ChronicSildenafil Citrate (Viagra) improves erectile function and endothelium-dependent cavernosal relaxations in rats: lack of tachyphylaxis.

OBJECTIVES:Sildenafil Citrate (Viagra) is a widely-prescribed effective on-demand treatment of Erectile Dysfunction (ED). Chronic treatment withSildenafil Citrate (Viagra) could help patients with ED. METHODS: The effects of an 8-week long treatment withSildenafil Citrate (Viagra) (60 mg/kg/d sc) in male Sprague Dawley rats were evaluated on electrically-elicited erectile responses in vivo before and after an acute injection ofSildenafil Citrate (Viagra) (0.3mg/kg iv). In addition, endothelium-dependent and -independent relaxations of strips of corpus cavernosum in vitro were examined. All experiments were performed 36 hours after the last injection of sildenafil. RESULTS: Endothelium-dependent relaxations of cavernosal strips to acetylcholine were enhanced after chronic treatment withSildenafil Citrate (Viagra) while relaxations to A23187 or sodium nitroprusside were unchanged. Frequency-dependent erectile responses elicited by cavernous nerve stimulation were significantly improved. Moreover, the erectile responses to acuteSildenafil Citrate (Viagra) were greater in chronically-treated rats with sildenafil. CONCLUSIONS: This is the first report providing experimental support for chronic dosing withSildenafil Citrate (Viagra) which could be of use for patients that are poor responders to on-demand treatment. ChronicSildenafil Citrate (Viagra) may regulate the transduction pathway leading to the activation of eNOS but has no effect on NO bioavailability or on the cGMP pathway, thereby eliminating a possible concern for tachyphylaxis

Recreational use and misuse of phosphodiesterase 5 inhibitors.

OBJECTIVE: To characterize the rationale for and extent of phosphodiesterase (PDE) 5 inhibitor use in recreational settings, describe risks from such misuse, and discuss postexposure clinical management strategies. DATA SOURCES: Published articles identified by searches through Medline, EMBASE, International Pharmaceutical Abstracts, and Toxline, from 1990 to March 2004, using the search terms sildenafil, tadalafil, vardenafil, phosphodiesterase inhibitor, abuse, overdose, adverse effects, recreational, and street drugs. Additional references identified within articles and information from the Internet were included. STUDY SELECTION: Clinical trials, epidemiologic reviews, case reports, and news releases concerning the misuse of sildenafil. DATA EXTRACTION: By the authors. DATA SYNTHESIS: PDE5 inhibitors, indicated for treatment of Erectile Dysfunction, can produce several adverse effects, including potentially fatal cardiovascular events. Reports of recreational use and misuse ofSildenafil Citrate (Viagra) appear in the medical literature and the media. The potential for abuse also exists for the two more recently approved drugs in this class, vardenafil and tadalafil. Increasing access to these drugs via the Internet may facilitate such misuse. Use in social settings has gained popularity, both in young, healthy patients, as well as those with chronic medical conditions, including human immunodeficiency virus infections. In these settings, the PDE5 inhibitors are sometimes used concomitantly with "club drugs" such as ketamine and amyl nitrite, leading to potentially harmful or fatal drug interactions. CONCLUSION: Pharmacists should be cognizant of the potential for PDE5 inhibitors to be misused, particularly in patients who are at greater risk of cardiovascular complications, and should advise patients and other health care professionals accordingly

Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil.

AIMS: To characterize the absorption, metabolism and excretion of an oral and intravenous (IV) dose of radiolabelled [14C]-Sildenafil Citrate (Viagra) in healthy male subjects. Specific objectives were to measure the cumulative amount of drug-related radiolabelled material excreted in the urine and faeces to characterize urinary and faecal radioactivity as unchangedSildenafil Citrate (Viagra) or its metabolites, and to quantify blood and plasma total radioactivity and unchanged drug concentrations. METHODS: Six healthy male subjects between the ages of 45 and 58 years were enrolled in an open-label, parallel-group study; three subjects received the oral dose and three received the IV dose. Oral drug was administered as a single dose of 50-mg [14C]-sildenafil, and IV drug was administered as a single dose of 25-mg [14C]-sildenafil infused over 25 min. Each dosage form contained 50 microCi of radioactivity. For radioactivity assays, whole blood, plasma, urine and faeces samples were taken predose and at specified intervals up to 5 days postdose. Plasma samples were assayed forSildenafil Citrate (Viagra) and the metabolites UK-103,320 and UK-150,564. Metabolite profiling was also performed in plasma, faeces and urine. RESULTS: Absorption ofSildenafil Citrate (Viagra) after oral administration was rapid and approximately 92% whilst the absolute bioavailability was limited to 38%, due to first-pass metabolism. Mean AUCt values showed thatSildenafil Citrate (Viagra) accounted for about 60% of the total circulating radioactivity in the plasma after IV administration and for 32% after oral administration. Concentrations of radioactivity in whole blood were lower than in plasma, indicating limited penetration ofSildenafil Citrate (Viagra) into blood cells. No unchangedSildenafil Citrate (Viagra) was detected in either urine or faeces, demonstrating that metabolism was the major mechanism of drug clearance. The principal routes of metabolism were N-demethylation, oxidation and aliphatic dehydroxylation.Sildenafil Citrate (Viagra) was well tolerated, with treatment-related adverse events reported by three subjects. Two of these were mild, and there was one case of moderate leg pain. CONCLUSIONS: The pharmacokinetics of radiolabelled [14C]-sildenafil were consistent with rapid absorption, first-pass metabolism and primarily faecal elimination of N-demethylated metabolites

Comparison of the relaxant effects of alfuzosin, phentolamine andSildenafil Citrate (Viagra) on rabbit isolated corpus cavernosum.

OBJECTIVE: To compare the direct relaxant effects of alfuzosin, phentolamine andSildenafil Citrate (Viagra) in rabbit isolated corpus cavernosum (CC) pre-contracted with phenylephrine or KCl. MATERIALS AND METHODS: Penile erectile tissue was obtained from male New Zealand White rabbits (22-26 weeks old). The CC was cut into longitudinal strips and mounted under 2 g resting tension in 5-mL jacketed organ baths containing a modified Krebs solution bubbled with 95% O2, 5% CO2 and maintained at 37 degrees C. Tissue strips were pre-contracted by 60 mmol/L KCl or 10 micro mol/L phenylephrine. After obtaining a stable plateau of contractions, test compounds were added to the organ bath. The relaxant potencies were expressed as the percentage of inhibition of the plateau of contraction induced by 10 micro mol/L phenylephrine. RESULTS: Alfuzosin showed a concentration-dependent relaxing effect on rabbit CC pre-contracted by 10 micro mol/L phenylephrine, with a mean (sd) pIC50 of 7.64 (0.06). The relaxant effect was unaffected by pre-incubation with 100 micro mol/L Nomega-nitro-l-arginine methyl ester (L-NAME). Phentolamine had a potency similar to alfuzosin, with a pIC50 of 7.44 (0.08). Both alfuzosin and phentolamine were completely ineffective on the plateau of contraction induced by 60 mmol/L KCl. In contrast to alfuzosin,Sildenafil Citrate (Viagra) was equipotent in relaxing the rabbit CC against each contractile agent, with pIC50 values of 7.25 (0.09) and 7.23 (0.22) with 10 micro mol/L phenylephrine and 60 mmol/L KCl, respectively. The relaxant response toSildenafil Citrate (Viagra) was partly blocked by pretreatment with 100 micro mol/L L-NAME, with pIC50 values of 7.94 (0.09) and 6.63 (0.32) without and with L-NAME, respectively. Sildenafil, incubated for 45 min at 10 micro mol/L, had no relaxant effect on the resting tension of the preparation or on the concentration-response curve to phenylephrine. CONCLUSIONS: The direct relaxant effect of alfuzosin is mediated through alpha1-adrenoceptor blockade. The relaxations induced by phentolamine and alfuzosin are independent of nitric oxide, whereas those induced bySildenafil Citrate (Viagra) are, at least partly, sensitive to L-NAME and a selective soluble guanylate cyclase inhibitor, indicating the involvement of nitric oxide and soluble guanylate cyclase. Alfuzosin and phentolamine effectively counteract alpha1-adrenoceptor-mediated contractions of rabbit CC. If valid for human CC, such an effect may contribute to an improved erectile function in patients treated for benign prostatic hyperplasia

Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension.

BACKGROUND: Phosphodiesterase type 5 (PDE5) is a novel therapeutic target for the treatment of pulmonary hypertension. This study examined the distribution of PDE5 in normal and hypoxic lung and the effect of chronic PDE5 inhibition with sildenafil, initiated before and during exposure to hypoxia, on pulmonary artery pressure (PAP) and structure. METHODS AND RESULTS: Sprague-Dawley rats were exposed to hypoxia (10% O2) for up to 42 days. PAP, measured continuously by telemetry, increased gradually by 20 to 40 mm Hg, reaching a plateau between 10 and 14 days, and declined to normal levels on return to normoxia. PDE5 immunoreactivity was localized to smooth muscle cells in the medial layer of pulmonary arteries and veins in the normal lung and in distal muscularized arteries (<25 microm diameter) after hypoxia-induced pulmonary hypertension.Sildenafil Citrate (Viagra) (25 or 75 mg x kg(-1) x d(-1)) given before hypoxia produced marked dose-dependent inhibition in the rise of PAP (60% to 90% reduction; P<0.0001) and vascular muscularization (28.4+/-5.0% reduction; P<0.001). When begun after 14 days of hypoxia,Sildenafil Citrate (Viagra) significantly reduced PAP (30% reduction; P<0.0001) and partially reversed pulmonary artery muscularization (39.9+/-4.9% reduction; P<0.001). CONCLUSIONS: PDE5 is found throughout the muscularized pulmonary vascular tree, including in newly muscularized distal pulmonary arteries exposed to hypoxia. PDE5 inhibition attenuates the rise in PAP and vascular remodeling when given before chronic exposure to hypoxia and when administered as a treatment during ongoing hypoxia-induced pulmonary hypertension

Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension.

Exposure to high altitude induces pulmonary hypertension that may lead to life-threatening conditions. In a randomized, double-blind, placebo-controlled study, the effects of oralSildenafil Citrate (Viagra) on altitude-induced pulmonary hypertension and gas exchange in normal subjects were examined. Twelve subjects (sildenafil [SIL] n = 6; placebo [PLA] n = 6) were exposed for 6 days at 4,350 m. Treatment (3 x 40 mg/day) was started 6 to 8 hours after arrival from sea level to high altitude and maintained for 6 days. Systolic pulmonary artery pressure (echocardiography) increased at high altitude before treatment (+29% versus sea level, p < 0.01), then normalized in SIL (-6% versus sea level, NS) and remained elevated in PLA (+21% versus sea level, p < 0.05). Pulmonary acceleration time decreased by 27% in PLA versus 6% in SIL (p < 0.01). Cardiac output and systemic blood pressures increased at high altitude then decreased similarly in both groups. Pa(O(2)) was higher and alveolar-arterial difference in O(2) lower in SIL than in PLA at rest and exercise (p < 0.05). The altitude-induced decrease in maximal O(2) consumption was smaller in SIL than in PLA (p < 0.05).Sildenafil Citrate (Viagra) protects against the development of altitude-induced pulmonary hypertension and improves gas exchange, limiting the altitude-induced hypoxemia and decrease in exercise performance

Sildenafil versus the vacuum erection device: patient preference.

PURPOSE: We evaluated the preference of patients with Erectile Dysfunction who had been effectively treated with a vacuum erection device and then switched to sildenafil. MATERIALS AND METHODS: A total of 52 patients with Erectile Dysfunction who achieved satisfactory erectile function according to the International Index of Erectile Function (IIEF) while using a vacuum erection device were switched to an increasing dose ofSildenafil Citrate (Viagra) (range 25 to 100 mg.) until satisfactory erection was maintained at least twice a week for at least 1 month. The 2 treatment methods were not used concomitantly. A total of 36 patients with a mean age of 59 years (range 35 to 77) who claimed to have achieved satisfactory erections with a vacuum erection device andSildenafil Citrate (Viagra) reported their preference to continueSildenafil Citrate (Viagra) or resume the use of a vacuum erection device, reasons for the choice and any adverse side effects. RESULTS: Of the 36 participants in whom the efficacy ofSildenafil Citrate (Viagra) was similar to that of a vacuum erection device according to the IIEF scores (mean plus or minus standard deviation 61.6 +/- 10.4 and 62.5 +/- 6, respectively), 12 (33.3%) decided to resume use of a vacuum erection device (group 1) while 24 (66.6%) preferred to continueSildenafil Citrate (Viagra) (group 2). There were no statistically significant differences between the groups regarding patient age or the etiology and duration of Erectile Dysfunction. The increase in the IIEF score while using a vacuum erection device was higher in group 1 than 2, with a mean of 66.75 versus 60.4, respectively (p = 0.002). The adverse side effects ofSildenafil Citrate (Viagra) were the main reasons for preferring a vacuum erection device. Fewer ejaculatory difficulties, efficacy, comfort and ease of use were the main reasons for choosing sildenafil. CONCLUSIONS: Even in an era of effective oral medication, the vacuum erection device remains a preferred treatment option for a substantial number of patients with Erectile Dysfunction

Simultaneous assay ofSildenafil Citrate (Viagra) and desmethylsildenafil in human plasma using liquid chromatography-tandem mass spectrometry on silica column with aqueous-organic mobile phase.

A liquid chromatography-tandem mass spectrometry method was developed for the analysis ofSildenafil Citrate (Viagra) (SIL) and its metabolite desmethylsildenafil (DMS) in human plasma. Samples were accurately transferred to 96-well plates using a liquid handler (Multiprobe II). Solid-phase extraction was carried out on a 96-channel programmable liquid handling workstation (Quadra 96) using a C8 and cation-exchange mixed-mode sorbent. The extract was injected onto a silica column with an aqueous-organic mobile phase, a combination that was novel for improving the method sensitivity. The low limit of quantitation was 1.0 ng/ml for both SIL and DMS. The method was validated to meet the criteria of current industrial guidance for quantitative bioanalytical methods