Assessment of heme oxygenase-1 （HO-1） activity in the cavernous tissues of sildenafil citrate-treated rats

Aim： To assess heine oxygenase-1 （HO-1） activity in the cavemous tissue of sildenafil citrate-treated rats. Methods： One hundred and ninety-two Sprague-Dawley male rats, divided into four equal groups, were investigated. Group 1, the control group, received regular animal chow; group 2 received sildenafil citrate by intragastric tube; group 3 received sildenafil and HO inhibitor （zinc protoporphyrin, ZnPP）; and group 4 received sildenafil and nitric oxide synthase （NOS） inhibitor L-nitroarginine methyl ester （L-NAME）. Twelve rats from each group were killed after 0.5 h, 1 h, 2 h and 3 h of drug administration. Then HO-1 activity, cGMP levels and NOS enzymatic activity in the cavernous tissues were estimated. Results： In cavemous tissue, HO-1 activity, NOS enzymatic activity and cGMP concentration increased significantly in sildenafil-treated rats compared to other groups throughout the experiment. Rats receiving either HO or NOS inhibitors showed a significant decrease in these parameters. HO- 1 cavemous tissue activity and NOS enzymatic activity demonstrated a positive significant correlation with cGMP levels （r = 0.646, r = 0.612 respectively; P 〈 0.001）. Conclusion： The actions of PDE5 inhibitor sildenafil citrate in the cavernous tissue are partly mediated through the interdependent relationship between both HO-1 and NOS activities.

Treatment preferences in men with erectile dysfunction： an open label study in Korean men switching from sildenafil citrate to tadalafil

To evaluate patient preferences for sildenafil citrate or tadalafil （PDE-5 inhibitors available for the treatment of erectile dysfunction [ED]） and assess potential reasons for these preferences. Methods： This open-label study was conducted on Korean men taking sildenafil, at least 6 weeks prior to study entry, for ED. Following screening, patients continued sildenafil treatment for 4 weeks, then after a 1-week washout period, switched to tadalafil for 8 weeks. Patients then continued with their treatment of choice during an extension phase. Psychosocial factors （time concern, spontaneity, sexual self-confidence） were evaluated using Psychological and Interpersonal Relation- ship Scales （PAIRS）, while timing of dose to sexual attempt patterns were assessed from patient diaries. Results： The present study enrolled 160 Korean men （mean age 55 years） with prior median sildenafil use of 585 days. During the extension phase, 73.7% of patients elected to take tadalafil, whereas 26.3% chose sildenafil （P 〈 0.001）. After switching from sildenafil to tadalafil, mean PAIRS time concern scores decreased from 2.54 to 2.42 （P = 0.002）, with no statistically significant differences observed between the sildenafil and tadalafil assessment phases in sexual spontaneity and self-confidence scores. Sexual attempts made 〉 4 h to 〈 36 h post-dose occurred in 4.5% of patients during the sildenafil assessment phase compared with 17.5% during the tadalafil assessment phase. Conclusion： After experiencing both sildenafil and tadalafil, the majority of patients exhibited a preference for tadalafil. This preference might be influenced by psychosocial factors, such as decreased time concerns, and a broader window of opportunity available for sexual activity.

Micro-recanalization in a biodegradable graft for reconstruction of the vas deferens is enhanced by sildenafil citrate

This study investigated the effect of sildenafil citrate on micro-recanalization and neovascularization, which were previously demonstrated in a rat model using biodegradable grafts （BGs） for vas deferens reconstruction. A total of 24 male rats underwent bilateral vasectomy with removal of a 0.5-cm vasal segment and were randomly assigned to four groups. Groups 1 and 2 underwent immediate vasovasostomy. Groups 3 and 4 underwent interposition of a 0.5-cm BG in the vasal gap. Groups 1 and 3 were given 5 mg kg-1 day-1 oral sildenafil. Other groups were given placebo. Rats were housed with females 12 weeks postoperatively. Reconstructed vasal segments were harvested 16 weeks postoperatively and analyzed histologically. Fluid from the distal vasal stump was analyzed for motile sperm. Urine samples obtained 16 weeks postoperatively were analyzed for cGMP levels. cGMP levels in rats treated with sildenafil were signifcantly higher than in control rats. No pregnancies were sired by grafted groups. In all, 5/6 rats in group 1 and 3/6 rats in group 2 sired litters. No motile sperm were noted in the vasal fluid of the grafted groups. Motile sperm were noted in all rats in group 1 and in 5/6 rats in group 2. In addition, 29 and 4 microcanals were detected in the sildenafil and placebo groups, respectively （P = 0.023）. No microcanal exceeded 3 mm in length. An average of 12 and 28 blood vessels per graft were noted in the placebo and sildenafil groups, respectively （P 〈 0.0001）. In conclusion, sildenafil enhances micro-recanalization and neovascularization in BG used for vas deferens reconstruction, but does not increase the microcanal length after 16 weeks.

Successful Management of a Complicated Ulcer Caused by Autoimmune Vasculitis, with Sildenafil Citrate in a Patient with Primary Antiphospholipid Syndrome and Transient Steroid-Induced Diabetes Mellitus: A Case Report and Literature Review

Antiphospholipid syndrome (APS) is a prothrombotic condition that can affect both the venous circulation and the arterial system. The deep veins of the lower extremities and cerebral blood flow are the most common sites of venous and arterial thrombosis, respectively. Skin ulceration and gangrene may be associated with an active vasculitis in patients with APS. These kinds of ulcers are considered intractable because healing is difficult to achieve. Using steroids as immunesuppressant therapy is still a basic part of managing APS and vasculitis. Nevertheless, in the presence of steroid-induced diabetes mellitus, the priority is to achieve faster wound healing, because of the potential complications that can develop due to metabolic dysfunction and augmented vulnerability to infection. Until recently, there were few reports demonstrating the benefits of the use of adjuvant phosphodiesterase-5 inhibitors like sildenafil citrate in different clinical entities with courses like Raynaud’s phenomenon, scleroderma, and resistance to vasodilator therapy. We present the first report demonstrating the additional benefit of sildenafil citrate for the integration of grafts in a patient with steroid-induced diabetes and APS who had ulcers due to vasculitis resistant to the usual vasodilator therapy.

Improved spontaneous erectile function in men with mild-tomoderate arteriogenic erectile dysfunction treated with a nightly dose of sildenafil for one year： a randomized trial

Aim： To test the hypothesis that sildenafil （50 mg nightly for one year） can improve spontaneous erectile function （EF） in men with mild-to-moderate arteriogenic erectile dysfunction （ED） responsive to erectogenic treatment. Methods： In a prospective open-label trial, 112 men with ED were randomized to sildenafil 50 mg nightly or sildenafil 50 or 100 mg as needed for 12 months, followed by one-month and 6-month non-medicated periods. Non-randomized, non-medicated men with ED were also assessed. The EF domain of the International Index of Erectile Function （IIEF EF） and the peak systolic velocity （PSV） of penile cavernous arteries were used to measure the efficacy. Results： After sildenafil treatment and a subsequent non-medicated month, IIEF EF was normal in 29 of 48 （60.4%, 95% confidence interval [CI]： 45.3-74.2%） of the nightly group vs. 4 of 49 （8.2%, 95% CI： 2.3-19.6%） of the as-needed group. PSV improved by 11.2 cm/s （95% CI： 4.7-21.4; P = 0.012） in the nightly group but only by 3.4 cm/s （-5.1- 14.7; P = 0.435） in the as-needed group. IIEF EF normalized in 1 of 18 （5.6%, 95% CI： 0.1-27.3%） non-medicated men and the PSV declined slightly. Six months after treatment, the IIEF EF remained normal and PSV was stabilized in most （28/29, 97%） nightly group men who had initially normalized. Conclusion： Sildenafil nightly for one year resulted in ED regression that persisted well beyond the end of treatment, so that spontaneous EF was characterized as normal on the IIEF in most men. The results from this open-label, randomized trial warrant verification under double-blind, placebo-controlled conditions.

Different hemodynamic responses by color Doppler ultrasonography studies between sildenafil non-responders and responders

Aim： To determine if there are different penile hemodynamic patterns between sildenafil non-responders and responders by using color Doppler ultrasonography. Methods： A total of 69 erectile dysfunction （ED） patients aged 22-79 years were enrolled into the present study. Thirty-eight （55.1%） men with ED who did not respond to four attempts of treatment with 100 mg sildenafil after re-education were classified as sildenafil non-responders. A com- bination of three vasodilator drugs, 1.25 mg papaverine, 0.4 mg phentolamine and 5 ug prostaglandin E1, was given by intracavernous injection before penile Doppler ultrasonography was carried out. The erectile response to intracavernous injection and vascular parameters including peak systolic velocity （PSV）, resistance index （RI）, end diastolic velocity （EDV） and cavernosa artery diameter （CD） were measured and the results between sildenafil nonresponders and responders were compared. Results： No statistical difference in vascular parameters measured by Doppler ultrasonography studies between non-responders and responders was noted. Sildenafil non-responders had a poorer penile rigidity response to intracavernous injection than responders （P 〈 0.05）. Among patients with adequate PSV （〉 30 cm/s） and abnormal EDV （〉 5 cm/s）, individuals in the non-responder group had fewer positive responses to intracavernous vasodilator injection than in the responder group （35.3% vs. 72.2%, P 〈 0.05）. Advanced age and comorbidity with diabetes mellitus were significantly associated with sildenafil non-response （P 〈 0.05）. Conclusion： Sildenafil non-responders were characterized by a poorer penile rigidity response to intracavernous injection and had an associated impaired veno-occlusive mechanism. Advanced age and comorbidity with diabetes mellitus were two common factors associated with non-response.

Characteristics of sildenafil erections in healthy young men

Aim： To determine the effect of sildenafil citrate on the nocturnal penile erections （i.e. time to onset, the duration of erection, and the interval between first and second erections） of healthy young men. Methods： Twenty-two potent men, 23-29 years old, were recruited for the study. All subjects completed three sessions over consecutive nights using the RigiScan monitoring device （Dacomed, Minneapolis, USA）. After a first night of adaptation, night 2 records were their baseline values, and on night 3 they received 100 mg of sildenafil citrate. Statistical comparisons were done between the second and third night data. Results： The mean time to onset of the first erection with sildenafil citrate was （34 ± 18） min, whereas it was （74 ± 24） min （P 〈 0.001） without sildenafil citrate. The number of erections observed during the first 5 h after sildenafil citrate medication was 3.6 ± 0.5 in contrast to 2.4 ± 0.5 with no medica- tion （P = 0.001）. The interval between first and second erections was shorter with sildenafil citrate： （52 ± 26） min vs. （85 ± 34） min （P = 0.01）. The duration of the last erection was statistically significantly longer with the sildenafil citrate： （64 ± 33） min vs. （42 ± 28） min （P 〈 0.01）. Conclusion： Healthy young men achieved erection within 34 min after sildenafil citrate administration, which is shorter than the 1 h interval proposed by the manufacturer. The interval between the first and second erections was shorter and the duration of the last nocturnal erection was longer.

Sildenafil plus Low Dose Aspirin for Prevention of Preeclampsia: A Randomized Controlled Trial

Objective: To compare between the efficacy of the use of oral sildenafil plus low dose aspirin versus the use of oral low dose aspirin alone in pregnancy as preventive measure in women at risk for preeclampsia (PE). Design: A randomized clinical trial. Setting: Outpatient Obstetric clinic of Ain Shams University Maternity Hospital. Population or sample: Women at gestational age of ≤16 weeks who at risk for PE between June 2018 and June 2019. Methods: Participants were randomly allocated into two groups: Group I Included 200 women who received a 25 mg tablet of oral sildenafil citrate tid until delivery plus 100 mg tablet of aspirin orally once daily until gestational age of 36 weeks, Group II Included 200 women who received a 100 mg tablet of aspirin orally once daily until gestational age of 36 weeks. Main Outcome Measures: Incidence of preeclampsia diagnosed per ACOG criteria. Results: The incidence of PE in both groups showed no statistically significant difference. The incidence of PE in the first group is 11.0%, and it is 12.0% in the second group (p-value 0.754). Conclusion: The addition of sildenafil citrate to low dose aspirin had no impact on the prevention of preeclampsia for women at risk of PE, in addition, sildenafil did not improve maternal and fetal outcomes.

Efficacy and safety of oral SK3530 for the treatment of erectile dysfunction in Korean men： a multicenter, randomized, doubleblind, placebo-controlled, fixed dose, parallel group clinical trial

Aim： To evaluate the efficacy and safety of SK3530, a newly developed type 5 phosphodiesterase inhibitor （PDE5I）, in Korean men with erectile dysfunction （ED）. Methods： A total of 119 patients were randomized at 10 centers in Korea to receive either SK3530 （50, 100, or 150 mg; n = 89） or placebo （n = 30） taken 1 h before anticipated sexual activity for an 8-week period. The patients were evaluated at baseline and 4 and 8 weeks after beginning therapy. Efficacy was assessed using the International Index of Erectile Function （IIEF）, Sexual Encounter Profile （SEP）, and the Global Assessment Question （GAQ）. Safety was analyzed by adverse events, laboratory values and vital signs. Results： At the end of the study, all the primary and secondary efficacy end-points were statistically significantly improved by SK3530 compared with placebo （P 〈 0.05）. Of the 89 patients in the treatment arm, 36 （42.3 %） achieved normal erectile function after treatment, including six patients with severe ED. Treatment-related adverse events occurred in 32 patients. The most common adverse events were flushing, headache, dizziness and eye redness （10.9%, 7.6%, 2.5% and 2.5%, respectively）, and most were mild. Only two patients discontinued treatment during the study period because of adverse events. Conclusion： The results of our phase Ⅱ study have confirmed the efficacy and safety of SK3530 in a broad population of men with ED of various etiologies and severity. The optimal doses in terms of efficacy and safety were determined to be 50 mg and 100 mg, respectively.

Adsorption of Pharmaceuticals and Personal Care Products on Granular Activated Carbon

We investigated the adsorption to granular activated carbon of two pharmaceuticals (carbamazepine and sildenafil citrate) and a personal-care product (methylparaben) in aqueous solution, characterized the carbon, and evaluated its influence on the kinetics and adsorption equilibrium of the compounds under study. We adjusted data for the analysis of equilibrium to Langmuir and Freundlich models of adsorption isotherms and described adsorption rate using pseudo first- and second-order models;that same analysis was made on the basis of the behavior of the initial rate. In addition, we analyzed the potentiality of a nonlinear adjustment for studying kinetics and equilibrium of adsorption, an approach requiring neither knowledge of equilibrium conditions nor a-priori hypothetical suppositions regarding the order of reaction. The results indicated that the nonlinear model was capable of describing adsorption kinetic behavior, in order to determine concentrations adsorbed at equilibrium, adsorption rates of the system, maximum adsorption capacity, and global rate constant. Granular carbon exhibited an adsorption capacity for carbamazepine and methylparaben of ca. 323 mg/g and for sildenafil citrate of ca. 142 mg/g, though with slow adsorption kinetics characterized by average adsorption times of at least 168 h.

The safety,efficacy and pharmaceutical quality of male enhancement nutraceuticals bought online:Truth versus claim

Objective:Nutraceutical products are widely used for their claimed therapeutic benefits.However,falsified or adulterated nutraceuticals present a major health threat to consumers.This study investigates the pharmaceutical quality,safety and anti-inflammatory effects of six male enhancement nutraceuticals that claim to be 100%natural.Methods:Three batches of six male enhancement products were tested to detect the presence and levels of adulterants via high-performance liquid chromatography(HPLC).The pharmaceutical quality of the selected nutraceuticals was tested with near infrared spectroscopy(NIR)and Se De M.The cytotoxic effects of these products on HepG2 cells were determined through cell proliferation(XTT)and lactate dehydrogenase(LDH)cytotoxicity assays.Lastly,the in vitro inflammatory effects of these products were investigated using murine J774 macrophages through cytokine release analysis.Results:HPLC analysis detected the presence of sildenafil citrate,a vasodilator,and the active ingredient in Viagra and Revatio,in all batches of the products we analyzed.Amount of sildenafil citrate ranged from 0.45 mg to 51.85 mg among different batches.NIR assessment showed inter-and intra-batch heterogeneity in product composition.Results of the XTT and LDH assays showed significant cytotoxic effects of the analyzed products.XTT analysis revealed that the viability of HepG2 treated with tested products varied from 27.57%to 41.43%.Interestingly,the male enhancement products also showed anti-inflammatory effects.Conclusion:Despite their labeling as 100%natural,all products tested in this study contained levels of sildenafil citrate,which was not reported on the packaging.There was a lack of pharmaceutical uniformity among products of the same batch and across different batches.Additionally,the products we tested had cytotoxic effects.These study findings highlight the adulteration,poor quality and hazard of these nutraceuticals.Therefore,strict regulation of these products and standardization of the definition of nutraceuticals are urgently needed.Further,these falsely advertised products should be withdrawn from the market due to potential adverse effects on the health of their consumers.