Comparison of trimetazidine plus sildenafil to chronic nitrates in the control of myocardial ischemia during sexual activity in patients with coronary artery disease.

Rosano GM, Marazzi G, Patrizi R, Cerquetani E, Vitale C, Volterrani M, Fini M, Mercuro G.

Department of Medical Sciences, Cardiovascular Research Unit, San Raffaele, Rome, Italy.

A large proportion of patients who have erectile dysfunction also have coronary artery disease (CAD). In these patients, nitrate therapy is a contraindication to the use of sildenafil. To assess whether the metabolic anti-ischemic agent, trimetazidine, is effective in controlling episodes of myocardial ischemia during sexual activity in patients who have CAD and use long-term nitrate therapy, we studied 38 men (57 +/- 6 years of age) who had proved CAD. Patients underwent 24-hour ambulatory electrocardiographic monitoring at baseline, after 1 week of oral nitrate therapy (20 mg 3 times a day), and after 1 week of trimetazidine (20 mg 3 times a day). Patients were asked to engage in >/=1 session of sexual intercourse during each session of ambulatory electrocardiographic monitoring. They were instructed to take sildenafil (100 mg) 1 hour before sexual intercourse performed at baseline and during therapy with trimetazidine and sildenafil or placebo (blinded) during therapy with nitrates. A decrease in total ischemic burden was observed with nitrates and trimetazidine compared with baseline (-3 +/- 1.2 episodes/patient/24 hours vs -5 +/- 1.3 episodes/patient/24 hours and -6 +/- 5 min/patient/24 hours vs -8 +/- 3 min/patient/24 hours, p <0.01 for nitrates and trimetazidine vs baseline). Trimetazidine plus sildenafil was more effective in controlling episodes of myocardial ischemia during sexual activity than nitrates alone (-45 +/- 11% vs -18 +/- 7%, p <0.04). In conclusion, in patients who have CAD, combination therapy with sildenafil and trimetazidine is more effective than nitrate therapy in the control of ischemic episodes during sexual activity, suggesting that long-term nitrate therapy may be safely switched to trimetazidine therapy when therapy for erectile dysfunction is required.

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Salvage of sildenafil failures referred from primary care physicians.

Atiemo HO, Szostak MJ, Sklar GN.

Department of Surgery, University of Maryland School of Medicine, Baltimore, USA.

PURPOSE: Sildenafil citrate is an effective first line agent for most causes of erectile dysfunction. Primary care providers (PCPs) write the majority of these prescriptions and most failures of sildenafil therapy are subsequently referred to urologists for alternative therapies. Often it is concluded that the drug is ineffective when in actuality the failure is do to inadequate patient education. We examined patients referred from PCPs who were nonresponders to sildenafil therapy and attempted to convert them to responders through reeducation. MATERIALS AND METHODS: In a 2-year period 253 sildenafil nonresponders were evaluated by the same urologist (GNS). Patient reeducation consisted of viewing a brief videotape, personal instruction and detailed instruction sheets for the patient and his partner. Outcome measures were obtained through patient self-reporting of the Sexual Health Inventory for Men and a global assessment question. Responders were identified as those who answered positively latter or had a statistical improvement in the score of the former. RESULTS: Of the 253 patients reeducated 17 were excluded due to contraindications. Of the remaining nonresponders 41.5% achieved salvage with reeducation. Incorrect administration accounted for 81% of the failures. Average time with the physician was 12 minutes and 94% of the patients continued to respond at 26 months. CONCLUSIONS: Approximately 40% of patients with sildenafil failures referred from PCPs can be converted to responders through reeducation. Incorrect drug administration was the most common reason for correctable failure. Reeducation can be done in an efficient manner. New package materials may improve sildenafil outcomes and compliance.

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Sildenafil in the treatment of erectile dysfunction in men with diabetes: demand, efficacy and patient satisfaction.

Behrend L, Vibe-Petersen J, Perrild H.

1Internal Medical Clinic I, University Hospital, Copenhagen NV, Denmark.

The objective of this study is to describe the eligibility, consumption, efficacy and patient satisfaction when treating men with diabetes with Sildenafil. The study is a prospective, self-reported, flexible-dose study. In total, 45 patients with diabetes (type 1 or 2), complaining of erectile dysfunction, were treated with Sildenafil over a 12-week period. Efficacy was assessed using a patientlog, a general satisfaction questionnaire and the International Index of Erectile Function (IIEF). Of 326 men, 192 reported erectile dysfunction, 79 did not fulfil the criteria for Sildenafil treatment and 49 declined to participate. In the group of 33 (age 45-75 y, mean+/-s.d.: 58.1+/-7.2) completing the study, erectile function was significantly improved (P<0.0001). A total of 12 patients (36.4%) experienced no treatment effect at all. Eligibility and desire for treatment was low. Sildenafil is far from being a 'cure all' in the treatment of ED in diabetes.International Journal of Impotence Research advance online publication, 27 January 2005; doi:10.1038/sj.ijir.3901302.

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A prospective evaluation of efficacy and compliance with a multistep treatment approach for erectile dysfunction in patients after non-nerve sparing radical prostatectomy.

Gontero P, Fontana F, Zitella A, Montorsi F, Frea B.

Clinica Urologica, Universita del Piemonte Orientale, Novara, Italy. gontero med.unipmn.it

OBJECTIVE: To assess the response rate to different erectile aids in a consecutive series of patients treated with non-nerve sparing radical prostatectomy (NNSRP). PATIENTS AND METHODS: Ninety-four potent men were counselled about the different treatment options to restore an assisted erection before they had NNSRP. They were invited to participate in a multiphase protocol involving the sequential use of different erectile aids which aimed at restoring erectile function after surgery. The first proposed treatment was oral apomorphine sublingual. Patients with a positive response to the 1-item overall efficacy question and a minimum score of 3 in both question 3 and 4 of the International Index of Erectile Function were considered responders to oral pharmacotherapy. Treatment with sildenafil was then suggested to those not responding. If patients did not respond to oral pharmacotherapy a trial with a vacuum erectile device was offered; those not responding to this were then offered intracavernosal injection therapy with prostaglandin-E alone as the first option, followed by a mixture of vasoactive agents if needed. In those in whom injections also failed, a penile implant was recommended. At the 1-year follow-up visit all patients were offered a second trial with oral therapy regardless of the treatment currently in use. RESULTS: Seventy-six patients entered the protocol; there was no response to apomorphine. Five of 59 (8%) patients responded to sildenafil when they first used it at a mean of 7 months after NNSRP, while there were three additional responders in 22 patients who tried it for a second time a year later. Of patients achieving at least a complete tumescence sufficient for vaginal penetration, 52% and 60% were considered responders to the vacuum device and intracavernosal injections, respectively. Overall, 44% of patients enrolled in the protocol chose to use an erectile aid for at-home use. At the 1-year follow-up, only 20% of patients were still using an erectile aid, including two who had had a penile implant. CONCLUSIONS: Up to 10% of patients may achieve a clinically significant erection with sildenafil after NNSRP, but 80% will not be using any erectile aid at 1 year after surgery. In the present study protocol the proposed erectile aids were largely inadequate for treating the permanent erectile dysfunction that follows NNSRP.

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Risk factors in predicting a poor response to sildenafil citrate in elderly men with erectile dysfunction.

Park K, Ku JH, Kim SW, Paick JS.

Department of Urology, Seoul National University Hospital, 28 Chongno-Gu, Yongon-Dong, Seoul, Korea.

OBJECTIVE: To assess the clinical efficacy of sildenafil and the potential predictors of poor response to sildenafil in elderly patients with erectile dysfunction (ED). PATIENTS AND METHODS: The study included 162 patients (aged > or = 60 years) treated with sildenafil for at least 8 weeks; all patients were evaluated with a history, physical examination, measurement of total testosterone and a pharmacological erection test. Sexual function before and 8 weeks after treatment was assessed using the self-administered International Index of Erectile Function (IIEF). Treatment was considered successful when the patient attained a higher grade on the erectile function (EF) domain score, and an affirmative response to the overall assessment question. Factors influencing treatment outcome were evaluated by univariate and multivariate statistical analysis. RESULTS: The overall efficacy with sildenafil was 47% (76/162). On univariate analysis, uncontrolled diabetes, current smoking, hypogonadism (<3 microg/L testosterone) and low pretreatment EF domain score (<17) were selected as predictors of a poor response. On multivariate logistic regression, a low pretreatment EF domain score was the strongest independent prognostic factor for a poor response (odds ratio 2.25, 95% confidence interval, 1.45-7.33), and this was followed by hypogonadism (1.89, 1.12-3.16) and current smoking (1.34, 1.04-3.52). CONCLUSION: In a real clinical setting, sildenafil was effective for about half of the elderly men. The baseline EF domain score, hypogonadism and current smoking were significantly associated with failure of sildenafil. These results suggest that modifying reversible risk factors, e.g. stopping smoking and replacing testosterone, would be beneficial in augmenting the efficacy of sildenafil in elderly men.

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Pulmonary vascular effects of sildenafil on the development of chronic pulmonary hypertensionin the ovine fetus.

Larrue B, Jaillard S, Lorthioir M, Roubliova X, Butrous G, Rakza T, Warembourg H, Storme L.

Cardiothoracic Surgery, Lille University Hospital, Lille, France; Biophysics, EA 1049, Lille University Hospital, Lille, France.

Introduction: Cyclic guanosine-monophosphate (cGMP) is critical in determining pulmonary vascular tone and reactivity. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases-5 (PDE-5). We hypothesized that enhanced PDE-5 activity contributes to consequences of chronic pulmonary hypertension in the perinatal lung. To test this hypothesis, we investigated the pulmonary vascular effects of prophylactic use of sildenafil - a specific PDE-5 inhibitor- in chronically - prepared late-gestation fetal lambs with chronic pulmonary hypertension. Methods: 10 fetal lambs were operated between 128 and 130 days gestation (term=147 days). An inflatable vascular occluder was placed around the ductus arteriosus (DA). DA was compressed for 8 full days, starting 24 hours after the surgery, to cause chronic pulmonary hypertension. To test the hypothesis, the animals were treated with continuous infusion of sildenafil (24 mg/day; sildenafil group; n=5) or with saline (control group; n=5). Treatment was begun before DA compression and continued during the study period. Pulmonary hemodynamic responses to increase in shear stress and in fetal PaO2 were studied at respectively day 4 and day 6. Percent wall thickness of the small pulmonary arteries (%WT) and the right ventricle-to-left ventricle plus septum ratio (RVH) were measured after the completion of the study. Results: In the control group, chronic DA compression increased PA pressure (48+/-5 to 72+/-8 mmHg (p<0.01)) and pulmonary vascular resistance (PVR) (0.62+/-0.08 to 1.15+/-0.11 mmHg/ml/min (p<0.05)). Similar increase in PAP was observed in the sildenafil group, but PVR did not change significantly (0.54+/-0.06 to 0.64+/-0.09 mmHg/ml/min). At day 4, acute DA compression -after a brief decompression- elevated PVR by 25 % in the control group. At the opposite, DA compression at day 4 decreased PVR by 35 % in the sildenafil group. At day 6, increase in fetal PaO2 did not change PVR in the control group. Similar increase in fetal PaO2 decreased PVR by 60% in the sildenafil group. %WT and RVH in control and sildenafil groups were not different. Conclusion: Prophylactic sildenafil treatment prevents from the rise in pulmonary vascular tone and from altered vasoreactivity caused by DA compression in fetal lambs. These results support the hypothesis that elevation of PDE-5 activity is involved in the consequences of chronic pulmonary hypertension in the perinatal lung.

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The efficacy of sildenafil for the treatment of erectile dysfunction in male peritoneal dialysis patients.

Mahon A, Sidhu PS, Muir G, Macdougall IC.

Department of Renal Medicine, King's College Hospital, London, UK.

BACKGROUND: The aim of this study was to evaluate the safety and effectiveness of sildenafil in male peritoneal dialysis patients with erectile dysfunction. METHODS: Sixteen peritoneal dialysis patients were recruited to this prospective, randomized, double-blind, placebo-controlled, crossover study of sildenafil during a period of 8 weeks. Efficacy was assessed by using the International Index of Erectile Function and a Global Assessment Question. Penile arterial supply was assessed by means of Doppler ultrasound in all patients, and adverse events were recorded. RESULTS: Three patients failed to complete the study (1 patient received a renal transplant, 1 patient died unrelated to the study, and 1 patient withdrew for personal reasons). In the remainder, there was a significant improvement in erectile function with sildenafil compared with placebo (P = 0.01) and the baseline assessment (P = 0.002). There were also significant improvements in intercourse satisfaction (P = 0.002) and overall satisfaction (P = 0.005) compared with baseline. In response to the Global Assessment Question, 75% of patients reported improvement in erections. Only 1 adverse event was reported: a headache, which resolved after the third dose of sildenafil. CONCLUSION: Sildenafil caused a significant improvement in erectile function in peritoneal dialysis patients, with a success rate at least as high as that reported in other patient groups. The drug was well tolerated, with few adverse events.

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Sildenafil prevents endothelial dysfunction induced by ischemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: a human in vivo study.

Gori T, Sicuro S, Dragoni S, Donati G, Forconi S, Parker JD.

Department of Internal, Cardiovascular, and Geriatric Medicine, Azienda Universitaria Ospedaliera Senese, Siena, Italy. tommaso.gori utoronto.ca

BACKGROUND: Animal studies have demonstrated that administration of sildenafil can limit myocardial damage induced by prolonged ischemia, an effect that appears to be mediated by opening of adenosine triphosphate-sensitive potassium (K(ATP)) channels. No study has investigated whether sildenafil can also prevent the impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) in humans. METHODS AND RESULTS: In a double-blind, placebo-controlled, crossover design, 10 healthy male volunteers (25 to 45 years old) were randomized to oral sildenafil (50 mg) or placebo. Two hours later, endothelium-dependent, flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). Seven days later, subjects received the other treatment (ie, placebo or sildenafil) and underwent the same protocol. Pre-IR radial artery diameter and FMD, as well as baseline radial artery diameter after IR, were similar between visits (P=NS). After placebo administration, IR significantly blunted FMD (before IR: 7.9+/-1.1%; after IR: 1.2+/-0.7%, P<0.01). Importantly, sildenafil limited this impairment in endothelium-dependent vasodilatation (before IR: 7.0+/-0.9%; after IR: 6.2+/-1.1%, P=NS; P<0.01 compared with placebo). In a separate protocol, this protective effect was completely prevented by previous administration of the sulfonylurea glibenclamide (glyburide, 5 mg), a blocker of K(ATP) channels (n=7; FMD before IR: 10.3+/-1.5%; after IR: 1.3+/-1.4%, P<0.05). CONCLUSIONS: In humans, oral sildenafil induces potent protection against IR-induced endothelial dysfunction through opening of K(ATP) channels. Further studies are needed to test the potential clinical implications of this finding.

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