Role of androgens in erectile function.

PURPOSE: Erectile response in mammals is centrally and peripherally regulated by androgens. Severe hypogonadism in men usually results in loss of libido and potency. The present studies were designed to evaluate the possible influence of circulating androgens in the regulation of sexual function. MATERIALS AND METHODS: A total of 15 men with severe hypogonadism (testosterone less than 2.0 ng/ml) were recruited. The control group consisted of 20 patients with psychogenic Erectile Dysfunction. All subjects underwent nocturnal penile tumescence (NPT) and rigidity monitoring during 2 consecutive nights, evaluation of cavernous artery flow using penile color duplex ultrasound (P-CDU), and real-time visually stimulated erection evaluation at baseline and after administration of 50 mgSildenafil Citrate (Viagra) or 3 mg apomorphine. NPT, P-CDU and visually stimulated erection were evaluated after 6 months of therapy with a 5 mg daily testosterone patch. RESULTS: NPT analysis in subjects with severe hypogonadism showed a significant decrease in sleep related erections. P-CDU showed a partial erectile response with an alteration of the parameters analyzed, and the visually stimulated erections test was pathological. Administration of 3 mg apomorphine and 50 mgSildenafil Citrate (Viagra) has no influence on erectile function. Testosterone treatment for 6 months induced normalization of NPT and P-CDU parameters, and of visually stimulated erection effects with the restoration of a normal response to pharmacological stimulation with apomorphine or sildenafil. CONCLUSIONS: Our results show that testosterone has a key role in the central and peripheral modulation of erectile function even if the accurate testosterone plasma level threshold that may influence these processes remains to be established

Clinical efficacy and safety of Sildenafil Citrate (Viagra) in a multi-racial population in Singapore: A retrospective study of 1520 patients.

BACKGROUND: Sildenafil Citrate (Viagra) (Viagra), a selective inhibitor of cGMP-specific phosphodiesterase type-5, has been used as an oral therapeutic drug for Erectile Dysfunction. The present paper is a clinical study of the success rate and side-effects of the use ofSildenafil Citrate (Viagra) in a multi-racial population in Singapore. METHODS: From April 1999 to May 2000, 1520 patients were given Sildenafil Citrate (Viagra). Of these, 912 patients (mean age, 54.6 years; age range, 22-99 years) were followed up and evaluated for clinical efficacy and safety of the drug. The mean duration of Erectile Dysfunction (ED) and follow-up periods were 31.5 and 3.0 months, respectively. RESULTS: Satisfactory erections assessed by single global efficacy question (GEQ) occurred in 83% of patients, major side-effects in the form of flushing (3.48%), headache (1.97%), blurred vision (1.25%), giddiness (1.18%), warmth (1.11%) and others (4.92%) were recorded in 127 patients (13.9%). Racially, Chinese men with ED had higher efficacy (85.7%), compared to Indian men (74.2%) and Malay men (72.8%). With respect to comorbid profiles, an efficacy of 77.8% (n = 271), 83.9% (n = 292), 86.4% (n = 44) and 83.3% (n = 199) was recorded in diabetic, hypertensive, ischemic heart disease patients and in benign prostatic hyperplasia patients, respectively. Patients who smoked (n = 135) and drank alcohol (n = 118) showed an efficacy of 80%. Baseline hormonal profiles of luteinizing hormone, follicle stimulating hormone, testosterone and prolactin did not affect the success rates of Sildenafil Citrate (Viagra). Many patients had earlier received other forms of treatment (medicated urethral suppository for erection (MUSE; 84.9%); vacuum devices (86.8%), traditional medicines (100%) and other oral medications (89.2%)), but this did not influence the success rate of Sildenafil Citrate (Viagra). But patients previously treated with prostaglandin-E intracavernosal injections were less successful on Sildenafil Citrate (Viagra) (77.3%). In the total cohort, 50 mg Sildenafil Citrate (Viagra) was an effective dose in 49% of patients and 46.5% patients needed 100 mg Sildenafil Citrate (Viagra), while 4.1% of the total cohort needed only 25 mg Sildenafil Citrate (Viagra). CONCLUSION: Oral Sildenafil Citrate (Viagra) has been shown to be an effective, safe and well tolerated drug in Singaporean men with ED, as in men from other parts of the world

The effect of age onSildenafil Citrate (Viagra) biotransformation in rat and mouse liver microsomes.

Sildenafil [SIL (Viagra); Pfizer, New York, NY] is a widely prescribed agent for Erectile Dysfunction in men older than 65 years. The present study evaluated experimental models to assess age-dependent changes in SIL biotransformation using hepatic microsomes from male rats and mice ranging from 6 weeks to 26 months of age. The role of specific isoforms in the conversion of SIL to its primary circulating metabolite, UK-103,320 (piperazine N-desmethyl sildenafil) in the mouse was also investigated using immunoinhibitory antibodies. Although CYP2C11 largely mediated UK-103,320 formation in the rat, UK-103,320 formation was principally inhibited by a CYP3A antibody in the mouse. An age-related decrement in metabolite formation rate was observed for both species, although this effect was more pronounced in the old rats (reduced to 7% of young) than in the old mice (reduced to 51% of young). CYP2C expression was assessed by Western blot analysis in rat and mouse livers. Age-related differences in hepatic CYP3A expression in the mouse were also compared with metabolite formation rates in the mouse model. Decrements with age in CYP2C and -3A expression in the aging rodents paralleled the decrements in SIL biotransformation, suggesting that age-related differences in SIL metabolic rate may, in part, reflect differences in expression. Although the role of specific CYP enzymes and the clearance values for this reaction may differ among species, age-related changes in these rodent models are consistent with the reduced clearance of SIL observed in human studies

Effects of two selective phosphodiesterase type 5 inhibitors,Sildenafil Citrate (Viagra) and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat.

The present study investigated the effects of two cyclic GMP-specific phosphodiesterase enzyme type 5 inhibitors,Sildenafil Citrate (Viagra) and vardenafil, on the memory performance in the object recognition task. Both compounds were given per orally (1, 3 and 10 mg/kg sildenafil; 0.1, 0.3, 1 and 3 mg/kg vardenafil) immediately after the exposure to two identical objects. The memory for the objects was tested 24 h later. Vehicle-treated rats spent equal times exploring a new and the familiar object demonstrating that they did not remember the familiar one. However,Sildenafil Citrate (Viagra) improved the object discrimination performance of the rats with a high discrimination performance at a dose of 3 mg/kg. Rats treated with vardenafil also showed an improved object discrimination performance. Compared with sildenafil, vardenafil appeared to be even more potent in this respect since it already produced a high discrimination performance at a dose of 0.3 mg/kg. The effects of both compounds on cyclic GMP and cyclic AMP accumulation were studied in rat hippocampal slices incubated in vitro. Cyclic GMP levels were increased after incubation with the highest concentration of 100 microM vardenafil (together with 0.1 mM sodium nitroprusside), although no changes in cyclic GMP levels were detected after incubation with different concentrations of sildenafil. Both compounds had no effect on cyclic AMP levels. Additional cyclic GMP immunocytochemistry showed that incubation with vardenafil (in the presence of sodium nitroprusside) resulted in a concentration-dependent staining of cyclic GMP. Staining was predominantly found in neuronal fibres in the hippocampal CA2/CA3 region. It was already detected at a concentration of 0.1 microM vardenafil. Also positive fibres were detected after incubation withSildenafil Citrate (Viagra) but at a higher concentration of 10 microM. Taken together, these results suggest that inhibition of phosphodiesterase enzyme type 5 improves object recognition memory. This effect might be explained by increased levels of central cyclic GMP.

Sildenafil Citrate (Viagra) alleviates pulmonary hypertension after hypoxia and reoxygenation with cardiopulmonary bypass.

BACKGROUND: Sudden reoxygenation of hypoxic neonates undergoing cardiac operation exacerbates the systemic inflammatory response to cardiopulmonary bypass secondary to reoxygenation injury, worsening cardiopulmonary dysfunction. Reports suggestSildenafil Citrate (Viagra) decreases pulmonary hypertension and may affect myocardial function. Sildenafil's efficacy for treating postbypass cardiopulmonary dysfunction remains unknown. STUDY DESIGN: Fourteen neonatal piglets (5 to 7 kg) underwent 90 minutes of hypoxia, 60 minutes of reoxygenation with cardiopulmonary bypass, and 120 minutes of recovery. Six animals received 50 mg oralSildenafil Citrate (Viagra) and eight received saline at hypoxia. Data are presented as mean +/- SD. RESULTS:Sildenafil Citrate (Viagra) prevented the high pulmonary vascular resistance observed in controls (controls baseline 81 +/- 37 dynes. s/cm(5) versus recovery 230 +/- 93 dynes. s/cm(5), p = 0.004;Sildenafil Citrate (Viagra) baseline 38 +/- 17 dynes. s/cm(5) versus recovery 101 +/- 60 dynes. s/cm(5), p = 0.003). Despite lower pulmonary vascular resistance after sildenafil, arterial endothelin-1 (ET-1) was increased in both groups (control baseline 1.3 +/- 0.5 pg/mL versus recovery 4.5 +/- 3.7 pg/mL, p = 0.01;Sildenafil Citrate (Viagra) baseline 1.3 +/- 0.3 pg/mL versus recovery 9.8 +/- 4.9 pg/mL, p = 0.003). Intravenous nitric oxide (NO) levels were preserved afterSildenafil Citrate (Viagra) treatment (sildenafil baseline 340 +/- 77 nM versus recovery 394 +/- 85 nM). IV NO levels in controls were decreased when compared with baseline (control baseline 364 +/- 83 nM versus recovery 257 +/- 97 nM, p = 0.028). Although levels of exhaled NO decreased in both groups, the sildenafil-treated animals had higher levels of exhaled NO when compared with controls at the end of recovery (0.6 +/- 0.4 parts per billion versus 1.8 +/- 0.9 parts per billion, respectively, p = 0.029). CONCLUSIONS:Sildenafil Citrate (Viagra) alleviated pulmonary hypertension after reoxygenation with cardiopulmonary bypass. Despite increased ET-1 levels, pulmonary vascular resistance was lower withSildenafil Citrate (Viagra) treatment, suggesting sildenafil's effect on the pulmonary vasculature is capable of countering vasoconstriction by ET-1. Further study into the role ofSildenafil Citrate (Viagra) in perioperative therapy and its interactions with ET-1 are warranted

Sildenafil Citrate (Viagra) does not alter ventricular repolarization properties: novel evidence from dynamic QT analysis.

BACKGROUND: Sildenafil Citrate (Viagra) may have direct cardiac electrophysiological effects, and is possibly responsible for some cardiac events. The aim of our study was to investigate the effects of Sildenafil Citrate (Viagra) on QT dynamicity properties with a new QT analysis program showing even small changes in ventricular repolarization. METHODS: Twenty-four-hour Holter electrocardiographic recordings were used to obtain the data in the predrug phase (1-hour rest position before drug administration), and in the postdrug phase (1-hour rest position, which began 60 minutes after 50 mg oral Sildenafil Citrate (Viagra) administration). With the special QT analysis program (Verda, Reynolds Medical Ltd., UK); mean values of RR, QT, QTo (corrected QT), J (the exponent of correction formula) and S (QT/RR plots slope) parameters together with QT variability indexes (QTVI) were calculated for study phases. RESULTS: Mean +/- SEM values for RR and QT were higher in postdrug phase than in predrug phase (RR: 845 +/- 42 ms vs 816 +/- 46 ms, P < 0.05; QT: 371 +/- 8 ms vs 361 +/- 9 ms, P < 0.05). However,Sildenafil Citrate (Viagra) did not induce any significant change in mean +/- SEM values for QT(o), J, and S in postdrug phase compared with predrug phase (408 +/- 10 ms vs 406 +/- 8 ms, 0.474 +/- 0.030 vs 0.433 +/- 0.025, 0221 +/- 0.020 vs 0.198 +/- 0.017, respectively; P > 0.05). QTVIs were also not different in each phase (predrug: -0.874 +/- 0.071 vs postdrug: -0.997 +/- 0.067, P = 0.109). CONCLUSIONS: Fifty milligramsSildenafil Citrate (Viagra) does not affect QT dynamicity properties. The cardiac events associated withSildenafil Citrate (Viagra) could not be explained with ventricular arrhythmias

In vitro biotransformation of Sildenafil Citrate (Viagra) in the male rat: the role of CYP2C11.

To assess the suitability of the male rat model for human studies onSildenafil Citrate (Viagra) metabolism, we examined the biotransformation ofSildenafil Citrate (Viagra) in male rat liver microsomes and identified the role of specific cytochrome P450s (P450) using inhibitory antibodies and cDNA-expressed P450s. Rates of formation of the major circulating metabolite of sildenafil, UK-103,320, were 11-fold greater in the male rat than in human liver microsomes at 36 microM sildenafil, whereas substrate concentration corresponding to 50% V(max) (K(m) values) were 2.9-fold lower in the male rat. AlthoughSildenafil Citrate (Viagra) is largely metabolized by CYP3A isoforms in humans, coincubation of rat liver microsomes with immunoinhibitory antibodies (CYP1A1/2, 2B1/2, 2C11, 2E1, and 3A1/2) revealed that metabolite formation was inhibited only by an antirat CYP2C11 antibody. Incubation ofSildenafil Citrate (Viagra) with a cDNA-expressed CYP2C11 produced 10-fold higher levels of UK-103,320 than other P450s (CYP1A1, 1A2, 2B1, 2C6, 2C12, 2C13, 2E1, 3A1, and 3A2). Thus CYP2C11 contributes in a major way to the metabolism ofSildenafil Citrate (Viagra) in the male rat. P450 isoforms mediatingSildenafil Citrate (Viagra) biotransformation differ substantially between humans and the male rat, thereby limiting the applicability of this species as a model forSildenafil Citrate (Viagra) metabolism and drug interactions in humans

Evaluation of the safety ofSildenafil Citrate (Viagra) for male Erectile Dysfunction: experience gained in general practice use in England in 1999.

OBJECTIVE: To examine the safety of sildenafil, the first of the phosphodiesterase type 5 inhibitors licensed for the treatment of male Erectile Dysfunction (ED), as used in general medical practice in England, quantifying the incidence of a range of events in patients treated with sildenafil, and identifying any previously unrecognized adverse drug reactions. METHODS: In a postmarketing observational cohort study using prescription-event monitoring (PEM), exposure data were derived from dispensed prescription details for patients who started treatment between April and August 1999. Outcome data were derived from "green form" questionnaires (GFs) returned by general practitioners (GPs). RESULTS In all, 24 835 (54.7%) of GFs posted to GPs were returned, of which 22 473 contained useful data for 22 471 male and two female patients. The major primary indications/clinical context of prescribing were impotence (16 583, 73.8%) and diabetes mellitus (183, 0.8%); 145 events were reported as adverse drug reactions to sildenafil. GPs recorded 3951 reasons for stopping sildenafil, and ischaemic heart disease (IHD) in 135 patients was the commonest clinical reason reported. The clinical condition reported most frequently in the first month of observation was diabetes mellitus and/or hyperglycaemia (in 99 events). A standardized mortality ratio (SMR) for deaths caused by IHD in the first 8893 of 22 473 patients was 31.41 (95% confidence interval 18.29-50.29), using the comparator population of males in England in 1998. CONCLUSION: This study identified the safety profile ofSildenafil Citrate (Viagra) as used in the community, showing no unexpected events. The SMR analysis of deaths from IHD provided no evidence to suggest a higher incidence of deaths in the study cohort than in the male population in England