In vitro effects of sildenafil and phentolamine, drugs used for erectile dysfunction, on human sperm motility.

Andrade JR, Traboulsi A, Hussain A, Dubin NH.

Department of Gynecology and Obstetrics, Union Memorial Hospital, and the College of Pharmacy, University of Kentucky, USA.

OBJECTIVE: The aim of this study was to determine the effects of sildenafil and phentolamine on sperm motility in vitro. STUDY DESIGN: Semen or washed sperm was mixed with various doses of sildenafil or phentolamine and analyzed for motility during a 30-minute period. The pH was measured for each of the samples tested. Statistical analyses were performed with analysis of variance. RESULTS: A 200-microg/mL dose of sildenafil had no effect on sperm motility. However, the highest dose (2000 microg/mL) significantly reduced motility by about 50%. The pH was reduced in this high-dose sample. The lowest dose of phentolamine (20 microg/mL) had no effect, whereas a dose of 200 microg/mL resulted in a significant reduction in sperm motility. The highest dose (2000 microg/mL) stopped virtually all sperm from moving. CONCLUSION: This study demonstrated a direct dose-related effect of phentolamine on reducing sperm motility. Only the highest dose of sildenafil had an effect, which may have been caused by a decline in pH.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10819837&dopt=Abstract sildenafil Viagra online



Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension.

Weimann J, Ullrich R, Hromi J, Fujino Y, Clark MW, Bloch KD, Zapol WM.

Departments of Anesthesia and Critical Care, Respiratory Care, and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

BACKGROUND: Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction. METHODS: In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6). RESULTS: Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation. CONCLUSIONS: Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.

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Alpha-adrenergic receptor blockade by phentolamine increases the efficacy of vasodilators in penile corpus cavernosum.

Kim NN, Goldstein I, Moreland RB, Traish AM.

Department of Urology, Boston University School of Medicine, Massachusetts 02118, USA. nnkim bu.edu

Penile trabecular smooth muscle tone, a major determinant of erectile function, is highly regulated by numerous inter- and intracellular pathways. The interaction between pathways mediating contraction and relaxation has not been studied in detail. To this end, we investigated the functional effects of alpha adrenergic receptor blockade with phentolamine and its interaction with vasodilators (sildenafil, vasoactive intestinal polypeptide (VIP) and PGE1) that elevate cyclic nucleotides on penile cavernosal smooth muscle contractility. In organ bath preparations of cavernosal tissue strips contracted with phenylephrine, phentolamine significantly enhanced relaxation induced by sildenafil, VIP and PGE1. Sildenafil, VIP or PGE1 also significantly enhanced relaxation induced by phentolamine in cavernosal tissue strips contracted with phenylephrine. To study the effects of alpha adrenergic receptor blockade and modification of cyclic nucleotide metabolism during active neurogenic input, cavernosal tissue strips in organ bath preparations were contracted with the non-adrenergic agonist endothelin-1 and subjected to electrical field stimulation (EFS) in the absence or presence of phentolamine and/or sildenafil. EFS (5-40Hz) typically caused biphasic relaxation and contraction responses. Phentolamine alone enhanced relaxation and reduced or prevented contraction to EFS. Sildenafil enhanced relaxation to EFS at lower frequencies (< or = 5 Hz). The combination of phentolamine and sildenafil enhanced EFS-induced relaxation at all frequencies tested. EFS, in the presence of 10 nM phentolamine and 30 nM sildenafil, produced enhanced relaxation responses which were quantitatively similar to those obtained in the presence of 50 nM sildenafil alone. Thus, blockade of alpha-adrenergic receptors with phentolamine increases the efficacy of cyclic nucleotide-dependent vasodilators. Furthermore, phentolamine potentiates relaxation and attenuates contraction in response to endogenous neurotransmitters which are released during EFS. These findings suggest that antagonism of alpha-adrenergic signaling enables other independent relaxatory pathways to predominate within penile trabecular smooth muscle.

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Sildenafil and erectile dysfunction: new preparation. Helpful.

[No authors listed]

(1) The clinical file is bulky, including 14 double-blind, placebo-controlled trials conducted in normal conditions of use. (2) Sildenafil effectively treats the symptoms of erection disorders, whatever their origin (psychogenic or organic, especially spinal injuries). Efficacy seems slightly lower in case of diabetes or total prostatectomy. (3) Overall, sildenafil allows 80 to 90% of patients to have an erection adequate for sexual intercourse, but only one in two sexual acts on average were considered "satisfactory" by the clinical trial investigators. (4) Sildenafil does not affect sexual desire. It has not been studied in men without erection disorders. The results of ongoing trials in women are not yet known. (5) The adverse effects of sildenafil seem infrequent and generally mild. However, the risk of sudden arterial hypotension if the drug is combined with nitrate derivatives calls for careful safety monitoring. This combination is contraindicated. (6) In our opinion sildenafil should not be prescribed to anyone with cardiovascular risk factors or a history of heart problems.

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Algorithm for diagnosis and treatment of erectile dysfunction in the era of sildenafil citrate.

Kim YC.

Department of Urology, Pundang Je-Saeng General Hospital, Dae-Jin Medical Center, Korea. androyck dmc.or.kr

Since Viagra (sildenafil citrate) was released as a pharmaceutical agent for the treatment of erectile dysfunction, it has had a big impact on the work undertaken in our practice. I herewith present an algorithm for the diagnosis and treatment of erectile dysfunction in the era of sildenafil citrate.

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Effect of phosphodiesterase-5 inhibitor, sildenafil (Viagra), in animal models of airways disease.

Toward TJ, Smith N, Broadley KJ.

Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom.

Phosphodiesterase (PDE)-5 degrades guanosine 3',5'cyclic monophosphate (cGMP) and its inhibitor sildenafil citrate (Viagra) treats erectile dysfunction by smooth muscle relaxation through elevated cGMP. Sildenafil was examined in two guinea pig models of airways disease: guinea pigs exposed to LPS or sensitized guinea pigs with atopy exposed to ovalbumen. Ovalbumen exposure caused early- and late-phase bronchoconstrictor responses, measured in conscious animals by whole-body plethysmography. Twenty-four hours after ovalbumen exposure there was airway hyperreactivity (AHR) to inhaled histamine and significantly elevated macrophages, eosinophils, and nitric oxide (NO) metabolites in bronchoalveolar lavage fluid. Sildenafil treatment (1 mg/kg, intraperitoneally) failed to affect the early and late responses but significantly reduced AHR, leukocyte influx, and elevated NO. LPS exposure (30 microg/ml) caused AHR to histamine at 1 hour and macrophage, eosinophil, and neutrophil influx at 24 hours with raised NO. Sildenafil pretreatment inhibited LPS-induced AHR, leukocyte influx, and NO generation. The effectiveness of sildenafil was not dependent on endogenous NO because inhibition of NO synthase with Nomega-nitro-L-arginine methyl ester did not prevent its action. Inhibition of PDE5 by sildenafil was confirmed by elevated S-nitroso-N-acetylpenicillamine-induced cGMP generation in isolated lungs. These antiinflammatory actions of sildenafil in guinea pig models suggest that PDE5 inhibitors may have potential in treating airways disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14597480&dopt=Abstract sildenafil Viagra online



The cost-effectiveness of sildenafil.

Smith KJ, Roberts MS.

Mercy Hospital of Pittsburgh and the Center for Research on Health Care, University of Pittsburgh School of Medicine, Pennsylvania, USA. ksmith pmhs.mercy.org

BACKGROUND: Coverage of sildenafil by health insurance plans is a contentious issue. OBJECTIVE: To evaluate the cost-effectiveness of sildenafil treatment for erectile dysfunction. DESIGN: A Markov decision model to estimate the incremental cost-effectiveness of sildenafil compared with no drug therapy. DATA SOURCES: Values for the efficacy and safety of sildenafil and quality-of-life utilities were obtained from the published medical literature. Base-case values were chosen to bias against sildenafil use. TARGET POPULATION: Men 60 years of age with erectile dysfunction. TIME HORIZON: Lifetime. PERSPECTIVE: Societal and third-party payer. INTERVENTION: Sildenafil or no treatment in identical hypothetical cohorts. OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) gained. RESULTS OF BASE-CASE ANALYSIS: The cost per QALY gained for sildenafil treatment compared with no therapy was $11,290 from the societal perspective and $11,230 from the third-party payer perspective. RESULTS OF SENSITIVITY ANALYSIS: From the societal perspective, the cost per QALY gained associated with sildenafil was less than $50,000 if treatment-related morbidity was less than 0.8% per year, mortality was less than 0.55% per year, treatment was successful in more than 40.2% of patients, or sildenafil cost less than $244 per month. The results were sensitive to variation of erectile dysfunction utilities, but cost per QALY gained was less than $50,000 if successful treatment increased utility values by 0.05 or more on a scale of 0 (death) to 1 (perfect health). CONCLUSIONS: In an analysis biased against use of sildenafil, the cost-effectiveness of sildenafil treatment compared favorably with that of accepted therapies for other medical conditions.

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Initial results utilizing combination therapy for patients with a suboptimal response to either alprostadil or sildenafil monotherapy.

Mydlo JH, Volpe MA, Macchia RJ.

Department of Urology, State University of New York Downstate Medical School, Brooklyn 11203, USA. mydloj06 hscbklyn.edu

OBJECTIVE: Intraurethral alprostadil and oral sildenafil are useful in selected patients. However, there continues to be a significant treatment failure rate. Since their mechanisms of action are different, we wanted to evaluate the effectiveness of combination therapy. MATERIALS AND METHODS: Of 214 patients treated for erectile dysfunction (ED), 65 were not fully satisfied with the firmness of their erections via monotherapy. Responses were evaluated using the International Index for Erectile Function (IIEF) questionnaire before and after treatment. Group I consisted of 33 patients who tried maximal dose intraurethral alprostadil monotherapy initially, followed by the maximal dose of sildenafil monotherapy, and were still unsatisfied. Group II consisted of 32 patients who tried the maximal dose sildenafil monotherapy initially, followed by the maximal dose of alprostadil monotherapy, and were also unsatisfied. There 65 patients then underwent combination therapy. RESULTS: 60 out of the 65 patients stated they were satisfied with combination therapy. Questionnaire scores for erectile function were 23.1+/-2.0 (114%) for combination therapy vs. 19.2+/-1.8 (77%) and 15.2+/-1.6 (41%) for sildenafil and alprostadil monotherapies (p<0.05). There were no significant differences in responses between the two groups. The men also reported improvement in intercourse and overall satisfaction. CONCLUSIONS: Combination therapy may be an option for motivated patients who have a suboptimal response from monotherapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10859438&dopt=Abstract sildenafil Viagra online