Sildenafil citrate does not affect QT intervals and QT dispersion: an important observation for drug safety.

Alpaslan M, Onrat E, Samli M, Dincel C.

Department of Cardiology Department of Urology, Faculty of Medicine, Afyon Kocatepe University, 03200 Afyon, Turkey.

BACKGROUND: Sildenafil is an effective and widely used therapeutic agent for erectile dysfunction. Deaths have been reported due to sildenafil use and most of them are attributed to concurrent use of nitrates. However, the effects of sildenafil on QT intervals, QT dispersion, and the possible risk of ventricular arrhythmia have not been studied before. Our aim in this study was to evaluate the effect of sildenafil citrate on QT intervals and QT dispersion. METHODS: Thirty-six patients with erectile dysfunction were included in this study. Twenty-one patients had coronary artery disease whereas 12 of them also had accompanying diabetes mellitus. Standard 12-lead electrocardiograms (ECG) were recorded three times: before, and at the first and fourth hours of 50 mg sildenafil citrate ingestion. All QT parameters were corrected for heart rate. RESULTS: Mean age of the patients was 54 +/- 12 years. The mean heart rate did not differ significantly between the three ECG examinations. The corrected and uncorrected maximum and minimum QT intervals were not significantly different between the three ECG examinations. The QT dispersion and corrected QT dispersion before and 1 hour and 4 hours after sildenafil ingestion were 31 +/- 9 ms, 36 +/- 10 ms; 32 +/- 11 ms, 37 +/- 14 ms; 27 +/- 8 ms, 32 +/- 9 ms, respectively (P > 0.05). CONCLUSIONS: Sildenafil does not prolong QT intervals or increase QT dispersion in patients with erectile dysfunction. Our results suggest that the risk of ventricular arrhythmia does not increase with ingestion of 50 mg sildenafil.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12848808&dopt=Abstract sildenafil Viagra online



Chronic ischemia increases prostatic smooth muscle contraction in the rabbit.

Azadzoi KM, Babayan RK, Kozlowski R, Siroky MB.

Department of Urology, Boston University School of Medicine, Massachusetts 02130, USA.

PURPOSE: We studied the effect of chronic ischemia on prostatic smooth muscle contraction in the rabbit. MATERIALS AND METHODS: New Zealand male rabbits weighing 3 to 3.5 kg were assigned to 2 groups. Group 1 (10 rabbits) underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet for 4 weeks and then a regular diet for 8 weeks. Control group 2 (10 rabbits) received a regular diet. After 12 weeks the animals were anesthetized. Iliac artery and prostate blood flow was recorded. Prostate tissues were prepared for isometric tension measurement, enzyme immunoassay to determine cyclic guanosine monophosphate (cGMP) release and histological examination. RESULTS: In group 1 atherosclerosis as well as a significant decrease in iliac artery and prostate blood flow were observed. Ischemia significantly increased prostatic tissue contraction, decreased cGMP release and led to capsular and stromal thickening, and epithelial atrophy. The alpha1-adrenoceptor blocker doxazosin and the phosphodiesterase-5 inhibitor sildenafil citrate significantly decreased the contraction of control and ischemic tissues. Doxazosin was more effective in decreasing contractions when it was combined with sildenafil or the nitric oxide (NO) precursor L-arginine. In contrast, doxazosin was less effective when it was combined with the NO synthase inhibitor N omega-nitro-L-arginine or with the guanylate cyclase inhibitor methylene blue. Doxazosin significantly increased cGMP release in control tissues but not in ischemic tissues. Sildenafil significantly increased cGMP release in control and ischemic tissues. CONCLUSIONS: Ischemia increased prostatic smooth muscle contraction and led to marked structural damage. Stimulators of NO synthesis and cGMP production enhanced the efficacy of doxazosin in decreasing prostatic tissue contraction. Sildenafil decreased contractility and increased cGMP release. Increased smooth muscle tone and structural changes in the ischemic prostate may suggest a role for prostate ischemia in resistance to urinary flow independent of prostate size.

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Sildenafil improves acquisition and retention of memory in mice.

Singh N, Parle M.

Pharmacology Division, Department of Pharmaceutical Sciences, Guru Jambheshwar University (G.J.U.) Post Box 38, Hisar 125 001.

Sildenafil (Viagra) has been introduced recently in market to correct male impotency and has gained immense popularity for its dramatic effects all over the world. The present study was designed to investigate the effect of sildenafil on learning and memory in mice using elevated plus maze. A total of XV groups of animals were employed in the present study. Central cholinergic pathways play a crucial role in learning and memory processes. Physostigmine, an anticholinesterase agent (0.5 mg, 1.0 mg kg(-1), i.p) was employed for its memory enhancing property and alprazolam a benzodiazepine receptor agonist served as a memory-impairing agent. In the present study, alprazolam produced anterograde amnesia (at 0.5 mg kg(-1), i.p) and retrograde amnesia (at 0.25 mg, 0.5 mg, 0.75 mg kg(-1), i.p.) in separate groups of animals. Caffeine at 5 mg, 10 mg and 20 mg kg(-1), i.p. (an established psychostimulant) did not show any significant change in learning and memory of mice. Sildenafil (at 8 mg kg(-1), i.p.) administered 30 minutes prior to training on first day produced a marginal decrease in transfer latency time on first day; whereas, sildenafil (at 2 mg, 4 mg, 8 mg kg(-1), i.p.) administered immediately after training on first day produced a dose-dependent improvement of memory in mice. However, further studies need to be carried out to elucidate the underlying mechanism of sildenafil as a memory enhancer.

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Separation and determination of synthetic impurities of sildenafil (Viagra) by reversed-phase high-performance liquid chromatography.

Nagaraju V, Sreenath D, Rao JT, Rao RN.

Chemistry Section, A. P. State Forensic Science Laboratory, Red Hills, Hyderabad-500 004, India.

A simple and rapid high-performance liquid chromatographic method for the separation and determination of process-related impurities of sildenafil was developed. The separation was achieved on a reversed-phase C18 column using acetonitrile-0.05 M potassium dihydrogen orthophosphate (70:30 v/v) as a mobile solvent at a flow rate of 1.0 ml/min and UV detection at 230 nm. The method was used not only for quality assurance, but also for monitoring the chemical reactions during the synthesis of sildenafil. It was found to be specific, precise and reliable for the determination of all process-related impurities of sildenafil in bulk drugs and formulations.

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Preference for oral sildenafil or intracavernosal injection in patients with erectile dysfunction already using intracavernosal injection for > 1 year.

Kim SC, Chang IH, Jeon HJ.

Department of Urology, College of Medicine, Chung-Ang University, Seoul, Korea. saeckim unitel.co.kr

Authors from Seoul describe their experience with patients already on triple therapy by intracavernosal injection who changed to oral sildenafil. Rather surprisingly, they found that patients had had a greater preference than expected for triple therapy, feeling that they had a better quality of erection on intracavernosal injection. The subject of the effect of renal transplantation on sperm quality and sex hormone levels is discussed by authors from Teheran. They found that sperm morphology and density remained unchanged, but there were significant improvements in sperm mobility. There was also an improvement in hormone levels and sexual function. OBJECTIVE: To investigate the efficacy and preference for oral sildenafil or intracavernosal injection (ICI) therapy in patients with erectile dysfunction (ED) already using ICI. PATIENTS AND METHODS: In all, 69 patients with ED (mean age 55.1 years, sd 12.3) on ICI therapy with triple solution (papaverine/phentolamine/prostaglandin-E1) for > 1 year were recruited for the study. Their erection quality, adverse reactions and selection rate of oral sildenafil or ICI as treatment, after using sildenafil for 3 months, and the reasons for their preferences, were compared between the regimens, RESULTS: Overall, 52 men (75%) responded to sildenafil; of these men, the erection quality with ICI was better than that with sildenafil in 46 (89%) and 16 (31%) preferred ICI as their treatment. Eighteen patients (35%) used each treatment alternately and 18 (35%) used sildenafil exclusively. The main reason given by patients for choosing ICI was a better quality of erection (74%). CONCLUSION: More patients with ED and using ICI preferred it as their main treatment than was expected, even though they had a good response to oral sildenafil. A better quality of erection with ICI was the reason why experienced patients chose this method, differing from the choice of patients starting treatment for ED.

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Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone.

Kalinchenko SY, Kozlov GI, Gontcharov NP, Katsiya GV.

National Research Center for Endocrinology, Moscow, Russia.

AIMS: To evaluate the cause of failure of sildenafil citrate (Viagra) to restore erections in patients with organic erectile dysfunction (ED) associated with type II diabetes mellitus (DM) and receiving oral antidiabetic drugs. METHODS: Diabetic ED patients (n = 120), aged 43-74 years, failing to respond at least three times to 100 mg Viagra were evaluated. After at least 2 weeks' treatment with oral testosterone undecanoate (Andriol), 100 mg Viagra was used before coitus. ED was assessed with the International Index of Erectile Function (IIEF). Serum total testosterone, prolactin, thyroid stimulating hormone, lipid profile and prostate-specific antigen (PSA) were determined by standard methods and prostate volume by digital rectal examination. Age-matched diabetic ED patients (n = 100) served as controls for baseline values. RESULTS: Viagra non-responders had, at baseline, significantly lower testosterone and more depressed libido than controls. Andriol restored testosterone to normal levels and increased libido. In 84/120 (70%) Viagra non-responders, combined therapy with Andriol induced satisfactory erections, a significant increase in IIEF scale (question (Q) 3 from 2.0 +/- 0.2 to 3.7 +/- 0.3, Q4 from 1.9 +/- 0.1 to 3.4 +/- 0.2, Q12 from 1.0 +/- 0.1 to 4.2 +/- 0.4) and increased sexual contacts from 0.5 to 3-4 per month. No adverse events were noted, and PSA levels remained below 4 ng/ml. CONCLUSION: Decreased testosterone levels in patients with ED and type II DM receiving oral antidiabetic against may be responsible for failure to respond to sildenafil citrate therapy. Combination with oral testosterone undecanoate restores sexual function in these patients.

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Effects of sildenafil on myocardial infarct size, microvascular function, and acute ischemic left ventricular dilation.

Reffelmann T, Kloner RA.

The Heart Institute, Good Samaritan Hospital, University of Southern California, 1225 Wilshire Boulevard, Los Angeles, CA 90017-2395, USA.

OBJECTIVE: Adverse cardiac events in patients treated with the phosphodiesterase-5 inhibitor sildenafil for erectile dysfunction raised concerns about its safety in ischemic heart disease. METHODS: In anesthetized open-chest rabbits, receiving 1.45 mg/kg sildenafil intravenously or saline 30 min prior to ischemia (n=12, each), infarct size (IS, triphenyltetrazolium), the area of no-reflow (ANR, thioflavin S) (% of the risk area, RA, blue dye), and regional myocardial blood flow (RMBF, radioactive microspheres) were measured after 30 min of coronary occlusion and 180 min of reperfusion. Left ventricular hemodynamics and dimensions (echocardiography) were determined in a separate series of animals (n=5, each). RESULTS: Sildenafil significantly lowered arterial blood pressure before occlusion (-17 to -19 mmHg over 30 min), but during ischemia and reperfusion hemodynamics were comparable to controls. IS in treated animals (51+/-4%) did not significantly differ from control animals (47+/-4%). No major arrhythmias or lengthening of QT/QTc occurred. While sildenafil slightly increased RMBF and significantly reduced specific vascular resistance in the RA during reperfusion (51+/-7 versus 73+/-10 mmHg g min/ml, P<0.05), the ANR (46+/-3%) was similar to control animals (44+/-4%). Sildenafil reduced left ventricular dP/dt(max) (P<0.05) and dP/dt(min) (P<0.01) in non-ischemic conditions, and slightly during ischemia, along with a pronounced decrease in ischemic left ventricular end-diastolic pressure (9+/-2 versus 15+/-2 mmHg after saline, P<0.05), but did not attenuate acute ischemic left ventricular dilation. CONCLUSIONS: Sildenafil reduced cardiac pre- and afterload, and parameters of left ventricular contractility. Myocardial necrosis and microvascular dysfunction were neither exacerbated nor attenuated.

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Effect of sildenafil citrate on an orthotopic prostate cancer growth and metastasis model.

Qian CN, Takahashi M, Kahnoski RJ, Teh BT.

Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI, USA.

PURPOSE: We characterized the effects of sildenafil citrate on the growth and metastasis of human prostate cancer cells in nude mice. MATERIALS AND METHODS: The androgen independent human prostate cancer cell line PC-3 was inoculated into the prostate of nude mice to produce orthotopic primary prostate cancers and metastases. Sildenafil citrate gavage was started on day 31 after tumor cell inoculation and given every other day 15 times (30 days). The 7 mice in the low dose group received 25 mg/kg body weight sildenafil citrate per gavage, while the 7 in the high dose group received 50 mg/kg body weight sildenafil citrate and the 9 in the control group received water. Autopsy was performed on day 75 to evaluate primary tumor growth and metastasis. Plasma cyclic guanosine monophosphate concentrations were measured after the single dose of 50 mg/kg sildenafil citrate in the mice. RESULTS: Plasma cyclic guanosine monophosphate concentration increased 4-fold 1 hour after sildenafil citrate administration. The plasma concentration decreased rapidly and returned to normal after 8 hours. There was no significant difference in tumor weight between any of the 3 groups. The number of metastatic lymph nodes correlated significantly with primary tumor weight (p = 0.03) with a correlation coefficient of 0.454 but there was no significant correlation between the number of involved lymph nodes and sildenafil administration. Distant metastases were not significantly promoted by sildenafil administration. CONCLUSIONS: Incontinuous oral administration of sildenafil citrate did not promote primary tumor growth and metastasis in an orthotopic prostate cancer model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12913757&dopt=Abstract sildenafil Viagra online