Comparative effectiveness of sildenafil citrate and estradiol valerate as adjuvants during clomiphene citrate-assisted ovarian stimulation cycles in patients with unexplained infertility: a double-blind randomized controlled trial.

OBJECTIVE: This study aimed to assess the effect of sildenafil citrate and estradiol valerate as adjuvant therapy during ovarian stimulation cycles with clomiphene citrate in patients with unexplained infertility in Kisangani. METHOD: A double-blind, randomized controlled trial was conducted for two years at two specialized health facilities in Kisangani (University Clinics of Kisangani and "Clinique des Anges Kisangani"). The population included 148 patients, 74 of whom were on clomiphene citrate + sildenafil citrate (CCSC) regimens and 74 of whom were on clomiphene citrate + estradiol valerate (CCEV) regimens for three months. The primary indicator was the conception rate, with secondary outcomes encompassing endometrial thickness, appearance and vascularity, the number of mature follicles and ovulation rate. RESULTS: The two groups were comparable in terms of sociodemographic and clinical characteristics. The mean duration of attempting to conceive was 4.39 years versus 4.36 years (P = 0.839), while the mean AFC was 11.51 versus 11.46 (P = 0.831), in the CCSC group versus CCEV group respectively. Secondary infertility was the most frequent diagnosis in each of the two groups. The biochemical pregnancy rate was comparable between the two groups (P = 0.385), while the clinical pregnancy rate was significantly higher in the CCSC group versus CCEV group (P = 0.04). Both perifollicular flow and the ovulation rate were significantly higher in the CCSC group versus the CCEV group (P = 0.006 and P = 0.002 respectively). However, endometrial vascularity/thickness, and the number of Graafian follicles were not significantly different between the two groups. CONCLUSION: As an adjuvant, sildenafil increases the rate of clinical pregnancy more than does estradiol in patients with unexplained infertility undergoing ovarian stimulation with clomiphene citrate. STUDY REGISTRATION: PACTR 202,310,849,449,401 (Pan African Clinical Trials Registry).

Development and Ex-Vivo Skin Permeation of Sildenafil Citrate Microemulsion System for Transdermal Delivery.

Background: This study aimed to develop a microemulsion (ME)-based skin delivery platform containing sildenafil citrate (SC)-ME and evaluate its in vitro skin permeability. Methods: Accurate MEs were prepared using pseudo-ternary phase diagrams and a full factorial design with three variables at two levels. After the design phase, suitable ratios of oil, water, and a mixture of surfactant (S) and cosurfactant (CS) were selected to prepare various SC-ME formulations. These SC-MEs were analyzed for stability, droplet size, in vitro SC release, skin permeability, and viscosity properties. Results: The droplet size of the ME samples ranged from 6.24 to 32.65 nm, with viscosities between 114 to 239 cps. Release profiles indicated that 26 to 60% of SC was released from the different SC-MEs within 24 hours. All ME formulations significantly enhanced the permeability coefficient (P) through rat skin. Specifically, the flux (Jss) in SC-ME7 increased by approximately 117 times (Jss = 0.0235 mg/cm2.h) compared to the control sample (0.0002 mg/cm2.h). Conclusions: The study concluded that the proportions of the water or oil phase and the S/CS mixture in the MEs significantly influenced the physicochemical characteristics and permeation parameters. The selected MEs improved both the permeability coefficient and the rate of permeation through rat skin. The enhanced drug delivery through and into deep skin layers is a key attribute of an ideal dermal ME. These findings suggest that MEs could serve as effective transdermal delivery systems for SC and similar drugs. However, in vivo assays and clinical research are needed to confirm the therapeutic efficacy of MEs.

Drug Reaction With Eosinophilia and Systemic Symptoms Syndrome Preceding Toxic Epidermal Necrolysis Secondary to Sildenafil: A Case Report.

Drug reactions with eosinophilia and systemic symptoms (DRESS) syndrome and Stevens-Johnson syndrome-toxic epidermal necrolysis (SJS-TEN) are reactive entities of aberrant cytotoxic immunologic reactions to exogenous medications. While they are conventionally seen as distinct, separate conditions, we present a case of a rare evolution of DRESS syndrome into SJS-TEN in the setting of simultaneous amoxicillin-clavulanate initiation and long-term sildenafil use in a 66-year-old South Asian female with a known history of prior DRESS syndrome and pulmonary arterial hypertension. We discuss the conditions leading to her unique clinical presentation and provide considerations for future clinical encounters.

Dose Sildenafil Citrate Reduce the Incidence of Emergency Cesarean Section and Fetal Distress During Labor? A Randomized Double-Blinded Clinical Trial.

Background: Fetal distress (FD) is one of the most frequent causes of emergency cesarean section (CS) due to the insufficient uteroplacental blood supply during labor. There is a theory that Sildenafil citrate (SC) may improve the uteroplacental blood supply and decrease fetal hypoxia and FD. Methods: In a randomized double-blinded clinical trial, a total of 208 low-risk subjects who met our stringent inclusion criteria were randomly assigned into two groups: the Sildenafil citrate group (n=104) and the placebo group (n=104). These participants were referred to our referral gynecology and obstetrics department for delivery between July 2022 to September 2022. The SC group received oral SC at a dose of 50 mg every 6 hr, up to a maximum of three times. The final maternal-fetal-neonatal results were recorded and all data were analyzed using SPSS version 23. Results: The mean age of mothers was 28.98±5.6 years and 120 cases were primigravid (57.7%). Out of a total of 208 pregnant subjects, 168 subjects delivered through normal vaginal delivery (80.8%) and 40 cases underwent emergency CS (19.2%). The number of NVD in Sildenafil group was significantly more than placebo group (87.5% vs. 74%) and SC decreased the rate of emergency CS to 87.5% (RR=2.46%, 95%CI 1.19-5.08). Also, SC decreased the rate of FD to 53.8% (RR=2.83%, 95%CI of 1-8.24). Conclusion: The results showed that SC can effectively decrease the rate of emergency CS and FD during labor.

UHPLC-MS/MS profiling and in vivo aphrodisiac and androgenic effects of the aqueous extract of the roots of Schumanniophyton magnificum (K. Schum.) Harms.

ETHNOPHARMACOLOGICAL RELEVANCE: Schumanniophyton magnificum is a medicinal plant used to manage many ailments including malaria, skin diseases, parasitic infections, male sexual dysfunctions, female infertility and typhoid fever. However, no scientific investigation has been made for its folkloric use by the "Baka" Pygmies of Cameroon as an aphrodisiac. AIM OF THE STUDY: To investigate the aphrodisiac and androgenic activities of the aqueous extract of the roots of Schumanniophyton magnificum in male rats and analyze the phytoconstituents by UHPLC/MS. MATERIALS AND METHODS: Twenty-five male rats of 16-weeks old were divided into 5 groups and orally treated for 30 days with distilled water (10 ml/kg), or sildenafil citrate (5 mg/kg), or the aqueous extract of Schumanniophyton magnificum (43 mg/kg, 86 mg/kg and 172 mg/kg). The sexual behaviour parameters were monitored on day 1 and 30 by pairing male rats to receptive females. At the end of the experiment, rats were killed and the blood and reproductive organs were collected for histological sectioning, sperm analysis and biochemical analysis. The presence of phytoconstituents and their structures were revealed by UHPLC/MS. RESULTS: The plant extract significantly increased the mount, ejaculation and intromission frequencies in comparison to those in the normal control group; and significantly doubled the serum testosterone levels (2.15 ± 0.70 ng/ml) compared to the normal control group. UHPLC/MS of the aqueous extract of Schumanniophyton magnificum identified 7 major compounds such as Schumanniofioside A, Noreugenin and Rohitukine, with antioxidant and antibacterial activities. The plant extracts significantly increased the penile nitric oxide levels (P <0.05). These results were similar to those obtained after administration of sildenafil citrate. CONCLUSIONS: The aqueous extract of Schumanniophyton magnificum could be an alternative for erectile dysfunction management.

A Web-Based Survey of Patients Dispensed Viagra Connect® Behind the Counter in UK: An Evaluation of Effectiveness of Additional Risk Minimization Measures.

Purpose: A national additional risk minimization measures (aRMMs) program was implemented to train pharmacists for safe supply of non-prescription Viagra Connect® (VC) to erectile dysfunction (ED) patients in United Kingdom (UK). A survey aimed to evaluate the effectiveness of aRMMs. Methods: A cross-sectional, web-based survey enrolled ED patients who purchased at least 1 supply of VC in UK, using a structured self-administered questionnaire. Patients were assessed for the suitability of VC and received appropriate advice from pharmacists. Descriptive statistics were used. Results: The final sample had 297 patients, who reported that pharmacists inquired about blood pressure and heart comorbidities (91.9%), relevant illnesses (87.9%), medications (86.5%), ED diagnosis (82.2%), and were advised to consult their doctor regarding ED (51.2%). Furthermore, 85.5% of patients were advised on how to take VC correctly, 82.2% on possible side effects for which they might have to discontinue taking VC and consult their doctor, 80.1% on being informed that ED could be caused by underlying conditions. About 65.0% reported that they had visited (19.2%) or planned to visit (45.8%) their doctor. A majority (68.7%) also indicated that they had received advice on lifestyle modifications to manage their ED-related health risks. Conclusion: This survey provided a reasonable confirmation of the effectiveness of the VC aRMMs program and assurance that ED patients, when requesting and purchasing VC in UK pharmacies, are assessed appropriately for suitability of VC and receive the appropriate advice from pharmacists.

A national additional risk minimization measures (aRMMs) program was implemented to train pharmacists for safe supply of non-prescription VC to erectile dysfunction (ED) patients in United Kingdom (UK). A cross-sectional, web-based survey enrolled ED patients who purchased at least 1 supply of VC in UK, using a structured self-administered questionnaire. Patients were assessed for the suitability of VC and received appropriate advice from pharmacists. The final sample had 297 patients, who reported that pharmacists inquired about blood pressure and heart comorbidities, relevant illnesses, medications, ED diagnosis, and were advised to consult their doctor regarding ED. Additionally, most of the patients had consulted or planned to consult their doctors, on how to take VC correctly, on possible side effects for which they might have to discontinue taking VC and consult their doctor, on being informed that ED could be caused by underlying conditions, and on lifestyle modifications. A majority also indicated that they had received advice on lifestyle modifications to manage their ED-related health risks. This survey provided a reasonable confirmation of the effectiveness of the VC aRMMs program and assurance that ED patients, when requesting and purchasing VC in UK pharmacies, are assessed appropriately for suitability of VC and receive the appropriate advice from pharmacists.

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.

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.

Formulation and evaluation of inhaled Sildenafil-loaded PLGA microparticles for treatment of pulmonary arterial hypertension (PAH): A novel high drug loaded formulation and scalable process via hot melt extrusion technology (Part â ).

In recent years, several techniques were employed to develop a local sustained pulmonary delivery of sildenafil citrate (SC) as an alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). Most of these methods, however, need to be improved due to limitations of scalability, low yield production, low drug loading, and stability issues. In this study, we report the use of hot-melt extrusion (HME) as a scalable process for making Poly (lactic-co-glycolic acid) (PLGA) microparticles with high SC load. The prepared particles were tested in vitro for local drug delivery to the lungs by inhalation. Sodium bicarbonate was included as a porogen in the formulation to make the particles more brittle and to impart favorable aerodynamic properties. Six formulations were prepared with different formulation compositions. Laser diffraction analysis was used to estimate the geometric particle size distribution of the microparticles. In-vitro aerodynamic performance was evaluated by the next-generation cascade impactor (NGI). It was reported in terms of an emitted dose (ED), an emitted fraction (EF%), a respirable fraction (RF%), a fine particle fraction (FPF%), a mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD). The formulations have also been characterized for surface morphology, entrapment efficiency, drug load, and in-vitro drug release. The results demonstrated that PLGA microparticles have a mean geometric particle size between 6 and 14 µm, entrapment efficiency of 77 to 89 %, and SC load between 17 and 33 % w/w. Fifteen percent of entrapped sildenafil was released over 24 h from the PLGA microparticles, and seventy percent over 7 days. The aerodynamic properties included fine particle fraction ranging between 19 and 33 % and an average mass median aerodynamic diameter of 6-13 µm.

Combined on-demand sildenafil citrate and tramadol hydrochloride is an effective and safe treatment for premature ejaculation: A randomized placebo-controlled double-blind clinical trial.

Background: Premature ejaculation (PE) is a common sexual dysfunction that harms both sex partners. Aim: To evaluate the safety, efficacy and impact on sexual satisfaction scores of the combined use of tramadol HCl and sildenafil citrate for the treatment of PE. Methods: One hundred and sixty otherwise healthy males complaining of PE (primary/secondary) were enrolled in this randomized, double-blind, placebo-controlled study. Only 155 patients (age range 22-48 years) completed the study. Of them, 81 patients had primary PE, and 74 had secondary PE. The comparative groups included the placebo group (n = 34), sildenafil citrate 50 mg group (n = 39), tramadol HCl 100 mg group (n = 40), and the combination therapy group (n = 42). The treatment duration for all groups was 10 weeks. Outcomes: This combination is safe and effective. Results: Five patients discontinued the study, all from the placebo group, due to a lack of improvement over the treatment course. No significant differences were reported between groups before treatment as regards Intravaginal ejaculatory Latency Time (p = 0.8), satisfaction score (p = 0.7), age (p = 0.9), or duration of marriage (p = 0.9). There was a significant improvement in IELT after treatment with a placebo (p = 0.0001), associated with an insignificant improvement in satisfaction score (p = 1.0). In the other three groups, there was a significant improvement in IELT after treatment (p = 0.0001 for all), which coincided with a significant improvement in satisfaction scores in all three groups (p = 0.0001 for all). Clinical Implications: We recommend this combination in the treatment of premature ejaculation. Strengths: It is a prospective randomized double-blind placebo-controlled clinical trial. Limitations: Limited number of participants. Conclusion: Combined therapy of PE, whether primary or secondary, with sildenafil citrate 50 mg and tramadol HCl 100 mg is safe and effective; and its therapeutic effect is superior to the utilization of either agent alone.

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.

3D human foreskin model for testing topical formulations of sildenafil citrate.

Sildenafil citrate is an approved drug used for the treatment of erectile dysfunction and premature ejaculation. Despite a widespread application, sildenafil citrate shows numerous adverse cardiovascular effects in high-risk patients. Local transdermal drug delivery of this drug is therefore being explored as an interesting and noninvasive alternative administration method that avoids adverse effects arised from peak plasma drug concentrations. Although human and animal skin represents the most reliable models to perform penetration studies, they involve a series of ethical issues and restrictions. For these reasons new in vitro approaches based on artificially reconstructed human skin or "human skin equivalents" are being developed as possible alternatives for transdermal testing. There is little information, however, on the efficiency of such new in vitro methods on cutaneous penetration of active ingredients. The objective of the current study was to investigate the sildenafil citrate loaded in three commercial transdermal vehicles using 3D full-thickness skin equivalent and compare the results with the permeability experiments using porcine skin. Our results demonstrated that, while the formulation plays an imperative role in an appropriate dermal uptake of sildenafil citrate, the D coefficient results obtained by using the 3D skin equivalent are comparable to those obtained by using the porcine skin when a simple drug suspension is applied (1.17 × 10-10 ± 0.92 × 10-10 cm2/s vs 3.5 × 102 ± 3.3 × 102 cm2/s), suggesting that in such case, this 3D skin model can be a valid alternative for ex-vivo skin absorption experiments.

The combined uterorelaxant effect of sildenafil and terbutalin in the rat: The potential benefit of co-administration of low doses.

Aims: Our aims were to investigate the uterus relaxant effect of sildenafil alone and co-administered with ß2-mimetic terbutaline in an isolated organ bath and to perform in vivo smooth muscle electromyographic studies in pregnant rats. The modifications in uterine cAMP/cGMP levels were also detected. Main methods: Contractions of non-pregnant and 5/15/18/20/22-day pregnant uterine rings were measured in an isolated organ bath system in the presence of sildenafil alone or with terbutaline. The uterine levels of cAMP and cGMP were determined by commercial ELISA assays. The in vivo efficacy of the combination was measured by smooth muscle electromyography. Key findings: Sildenafil reduced uterine contractions in vitro and in vivo; additionally, terbutaline significantly increased the uterorelaxant effect of sildenafil in the lower concentration or dose ranges. Terbutaline enhanced the cGMP level increasing effect of sildenafil. Significance: The co-administration of sildenafil and terbutaline could be a promising tocolytic combination to reduce maternal and foetal adverse events and increase efficacy.

What is the effect of sildenafil citrate intake on women undergoing assisted reproduction? A systematic review and meta-analysis of randomized controlled trials.

Assisted reproductive technologies (ART) have become a vital option for women facing fertility challenges. One of the potential interventions being explored is the use of sildenafil citrate (SC) to improve clinical outcomes in ART procedures. The aim of this study was to assess the impact of SC on clinical outcomes in women undergoing ART. A comprehensive literature search was conducted using multiple databases, including PubMed, Scopus, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. The search covered studies from inception until April 15, 2023, and identified relevant randomized controlled trials (RCTs) for inclusion in the analysis. The endpoints were summarized as risk ratio (RR) or standardized mean difference (SMD) with 95% confidence interval (CI). After meticulous analysis, twenty-eight RCTs comprising 3,426 women were included in the study. The results revealed significant findings regarding the impact of SC on clinical pregnancy (CP) rates. Women receiving SC demonstrated a significantly higher probability of CP compared to the control group (n=21 RCTs, RR=1.43; 95% CI: 1.29, 1.59). Additionally, when SC was combined with other medications like clomiphene citrate (CC) or estradiol valerate, it further improved the likelihood of CP compared to these medications alone (RR=1.35, 95% CI: 1.19, 1.53; RR=1.55, 95% CI: 1.08, 2.22, respectively). Furthermore, the study observed that the mean endometrial thickness (ET) was significantly higher in women who received SC compared to the control group, which involved other active interventions or placebo (SMD=0.77, 95% CI: 0.20, 1.34). Particularly, the administration of SC resulted in a notably higher ET level compared to the placebo (SMD: 1.33, 95% CI: 0.15, 2.51). The findings suggest that luteal supplementation of SC can be considered a beneficial approach to enhance ET and improve the CP rate in women undergoing ART.

Polyelectrolyte-based solid dispersions for enhanced dissolution and pH-Independent controlled release of sildenafil citrate.

The aim of this study was to design a novel matrix tablet with enhanced dissolution and pH-independent controlled release of sildenafil citrate (SIL), a drug with pH-dependent solubility, by using solid dispersions (SDs) and polyelectrostatic interactions. SIL-loaded SDs were prepared using various polymeric carriers such as poloxamer 188, poloxamer 407, Soluplus®, polyvinylpyrrolidone (PVP) K 12, and PVP K 17 by the solvent evaporation method. Among these polymers, Soluplus® was found to be the most effective in SDs for enhancing the drug dissolution over 6 h in pH 6.8 intestinal fluid. SIL was well dispersed in Soluplus®-based SDs in an amorphous form. When the Soluplus®-based SDs were added in the tablet containing positively charged chitosan and negatively charged Eudragit® L100, the drug release rate was further modulated in a controlled manner. The charge density of the tablet was higher at pH 6.8 than at pH 1.2 due to the polyelectrostatic interaction between chitosan and Eudragit® L100. This interaction could provide a pH-independent controlled release of SIL. Our study demonstrates that a combinatory approach of Soluplus®-based SDs and polyelectrostatic interactions can improve the dissolution and pH-independent release performance of SIL. This approach could be a promising pharmaceutical strategy to design a matrix tablet of poorly water-soluble drugs for the enhanced bioavailability.

Predictors of the response to phosphodiesterase-5 inhibitors in pulmonary arterial hypertension: an analysis of the Spanish registry.

BACKGROUND: Achieving and maintaining a low-risk profile is associated with favorable outcome in pulmonary arterial hypertension (PAH). The effects of treatment on risk profile are variable among patients. OBJECTIVE: To Identify variables that might predict the response to treatment with phosphodiesterase-5 inhibitors (PDE-5i) in PAH. METHODS: We carried out a cohort analysis of the Spanish PAH registry in 830 patients diagnosed with PAH that started PDE5i treatment and had > 1 year follow-up. 644 patients started PDE-5i either in mono- or add-on therapy and 186 started combined treatment with PDE-5i and endothelin receptor antagonist (ERA). Responders were considered when at 1 year they: (1) were alive; (2) did not present clinical worsening; and (3) improved European Society of Cardiology/European Respiratory Society (ESC/ERS) risk score or remained in low-risk. Univariate and multivariate logistic regression models were used to analyze variables associated with a favorable response. RESULTS: Two hundred and ten patients (33%) starting PDE-5i alone were classified as responders, irrespective of whether it was mono- or add-on therapy. In addition to known predictors of PAH outcome (low-risk at baseline, younger age), male sex and diagnosis of portopulmonary hypertension (PoPH) or HIV-PAH were independent predictors of favorable response to PDE-5i. Diffusing capacity for carbon monoxide (DLco) ≤ 40% of predicted was associated with an unfavorable response. When PDE-5i were used in upfront combination, 58% of patients were responders. In this group, diagnosis of idiopathic PAH (IPAH) was an independent predictor of favorable response, whereas connective tissue disease-PAH was associated with an unfavorable response. CONCLUSION: Male sex and diagnosis of PoPH or HIV-PAH are predictors of favorable effect of PDE-5i on risk profile when used as mono- or add-on therapy. Patients with IPAH respond more favorably to PDE-5i when used in upfront combination. These results identify patient profiles that may respond favorably to PDE-5i in monotherapy and those who might benefit from alternative treatment strategies.

Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain structures, likely contributes to these failures. Biomarkers have been recommended to identify patients with relevant pathology (predictive biomarkers) and confirm target engagement and monitor therapy response (pharmacodynamic biomarkers). Our group focuses on traumatic cerebrovascular injury as an understudied endophenotype of TBI and is validating a predictive and pharmacodynamic imaging biomarker (cerebrovascular reactivity; CVR) in moderate-severe TBI. We aim to extend these studies to milder forms of TBI to determine the optimal dose of sildenafil for maximal improvement in CVR. We will conduct a phase II dose-finding study involving 160 chronic TBI patients (mostly mild) using three doses of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The study measures baseline CVR and evaluates the effect of escalating sildenafil doses on CVR improvement. A 4-week trial of thrice daily sildenafil will assess safety, tolerability, and clinical efficacy. This dual-site 4-year study, funded by the Department of Defense and registered in ClinicalTrials.gov (NCT05782244), plans to launch in June 2023. Biomarker-informed RCTs are essential for developing effective TBI interventions, relying on an understanding of underlying pathomechanisms. Traumatic microvascular injury (TMVI) is an attractive mechanism which can be targeted by vaso-active drugs such as PDE-5 inhibitors. CVR is a potential predictive and pharmacodynamic biomarker for targeted interventions aimed at TMVI. (Trial registration: NCT05782244, ClinicalTrials.gov ).

The effects of sildenafil citrate on intrauterine growth restriction: a systematic review and meta-analysis.

BACKGROUND: An increase in vascular resistance of uterine vessels is associated with intrauterine growth restriction (IUGR). Sildenafil citrate, a phosphodiesterase-5 inhibitor that stabilizes cyclic guanosine monophosphate (cGMP) and increases nitric oxide levels, improves placental perfusion by dilation of spiral arteries and is beneficial in managing IUGR. This study aims to determine the effectiveness of sildenafil citrate in improving perinatal outcomes in IUGR pregnancies. METHODS: Meta-analysis was performed on data extracted from all studies specific to sildenafil citrate in IUGR management, searching relevant articles on PubMed, Medline, Google Scholar, Embase, and Cochrane databases. Publications identified by the manual search, based on references in reviews, were also included. Dichotomous results were presented as risk ratio (95% confidence interval), while continuous results were expressed as mean difference (MD); samples represented by the random effects model. RESULTS: Nine trials were included where the sildenafil citrate effect was compared with a placebo or no intervention. A significant increase in birth weight [SMD (95% CI), 0.69 (0.31, 1.07)] was seen in IUGR pregnancies managed with sildenafil. However, gestational age (SMD (95% CI), 0.44 (-0.05, 0.94], fetal death rate [RR (95% CI), 0.56 (0.17, 1.79)] in IUGR pregnancies was not changed by sildenafil. Neonatal death [RR (95% CI), 0.93 (0.47, 1.86)] and neonatal intensive care unit (NICU) admissions [RR (95% CI), 0.76 (0.50, 1.17)] were not significantly different between sildenafil and control groups. CONCLUSION: Sildenafil citrate increases birth weight and prolonged pregnancies but did not affect stillbirth rate, neonatal death, and NICU admission. TRIAL REGISTRATION: The study was registered in PROSPERO on September 18, 2021 (CRD42021271992).

Effect of nifedipine with and without sildenafil citrate for the management of preterm labor in pregnant women: A randomized clinical trial.

Background: Preterm labor is one of the main causes of neonatal mortality and its treatment is still challenging. Objective: The study aimed to compare the effectiveness of nifedipine (Nif) with and without sildenafil citrate (SC) for the treatment of preterm labor in pregnant women. Materials and Methods: In this clinical trial study, 126 pregnant women referred to the Fatemieh hospital, Hamadan, Iran with a complaint of preterm labor were evaluated. Participants were randomly divided into 2 groups of Nif 20 mg orally (single dose), then 10 mg every 6-hr, and at the same time vaginal SC 25 mg every 8 hr (Nif + SC) or Nif alone. Treatment was continued for 48-72 hr if uterine contractions did not resolve in both groups. Delivery rates at the time of hospitalization and neonatal outcome were compared between the 2 groups. Results: No statistically significant difference was observed between the 2 study groups in terms of mean age, gestational age, body mass index, and parity. 76.2% of Nif + SC participants in the first 72 hr of hospitalization and 57.2% of Nif participants remained without delivery (p = 0.02). The neonatal hospitalization rate of the Nif + SC group in the neonatal intensive care unit was 25.4% and in the Nif group was 42.9% (p = 0.03). Conclusion: Nif with SC is superior to Nif alone in women at risk of preterm labor due to increasing gestational age and better neonatal outcomes.

Spider diagram and sustainability evaluation of UV-methods strategy for quantification of aspirin and sildenafil citrate in the presence of salicylic acid in their bulk and formulation.

The cutting-edge combination of aspirin (ASA) and sildenafil citrate (SIC) has been presented as a suggested dosage form for the treatment of thin endometrium and erectile dysfunction, particularly in patients with cardiovascular diseases. However, ASA is highly sensitive to degradation into its major deterioration product, known as salicylic acid (SA). Consequently, it is eminently essential to evolve approaches for the synchronous quantification of ASA and SIC in the presence of SA. The main objective of this work is to develop three approaches for the synchronous quantification of ASA and SIC in the presence of SA in their commixtures and suggested formulations without any prior separation. Three green UV-methods were employed for the synchronous quantification, namely: Dual Wavelength in Ratio Spectra (DW-RS), Advanced Amplitude Centering (AAC), and Double Divisor of Ratio Difference Derivative (DDRD-D1). In DW-RS and AAC two-wavelength manipulation was used for resolution, while in DDRD-D1 only an appropriate wavelength for the synchronous quantification of the triplex commixture was used. All approaches can be able to resolve the highly interfering spectrum of the three components presented in the triplex commixture. Good linearity was inspected in the range of 20.0-100.0, 5.0-50.0, and 4.0-60.0 µg/mL for the ASA, SIC, and SA, respectively. All developed approaches have been advocated in accordance with ICH guidelines. All results from these approaches are presented and statistically reconciled with the proclaimed HPLC method, with no considerable differences. Furthermore, the approaches' eco-friendliness was predestined by Analytical Greenness (AGREE), and the complex GAPI. Moreover, the sustainability of the used solvent was evaluated by Green Solvents Selecting Tool (GSST); in addition, the greenness of the solvent was evaluated by Greenness Index tool with a spider diagram. The suggested UV-methods may be employed for routine quality control studies of the suggested formulations ASA & SIC since they were considered sustainable, economical, and effective.