The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil.

We investigated the potency and the selectivity profile of vardenafil on phosphodiesterase (PDEs) enzymes, its ability to modify cGMP metabolism and cause relaxation of penile smooth muscle and its effect on erections in vivo under conditions of exogenous nitric oxide (NO) stimulation. PDE isozymes were extracted and purified from human platelets (PDE5) or bovine sources (PDEs 1, 2, 3, 4 and 6). The inhibition of these PDEs and of human recombinant PDEs by vardenafil was determined. The ability to potentiate NO-mediated relaxation and influence cGMP levels in human corpus cavernosum strips was measured in vitro, and erection-inducing activity was demonstrated in conscious rabbits after oral administration together with intravenous doses of sodium nitroprusside (SNP). The effects of vardenafil were compared with those of the well-recognized PDE5 inhibitor,Sildenafil Citrate (Viagra) (values forSildenafil Citrate (Viagra) in brackets). Vardenafil specifically inhibited the hydrolysis of cGMP by PDE5 with an IC50 of 0.7 nM (6.6 nM). In contrast, the IC50 of vardenafil for PDE1 was 180 nM; for PDE6, 11 nM; for PDE2, PDE3 and PDE4, more than 1000 nM. Relative to PDE5, the ratios of the IC50 for PDE1 were 257 (60), for PDE6 16 (7.4). Vardenafil significantly enhanced the SNP-induced relaxation of human trabecular smooth muscle at 3 nM (10 nM). Vardenafil also significantly potentiated both ACh-induced and transmural electrical stimulation-induced relaxation of trabecular smooth muscle. The minimum concentration of vardenafil that significantly potentiated SNP-induced cGMP accumulation was 3 nM (30 nM). In vivo studies in rabbits showed that orally administered vardenafil dose-dependently potentiated erectile responses to intravenously administered SNP. The minimal effective dose that significantly potentiated erection was 0.1 mg/kg (1 mg/kg). The selectivity for PDE5, the potentiation of NO-induced relaxation and cGMP accumulation in human trabecular smooth muscle and the ability to enhance NO-induced erection in vivo indicate that vardenafil has the appropriate properties to be a potential compound for the treatment of Erectile Dysfunction. Vardenafil was more potent and selective thanSildenafil Citrate (Viagra) on its inhibitory activity on PDE5

The effect ofSildenafil Citrate (Viagra) on electrostimulation-induced erection in the rat model.

This study was conducted to show the effect ofSildenafil Citrate (Viagra) on electrostimulation-induced erection in the rat model. Fifteen 12-week-old male Wistar Kyoto rats were used. The intracavernous pressure and arterial blood pressure were simultaneously monitored through electric cavernous nerve stimulation before and after the administration ofSildenafil Citrate (Viagra) (2 mg/kg). Statistical analysis was performed on maximal intracavernous pressure (MIP), mean arterial blood pressure (MAP), the MIP/MAP and detumescence time. MAP decreased significantly by about 20 mmHg afterSildenafil Citrate (Viagra) administration. The MIP/MAP increased significantly afterSildenafil Citrate (Viagra) administration. The effect ofSildenafil Citrate (Viagra) on the MIP/MAP was marked especially at lower (2-3 Hz) frequencies. The detumescence time significantly increased afterSildenafil Citrate (Viagra) administration. We have shown thatSildenafil Citrate (Viagra) is effective for enhancing erection at lower frequencies and prolonging penile erection in rats. After the administration of sildenafil, penile erection would be induced by weak stimuli that will not cause penile erection under normal conditions

Erectile Dysfunction after kidney transplantation: our 22 years of experience.

AIM: To evaluate the results of treatment of Erectile Dysfunction (ED) in kidney transplant recipients before and after the advent of sildenafil. MATERIALS AND METHODS: From 1981 through 2002, 971 male patients of mean age 53.4 years received a renal graft. Erectile Dysfunction (ED) was investigated in all patients at the first urologic visit posttransplantation. Psycho-sexual support was offered to all patients. BeforeSildenafil Citrate (Viagra) use (1998), our diagnostic approach was complex. From 1998 we tested: serum levels of testosterone, prolactin, and glucose with penile duplex ultrasonography and NPT reserved for selected cases. RESULTS: From 1981 through 1998, 365 male kidney transplant recipients (45%) reported ED. Only 169 patients chose to be treated: 27 responded to psycho-sexual therapy; 3 received testosterone with benefit; 133 had a good results from intracavernosal injection of vasoactive drugs; and 6 received a penile prosthesis. Since 1998, 126 patients reported ED (78.3%). Only 78 chose treatment: 24 patients had a satisfactory response toSildenafil Citrate (Viagra) (65% with 50 mg and 35% with 100 mg). PGE1 alone or in combination with papaverine and phentolamine produced a good response in 37 patients; 17 patients did not respond to pharmacotherapy; and 5 received a tricomponent penile prosthesis without complications. The side effects ofSildenafil Citrate (Viagra) and PGE1 therapy were similar to those reported in the literature. CONCLUSIONS: ED is an important problem in male renal transplant recipients. Cultural resistance to treatment is common. However, treatment with Sildenafil Citrate (Viagra) and intracavernosal self-injection of PGE1 are well accepted, and prosthetic devices may help in resistant cases

Long-term intracavernous therapy responders can potentially switch to Sildenafil Citrate (Viagra) after radical prostatectomy.

OBJECTIVES: To assess whether long-term users of intracavernous (IC) injections after radical prostatectomy can switch to oral therapy with Sildenafil Citrate (Viagra). METHODS: Forty-nine patients (mean age 60.9 years) with Erectile Dysfunction after radical prostatectomy were identified as long-term users of IC injections (3.7 +/- 1.9 years). These patients received open-label treatment with Sildenafil Citrate (Viagra) (50 to 100 mg) for a minimum of 4 weeks or five attempts. The primary outcome measure of our study was assessed by the Sexual Health Inventory of Men (SHIM) questionnaire (International Index of Erectile Function-5 [IIEF]). A successful switch was prospectively defined as erection sufficient for vaginal penetration afterSildenafil Citrate (Viagra) use and compliance to therapy. Patients were designated as responders or nonresponders on the basis of their ability to achieve vaginal penetration. RESULTS: Of 49 patients, only 36 agreed to receive oral open-labelSildenafil Citrate (Viagra) (50 to 100 mg) for a minimum of 4 weeks or five attempts. Prostaglandin E1 (PGE1) was used in 70% and triple therapy (PGE1, papaverine, and phentolamine) in the remaining 30%. Of the 36 patients, 15 (41%) successfully switched toSildenafil Citrate (Viagra) and discontinued IC injections. When the results were stratified by the type of IC solution, patients with high-dose triple therapy had a poor success rate of switch (7%) compared with patients using PGE1 treatment (67%). Of the 36 patients, 14 (38%) foundSildenafil Citrate (Viagra) ineffective and continued using IC injections. Patients who switched to oral therapy had had a greater (P <0.001) total mean SHIM (IIEF-5) score with IC injections than those who did not switch (12.3 +/- 7.8 versus 20.0 +/- 4.9). Of the 36 patients, 7 (19%) foundSildenafil Citrate (Viagra) alone to be suboptimal but continued using it, enhancing the efficacy of IC injections alone. The three predictive factors for a successful switch were high preoperative SHIM (IIEF-5) score, high post-IC injection SHIM score, and type of IC medication used (PGE1 alone versus high-dose triple therapy). CONCLUSIONS: Long-term users of IC injection therapy can potentially switch to Sildenafil Citrate (Viagra) with acceptable sexual satisfaction. Patients will accept a lower degree of sexual satisfaction as measured by the IIEF-5 (SHIM) score if oral therapy is effective

Cardiac electrophysiologic and hemodynamic effects of sildenafil, a PDE5 inhibitor, in anesthetized dogs.

A recent in vitro study demonstrated that supratherapeutic concentrations of sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, blocked I(Kr) and prolonged cardiac repolarization. This study assessed the in vivo cardiohemodynamic and electrophysiologic effects ofSildenafil Citrate (Viagra) using a halothane-anesthetized, closed-chest canine model (n = 5) to bridge the gap between basic observation and clinical experience. Intravenous administration of Sildenafil Citrate (Viagra) in doses of 0.03, 0.3, and 3.0 mg/kg for 10 min, which provided sub-to supratherapeutic plasma drug concentrations, did not affect the monophasic action potential duration or effective refractory period of the right ventricle during the sinus rhythm as well as the ventricular pacing at the cycle length of 400 and 300 ms. However,Sildenafil Citrate (Viagra) decreased the total peripheral resistance, simultaneously inducing positive chronotropic and inotropic effects at the top dose, which gave plasma concentrations at least 10 times higher than the therapeutic range. This cardiohemodynamic profile ofSildenafil Citrate (Viagra) can be largely explained by reflex sympathetic activation associated with its vasodilator effect. Meanwhile, the lack of prolongation of the ventricular repolarization phase at the therapeutically relevant to moderately supratherapeuticSildenafil Citrate (Viagra) concentrations supports the earlier clinical studies that indicate thatSildenafil Citrate (Viagra) has no effect on electrocardiogram

Early haemodynamic benefit ofSildenafil Citrate (Viagra) in patients with coexisting chronic thromboembolic pulmonary hypertension and left ventricular dysfunction.

Sildenafil, a phosphodiesterase type-5 inhibitor, offers potential to treat pulmonary hypertension associated with a variety of conditions. We assessed the early impact ofSildenafil Citrate (Viagra) on a cohort of patients referred to our unit who had severe pulmonary hypertension secondary to chronic thromboembolic disease which was not amenable to pulmonary thromboendarterectomy and who also had coexisting left ventricular dysfunction. Six patients were studied. Diagnosis of pulmonary embolic disease was made by ventilation perfusion scanning and/or CT pulmonary angiography. All patients were anticoagulated with oral coumarin derivatives and none were considered suitable for pulmonary thromboendarterectomy. Pulmonary hypertension was diagnosed by right heart catheterisation and each patient had Medical Research Council (MRC) dyspnoea score and New York Heart Association (NYHA) class noted and 2D echocardiography prior to commencement ofSildenafil Citrate (Viagra) 50 mg three times a day. After 6 weeks ofSildenafil Citrate (Viagra) therapy, right heart catheterisation and 2D echocardiography were repeated, and MRC dyspnoea score, NYHA class and exercise capacity were recorded. All patients demonstrated an improvement in mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, MRC dyspnoea score, NYHA class and gas transfer. No adverse effects ofSildenafil Citrate (Viagra) were noted. Our data suggests thatSildenafil Citrate (Viagra) is an effective and well-tolerated therapy for patients with severe pulmonary hypertension associated with pulmonary thromboembolic disease and impaired left ventricular function, producing beneficial effects as early as 6 weeks

Initial uptake in use ofSildenafil Citrate (Viagra) in general practice.

OBJECTIVE: To assess the initial uptake in use and co-prescribing patterns of sildenafil. METHODS: We examined prescription details of the Eastern Health Board Region (including Dublin) of the General Medical Services (GMS) in Ireland, which provides detail on prescriptions dispensed in primary care for this population (n = 334,031). We identified 1422 patients who received 3740 prescriptions forSildenafil Citrate (Viagra) over a 6-month period (July 1999-December 1999) and determined the percentage of patients who were co-prescribed nitrate therapy, medications which may interact withSildenafil Citrate (Viagra) and medications associated with impotence. RESULTS: We identified 1422 (1.4% of the male population over 16 years who might be expected to suffer from Erectile Dysfunction given an overall prevalence of 10%) who received a prescription forSildenafil Citrate (Viagra) over the study period at a cost of 0.14% of the annual drug budget. Up to 2.5%, 6% and 25% of patients were co-prescribed, respectively, nitrate therapy, potentially interacting drugs and drugs associated with impotence. CONCLUSION: The initial uptake and cost associated withSildenafil Citrate (Viagra) was lower than expected. The rate of prescribing of nitrates and other potentially interacting medications was found to be low. Medication use may also contribute to Erectile Dysfunction in this population of patients

Effects ofSildenafil Citrate (Viagra) on cardiac repolarization.

OBJECTIVES: Sudden death has occasionally been reported in patients taking sildenafil. The objective of this study was to investigate the effect ofSildenafil Citrate (Viagra) on cardiac repolarization. METHODS: We used conventional microelectrode recording technique in isolated guinea pig papillary muscles and canine Purkinje fibers, whole-cell patch clamp techniques in guinea pig ventricular myocytes, and in vivo ECG measurements in guinea pigs. RESULTS: Action potential duration at 90% repolarization (APD(90)) was not affected bySildenafil Citrate (Viagra) in the therapeutic ranges (< or =1 microM), but shortened by higher concentration (> or =10 microM) in both guinea pig papillary muscles and canine Purkinje fibers. D-Sotalol prolonged APD(90) in the same preparations with concentrations > or =1 microM in a reverse frequency-dependent manner. Co-administration ofSildenafil Citrate (Viagra) (10 and 30 microM) abolished the APD-prolonging effects of D-sotalol (30 microM) and amiodarone (100 microM). Sildenafil, with concentrations up to 30 microM, had no significant effect on both the rapid (I(Kr)) and the slow (I(Ks)) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes.Sildenafil Citrate (Viagra) dose-dependently blocked L-type Ca(2+) current (I(Ca,L)), but had no effect on persistent Na(+) current in guinea pig ventricular myocytes. ECG recordings in intact guinea pigs revealed significant shortening of QTc interval bySildenafil Citrate (Viagra) (10 and 30 mg/kg orally). The QT-prolonging effects by D,L-sotalol (50 mg/kg) and amiodarone (100 mg/kg) were abolished bySildenafil Citrate (Viagra) (30 mg/kg). CONCLUSIONS:Sildenafil Citrate (Viagra) does not prolong cardiac repolarization. Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably through its blocking effect on I(Ca,L)