Sildenafil causes a dose- and time-dependent downregulation of phosphodiesterase type 6 expression in the rat retina.

Gonzalez CM, Bervig T, Podlasek C, Huang CF, McKenna KE, McVary KT.

Department of Urology, Northwestern University Medical School, Chicago, Illinois 60611, USA.

OBJECTIVES: Some authors have advocated the daily use of sildenafil for prophylaxis against, or treatment of, erectile dysfunction. However, no information has been published to support such a dosage regimen. The safety profile of uninterrupted use of sildenafil has not been evaluated as it pertains to alteration of PDE type 6 in the retina. In the present study we investigated whether short- or long-term exposure to a variety of sildenafil doses affect the expression of an enzyme important in the normal phototransduction cascade. METHODS: Sustained-release sildenafil pellets were implanted in 120-day-old male rats with concentrations from 1-200mg. Rat retinal tissue was harvested 7, 14, and 29 days after implantation. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) using GAPDH as an endogenous internal standard was used to quantitate PDE type 6 gene expression. RESULTS: Expression of PDE type 6 was upregulated after 7 days with dosages < or =5 mg (P<0.02). Significant downregulation of PDE type 6 expression was first noted with high dose sildenafil 14 days after implantation (P<0.02). Expression of PDE type 6 was significantly and profoundly downregulated 29 days after implantation for all pellet formulations > or =10 mg (P<0.01). CONCLUSIONS: Sildenafil downregulates PDE type 6 expression in a dose- and time-dependent fashion. These findings support the explanation that PDE type 6 inhibition causes the dose-dependent clinical effects of visual disturbance in men taking sildenafil. Implications for long-term, daily use of sildenafil in men are not clear.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10554924&dopt=Abstract sildenafil Viagra online



Time dependent patient satisfaction with sildenafil for erectile dysfunction (ED) after nerve-sparing radical retropubic prostatectomy (RRP).

Hong EK, Lepor H, McCullough AR.

Department of Urology, New York University School of Medicine, NY 10016, USA.

PURPOSE: The response to sildenafil after radical retropubic prostatectomy (RRP) has been reported to be approximately 40% by the Sildenafil Study Group. We undertook a study in a large cohort of post-RRP erectile dysfunction (ED) patients in order to examine the relationship between satisfaction with sildenafil and time from surgery to start of sildenafil treatment. METHODS: Pre- and post-operative erectile function was assessed by the O'Leary Brief Sexual Function Inventory questionnaire. Patient satisfaction with sildenafil before and after sildenafil treatment was assessed by the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire. Between April and October 1998, EDITS questionnaires were given to 579 patients who had undergone RRP between 1994 and 1998. 316 (55%) patients returned questionnaires. Of these, 198 (63%) had sildenafil treatment and completed post-treatment questionnaires and were included in the study group. RESULTS: In the study group, mean age was 61y. Pre-operatively, 92% had erections sufficient for vaginal penetration, 95% had bilateral nerve-sparing (NS) RRP. There was a significant increase in the treatment satisfaction rate with increasing time from surgery. Between zero and six months after surgery, the treatment satisfaction rate was 26%, which improved with time, peaking at 60% between 18 months and 2y. Self-perceived erectile function as determined by post-RRP pre-sildenafil treatment O'Leary questionnaires was not as predictive of response to sildenafil as time from surgery. CONCLUSIONS: The response to sildenafil appears to be dependent upon the interval between RRP and the start of sildenafil. The treatment satisfaction rate was found to peak at 60% between 18 months and 2y. Early nonresponders to sildenafil should not be disheartened, as they will more likely later respond.

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[Sildenafil, the heart patient and the cardiologist]

[Article in French]

Danchin N.

Service de cardiologie, CHU Nancy-Brabois, Vandoeuvre-les-Nancy.

Sildenafil (Viagra), an inhibitor of phosphodiesterase 5, has a powerful vasodilatory effect on the corpus cavernosa. An evaluation of coronary risk is necessary before its prescription in order to answer two questions: does taking this drug expose the patient to any special risk? Does the return to sexual activity itself carry any risk? Sildenafil is associated with a slight decrease in systolic (10 mmHg) and diastolic (7 mmHg) blood pressure which does not seem to be accentuated by the concommittant use of antihypertensive drugs. The co-administration of nitrate derivatives (before or after taking sildenafil) causes potentially dangerous falls in blood pressure (on average 40 mmHg for the systolic blood pressure). Co-administration of sildenafil and NO-donors is formally contra-indicated. The safety of sildenafil has been shown to be satisfactory in clinical trials: in particular, the risk of myocardial infarction is no greater in treated patients. Sexual activity is a generally moderately intense physical exercise and only rarely causes myocardial infarction. In practice, in patients without known coronary artery disease, the clinical history should be sufficient to determine whether the return of sexual relations is possible without risk. In known cardiac patients, sildenafil is contra-indicated in unstable situations; in stable coronary disease, it would seem wise to take advantage of the annual exercise stress testing to make sure of the absence of ischaemia on effort. In all cases, the patient must be warned that co-administration of nitrate derivatives is an absolure contra-indication to sildenafil treatment.

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Impact of erectile dysfunction and its subsequent treatment with sildenafil: qualitative study.

Tomlinson J, Wright D.

Men's Health Clinic, Royal Hampshire County Hospital, Winchester SO22 5DG. john jptomlinson.comClays

OBJECTIVES: To determine the effects of erectile dysfunction and to explore the impact of treatment with sildenafil (Viagra). DESIGN: An exploratory qualitative study with semistructured interviews. SETTING: Men's health clinic in NHS hospital. PARTICIPANTS: 40 men who had had erectile dysfunction and had attended the clinic during the year before interview. MAIN OUTCOME MEASURES: Impact of erectile dysfunction on men, their expectations of sildenafil, and impact of treatment on men and their relationships. Issues explored with exploratory qualitative approach. RESULTS: Erectile dysfunction caused serious distress to all those men who experienced it, with marked effects on their self esteem and their relationships. Sildenafil, when it worked, caused a great improvement in wellbeing. The expectations raised by media hyperbole with the launch of sildenafil had an adverse effect on the morale of those who found it did not work. When, according to the patient, treatment did not work, the distress was severe and for many confirmed their lack of self worth. CONCLUSIONS: Further study is needed to explore the feelings of men affected by erectile dysfunction and their perception of treatment. Health professionals should be aware of the extreme distress erectile dysfunction can cause.

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Sildenafil citrate (Viagra).

MacConnachie AM.

Sildenafil is the first of a series of orally active treatments for MED which has resulted in unprecedented demand for treatment and potentially high cost to the NHS. Further oral therapies are likely to follow in the next year or so. In clinical trials, sildenafil produced an erection (sufficient to achieve intercourse) lasting up to 4 h on around 70% of occasions. This was reduced to 50% in 'high-risk' groups (e.g. diabetics) and a placebo response in as many as 10-20% has been reported. Whether or not sildenafil should be prescribed at NHS expense has been more a matter for political, than clinical, debate. A clearer picture is now emerging with treatment available to those considered the 'most deserving' cases. The bigger picture is of impotence in large numbers of men with hypertension who are on antihypertensive therapy and have obvious small vessel disease. One option is to consign sildenafil to Schedule 10 (Black List) so that it is only available on private prescription. This would allay fears of the cost of treatment for those merely seeking to 'boost' already adequate sexual performance.

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Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue.

Stief CG, Uckert S, Becker AJ, Harringer W, Truss MC, Forssmann WG, Jonas U.

Department of Urology, Hannover Medical School, Germany.

OBJECTIVES: To further investigate the mechanism of action of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5), that has been proved to be effective in the treatment of male erectile dysfunction. We assessed the effects of sildenafil on the in vitro formation of cGMP and cyclic adenosine monophosphate (cAMP) in isolated human corpus cavernosum and cardiac muscle. METHODS: Isolated segments of human corpus cavernosum and cardiac muscle were exposed to increasing concentrations of sildenafil. The dose-dependent accumulation of cGMP and cAMP was determined in the tissue samples by means of radioimmunoassays. Responses of the isolated tissue preparations to sildenafil were compared with those obtained with the reference compounds sodium nitroprusside, forskolin, and milrinone. RESULTS: In the concentration range 0.01 to 1 microM, there was only a minor effect of sildenafil on cGMP levels in isolated human cavernous and cardiac tissues. In contrast, sildenafil was found to increase cAMP significantly in both cavernous and cardiac tissue in physiologic and supraphysiologic concentrations. The stimulation of cAMP by sildenafil was more pronounced in cavernous than in cardiac tissue. Concentrations of cGMP in the cardiac strips were unaltered by milrinone; cAMP was stimulated starting at a concentration of 0.05 microM. In the range of 0.1 to 1.0 microM, the in vitro effect of sildenafil on cAMP levels in the cardiac samples was almost equivalent to that of milrinone. CONCLUSIONS: Our findings provide a potential mechanism for the cardiovascular side effects that have been reported with sildenafil use, highlighting the fact that a "cross-talk" between cGMP and cAMP-dependent signal transduction pathways might exist in human cavernous and cardiac muscle that may be of pharmacologic significance.

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Viagra and Cardiovascular Disease.

Speakman MT, Kloner RA.

Department of Cardiology, Southern California Permanente Medical Group, Baldwin Park, California, USA

BACKGROUND: The introduction of the drug sildenafil (Viagra; Pfizer, New York, NY) into the armamentarium for treatment of erectile dysfunction is a major advance. Many of the patients who will benefit from its use have cardiovascular disease. Erectile dysfunction and cardiovascular disease share common risk factors. Although the metabolic demands of sexual activity are modest and the associated risk for coronary events is low, the clinician caring for cardiac patients needs to be aware of the pharmacology and hemodynamic profile of sildenafil in those with heart disease who use cardioactive drugs. METHODS AND RESULTS: We reviewed the current literature relating to the pharmacology, hemodynamic profile, efficacy, safety, and clinical application of sildenafil in patients with cardiovascular disease. Sildenafil is highly effective in the treatment of erectile dysfunction. The overall incidence of cardiovascular adverse events is low and similar to placebo. Current postmarketing data do not suggest an increase in cardiovascular death in sildenafil users. The drug is contraindicated in those taking organic nitrates. It should be used with caution and on an individual basis in patients who have active coronary ischemia and heart failure with tenous blood pressure and volume status. CONCLUSIONS: When used with discretion, sildenafil is safe, effective, and has the potential to greatly enhance quality of life in the relatively large proportion of the population with heart disease.

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Role of Viagra after radical prostatectomy.

Zippe CD, Jhaveri FM, Klein EA, Kedia S, Pasqualotto FF, Kedia A, Agarwal A, Montague DK, Lakin MM.

Department of Urology, Cleveland Clinic Foundation, Ohio 44195, USA.

OBJECTIVES: To determine whether the response to sildenafil citrate (Viagra) in patients with erectile dysfunction after radical prostatectomy was influenced by the presence or absence of neurovascular bundles, the interval from surgery to the initiation of drug therapy, and the dose of the drug. METHODS: Baseline and follow-up data from 91 patients presenting with erectile dysfunction after radical prostatectomy were obtained. The patients were stratified according to the type of nerve-sparing (NS) procedure: bilateral NS, unilateral NS, and non-NS. They were interviewed using the Cleveland Clinic Post Prostatectomy (CCPP) questionnaire and the International Index of Erectile Function (IIEF) questionnaire. RESULTS: The presence or absence of the neurovascular bundles influenced the ability to achieve vaginal intercourse. In the patients who had undergone bilateral NS, 71.7% (38 of 53) responded; in those with unilateral NS, 50% (6 of 12) responded; and in those with non-NS, 15.4% (4 of 26) responded. The IIEF questionnaire confirmed the quality of the positive responses, with significant improvements in response to question 3 (frequency of penetration), question 4 (frequency of maintenance of erection), and question 7 (satisfaction with intercourse). The magnitude of improvement in responses was higher in the bilateral NS group than in the unilateral NS and non-NS groups (P <0.05). When the data of the 48 positive responders were analyzed, no difference in the response rate was found when the interval from surgery to drug therapy was stratified by the following three intervals: 0 to 6 months (44%), 6 to 12 months (55%), and greater than 12 months (53%). Of the positive responders, 14 (29.1%) required the 50-mg dose, and 34 (70.9%) required the 100-mg dose. The most common side effects were transient headaches (28.6%), flushing (21.9%), dizziness (8.8%), dyspepsia (6.5%), and nasal congestion (5.4%), with an increase in the incidence of headaches seen at the higher dose (P = 0.04). CONCLUSIONS: Successful treatment of erectile dysfunction with sildenafil citrate after radical prostatectomy depends on the presence of the neurovascular bundles. Our data suggest that the response to sildenafil is not related to the interval between the surgery and initiation of drug therapy but is related to the dose.

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