Sildenafil Group Research Articles

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

BackgroundAccess 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 designIn 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.ResultsThirty-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).ConclusionSildenafil 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].

The efficacy of sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction: the STRIDER RCT

Background Severe early-onset intrauterine growth restriction is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is no treatment for intrauterine growth restriction with timely delivery being the only management option. Placentas from intrauterine growth restriction pregnancies often show failure to remodel maternal spiral arteries leading to a persistent vasoactive responsiveness. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide, encouraging vasodilation of vasoactive vessels. Previous studies in animal models and humans show recovery of placental function and improvement in fetal growth. The STRIDER trial aimed to address whether treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Methods The STRIDER trial was a superiority, randomised double-blind placebo-controlled trial that was carried out in 19 fetal medicine units in the United Kingdom. Women with a singleton pregnancy between 22+0 and 29+6 weeks’ gestation, with severe early-onset intrauterine growth restriction, were asked to participate. Women were randomised (1 : 1) to receive either sildenafil 25-mg three times daily or placebo until 31+6 weeks’ gestation or delivery. Women were stratified by site and their gestational age at randomisation (before 26+0 or at 26+0 weeks or later). Severe intrauterine growth restriction was defined as a combination of estimated fetal weight or abdominal circumference below the 10th percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days with a 1-week difference deemed to be clinically significant. The phase 2 study followed up all babies alive at discharge to assess for cardiovascular function and neurodevelopment at 2 years of age. Results Between 21 November 2014 and 6 July 2016, a total number of 135 women were recruited to the study, of these 70 were assigned to sildenafil and 65 to the placebo. No difference was found in the median randomisation to delivery interval between sildenafil [17 days (interquartile range 7–24)] and placebo [18 days (8–28), p = 0.23]. Live births [relative risk 1.06, 95% confidence interval 0.84 to 1.33; p = 0.62], fetal deaths (relative risk 0.89, 95% confidence interval 0.54 to 1.45; p = 0.64), neonatal deaths (relative risk 1.33, 95% confidence interval 0.54 to 3.28; p = 0.53), and birthweight [mean difference −14 g (95% confidence interval −100 to 126); p = 0.81] did not differ between the treatment arms and no differences were found for other maternal or perinatal secondary outcomes. Eight serious adverse events were reported during the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Seventy-five babies were discharged alive from the neonatal unit and of those 61 were available for follow-up with 32 treated with sildenafil and 29 with placebo. Of those that did not have a follow-up 1 baby died (placebo) and 3 declined follow-up and 10 were uncontactable. There was no difference in neurodevelopment, or blood pressure for infants treated with sildenafil versus placebo. Infants who received sildenafil had a greater head circumference compared to those who received placebo (median difference 49.25 cm, interquartile range 46.4–50.26 vs. 47.17 cm, 95% confidence interval 44.71 to 48.95). Conclusion Sildenafil did not prolong pregnancy or improve pregnancy outcomes. There was no effect from sildenafil treatment on infant neurodevelopment. Our data show that sildenafil should not be prescribed for fetal growth restriction. Trial registration This trial is registered as ISRCTN39133303. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information.

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

BackgroundOn 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...

Long-term Efficacy of Pulmonary Artery Desnervation Treatment in Heart Failure With Preserved Ejection Fraction: A Subgroup Analysis of 3-year Results From the PADN-5 Study

Objective: The Pulmonary Arterial Denervation in Patients With Pulmonary Hypertension Associated With the Left Heart Failure (PADN-5) study proved that pulmonary artery denervation (PADN) is associated with significant improvements in hemodynamic and clinical outcomes in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH). This study aimed to assess the 3-year clinical results of PADN in patients who had heart failure with preserved ejection fraction (HFpEF) developing into CpcPH (HFpEF-CpcPH). Methods: In this post hoc analysis of the PADN-5 trial, 38 patients with HFpEF were included in screening out of 98 patients with CpcPH who were randomly assigned to treatment with sildenafil and sham PADN (sham PADN (plus sildenafil) group, abbreviated as sham group) or PADN (PADN group). HFpEF in the PADN-5 trial was defined as a left ventricular ejection fraction ≥50%, and CpcPH was defined as a mean pulmonary arterial pressure ≥25 mmHg, a pulmonary arterial wedge pressure >15 mmHg, and a pulmonary vascular resistance >3.0 WU. The changes in the 6-minute walk distance (6-MWD) and the plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) at 6-month and 3-year follow-up, as well as the clinical endpoint of the occurrence of clinical worsening, defined as cardiopulmonary-related death, rehospitalization, or heart or lung transplantation at 3-year follow-up were examined. Results: Thirty-eight patients with HFpEF-CpcPH were assigned to the PADN group (n = 19) or the sham group (n = 19). At the 6-month follow-up, 6-MWD (433 (275, 580)m vs. 342 (161, 552)m), and reductions in NT-proBNP (−47% (−99%, 331%) vs. −12% (−82%, 54%)) were significantly improved in the PADN group (all P < 0.05). Over the 3-year follow-up period, PADN treatment resulted in marked increases in 6-MWD (450 (186, 510)m vs. 348 (135, 435)m) and reductions in NT-proBNP (−55% (−99%, 38%) vs. −10% (−80%, 95%)) (all P < 0.05). Clinical worsening was experienced by 12 patients (63%) in the sham group, but by only 5 patients (26%) in the PADN group (hazard ratio = 0.149, 95% confidence interval: 0.038–0.584, P = 0.006). The 6-MWD and PADN treatments were independent predictors of clinical deterioration in patients with HFpEF-CpcPH. Conclusions: PADN therapy is associated with improvements in exercise capacity and clinical outcomes. PADN therapy may have a potential role in patients with HFpEF-CpcPH for whom current treatment options are limited.

Comparison of Milrinone with Sildenafil for the Treatment of Persistent Pulmonary Hypertension of the Newborn

Objective: To compare milrinone with sildenafil for the treatment of persistent pulmonary hypertension of the newborn. Methodology: A single blinded randomized control trial was conducted in Department of Pediatrics, Aziz Fatima Hospital Faisalabad from October 2022 to September 2023. 160 infants of persistent pulmonary hypertension were included through non probablity consecutive sampling. Group 1 infants (n = 80) received a loading dose of milrinone intravenously administered over a 60-minute period at a dose of 50 µg/kg. Group 2 infants (n = 80) received sildenafil (2mg per kg per dose three times a day). The medication was continued until extubation. The primary outcome variables were the mortality and duration of hospital stay. Results: Ninety two(57.5%) of the one hubdred & sixty newborns in total were male. 111(69.4%) of the total, were full-term babies. In 114(71.2%) infants, the mode of delivery was C-section. Mortality was observed in 7 (8.8%) patients in milrinone group and 17 (21.2%) patients in sildenafil group with p-value = 0.027. Duration of hospital stay was less in milrinone group as compared to sildenafil group (14.22±3.75 days vs 17.72±5.7 days) with p-value = 0.0001. Conclusion: Milrinone has been proven to be a promising therapeutic choice for persistent pulmonary hypertension in neonates, and it is effective in doing so in low resource settings.

Comparison of Adding Sildenafil Versus Estradiol to Clomiphene Citrate on the Applebaum Score and Pregnancy Rate in Patients With Unexplained Infertility: A Double-Blind Randomized Controlled Trial.

Both sildenafil and estradiol are seen to improve endometrial thickness in patients with infertility who are undergoing clomiphene induction cycles. However, the correlation between endometrial thickness and pregnancy rate is debatable. This study investigated the effect of adding oral sildenafil to clomiphene citrate (CC), compared to adding estradiol valerate, on the uterine biophysical profile (Applebaum score) and pregnancy rate. This was a double-blinded, randomized controlled trial conducted in Kisangani inthe Democratic Republic of the Congo from October 1, 2021, to October 31, 2023. Patients with unexplained infertility were randomly assigned to one of two groups: the interventional, which was given CC (2 x 50 mg/day from day 3 to day 7 of the menstrual cycle)+ sildenafil (2 x 25 mg/day orally from day 8 to day 12)or (ii) the control group, which was given CC (similar dosage as the intervention group) + EV (2 x 2 mg/day orally from day 8 to day 12), for a maximum of three cycles. Applebaum scores and clinical pregnancy rates were measured. Patients in the sildenafil and EV groups were similar in mean age (29.04 versus 28.89 years).Of the 74 patients enrolled in each group, 71 in the sildenafil group and 72 in the EV group received treatment and were followed to completion. The Applebaum scores were significantly higher in the sildenafil group than in the EV group (17.05 versus 15.14, respectively, P=0.000).In the sildenafil group, the clinical pregnancy rate was also significantly higher, at 28.92% versus 20.83% in the EV group (P=0.04). As compared to EV, the oral addition of sildenafil to CC is associated with a good Applebaum score and a high rate of clinical pregnancy in patients with unexplained infertility.

Sildenafil improves hemodynamic changes caused by acute pulmonary embolism by inhibiting Rho kinase activity.

This study examined the effects of sildenafil on acute pulmonary embolism (APE) using a rat model. Sprague-Dawley rats were randomly divided into the sham, pulmonary thromboembolism (PTE), and sildenafil groups. The sham and PTE groups received normal saline once daily via gavage for 14 consecutive days, whereas the sildenafil group received sildenafil (0.5 mg/kg/day) once daily via gavage for 14 consecutive days. Autologous emboli were prepared from blood samples collected from the left femoral artery of rats in each group on day 13, and autologous emboli were injected into the jugular vein cannula of rats in the PTE and sildenafil groups on day 14. Sham-treated rats received the same volume of saline. Right systolic ventricular pressure (RVSP) and mean pulmonary arterial pressure (MPAP) were used to assess pulmonary embolism, and western blotting and enzyme-linked immunosorbent assay were used to detect relevant markers. The Rho kinase signaling pathway was significantly activated in rats with APE, and sildenafil significantly inhibited this activation. Sildenafil protected against APE through inhibiting Rho kinase activity, thereby reducing pulmonary vasoconstriction and decreasing elevated pulmonary arterial pressure. These findings might provide new ideas for the clinical treatment of acute pulmonary thromboembolism.

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

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. 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. 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). The results showed that SC can effectively decrease the rate of emergency CS and FD during labor.

COMPARISON OF EFFICACY OF PDE5 INHIBITORS (SILDENAFIL) VERSUS ALPHA-BLOCKERS (TAMSULOSIN) IN TREATMENT OF LOWER URINARY TRACT SYMPTOMS (LUTS) SECONDARY TO BENIGN PROSTATIC HYPERPLASIA

Benign prostatic hyperplasia (BPH) is a prevalent condition leading to lower urinary tract symptoms (LUTS) in men, affecting their quality of life. Various medications, including phosphodiesterase five inhibitors (PDE5-Is) and alpha-blockers (ABs), are used for treatment, but direct comparison studies between these drugs are limited. This study aimed to compare the efficacy of sildenafil (PDE5 inhibitor) versus tamsulosin (alpha-blocker) in patients with LUTS secondary to BPH. A randomized controlled trial was conducted at the Department of Urology, KEMU/Affiliated Hospital, Lahore. A sample size of 100 patients (50 in each group) was calculated using the WHO calculator based on expected efficacy rates. Patients aged 40-70 years with BPH and LUTS were included. Exclusion criteria included high PSA levels, history of prostatic surgery, acute urinary retention, or active urinary tract infection. Patients were randomly assigned to receive sildenafil 25mg OD or tamsulosin 0.4mg HS for three months. Efficacy was assessed by changes in the International Prostate Symptom Score (IPSS) after treatment. The demographic characteristics of the study population showed a mean age of 60 years with a similar distribution of comorbidities between the groups. After three months of treatment, 80.9% of patients in the sildenafil group showed a significant improvement in IPSS compared to 55.5% in the tamsulosin group. The chi-square test indicated a significant difference in efficacy between the two groups (p < 0.05). Sildenafil demonstrated superior efficacy compared to tamsulosin in reducing LUTS secondary to BPH. These findings suggest that sildenafil may be considered as a first-line treatment option for patients with BPH and LUTS.

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.

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.

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

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. 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. This review included three RCTs (162 infants). There were no significant differences between theprophylactic 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. 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.

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

To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). 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 (2mg/kg/dose enterally every 12hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). 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. 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. ClinicalTrials.govNCT02812433.

Effects of Intramuscular Epinephrine Injection and Systemic Sildenafil Citrate on Rat Transverse Rectus Abdominis Musculocutaneous Flap Survival

Background and Objectives Flaps are commonly employed for reconstruction, and many studies have sought to improve flap survival. In this study, we determined whether sildenafil and epinephrine synergistically improve the survival rate of transverse rectus abdominis musculocutaneous (TRAM) flaps.Materials and Method Twenty-four Sprague-Dawley rats were divided into four groups of six rats each: a control group, an epinephrine group, a sildenafil group, and an epinephrineplus- sildenafil group. TRAM flaps were elevated on the upper abdomen.Results The average flap survival area and number of blood vessels differed significantly between the control and experimental groups; however, the various experimental groups did not differ significantly. The level of vascular epithelial growth factor was higher in the experimental groups than in the control group.Conclusion Both epinephrine and sildenafil citrate significantly improve TRAM flap survival in rats. However, whether effects are better when the drugs are combined rather than when used alone remains unclear. Further research is required.

Sildenafil as a Salvage Treatment for Ovarian Torsion: A Rat Model

OBJECTIVE: In this study, we aimed to investigate the effect of sildenafil, acting as an anti-oxidant on the ischemic rat ovarian torsion model by pointing out ovarian reserve via AMH levels which is the best marker for oocyte pool.STUDY DESIGN: This study is an experimental animal study conducted according to the principles of the Declaration of Helsinki. Twenty-seven rats were assigned into three groups, each consisting of nine individuals. Group 1: Sham operation (laparotomy only) was performed. Group 2: The torsion group had bilateral torsion and detorsion of the ovaries. Group 3: In Sildenafil and torsion group the rats received 0.7 mg/kg sildenafil (Viagra, Pfizer, New York, ABD) intraperitoneally one hour before torsion and detorsion operation. One month after the initial operation, blood was drawn via the intra-cardiac route, and serum antimullerian hormone (AMH) concentrations were studied.RESULTS: The mean weights of the rats were similar 224 g, 229 g, and 222 g for groups 1, 2, and 3 respectively. Only one rat from Group 2(T/D) died during the experiment leaving eight rats for analysis. The mean value for AMH was 24.9227±12.19124 ng/ml and the mean value for weight was 226.22±19.200. The differences in AMH groups were not statistically significant (p=0.873)CONCLUSIONS: As a result, as is shown in our study, the ovarian reserve may not be influenced by ischemia developed by ovarian torsion or any influences could not change AMH levels. Sildenafil which was given to the rats before detorsion to protect against reperfusion ischemia was found to be ineffective on ovary reserve according to AMH assessment.

Unmasking hidden risks: The surprising link between PDE5 inhibitors and seizure susceptibility.

Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants. The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001. After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs. PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.

Erectile response profiles of men using PDE5 inhibitors combined with intracavernosal injections as part of a penile rehabilitation program after radical prostatectomy.

Phosphodiesterase type 5 (PDE5) inhibitor labeling states that these agents should not be used in conjunction with other erectogenic medications for fear of priapism occurring. We explored the risk of priapism and prolonged erections in men in our post-radical prostatectomy (RP) penile injection program who were using regular PDE5 inhibitor and intracavernosal injections (ICIs) as part of their rehabilitation program. The study cohort included men on penile injection therapy who (1) were taking tadalafil 5mg daily or taking sildenafil 25mg on noninjection days, (2) had an RP, (3) were using their respective PDE5 inhibitor regularly at the time of penile injection training, and (4) complied with the program instructions regarding penile injection use. Demographics, comorbidity details, PDE5 inhibitor dose and utilization, and injection dose and utilization data were collected. All patients underwent in-office injection training and used trimix (papaverine/phentolamine/prostaglandin E1) as the intracavernosal medication. Priapism was defined as a patient self-reported penetration hardness erection ≥4hours in duration, while prolonged erection was defined as a penetration hardness erection lasting ≥2hours. A total of 112 tadalafil users and 364 sildenafil users were compared. Mean age and duration post-RP were 62 ± 14years and 5.2 ± 12months, respectively, and there was no difference between tadalafil and sildenafil groups. The mean trimix dose was tadalafil 24 ± 24units and sildenafil 31 ± 37units (P< .05). Priapism occurred in 2 (1.7%) of 112 tadalafil users and 5 (1.4%) of 364 sildenafil users (P= .47). Excluding those men experiencing priapism on any occasion, those with any reported penetration hardness erection lasting ≥2hours were 7 (6.3%) of 112 tadalafil users and 12 (3.3%) of 364 sildenafil users (P< .01). A total of 53% of these prolonged erections occurred within the first 6 injections at home (no difference between tadalafil and sildenafil groups). We emphasize the need for continued monitoring and education on proper injection techniques to minimize the risk of adverse events in ICI and PDE5 inhibitor combination therapy. This study has a relatively large patient population with a considerable follow-up time. Additionally, the rigorous training, education, and monitoring of the participants, as well as the use of formal definitions for priapism and prolonged erections, enhances the accuracy and reliability of the results. However, there are some limitations, such as social desirability, confounding factors, and recall bias. There is no significant difference in the incidence of priapism in an ICI program in which men combine ICI with tadalafil or sildenafil. However, tadalafil patients had a higher rate of prolonged erections, which was found to occur mostly early during the titration phase.

The effect of sildenafil on maternal mortality in pulmonary arterial hypertension associated with congenital heart disease

Abstract Background Maternal mortality in pulmonary arterial hypertension (PAH) is very high, around 30–56%, so that patients with PAH and congenital heart disease (CHD) are advised to prevent pregnancy with class I-C recommendations. If the pregnancy continues, it must be handled by a multidisciplinary team with pulmonary hypertension (PH) experts, at the PH referral center. One of the PH-specific drug included in the FDA criteria B for pregnant women available in Indonesia is sildenafil. Sildenafil was reported to improve clinical symptoms and pregnancy outcomes in pregnant women with mild-moderate PAH. Sildenafil also had a tendency to reduce all-cause mortality although it was not statistically significant. Pulmonary hypertension specific drugs could reduce maternal mortality15.8% in subjects with PAH. However, research on sildenafil in maternal clinical outcomes is still very limited. Purpose This study aims to determine the effect of sildenafil on maternal mortality with PAH associated with CHD. Methods This study is an analytic observational study with a retrospective cohort method. Patient data were taken from the maternal registry, the Congenital HeARt Disease in adult and Pulmonary Hypertension (COHARD-PH) registry, and from the medical records of our general hospital who met the research criteria from August 2015 to December 2022. We assess the effect of sildenafil compared with controlled (without sildenafil) group. The clinical outcome of the study was maternal death during pregnancy and/or after delivery up to 42 days due to all causes (all causes mortality). Results Of 68 pregnant women who met the inclusion and exclusion criteria there were 32 subjects in the sildenafil group and 36 subjects in the control group. Maternal mortality was found to be higher (17.6%) in the group without sildenafil vs 9.7% in the sildenafil group. The majority causes of death were HP crisis (7 patients), 1 patient died from thromboembolism (HELLP syndrome), and 1 patient died from massive bleeding due to retained placenta. In the bivariate analysis, it was found that the NYHA functional class had a significant effect on maternal mortality with a p value &amp;lt;0.05, but not significantly from multivariate analysis. In the bivariate and multivariate analysis, general anesthesia had a statistically significant effect on maternal mortality with p=0.018. Of the 9 pregnant women who died, 5 patients received general anesthesia. Of the five patients, NYHA III-IV was found in 4 subjects (4/5 = 80%) and the other patient was NYHA II but subject came in at 63% saturation. All of the subjects are Eisenmeinger syndrome. Conclusion Sildenafil can reduce maternal mortality by 45% although it is not statistically significant. Further studies with larger data are needed to confirm this result.Basic Characteristics of SubjectsRelationship of Sildenafil with Maternal

The alleviative efficacy of sildenafil and chrysin against zinc oxide nanoparticles-provoked hepatic and blood toxicity: role of MyD88/NF-κB1/TNF-α pathway

BackgroundZinc oxide nanoparticles are nanoparticles of metal oxide with semiconductor properties and proved many noxious effects on the mammalian cell. Sildenafil, a phosphodiesterase inhibitor, and chrysin, one of the flavonoids, proved to have anti-inflammatory and anti-oxidative stress effects.Methods48 rats were grouped into 8 groups equally. 1. (Control group) received normal diet and NaOH was added to water, 2. (chrysin group): 250 mg/kg, orally for 10 days, 3. (sildenafil group): 40 mg/kg, orally for 14 days, 4. (ZnO-NPs group): 200 mg/kg, intraperitoneal for 10 days, 5. (ZnO-NPs + chrysin as a prophylactic agent): given in the same previous doses and durations consecutively, 6. (ZnO-NPs + chrysin as a curative agent): given in the same previous doses and durations with chrysin given after ZnO-NPs administration for 10 days, 7. (ZnO-NPs + sildenafil as a curative agent): given in the same previous doses and durations with sildenafil given after ZnO-NPs administration for 10 days, and 8. (Combined treatment group chrysin + sildenafil) as combined treatment were given in the same previous doses and durations after ZnO-NPs administration for 10 days. Blood and samples from tissues were withdrawn for histopathological, biochemical studies, and comet assay at the end of the experiment.ResultsSildenafil and chrysin proved to protect from hepatotoxicity and hematotoxicity induced by zinc oxide nanoparticles as they lessened aspartate transaminase, alanine transferase, and alkaline phosphatase levels. They also reduced the oxidative stress enzyme levels. Gene expression of myeloid differentiation factor 88, nuclear factor kappa B1, tumor necrosis factor, and DNA damage decreased with treatment. Also, there was an improvement in the histopathological picture of the liver seen with treatment. Concurrent administration of sildenafil and chrysin revealed much better improvement than either drug used alone.ConclusionChrysin and sildenafil have ameliorative effects against ZnO-NPs-induced hepatotoxicity and hematotoxicity, their protective effect is either preventive with chrysin or curative with chrysin and sildenafil.

Preoperative Sildenafil in Pediatric Patients Undergoing Congenital Heart Surgeries: A Systematic Review and Meta-Analysis.

Background. Pulmonary hypertension (PH) is a common complication of congenital heart disease (CHD). With early surgical intervention, outcomes have improved over the last two decades. Persistent PH, however, may still occur following surgery. Sildenafil has been shown to be beneficial for postoperative pulmonary hypertensive crises. The role of preoperative sildenafil in controlling postoperative PH is poorly elucidated. This study aimed to evaluate the effect of preoperative sildenafil on pediatric patients undergoing congenital heart surgeries. Methods. A comprehensive literature search was conducted in scientific databases. We included randomized controlled trials which assessed the effect of preoperative sildenafil in pediatric patients with CHD undergoing repair surgeries. Primary outcomes were pre- and postoperative differences in mean pulmonary arterial pressure (mPAP) and mean pulmonary artery/aortic pressure ratio (PA/Ao ratio). Results. Four studies (n = 233) were retained for the final analysis. Dose of sildenafil ranged from .3 to .5mg/kg every 4-6hours via oral/nasogastric route, with timing of administration varied from 1 to 2weeks before surgery. Compared to controls, preoperative sildenafil was associated with greater reduction in postoperative mPAP (MD -5.02; 95% CI [-8.91, -1.13]) and mean PA/Ao ratio (MD -.11; 95% CI [-.17, -.06]). Shorter CPB time, ICU length of stay, and duration of mechanical ventilation were also observed in the sildenafil group. Conclusion. Preoperative sildenafil is beneficial in reducing PAP, thereby reducing the risk of postoperative PH crisis. Further studies are warranted to identify the optimal dosage and timing of administration of sildenafil in CHD patients prior to surgery.

Histopathological evaluation of the effects of sildenafil on organ damage in a diabetic rat model

Aims: In this study, it was aimed to show the effects of sildenafil on heart, liver and kidney tissues histopathologically by creating an experimental diabetes model with streptozocin.&#x0D; Methods: Male adult Sprague dawley rat (48) was used in the study. The rats were first divided into three groups as control group, the diabetes group and the diabetes+sildenafil group. Each group was divided into two groups within itself. Streptozotocin 40 mg/kg was administered intraperitoneally to the rats in the groups that would develop diabetes and diabetes+sildenafil diabetes. Rats with blood glucose levels of 250 mg/dl and above after 48 hours were considered diabetic. Sildenafil citrate 10mg/kg/day was given by gavage to the diabetes+sildenafil group. At the end of the experiment heart, liver and kidney tissues were placed in formaldehyde solution. Hematoxylin-Eosin staining was applied to the sections taken. Histological changes in the stained sections were evaluated by a histologist. Histological evaluation was performed semi-quantitatively in heart, liver and kidney tissue. In the assessment, the findings of the tissues were scored and statistical analysis was performed.&#x0D; Results: Histological findings of heart, liver and kidney tissues were examined. It was determined that less organ damage was seen in the diabetes+sildenafil group compared to the Diabetes group.&#x0D; Conclusion: In our study, it has been demonstrated histologically that sildenafil can be a drug that has an antioxidant effect in tissue by helping to protect cell structure and architecture against heart, liver and kidney tissue damage caused by diabetes. It should not be overlooked that it is important to determine the appropriate dose and frequency of use of sildenafil in revealing these effects.