[Effect of sildenafil citrate on the cortical visual responses]

[Article in Spanish]

Gonzalez F, Justo MS, Bermudez MA, Gomez-Ulla F, Perez R.

Departamento de Fisiologia (Laboratorios "Ramon Dominguez"), Facultad de Medicina y Unidad de Retina Medica, Complejo Hospitalario Universitario de Santiago, Universidad de Santiago de Compostela, Espana. ispaco usc.es

OBJECTIVE: To study the possible effect of oral sildenafil citrate on the response of cortical visual cells to visual stimulation. METHOD: Multiunit activity was recorded from cortical area V2 of one behaving monkey. Spatio-temporal receptive field maps were obtained by using a reverse cross correlation technique and white noise visual stimulation before and after oral administration of sildenafil citrate. RESULTS: The receptive field maps showed a reduction in response latency after administration of sildenafil citrate. CONCLUSIONS: Since sildenafil citrate is an inhibitor of retinal phosphodiesterase-6, an enhancement on light sensitivity in the photoreceptors is proposed as the cause of the observed reduction in response latency (Arch Soc Esp Oftalmol 2002; 77: 241-246).

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Sildenafil (Viagra) augments sodium nitroprusside-induced but not nitroglycerin-induced hypotension in dogs.

Yoo KY, Kim HS, Moon JD, Lee J.

Department of Anesthesiology, Research Institute of Medical Sciences, Chonnam National University Medical School, 5 Hak-dong, Gwangju 501-746, South Korea. kyyoo chonnam.ac.kr

We investigated whether sildenafil citrate (Viagra) may reduce the dose of nitrovasodilators to induce deliberate hypotension. Ten mongrel dogs were acutely instrumented with a femoral artery catheter and a pulmonary artery catheter. Sodium nitroprusside (SNP; 1-16 microg. kg(-1). min(-1)) or nitroglycerin (NTG; 2-32 microg. kg(-1). min(-1)) was IV given to induce hypotension. The study consisted of two occasions, in a random order, in each animal: one with sildenafil pretreatment (1 mg/kg IV followed by 0.3 mg. kg(-1). h(-1)) and the other without to serve as a control. Hemodynamic variables were continuously monitored. Plasma cyclic guanosine monophosphate (cGMP) concentrations were measured by radioimmunoassay. Both SNP and NTG produced dose-dependent decreases in mean arterial blood pressure without affecting the heart rate in the presence as well as in the absence of sildenafil. Systemic vascular resistance index and mean pulmonary arterial pressure were also decreased. The magnitude of mean arterial blood pressure and systemic vascular resistance index reductions caused by SNP was augmented by sildenafil, whereas that caused by NTG was not affected. Neither SNP nor NTG alone altered the plasma cGMP concentrations. Sildenafil increased the plasma cGMP concentration, which was further increased by SNP but not affected by NTG. These results indicate that sildenafil may reduce the dose of SNP in producing deliberate hypotension in the dog. The potentiation of SNP-induced hypotension by sildenafil may be related to an augmented accumulation of cGMP. IMPLICATIONS: Sildenafil may reduce the dose of sodium nitroprusside required to induce deliberate hypotension and hence the potential for cyanide toxicity.

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Efficacy and safety of sildenafil citrate in hemodialysis patients.

Sahin Y, Aygun C, Peskircioglu CL, Kut A, Tekin MI, Ozdemir FN, Ozkardes H.

Baskent University, Faculty of Medicine, Department of Urology, Ankara, Turkey.

Erectile dysfunction (ED) is more frequent among end-stage renal failure patients than the normal population. Sildenafil citrate has been successfully used for the symptomatic treatment of erectile dysfunction. The aim of this study was to determine the efficacy and safety of sildenafil citrate in the treatment of ED in patients on hemodialysis. Fifty-five hemodialysis patients above 18 years suffering from ED with steady sexual partners were included in the study. The first five and fifteenth questions of the International Index of Erectile Function were employed to evaluate ED in the patient group. A Single 50-mg sildenafil citrate tablet was prescribed for each patient. The patients were encouraged to take it on the day after hemodialysis and 1 hour before sexual intercourse. The erectile function of the patients after the treatment was re-evaluated in the same manner by International Index of Erectile Function. The ages of the patients ranged between 30 and 73 years (mean 50.6 +/- 10.9). The overall response rate was 74.5% (38/51). Side effects were nausea (n = 2), palpitation (n = 2), flushing (n = 1), and angina (n = 1). Sildenafil citrate (50 mg) was observed to be safe and effective for treatment of hemodialysis patients with careful evaluation and proper patient selection.

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Is sildenafil citrate an alternative agent in the evaluation of penile vascular system with color Doppler ultrasound?

Erdogru T, Usta MF, Ceken K, Koksal T, Ates M, Kabaalioglu A, Baykara M.

Department of Urology, Akdeniz University Faculty of Medicine, Antalya, Turkey.

IINTRODUCION: The ideal diagnosis and therapeutic agent for erectile dysfunction (ED) would be an oral drug taken prior to color Doppler ultrasound (CDU) examination and sexual intercourse. In the present study we have investigated if the efficacy of oral sildenafil is optimal in the diagnosis of underlying pathology of ED. MATERIAL AND METHODS: The study group comprised of 41 patients with ED. Firstly, all patients underwent CDU examinations after the combined intracavernosal injection of 60 mg of papaverine and sexual stimulation (CIS). Secondly, these patients were examined after taking 50 mg of oral sildenafil citrate combined with self-manual and visual sexual stimulation. RERSULTS The differences of peak systolic velocity values were statistically significant between CIS and sildenafil (right: 40.7 +/- 2.9 vs. 28.7 +/- 3.3; left: 41.2 +/- 3.3 vs. 25.7 +/- 2.4; p < 0.001) in patients with normal penile vascular system. However, end-diastolic velocity and resistance index values were not significant between the same groups. In addition, there were not significant differences for peak systolic and end-diastolic blood flow velocities and resistances index with CIS and sildenafil in cases with vasculogenic ED. CONCLUSIONS: Sildenafil citrate plus visual sexual stimulation is not reliable as CIS to make accurate interpretation of penile vascular status using CDU. On the other hand, in some cases suspected of psychogenic ED after detailed sexual history, sildenafil might be tried as an initial step of the functional evaluation with CDU in order to prevent prolonged erection risk with intracavernosal injection of vasoactive agents. Copyright 2002 S. Karger AG, Basel

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Potential for use of pulse wave analysis in determining the interaction between sildenafil and glyceryl trinitrate.

O'Rourke MF, Nichols WW.

Department of Medicine, St Vincent's Hospital, University of New South Wales, Sydney, Australia. M.ORourke unsw.edu.au

BACKGROUND: The early part of the central aortic pressure pulse, with amplitude (PI - Pd), is generated by left ventricular ejection, while the latter part (or augmented pressure), with amplitude (Ps - Pi), is generated by the reflected wave arriving during systole. The effects of arterial vasodilator agents, especially nitrates, on central aortic systolic blood pressure are grossly underestimated by sphygmomanometric measurements of brachial artery pressure. HYPOTHESIS: The objective of this study was to investigate the potential for use of central arterial pulse wave analysis, obtained noninvasively from the radial pulse, in determining the interaction between sildenafil and the nitric oxide donor drug glyceryl trinitrate (GTN). METHODS: Central aortic pressure waveforms were generated from noninvasively measured radial artery pressure wave-forms and subjected to pulse wave analysis to determine the interaction between sildenafil and transdermally applied GTN. RESULTS: Transdermal GTN (2.5, 5.0, and 15 mg per 24-h patches) alone caused no consistent change in sphygmomanometer-determined systolic or diastolic pressures, but there was a consistent, dose-related fall in amplitude of the augmented systolic pressure, (Ps - Pi), of 4.0, 7.0, and 11 mmHg, respectively, with little change in diastolic pressure. The 2.5 mg patch caused a fall of 4.0 mmHg in aortic systolic pressure, while augmentation index (AIx) fell from 20 to 11% and pulse pressure fell 18%. When oral sildenafil (50 mg) was administered after GTN (2.5 mg), aortic systolic pressure fell another 4.0 mmHg. This decrease in systolic pressure caused a fall in AIx to almost 0.0%; pulse pressure fell another 9.0%. CONCLUSION: These modifications in aortic systolic and pulse pressure are due primarily to reduction in wave-reflection amplitude and are not detected by sphygmomanometer-measured brachial artery pressure.

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Sildenafil in the Treatment of SSRI-Induced Sexual Dysfunction: A Pilot Study.

Damis M, Patel Y, Simpson GM.

Department of Psychiatry, University of Tennessee at Memphis Health Science Center, Memphis; and the Department of Psychiatry and the Behavioral Sciences, LAC/USC Medical Center, Los Angeles, Calif.

BACKGROUND: Sexual dysfunction is a well-documented side effect of selective serotonin reuptake inhibitors (SSRIs). Commonly reported side effects include erectile impotence, anorgasmia, ejaculatory delay, pain, loss of sensation, and decreased pleasure. Early reports of the reversal of sexual dysfunction after using sildenafil in male and female patients receiving various types and dosages of SSRIs are promising and prompted this study. Our aim was to evaluate the effects of oral sildenafil on reported secondary sexual dysfunction in patients concurrently treated with SSRIs. METHOD: Fourteen male patients who developed sexual dysfunction while receiving SSRIs were screened using the Arizona Sexual Experience (ASEX) scale. An electrocardiogram was obtained at the beginning and at the end of the study. Each patient was prescribed sildenafil tablets to be taken twice a week, 25-100 mg, prior to sexual activity and told to record the findings in a running diary which he was to keep during his treatment period. The patients were seen weekly and evaluated by clinical interview and ASEX scale. Patients were treated for a total of 8 weeks. RESULTS: All but 1 of the 14 patients experienced an improvement of sexual dysfunction, with 9 patients at the first dose of 25 mg and 4 at higher doses (3 at 50 mg and 1 at 75 mg). One patient required 100 mg to obtain minimal response. DISCUSSION: Sildenafil was shown to be helpful in the treatment of SSRI-induced sexual dysfunction. Three patients continued to experience ongoing positive effects after discontinuation of sildenafil; the other 10 patients relapsed.

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Sublingual apomorphine: new preparation. In erectile disorders: a narrow therapeutic margin.

[No authors listed]

(1) When drug treatment is indicated for erectile dysfunction, sildenafil is the first line oral treatment. Overall, about half of patients with erectile dysfunction can achieve satisfactory penetrative sex with sildenafil. (2) Apomorphine, a dopamine agonist, is now licensed in France for treatment of erectile dysfunction. It is available as sublingual tablets of 2 mg and 3 mg. (3) The evaluation dossier contains no data comparing apomorphine with sildenafil. Dose-finding studies and placebo-controlled trials in patients without a serious organic disorder show that about 90% consider the 2 mg dose of apomorphine to be insufficient. The 3-mg tablets are hardly more effective. Nearly 90% of patients prefer a dose of at least 4 mg. (4) The main side effects of sublingual apomorphine are nausea, dizziness, severe sweating and drowsiness. These effects are dose-dependent. Syncope and hypotension are also relatively common. Serious consequences of these side effects were reported during some clinical trials. (5) The safety profile of sublingual apomorphine is no better than that of sildenafil. Both drugs interact with nitrates, increasing the risk of hypotension. (6) In practice, sildenafil remains the first line treatment for men with erectile dysfunction.

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Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro.

Wallis RM, Corbin JD, Francis SH, Ellis P.

Pfizer Central Research, Sandwich, Kent, United Kingdom.

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5), which has been shown to be a clinically effective treatment for erectile dysfunction. Its action results from increased levels of cyclic guanosine monophosphate (cGMP), which is normally degraded by PDE5. This cyclic nucleotide is a second messenger for nitric oxide, which is involved in the regulation of numerous functions, including vascular smooth muscle tone. In an attempt to better predict the effects of sildenafil on cardiovascular function, the distribution of PDE activity was determined with anti-PDE1 and anti-PDE5 antibodies in the human cardiac ventricle and saphenous vein, and in vitro studies were performed on the isolated human cardiac ventricle, corpus cavernosum, saphenous vein, and mesenteric artery as well as on rabbit aorta, dog coronary artery, dog trabecular tissue, and rabbit and human platelets. The major PDE activity in the human cardiac ventricle was shown to be calcium/calmodulin-dependent PDE1, but there was no detectable level of PDE5. In contrast, the human saphenous vein contained PDEs 1, 4, and 5, and the human mesenteric artery contained PDEs 1, 2, 3, 4, and 5. The distribution of PDE5 in the cardiovascular system is consistent with the observed pharmacodynamic and clinical effects of sildenafil. Sildenafil, unlike milrinone, a selective PDE3 inhibitor, had no effect on the isolated trabeculae carneae; this is consistent with the lack of PDE5 expression in cardiac myocytes. Sildenafil selectively increased cGMP levels in coronary vascular smooth muscle tissue but produced no change in cyclic adenosine monophosphate (cAMP) levels, which is consistent with the drug's selectivity for PDE5. In phenylephrine-contracted isolated rabbit aortic rings, sildenafil enhanced the relaxation induced by the nitric oxide donor glyceryl trinitrate, suggesting that sildenafil may potentiate the hypotensive effects of nitric oxide donor agents on the vasculature, an effect that has been observed clinically. Human platelets were found to contain PDE5, which was inhibited by 50% (IC50) by sildenafil at a concentration of 6.3 nM, consistent with the IC50 value in the corpus cavernosum. Sildenafil alone had no direct effect on platelet function, but it potentiated the in vitro antiaggregatory activity of sodium nitroprusside on rabbit and human platelets. The pharmacodynamic and adverse event profiles observed in clinical trials with sildenafil are consistent with the in vitro profile of the tissue distribution of PDE5 and its known mechanism of action as a selective inhibitor of PDE5.

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