Demand, appropriateness and prescribing of 'lifestyle drugs': a consultation survey in general practice.

Ashworth M, Clement S, Wright M.

GKT Department of General Practice and Primary Care, Kings College London, 5 Lambeth Walk, London SE11 6SP, UK.

BACKGROUND: The simultaneous launch of orlistat and sildenafil in 1998 provoked much media attention, particularly around the role of lifestyle drugs and their potential costs if controls were not established. Fears were also expressed that primary care would be overwhelmed by demand, and little information was available about the attitude of GPs to their new role as prescribers of lifestlye drugs. Partly in response to these concerns, tight prescribing guidelines and licensed indications, for sildenafil and orlistat, respectively, were issued. OBJECTIVE: Our aim was to describe levels of demand for orlistat and sildenafil in general practice, whether this demand was translated into a prescription, adherence to prescribing guidelines/licensed indications and the GP perception of appropriateness of an NHS prescription for either of these drugs. METHOD: We carried out an observational study in primary care conducted over a 6-week period during 1999. Twenty-seven GPs were recruited, each from a different practice. All GP consultations were recorded for the study period and the GP completed a structured questionnaire each time sildenafil or orlistat were discussed in a consultation. RESULTS: Sildenafil was discussed in 0.5% (68/13 394) of consultations and orlistat in 0.3% (42/13 394). GPs thought that a corresponding NHS prescription would be highly appropriate in 57 and 74% of cases, respectively, although for both lifestyle drugs, nearly 20% of GPs thought such prescriptions were inappropriate. An NHS prescription was issued in 43% of consultations in which sildenafil had been discussed and 33% in which orlistat had been discussed. Five out of 29 NHS sildenafil prescriptions were issued to patients failing to fulfil the requirements of prescribing guidelines; similarly, one out of 14 orlistat prescriptions fell outside licensed indications. There were four examples of NHS prescriptions for sildenafil which were given even when the GP thought the drug to be inappropriate, whereas orlistat was never given when the GP thought it inappropriate. CONCLUSIONS: Levels of demand for the two lifestyle drugs, sildenafil and orlistat, were modest when compared with earlier media predictions. Neither was there evidence that GP was pitted against patient in their negotiation concerning a lifestyle drug NHS prescription since most GPs agreed with their patients that such a prescription was appropriate. Prescribing guidelines and licensed indications were generally adhered to, but the modest level of demand raises questions about expanding the guidelines for sildenafil.

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Sildenafil in the cardiologist's office: patients' attitudes and physicians' practices toward discussions about sexual functioning.

Bedell SE, Graboys TB, Duperval M, Goldberg R.

Lown Cardiovascular Center and Harvard Medical School, Brookline, MA 02446, USA.

Sildenafil is a medication increasingly prescribed to improve sexual function in patients who have erectile dysfunction. Because a major contraindication to the use of sildenafil is a history of coronary disease and the concomitant use of nitrates, it becomes increasingly important for cardiologists to prescribe this medication. We evaluated the nature of discussions in all 70 patients for whom sildenafil was prescribed in a cardiology practice between April and July 1998. We used a standardized questionnaire to determine the patients' perspective on the sexual history and the extent to which they wanted their physicians to take a detailed history about sexuality. A separate chart review evaluated the nature of physicians' discussions about sexual functioning before sildenafil was prescribed. Fifty-five of the 70 patients (79%) responded to the survey. The majority of patients (98%) felt that physicians should talk with patients about sexual functioning. However, only 73% of patients believed their doctor was comfortable talking with them about this subject. Sixty percent of patients reported that their doctor had ever talked with them about erectile function and only 15% had ever had a discussion with their doctors about specific difficulties during intercourse. Based on the results of the chart review, only 24% of the patients ever specifically discussed the used of sildenafil with their physician prior to the time that it was prescribed. The results of the study suggest that patients with coronary disease erectile dysfunction are comfortable talking with their physicians about sexual functioning, but these conversations occur infrequently. Copyright 2002 S. Karger AG, Basel

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Management of erectile dysfunction by combination therapy with testosterone and sildenafil in recipients of high-dose therapy for haematological malignancies.

Chatterjee R, Kottaridis PD, McGarrigle HH, Linch DC.

Department of Obstetrics and Gynaecology, University College London Hospital, London, UK.

Erectile dysfunction (ED) is a well recognised complication of bone marrow transplantation, which affects quality of life in adult patients. Although the major contributory factors include hypogonadism and psychogenic factors, the best treatment still remains to be established due to the complex aetiopathology of the condition. Here, we report our preliminary results in eight patients treated with testosterone replacement therapy and sildenafil. We studied eight male recipients of BMT aged 22-58 years, presenting with clinical features of hypogonadism, ED, diminished libido and ejaculatory disorders. ED was assessed clinically and by colour flow Doppler studies of the cavernosal vessels. Testicular function was assessed by testicular volume, FSH, LH and testosterone (T) measurements. Erectile performance, libido and ejaculatory function were determined by a structured interview. Patients had severe primary hypogonadism as evidenced by low mean testicular volume, elevated gonadotrophins and low normal mean testosterone levels compared with controls. All had Leydig cell insufficiency (LCI) with or without frank serum testosterone insufficiency. All except one had cavernosal arterial insufficiency. All patients received intramuscular injections of testosterone cypionate (250 mg 4 weekly) for 6 months and 50-100 mg of sildenafil orally, one to two times per week. All patients responded favourably as substantiated from the NIH consensus criteria. Our preliminary results suggest that this combined therapy is a safe and effective therapeutic approach in recipients of high-dose therapy presenting with ED after transplant.

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Effects of sildenafil citrate (viagra) on blood pressure in normotensive and hypertensive men.

Vardi Y, Klein L, Nassar S, Sprecher E, Gruenwald I.

Neuro-Urology Unit, Rambam Medical Center, Haifa, Israel.

OBJECTIVES: To determine the occurrence of clinically significant decreases in blood pressure (BP) with sildenafil use in normotensive and hypertensive men by means of ambulatory BP monitoring. METHODS: On 2 nights, 49 men (22 hypertensive, 27 normotensive) had their ambulatory systolic BP (SBP), diastolic BP (DBP), and heart rate monitored during the first 3 hours (waking period) and every 30 minutes after midnight for 3 additional hours (sleeping period). No medication was taken on one night; sildenafil 100 mg was taken on the other. RESULTS: Sildenafil decreased SBP (-6.0 mm Hg; P = 0.0003), DBP (-4.5 mm Hg; P = 0.001), and mean arterial pressure (-5.3 mm Hg; P = 0.00008). The BP-lowering effects of sildenafil did not differ significantly in the normotensive and hypertensive men. Age significantly affected the BP reductions; decreases in SBP, DBP, and mean arterial pressure were greater in men 49 years old and older than in those younger than 49 years old. According to readings averaged over the entire control and treatment periods, 22.7% of hypertensive men and 3.7% of normotensive men experienced SBP reductions of 20 mm Hg or greater (P = 0.08 for comparison of the two groups); the respective values for DBP were 9.1% and 3.7% (P not significant). These reductions were not associated with any hypotensive symptoms. All participants tolerated sildenafil well. CONCLUSIONS: Sildenafil caused small, clinically insignificant reductions in ambulatory BP in active and resting normotensive and hypertensive men. The results of this study suggest that, when used in accordance with the prescribing information and current treatment guidelines, sildenafil should be safe in younger and older men with or without hypertension.

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Community-based study of erectile dysfunction and sildenafil use: the Rancho Bernardo study.

Monga M, Bettencourt R, Barrett-Connor E.

Division of Urology, Department of Surgery, University of California, San Diego, School of Medicine, La Jolla, California 92093-0607, USA.

OBJECTIVES: To evaluate erectile dysfunction (ED) using a validated self-administered 5-item questionnaire (5-item version of the International Index of Erectile Function [IIEF-5]) and the use of sildenafil in community-dwelling older men. METHODS: In October 1998, the IIEF-5 was mailed to all surviving members of an established community-based cohort of older men. The degree of ED was stratified by the erectile function domain score as complete (4 or less), severe (5 to 10), moderate (11 to 14), mild (15 to 18), or none (19 to 20). Men were also asked about sildenafil use and its effectiveness. RESULTS: A total of 976 men (64%) responded to the questionnaire. The internal consistency of the questionnaire construct was confirmed, with a Cronbach's alpha coefficient of 0.96 for all 5 questions. Eighty-nine percent of men younger than 50 years were sexually active compared with 37% of men older than age 80. Twenty-six percent of sexually active men reported complete (3%), severe (10.5%), or moderate (12.6%) ED. The prevalence of moderate or complete ED increased with age and was reported by 58% of men aged 75 to 79 years. Eleven percent of sexually active men had used sildenafil one or more times, with 63% reporting good or "terrific" effects and 11% reporting no benefit. The response to sildenafil deteriorated with age and increasing degree of ED. CONCLUSIONS: The results of this community-based study confirm the strong correlation between advancing age and the prevalence and degree of ED, with 33% of men aged 75 and older reporting at least moderate ED. Nevertheless, more than 33% of men older than 75 years remained sexually active. Of the 660 sexually active men, 81% reported satisfaction with sexual intercourse; only 11% had tried sildenafil.

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Efficacy of vardenafil and sildenafil in facilitating penile erection in an animal model.

Choi S, O'Connell L, Min K, Kim NN, Munarriz R, Goldstein I, Bischoff E, Traish AM.

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

Vardenafil and sildenafil are potent and specific phosphodiesterase type 5 (PDE 5) inhibitors. In human penile cavernosal smooth muscle cells, we have previously shown that vardenafil has a lower biochemical inhibition constant (Ki) than sildenafil. In this study, we compared the efficacy of vardenafil and sildenafil in facilitating penile erection in a rabbit model. Penile erections were elicited by submaximal (2.5 or 6 Hz) pelvic nerve stimulation (PNS) repeated every 5 minutes for 30 minutes with or without intravenous (i.v.) administration of vardenafil (1-30 microg/kg) or sildenafil (10-30 microg/kg). Erectile response was assessed by continuously recording intracavernosal pressure (ICP) and systemic arterial pressure (SAP). All data were expressed as a ratio of ICP:SAP. I.v. administration of either PDE 5 inhibitor facilitated PNS-induced erection and increased ICP:SAP in a dose-dependent manner, reaching peak response at approximately 5 minutes. However, the threshold dose at which facilitation of erection occurred was lower for vardenafil (3 microg/kg) than for sildenafil (10 microg/kg). At the 10-microg/kg dose (i.v.), the response duration was significantly greater with vardenafil (169 +/- 23 seconds) than with sildenafil (137 +/- 31 seconds). Direct intracavernosal (i.c.) injection of 1-30 microg/kg vardenafil or sildenafil also caused dose-dependent increases in ICP:SAP in the absence of PNS. Response durations increased in a dose-dependent manner and lasted more than 5 times that of i.v. drug administration coupled with PNS. Irrespective of the route of administration (i.c. or i.v.), at equivalent doses, vardenafil was significantly more efficacious than sildenafil in facilitating pelvic nerve-mediated penile erection and in eliciting erection in the absence of PNS. The increases in ICPs occurred more quickly, were of larger magnitude, and were sustained for longer durations for vardenafil than for sildenafil. On the basis of the biochemical data and physiological responses from this study, further clinical evaluation of vardenafil as treatment for erectile dysfunction is warranted.

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Oral sildenafil (Viagra) in male erectile dysfunction: use, efficacy and safety profile in an unselected cohort presenting to a British district general hospital.

Sairam K, Kulinskaya E, Hanbury D, Boustead G, McNicholas T.

Department of Urology, Lister Hospital Coreys Mill Lane, Stevenage SG1 4AB, UK. ksairam baus.org.uk

INTRODUCTION: Sildenafil (Viagra) is one of the drugs used in the first line therapy of male erectile dysfunction (MED). We have recorded outcomes, adverse events and acceptability of Sildenafil (Viagra) therapy in an unselected group of men presenting with ED to a British district general hospital. METHODS: In this prospective observational study, 147 men with ED were seen since Oct 1999. Study patients were reviewed at 4, 12 and 52 weeks. All the patients filled the International Index of Erectile Function (IIEF) questionnaire and were asked about their willingness to pay (WTP) for treatment. RESULTS: All suitable men accepted Viagra as first line therapy. 91% of our patients found sildenafil treatment successful. 80% of these patients were willing to continue with sildenafil therapy. Side effect profile of sildenafil was different in this study with much higher incidence of headache, dyspepsia, flushing and abnormal vision. 92% of men with ED expect to be treated by the NHS. Of those men eligible for treatment in the NHS, 30% qualify under the clinical categories and 18% under the 'distress' category. Only 55% of those with cardiovascular risk factors qualify for NHS treatment. CONCLUSIONS: Sildenafil is widely accepted as first line therapy among British men with ED and has a success rate of 91%. Nearly half of men with ED qualify for NHS treatment. Nearly half of those with vascular risk factors do not qualify for NHS treatment. Most men with ED could possibly be managed in primary care.

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In vitro biotransformation of sildenafil (Viagra) in the male rat: the role of CYP2C11.

Warrington JS, Von Moltke LL, Shader RI, Greenblatt DJ.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts-New England Medical Center, Boston, MA 02111, USA.

To assess the suitability of the male rat model for human studies on sildenafil metabolism, we examined the biotransformation of sildenafil in male rat liver microsomes and identified the role of specific cytochrome P450s (P450) using inhibitory antibodies and cDNA-expressed P450s. Rates of formation of the major circulating metabolite of sildenafil, UK-103,320, were 11-fold greater in the male rat than in human liver microsomes at 36 microM sildenafil, whereas substrate concentration corresponding to 50% V(max) (K(m) values) were 2.9-fold lower in the male rat. Although sildenafil is largely metabolized by CYP3A isoforms in humans, coincubation of rat liver microsomes with immunoinhibitory antibodies (CYP1A1/2, 2B1/2, 2C11, 2E1, and 3A1/2) revealed that metabolite formation was inhibited only by an antirat CYP2C11 antibody. Incubation of sildenafil with a cDNA-expressed CYP2C11 produced 10-fold higher levels of UK-103,320 than other P450s (CYP1A1, 1A2, 2B1, 2C6, 2C12, 2C13, 2E1, 3A1, and 3A2). Thus CYP2C11 contributes in a major way to the metabolism of sildenafil in the male rat. P450 isoforms mediating sildenafil biotransformation differ substantially between humans and the male rat, thereby limiting the applicability of this species as a model for sildenafil metabolism and drug interactions in humans.

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