EF recovery probability over time. OUTCOMES: The primary outcome was EF recovery after discontinuation of tadalafil 5 mg OaD. RESULTS: Overall, median age was 39 (interquartile range [IQR], 32-45) years. Of all, 82 (85.4%) patients achieved EF recovery after tadalafil OaD discontinuation, while 14 (14.6%) patients were identified as nonresponders. Median tadalafil usage time (from beginning to discontinuation) was 3 (IQR, 2-11) months. The most common treatment-emergent adverse event was headache in 9 (9.4%) patients. Nonresponders were older (43 [IQR, 42-45] years vs 38 [IQR, 31-44] years; P = .03), had higher body mass index (25.5 [IQR, 23.4-29.9] kg/m2 vs 23.6 [IQR, 21.8-25.9] kg/m2; P = .04), and reported lower baseline IIEF EF domain scores (12 [IQR, 7-15] vs 15 [IQR, 10-22]; P = .02) than responders. Nonresponders and responders did not differ in terms of baseline ED severity, Charlson comorbidity index, smoking, alcohol consumption, regular physical exercise, and color Doppler ultrasound parameters. Upon Cox regression analysis, younger age (hazard ratio, 0.95; 95% confidence interval, 0.92-0.99; P = .01) was associated to EF recovery, after adjusting for baseline ED severity, body mass index, smoking, and Charlson comorbidity index ≥1. The Kaplan-Meier analysis displays the probability of EF recovery over time, indicating rates of 43%, 60%, and 72% at 3-, 6-, and 12-month follow-up intervals, respectively. CLINICAL IMPLICATIONS: Tadalafil 5 mg OaD is an effective short-term treatment for psychogenic ED, allowing its discontinuation after achieving a normal medication-free EF. STRENGTHS AND LIMITATIONS: The main limitations are the limited number of participants and the potential neglect of confounding factors. CONCLUSION: Almost 1 out of 2 young men with primary psychogenic ED who were prescribed with tadalafil 5 mg OaD recovered spontaneous medication-free EF after 3 months of treatment. Overall, the younger the patient was, the higher the chance there was of spontaneous EF recovery after drug discontinuation.

Pharmacokinetics and Bioequivalence of Vardenafil Hydrochloride in Healthy Chinese Volunteers.

Vardenafil hydrochloride tablet is an inhibitor of phosphodiesterase type 5, primarily for the treatment of erectile dysfunction. This postprandial study evaluated the pharmacokinetics and bioequivalence of the test and reference formulations of vardenafil hydrochloride tablets in healthy Chinese volunteers. An open, randomized, single-center, single-dose, 2-period, 2-sequence bioequivalence test was conducted on 66 healthy subjects under fed conditions. Subjects were randomly assigned to a 20-mg test or reference formulation with a 7-day washout period. Venous blood samples (4 mL) were collected from each subject 25 times spanning predose (0 hour) to 24 hours after dosing. The plasma concentration of vardenafil was determined by high-performance liquid chromatography-tandem mass spectrometry. Sixty-two volunteers completed the study. Under fed conditions, the maximum plasma concentration was 29.1 ng/mL, the area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration was 85.3 ng•h/mL, and AUC from time 0 to infinity was 87.1 ng•h/mL. The 90% confidence intervals of the geometric mean ratio of AUC time 0 to the time of the last measurable concentration and AUC from time 0 to infinity were within the bioequivalence acceptance range of 0.80-1.25. The test formulation was a bioequivalent alternative to the reference formulation when taken under fed conditions in healthy Chinese subjects.

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.

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.

Differences in ocular adverse events associated with phosphodiesterase-5 inhibitors: a real-world pharmacovigilance study.

OBJECTIVE: Our study aims to characterize the ocular safety profiles of phosphodiesterase type 5 (PDE5) inhibitors and explore the differences among different PDE5 inhibitors. METHODS: We analyzed reports on ocular adverse events associated with sildenafil, vardenafil and tadalafil submitted to the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the first quarter of 2023. Disproportionality analysis was conducted to evaluate reporting risk profiles. RESULTS: Among 61,211 reports qualifying for analysis, 5,127 involved sildenafil, 832 vardenafil, and 3,733 tadalafil. All PDE5 inhibitors showed increased reporting odds ratios (ROR) for ocular adverse events, with vardenafil highest (ROR 4.47) followed by sildenafil and tadalafil. Key ocular adverse events included cyanopsia, optic ischemic neuropathy, visual field defects, unilateral blindness and blindness. Sildenafil showed the highest disproportionality for cyanopsia (ROR 1148.11) while vardenafil and tadalafil showed the highest disproportionality for optic ischemic neuropathy. Time-to-onset analysis also revealed significant differences, with sildenafil having a later median time-to-onset compared to vardenafil and tadalafil. CONCLUSIONS: This comprehensive pharmacovigilance study reveals distinct patterns of ocular adverse events associated with PDE5 inhibitors. These findings contribute to a better understanding of the safety profiles of PDE5 inhibitors and may guide healthcare professionals in clinical decision-making.

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.

The effect of combination treatment with low-intensity shockwave therapy and daily tadalafil on severe erectile dysfunction: a double-blind, randomized, sham-controlled clinical trial.

BACKGROUND: Patients with severe erectile dysfunction (ED) remain the most challenging group in terms of available noninvasive treatment modalities. AIM: The study sought to assess the role of combination therapy with low-intensity shockwave therapy (LiST) and daily tadalafil 5 mg in a highly select group of patients with severe vasculogenic ED through a double-blind, randomized trial. METHODS: Forty-eight sexually active men were randomly assigned to 12 sessions of LiST 3 times weekly and tadalafil 5 mg once daily (n = 34) or sham therapy and tadalafil (n = 17) for 4 weeks. Patients were assessed at 1 and 3 months after completion of treatment. OUTCOMES: Improvement of erectile function was evaluated through the International Index of Erectile Function-Erectile Function domain (IIEF-EF) or 6-item IIEF and the Sexual Encounter Profile (SEP) diary. The primary outcome was the difference between the groups in the IIEF-EF at 3 months after completion of treatment. Secondary outcomes comprised (1) the difference between the groups in the IIEF-EF at 1 month after completion of treatment, (2) the difference between the groups in the "yes" responses to question 3 of the SEP diary at 1 and 3 months, and (3) the treatment-related adverse events. The number of patients attaining a minimal clinically important difference in the IIEF-EF (improvement of at least 7 points) was also assessed. RESULTS: After treatment, the absolute scores in the IIEF-EF were higher in patients receiving LiST and tadalafil vs sham therapy and tadalafil both at the 1-month (12.1 ± 2.4 vs 10.2 ± 1.7; P = .002) and at the 3-month (12.9 ± 2.1 vs 10.8 ± 1.8; P < .001) evaluation. Between the 2 groups, the proportion of "yes" responses to question 3 of the SEP diary was not statistically significant, whereas the number of patients attaining a minimal clinically important difference in the IIEF-EF was statistically significant only at the 3-month evaluation. No adverse events occurred. CLINICAL IMPLICATIONS: Application of LiST in patients with severe vasculogenic ED receiving daily dose tadalafil may further improve erectile function compared with tadalafil as a stand-alone treatment on the short term. STRENGTHS AND LIMITATIONS: Although we provided the first study in the field, severe vasculogenic ED was defined based on medical history and clinical examination and not based on penile ultrasound measures. CONCLUSION: The combination of 12 sessions LiST 3 times weekly and daily tadalafil for 4 weeks led to a 2-point difference in the IIEF-EF compared with sham therapy and daily tadalafil among patients with severe vasculogenic ED after 1 and 3 months from completion of treatment.

Fixed-dose combination therapy in pulmonary arterial hypertension: Pros & cons.

Quality of life of patients suffering from chronic diseases is inevitably conditioned by the number of pills taken during the day. To improve patients' tolerability, compliance and quality of life and reduce healthcare costs, pharmaceutical companies are focusing on the commercialization of fixed-dose combination (FDC) therapies. The last ESC/ERS guidelines for the treatment of pulmonary arterial hypertension (PAH) recommend initial dual combination therapy for newly diagnosed patients at low or intermediate mortality risk. In this regard, polypills including an endothelin receptor antagonist (ERA) and a phosphodiesterase 5 inhibitor (PDE5-i) could represent an useful therapeutic strategy, although with some limitations. To date, evidence about the use of FDCs in PAH is limited but future studies evaluating their safety and efficacy are welcome.

Maternal tadalafil treatment does not increase uterine artery blood flow or oxygen delivery in the pregnant ewe.

Increasing placental perfusion (PP) could improve outcomes of growth-restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)-5 inhibitors, which induce vasodilatation of vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116-117 days' gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120-123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then ∼15-75 min (TAD 1) and ∼75-135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T2 oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion-Relaxation Combined Imaging for Detailed Placental Evaluation-'DECIDE' technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal-placental blood volume fraction was increased in the TAD 2 period. Fetal D O 2 ${D_{{{\mathrm{O}}_2}}}$ and V ̇ O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal-placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA D O 2 ${D_{{{\mathrm{O}}_2}}}$ .

Evaluation of efficacy and safety profile of tadalafil 5 mg daily dose in the tablet form versus oral dispersible film in men with mild-to-moderate erectile dysfunction: a comparative placebo-controlled study.

PURPOSE: We aimed to compare the efficacy, safety, and compliance of tadalafil 5 mg daily dose in the tablet form versus oral dispersible film (ODF) in men with mild-to-moderate erectile dysfunction (ED). METHODS: One hundred thirty-five randomized patients were equally divided into three groups according to age where each group included forty-five patients. Within each group, 15 patients received oral tadalafil 5 mg, 15 patients received ODF tadalafil 5 mg and 15 patients received a placebo once daily for 1 month. All participants were assessed by the validated Arabic version of the international index of erectile function (ArIIEF-5) at baseline and after 1 month. Also, the efficacy of different forms of tadalafil 5 mg was assessed by responding affirmatively to a questionnaire. RESULTS: Patients aged > 25 to < 40 years and 40-55 years and > 55 years showed a statistically significant improvement of ArIIEF-5 scores after tadalafil 5 mg tablet and ODF tadalafil 5 mg compared to placebo ODF (23 ± 1.4; 22.7 ± 0.9; 20 ± 0.9; 20.4 ± 1.3; 20.2 ± 1.2; 16.6 ± 1.2; 18.5 ± 1.7; 19.6 ± 1.4; 16.3 ± 1.4; p < 0.001, respectively). Three patients (> 25 to < 40 years) who received tadalafil 5 mg tablet showed muscle and back pain. Gastrointestinal (GIT) upset (eight patients) followed by headache (seven patients) were the main side effects reported in patients (40-55 years) who received tadalafil 5 mg tablet. While GIT upset was the main side effect reported in patients (> 55 years) who received tadalafil 5 mg tablet. CONCLUSION: ODF tadalafil 5 mg is an effective, tolerable, and safe formulation that can be used in patients with mild-to-moderate ED.

Evaluation of tadalafil supplementation on the neutrophil/lymphocyte and the platelet/lymphocyte ratios in patients with erectile dysfunction: A prospective study.

OBJECTIVES: We aimed to evaluate the effect of daily 5 mg tadalafil on the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR) in patients with erectile dysfunction (ED). PATIENTS AND METHODS: 30 subjects with ED were given tadalafil as well as 30 subjects with ED who were not receiving tadalafil were recruited. 30 healthy individuals served as controls. RESULTS: Receiver operating characteristic curve (ROC) showed that the best cut off point of pre-treatment and post treatment NLR in the ED treatment group was found <1.51, <1.51, sensitivity of 68.3%, 58.3%, specificity of 53.3%, 53.3%, lower bound of 0.558, 0.517, upper bound of 0.789, 0.757, total accuracy of 67.4%, 63.7% and p 0.003, 0.0025, respectively. Additionally, the best cut off point of pre-treatment and post treatment PLR in the ED treatment group was found <5.89, <5.99, sensitivity of 65%, 63.3%, specificity of 63.3%, 53.3%, lower bound of 0.515, 0.435, upper bound of 0.755, 0.687, total accuracy of 63.5%, 56.1% and p 0.027, 0.341, respectively. CONCLUSION: Daily 5 mg Tadalafil supplementation significantly improves erectile function through decreasing these markers as well as depression and anxiety.