Sildenafil modulates hemodynamics and pulmonary gas exchange.

Kleinsasser A, Loeckinger A, Hoermann C, Puehringer F, Mutz N, Bartsch G, Lindner KH.

Department of Anesthesiology and Critical Care Medicine, Leopold-Franzens-University of Innsbruck, Innsbruck, Austria. axel.klleinsasser uibk.ac.at

The effects of sildenafil (Viagra) on hemodynamics and pulmonary gas exchange remain uncertain. The aim of this study was to investigate what effect sildenafil had on gas exchange. A total of 24 anesthetized pigs were randomly assigned into four groups of six animals each: Group Low received 25 mg of sildenafil, which is equivalent to half the recommended dose for humans; group Normal received 50 mg; group High received 100 mg; and one group served as control. Inert gas and hemodynamic measurements were performed to define dose-dependent effects of sildenafil on cardiac and pulmonary function. Measurements were taken 30, 60, and 90 min after the administration of sildenafil via gastric tube. All doses of sildenafil caused significant increases in intrapulmonary shunt flow (maximum amplitude, 4.4 +/- 0.3 to 11.9 +/- 0.5%; mean +/- SEM), which was reflected by marked decreases in PaO2. Sildenafil elicited some significant increases in cardiac index (CI) (high dose, 142 +/- 10 to 196 +/- 13 ml x kg(-1), mean +/- SEM). Mean arterial pressure was significantly depressed after the high dose of sildenafil. Pulmonary artery pressure was decreased after high-dose sildenafil (maximum amplitude, 16 +/- 1.6 to 14 +/- 1.8, mean +/- SEM). No significant differences between the three treatment groups were found. Sildenafil represents and orally active substance with phosphodiesterase V inhibitory and cardiac output-increasing actions. PaO2 decrease after 50 and 100 mg of sildenafil was observed in the presence of significant rises in pulmonary shunt flow and CI.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11179103&dopt=Abstract sildenafil Viagra online



Sildenafil: clinical toxicology profile.

Krenzelok EP.

Children's Hospital of Pittsburgh, Department of Pharmacy, University of Pittsburgh, Pennsylvania, USA. krenzee chplink.chp.edu

BACKGROUND: Sildenafil is indicated for the treatment of male erectile dysfunction. It has been used successfully in males to remediate problems associated with impaired neural and/or hemodynamic response to sexual stimulation. Sildenafil is a cyclic guanosine-specific phosphodiesterase type 5 inhibitor that prevents the metabolism of cyclic guanosine which produces arterial smooth muscle relaxation within the corpora cavernosa of the penis and ultimately enhances penile tumescence. Inherent to its pharmacology, sildenafil produces mild decreases in systolic and diastolic blood pressure and an array of minimal side effects due to the inhibition of other types of phosphodiesterase. Drug interactions involving the concurrent use of sildenafil with nitrates and nitrites are well-documented and can produce profound hypotension leading to decreased coronary perfusion and myocardial infarction. Sildenafil is metabolized primarily by cytochrome P450 3A4, and inhibitors of this enzyme (e.g., macrolide antibiotics, antifungals, cimetidine) may increase sildenafil serum concentrations and lead to enhanced pharmacological and toxicological effects. The antiviral protease inhibitors have been demonstrated to inhibit first-pass metabolism and increase serum concentrations and half-life of sildenafil. DISCUSSION: Previously unpublished data from the American Association of Poison Control Centers Toxic Exposure Surveillance System indicate that unintentional pediatric exposures to sildenafil are unlikely to be associated with adverse effects. Adults may experience effects similar to those identified in the preclinical trials. This may be due to larger doses in this population, preexisting cardiovascular pathology, or the concomitant use of contraindicated medications.

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T-0156, a novel phosphodiesterase type 5 inhibitor, and sildenafil have different pharmacological effects on penile tumescence and electroretinogram in dogs.

Mochida H, Noto T, Inoue H, Yano K, Kikkawa K.

Discovery and Pharmacology Research Laboratories, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan. mochida tanabe.co.jp

T-0156 (2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride) is a newly synthesized phosphodiesterase type 5 inhibitor, and its potency and selectivity are higher than those of sildenafil in an enzyme assay. In the present study with anesthetized dogs, we examined the effects of intravenous T-0156 or sildenafil on the pelvic nerve stimulation-induced penile tumescence and light-adapted flicker stimulation-induced electroretinogram, parameters of which are reported to be indicators for inhibition of phosphodiesterase type 5 and type 6, respectively. Both compounds potentiated the penile tumescence in a dose-dependent manner. T-0156 at 10 microg/kg and sildenafil at 100 microg/kg showed almost the same potentiating percentage (181.5+/-31.1% and 190.0+/-37.9%) in spite of the plasma concentration of T-0156 being about five times lower than that of sildenafil (16.7+/-1.6 and 78.8+/-5.3 ng/ml), indicating that the effect of T-0156 on tumescence is more potent than that of sildenafil. While the high dose of T-0156 (1000 microg/kg) reduced the amplitude and increased the latency of the electroretinogram positive wave, the effects of T-0156 were conversely weaker than those of sildenafil (reduction of amplitude; T-0156: 41.1+/-8.0%, sildenafil: 71.7+/-3.9%, increase of latency; T-0156: 3.9+/-0.6%, sildenafil: 14.5+/-1.4%, at 1000 microg/kg). These results clearly showed the difference in the properties of T-0156 and sildenafil in pharmacological studies with anesthetized dogs, and the difference appeared to correspond with their inhibitory potencies for phosphodiesterase type 5 and type 6. It was concluded that T-0156 would be a useful pharmacological tool as a potent and highly selective phosphodiesterase type 5 inhibitor.

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[Prescribing of sildenafil by national insurance program physicians. What basic sexual medicine qualification is required?]

[Article in German]

Vauth R, Berner M, Wetterauer U, Berger M.

Abteilung fur Psychiatrie und Psychotherapie der Universitatsklinik Freiburg.

The role of sildenafil in the treatment of erectile dysfunction is discussed. Especially in primary care there is a necessity to weigh the individual cost-benefit-ratio. Functional analysis of erectile dysfunction, exclusion of psychiatric and organic comorbidity, identification of sexual deviance and couple counseling about the advantages and disadvantages of sildenafil prescription are the core prerequisites of sildenafil application in primary care. The counseling model of PLIS-SIT is proposed as a guideline for counseling process. Current approaches of education for general practitioners are reviewed and the integration in a recently developed training for management of psychiatry and psychosomatic illness in general medical settings is proposed. Finally open questions for research and quality management are discussed.

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Combination of phentolamine and L-arginine or sildenafil synergistically improves neurogenic relaxation of rabbit corpus cavernosum smooth muscle.

Angulo J, Cuevas P, Fernandez A, Gabancho S, Saenz de Tejada I.

Fundacion para la Investigacion y el Desarrollo en Andrologia, Madrid, Spain

OBJECTIVES: To analyze the effects of combining an alpha-adrenergic receptor antagonist, phentolamine, with an enhancer of the nitric oxide/cyclic guanosine monophosphate pathway (L-arginine or sildenafil) on neurogenic relaxations of rabbit corpus cavernosum (RCC). METHODS: Studies were performed on isolated RCC tissue in organ chambers. Transmural electrical stimulation (TES) was applied at increasing frequencies (0.5 to 6 Hz) on endothelin-contracted RCC strips, and the responses were evaluated. RESULTS: The activation of alpha(2)-adrenergic receptors with UK 14304 (0.3 microM) significantly inhibited the relaxation induced by TES in RCC strips in which adrenergic neurotransmission was blocked with guanethidine (10 microM). The relaxant responses produced by TES application on RCC strips without guanethidine were not significantly affected by the treatment with L-arginine or sildenafil but were significantly augmented by phentolamine (2.7-fold increase in maximum relaxation). Furthermore, the combinations of phentolamine with L-arginine or sildenafil markedly increased the relaxations evoked by the application of TES in RCC tissue, significantly more than those obtained in the presence of phentolamine alone (4.5 or 4.7-fold increase of maximum relaxation, respectively). CONCLUSIONS: Our results demonstrated a synergistic interaction between the alpha-adrenergic blockade and the potentiation of the nitric oxide/cyclic guanosine monophosphate pathway to increase neurogenic relaxation of trabecular smooth muscle relaxation. This fact suggests that the combination of alpha-adrenergic receptor blockade with L-arginine or sildenafil could represent a therapeutic advantage in the treatment of erectile dysfunction.

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Comparison of FDA reports of patient deaths associated with sildenafil and with injectable alprostadil.

Cohen JS.

Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, USA. jacohen ucsd.edu

BACKGROUND: Sildenafil (Viagra) has been linked to 240 deaths (128 verified, 112 unverified) reported to the Food and Drug Administration (FDA) during 7.5 months of availability, and to 522 reported deaths after 13 months of availability. To date, no updated information about FDA-reported deaths has emerged, and no comparative analyses have been published. OBJECTIVE: To compare the mortality rates between sildenafil and injectable alprostadil, both of which are used exclusively for treating erectile dysfunction. METHODS: A comparison of the number of deaths per filled prescriptions reported to the FDA involving sildenafil and injectable alprostadil was undertaken to perhaps provide further insight into this issue. Materials included FDA statements on sildenafil adverse event reports to the FDA involving sildenafil and injectable alprostadil, and data on prescriptions filled for sildenafil and injectable alprostadil. RESULTS: The number of deaths per prescriptions filled reported in association with sildenafil was significantly greater (5.15-6.28 times) than in association with injectable alprostadil. DISCUSSION: Previous explanations for sildenafil-associated deaths have been based on the expected attrition within the population of men with erectile dysfunction and its commonly associated disorders, the physiologic stress of renewed sexual activity, and a pharmacologic effect of sildenafil. The results of this analysis may indicate that a pharmacologic effect of sidenafil is responsible for these deaths. However, other factors may also explain these findings: a greater frequency of reporting of sildenafil-associated events by physicians, a difference in the populations using these two drugs, or the number of prescriptions filled may not accurately reflect actual exposure. CONCLUSIONS: Further study should be undertaken to clarify the issues associated with sildenafil-related deaths. In the meantime, reasonable precautions might be considered in prescribing sildenafil, such as initiating treatment with a low test dose of sildenafil.

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Sildenafil citrate for the treatment of patients with cardiovascular diseases with exclusion of coronary artery disease and hypertrophic subaortic stenosis. Its beneficial effect on patients chronic Chagas's and diabetic cardioneuromyopathies, hypertensive and hypertrophic cardiomyopathies, with or without chronic congestive heart failure.

Iosa D.

Echo-Doppler Dept., Centro Privado de Diagnostico por Imagenes, Cordoba, Argentina. DANIELIOSA SONOGRAPHER.NET

Sildenafil citrate is a potent donor of nitric oxide that has been proved to be effective for the treatment of male erectile dysfunction, but it has been contraindicated in patients with cardiovascular diseases, because of sudden death occurred to some of them. Based on the known vasodilator effect of nitrix oxide, effect that should be beneficial for some cardiomyopathies, this work was carried out in order to prove the cardiovascular effects of sildenafil citrate on: 1) heart rate, rhythm and repolarization changes on the ecg; 2) systolic and diastolic arterial blood pressure; 3) left ventricular systolic function and 4) right and left ventricular diastolic function in 26 patients suffering from the following cardiomyopathies: chronic Chagas's and diabetic cardioneuromyopathies, hypertensive and/or hypertrophic cardiomyopathies with or without chronic congestive heart failure. RESULTS: sildenafil citrate 50 mgr after a single oral dose: 1) improved the ecg findings in some patients, worsening the basal ecg in none of the studied patients; 2) significantly reduced systolic and diastolic arterial blood pressure being such reduction very strong in those with basal high level 3) significantly improved left ventricular systolic function in those patients with basal reduced function and 4) Right ventricular diastolic function evaluation: Sildenafil citrate 50 mgr significantly modified to normal pattern the E/A basal altered ratio in those patients with the inverted pattern as well as in those with restrictive pattern of tricupid diastolic influx to the right ventricle during the echo-duplex interrogation (p < 0.0001) 5) Left ventricular diastolic function evaluation: Sildenafil citrate 50 mgr significantly modified to normal pattern the E/A basal altered ratio in those patients with the inverted pattern as well as in those with restrictive pattern of mitral diastolic influx to the left ventricle, during the echo-duplex interrogation (p 0 <.0001). CONCLUSIONS: Based on the above findings it is feasible to propose the use of sildenafil citrate to treat patients with cardiovascular diseases, with exclusion of severe obstructive coronary artery disease, hypertrophic subaortic stenosis and patients with funduscopic alterations that may be affected by a significant and acute increase of flow within the ophthalmic arteries. The right ventricular diastolic changes observed with Sildenafil Citrate may be useful in patients with abnormal right ventricular compliance such as pulmonary stenosis or hypertension.

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Central effects of sildenafil (Viagra) on auditory selective attention and verbal recognition memory in humans: a study with event-related brain potentials.

Schultheiss D, Muller SV, Nager W, Stief CG, Schlote N, Jonas U, Asvestis C, Johannes S, Munte TF.

Department of Urology, Hannover Medical School, Germany.

The purpose of this study was to assess possible central side-effects of sildenafil (Viagra) on attention and memory functions. Sildenafil and placebo were administered in young male subjects in a double-blind balanced cross-over design. Behavioral patterns and event-related brain potentials (ERP) were recorded in a spatial auditory attention and a visual word recognition task. While behavioral patterns did not reveal any overt effects of sildenafil, auditory ERPs were indicative of an enhanced ability to focus attention (amplitude enhancement of Nd-effect) and to select relevant target stimuli in the sildenafil condition (P3 component). In the memory task, CNS-effects of sildenafil were evident in a reduction of a negativity in the 150-250 ms range. No overt effects on behavior were observed. Nevertheless, the data reveal CNS-effects of sildenafil necessitating further studies.

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