Effect of PDE5 inhibition combined with free oxygen radical scavenger therapy on erectile function in a diabetic animal model.

Phosphodiesterase (PDE) inhibitors represent an important advance in the treatment of Erectile Dysfunction (ED). In spite of widespread use and generally good efficacy, as a class they remain ineffective in 15-57% of men. Specific cohorts of patients with severe vascular or neurogenic basis to their ED, such as diabetic men or those who have undergone radical pelvic surgery, demonstrate lower response rates with PDE inhibition treatment. We believe that circulating levels of nitric oxide (NO) may be enhanced through delivery of adequate concentrations of free oxygen radical scavenger molecules such as vitamin E. Higher levels of NO, theoretically, should produce increased penile blood flow with the potential for a synergistic effect when combined with a PDE5 inhibitor. With this hypothesis in mind, 20 adult male Sprague-Dawley streptozotocin-induced (60 mg/kg i.p.) diabetic rats were divided into four therapeutic groups (n=5). Group I--control animals received peanut oil, group II--vitamin E 20 IU/day, group III--sildenafil 5 mg/kg/day and group IV--vitamin E 20 IU/day plusSildenafil Citrate (Viagra) 5 mg/kg/day, by oral gavage daily for 3 weeks. Erectile function was assessed as a rise in intracavernous pressure following cavernous nerve electrostimulation. Penile tissue was harvested to determine the changes in tissue morphology including neuronal nitric oxide synthase, smooth muscle alpha-actin and endothelial cell integrity. PDE5 protein content and activity were measured. Significant increases in intracavernous pressure were measured in the animals receiving combined vitamin E plusSildenafil Citrate (Viagra) treatment. Immunohistochemical staining showed increases of neuronal nitric oxide synthase, endothelial cell and smooth muscle cell staining. Western blot analysis did not show significant differences of PDE5 protein between the groups. However, higher PDE5 activity was measured in theSildenafil Citrate (Viagra) group and lower activity of PDE5 was recorded in the cohort receiving vitamin E with sildenafil. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in a meaningful way in this animal model of diabetes. This study indicates a potential means of salvaging erectile function among patients who are refractory toSildenafil Citrate (Viagra)

Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure.

Inhibition of phosphodiesterase type 5 (PDE5) can relax systemic and coronary vessels by causing accumulation of cGMP. Both the endothelial dysfunction with decreased nitric oxide production and increased natriuretic peptide levels in congestive heart failure (CHF) have the potential to alter cGMP production, thereby influencing the response to PDE5 inhibition. Consequently, this study examined the effects of PDE5 inhibition withSildenafil Citrate (Viagra) in dogs with CHF produced by rapid ventricular pacing. CHF resulted in decreases of left ventricular (LV) systolic pressure, coronary blood flow, and the maximal first time derivative of LV pressure (LV dP/dt(max)) at rest and during treadmill exercise compared with normal, whereas resting LV end-diastolic pressure increased from 10 +/- 1.4 to 23 +/- 1.4 mmHg.Sildenafil Citrate (Viagra) (2 and 10 mg/kg per os) caused a 5- to 6-mmHg decrease of aortic pressure (P < 0.05), with no change of heart rate, LV systolic pressure, or LV dP/dt(max).Sildenafil Citrate (Viagra) caused no change in coronary flow or myocardial oxygen consumption in animals with CHF at rest or during exercise. In contrast to findings in normal animals,Sildenafil Citrate (Viagra) did not augment endothelium-dependent coronary vasodilation in response to acetylcholine in animals with CHF. Furthermore, Western blotting showed decreased PDE5 protein expression in myocardium from failing hearts. These findings demonstrate that PDE5 contributes little to regulation of coronary hemodynamics in CHF

Efficacy ofSildenafil Citrate (Viagra) in Erectile Dysfunction after radical prostatectomy.

Radical retropubic prostatectomy (RRP) is an important cause of iatrogenic Erectile Dysfunction (ED). WhileSildenafil Citrate (Viagra) has been widely used since its introduction as a new treatment option for ED, its efficacy in post-RRP patients has not been extensively studied. We retrospectively compared the efficacy ofSildenafil Citrate (Viagra) in post-RRP and non-surgical patients with ED (NSED) using a subset of questions from the International Index of Erectile Function (IIEF) and correlated results with their specific etiology of ED based on penile blood flow study (PBFS). A brief questionnaire regarding satisfaction withSildenafil Citrate (Viagra) was administered to 72 consecutive post-RRP patients (nerve sparing status unknown) and 32 consecutive NSED patients who had previously undergone PBFS with pharmacotesting as part of their evaluation for ED. PBFS diagnoses were arterial insufficiency (AI) for peak systolic velocity (PSV) < 25 cm/sec; venogenic (CVOD) for PSV > or = 35 cm/sec, mixed vascular for PV > 25 but < 35 cm/sec and resistive index (RI) < 0.9; a vascular normal diagnosis (neurogenic impotence) required excellent rigidity sustained for 20 min. Differences in the IIEF subscores for the different groups of patients were assessed. Success withSildenafil Citrate (Viagra) was defined as moderate or excellent improvement (3/4 or 4/4) with ability for penetration. No differences were found among the different subgroups of RRP patients with respect to IIEF scores or success rates with sildenafil. NSED patients had both significantly higher post-treatment IIEF scores (3.6/3.4 vs 2.5/2.2; t=4.50, P<0.0001) and success rates (63% vs 31%; t=3.11, P < 0.01) withSildenafil Citrate (Viagra) treatment than RRP patients. We found thatSildenafil Citrate (Viagra) is significantly less effective in impotent RRP patients than in age-matched patients with ED (31% vs 63%). We had postulated thatSildenafil Citrate (Viagra) would be least effective among RRP patients with excellent sustained rigidity to PGE1, as this subgroup is likely to have neurogenic impotence. We found thatSildenafil Citrate (Viagra) response rates among subgroups of RRP patients were statistically similar regardless of PBFS diagnosis. IIEF scores for the RRP subgroups were similar but statistically lower than in men with ED and no history of RRP. While individuals with normal vascular responses to PGE1 have an increased likelihood of having neurogenic impotence, in RRP patients, we were unable to demonstrate any difference in efficacy of sildenafil, regardless of the PBFS diagnosis

Potentiation of sildenafil-induced hypotension is minimal with nitrates generating a radical intermediate.

Recently the new specific phosphodiesterase-5 inhibitorSildenafil Citrate (Viagra) was introduced into therapy for Erectile Dysfunction. Because of the phosphodiesterase-5 inhibitor-induced increases of cyclic GMP in the vasculature, vasodilation in various vascular beds is induced, which in combination with various nitrovasodilators (e.g., when used simultaneously for the treatment of coronary artery disease), may lead to excessive hypotension. Thus nitrovasodilators are contraindicated whenSildenafil Citrate (Viagra) may be used and reports of a number of accidents have recently been published. We therefore studied the acute interactions of glyceryl trinitrate (GTN), pentaerythritol tetranitrate (PETN), and isosorbide dinitrate (ISDN) withSildenafil Citrate (Viagra) in six chronically instrumented conscious dogs for each nitrate to assess the magnitude of blood pressure drops (and compensatory increases in heart rate) during a 24-h nitrate administration (infusion into the pulmonary artery).Sildenafil Citrate (Viagra) (3 mg/kg) was given orally (after a 24-h fast) 30 min after start of nitrate infusion. GTN, PETN, or ISDN (which follow different steps of metabolic conversion to nitric oxide) were applied at submaximal dosages leading to 90% of maximal coronary artery dilation at 1.5 microg/kg per min, 0.75 microg/kg per min, or 6 microg/kg per min, respectively. During GTN infusionSildenafil Citrate (Viagra) caused a maximum drop in mean blood pressure of 21 +/- 3 mm Hg (rise in heart rate from 117.0 +/- 7.2 to 126.0 +/- 6 .0/min) and during ISDN infusion of 18 +/- 3 mm Hg (rise in heart rate from 115.0 +/- 7.0 to 125 +/- 6/min), which was significantly less (p < 0.01) during PETN (only 6 +/- 1 mm Hg with a rise in heart rate from 107.0 +/- 5.0 to 122.0 +/- 7.0/min). WhenSildenafil Citrate (Viagra) is used during exposure to nitrates (e.g., in coronary artery disease), the PETN-induced drop in blood pressure at equi-effective dosages (with regard to coronary dilation) is substantially smaller compared with that of GTN or ISDN, which is probably because of lesser potentiation of phosphodiesterase-5 inhibitor-induced effects in the arteriolar bed, thus minimizing critical drops in blood pressure

Marked improvement withSildenafil Citrate (Viagra) in a patient with primary pulmonary hypertension unresponsive to epoprostenol.

We report a 48-year-old woman with right heart failure due to primary pulmonary hypertension. Continuous infusion of epoprostenol (prostaglandin I2) for 1.5 years failed to control her condition, but she was later successfully treated with additionalSildenafil Citrate (Viagra) for a few months. Her mean pulmonary artery pressure was originally 57 mmHg, increased to 62 mmHg with epoprostenol, and decreased to 45 mmHg with sildenafil. AdditionalSildenafil Citrate (Viagra) may be an effective and life-saving agent in patients with primary pulmonary hypertension who show a poor response to epoprostenol, which is considered to be very powerful medical treatment for the disease

Combined treatment with intravenous prostacyclin andSildenafil Citrate (Viagra) in patients with pulmonary hypertension: report of 4 cases

BACKGROUND AND OBJECTIVE: Here we report the experience obtained from a combined treatment with intravenous (i.v) prostacyclin and oralSildenafil Citrate (Viagra) in patients with severe pulmonary hypertension (PHT) who had a poor response to prior treatment with prostacyclin alone. PATIENTS AND METHOD:Sildenafil Citrate (Viagra) was added to the treatment in four patients with PHT (primary in two patients and secondary to collagenosis in the other two) with no adequate response to i.v. prostacyclin treatment. The clinical course, 6minutes walking test and echocardiogram were evaluated. RESULTS: InitialSildenafil Citrate (Viagra) dose was 12.5 mg three times daily, which was increased up to 50 mg three times daily in one patient and up to 50 mg four times daily in the other three. The symptoms of right heart failure were controlled in all cases. Before the start ofSildenafil Citrate (Viagra) administration, two patients had class III dyspnea and two patients had class IV dyspnea. Two patients converted to class I (previously class III and IV), and the other two converted to class II. The distance walked within 6 minutes increased (average increase 55%) and systolic pulmonary artery pressure decreased in all patients (average reduction 27%). Effects ofSildenafil Citrate (Viagra) were substained. The only side effect seen was mild headache. CONCLUSIONS: Our experience supports the value ofSildenafil Citrate (Viagra) in the treatment of PHT and suggests that combined treatment is useful for rescuing patients who fail to respond to initial treatment with i.v. prostacyclin

Sensitivity to change and minimally important diference of the Spanish version of the Life-Satisfaction questionnaire LISAT-8 in male patients with Erectile Dysfunction.

Background and objective: We determined the sensitivity to change and minimally important difference (MID) of the Spanish version of the life-satisfaction check list LISAT-8. Patients and method: We included a random sample obtained from an open, naturalistic, prospective and multicenter study, which assessed the effectiveness ofSildenafil Citrate (Viagra) as Erectile Dysfunction (ED) therapy. A total of 537 patients, males older than 18 years, with ED and > active sexual desire, received flexible and at demand doses ofSildenafil Citrate (Viagra) for 10 weeks. IIEF and LISAT-8 questionnaires were used. MID was determined from the patient's classification according to change in erectile function domain of the IIEF after treatment as follows: no change (< 5 pts), small change (6 to 10 pts), moderate change (11 to 15 pts) and big change (> 15 pts). Results:Sildenafil Citrate (Viagra) significantly modified the baseline punctuation of the LISAT 8 from a crude value of 30.2 (5.9) pts (mean [standard deviation]), at baseline, to 34.7 (5.6) pts after treatment., and from 55.4% (14.7%) to 66.8% (14.3%) in standardized punctuation (p < 0.0001 in both cases).Sildenafil Citrate (Viagra) responders showed a response increase of the total punctuation which was significantly higher than non-responders: 12.5% versus 4.3% (p < 0.001). MID was 3.2 pts as crude punctuation, and 8.1% in normalized score. Statistically significant correlations were found between changes in LISAT-8 and changes in IIEF. Conclusions: The Spanish version of the LISAT-8 showed to be responsive to change in male ED patients. Meaningful MID was 3.1 pts (crude) and 8.1% (normalized)

Are adverse effects ofSildenafil Citrate (Viagra) also caused by inhibition of diamine oxidase?

BACKGROUND: Sildenafil Citrate (Viagra) (Viagra), a drug used to treat Erectile Dysfunctions, causes adverse reactions such as headache, flushing or nasal congestion. Sildanefil's potency as inhibitor of diamine oxidase was investigated, as side effects may also be induced by histamine itself due to an impaired histamine metabolism. METHODS: Placental diamine oxidase inhibition experiments were performed with consecutive dilutions of Sildenafil Citrate (Viagra) (10(-5) to 10(-9) mol/l). In 9 male volunteers in vivo diamine oxidase inhibition was investigated after taking 100 mg Sildenafil Citrate (Viagra). RESULTS: Sildenafil Citrate (Viagra) did not inhibit placental diamine oxidase either in vitro or in vivo. However, infusion of 300 mg of cimetidine inhibited diamine oxidase activity by 27 +/- 7% 15 min after infusion, demonstrating that drugs may inhibit diamine oxidase in vivo. CONCLUSION: As side effects ofSildenafil Citrate (Viagra) are not caused due to inhibition of diamine oxidase, Sildenafil Citrate (Viagra) seems to be harmless for patients suffering from histamine intolerance.