Clinical efficacy and safety of sildenafil citrate (Viagra) in a multi-racial population in Singapore: A retrospective study of 1520 patients

Transcription

1 Blackwell Science, LtdOxford, UK IJU International Journal of Urology Blackwell Science Asia Pty Ltd 96March Efficacy of Viagra in Singaporean male patients PHC Lim et al /j x Original Article308315BEES SGML International Journal of Urology (2002) 9, Original Article Clinical efficacy and safety of sildenafil citrate (Viagra) in a multi-racial population in Singapore: A retrospective study of 1520 patients PETER HUAT CHYE LIM, 1 MAN KAY LI, 2 FOO CHEONG NG, 1 SING JOO CHIA, 3 DAVID CONSIGLIERE, 3 LOUIS GOOREN, 4 KOK KIT NG, 1 MALATHY MUNISAMY 1 AND MOORTHY PERIANAN 1 1 Department of Urology, Changi General Hospital, 2 Urology Center, National University Hospital, 3 Section of Urology, Tan Tock Seng Hospital, Singapore and 4 Free University Medical Hospital, Amsterdam, The Netherlands Abstract Key words Background: Sildenafil citrate (Viagra), a selective inhibitor of cgmp-specific phosphodiesterase type-5, has been used as an oral therapeutic drug for erectile dysfunction. The present paper is a clinical study of the success rate and side-effects of the use of sildenafil in a multi-racial population in Singapore. Methods: From April 1999 to May 2000, 1520 patients were given sildenafil citrate. Of these, 912 patients (mean age, 54.6 years; age range, years) were followed up and evaluated for clinical efficacy and safety of the drug. The mean duration of erectile dysfunction (ED) and follow-up periods were 31.5 and 3.0 months, respectively. Results: Satisfactory erections assessed by single global efficacy question (GEQ) occurred in 83% of patients, major side-effects in the form of flushing (3.48%), headache (1.97%), blurred vision (1.25%), giddiness (1.18%), warmth (1.11%) and others (4.92%) were recorded in 127 patients (13.9%). Racially, Chinese men with ED had higher efficacy (85.7%), compared to Indian men (74.2%) and Malay men (72.8%). With respect to comorbid profiles, an efficacy of 77.8% (n = 271), 83.9% (n = 292), 86.4% (n = 44) and 83.3% (n = 199) was recorded in diabetic, hypertensive, ischemic heart disease patients and in benign prostatic hyperplasia patients, respectively. Patients who smoked (n = 135) and drank alcohol (n = 118) showed an efficacy of 80%. Baseline hormonal profiles of luteinizing hormone, follicle stimulating hormone, testosterone and prolactin did not affect the success rates of sildenafil citrate. Many patients had earlier received other forms of treatment (medicated urethral suppository for erection (MUSE; 84.9%); vacuum devices (86.8%), traditional medicines (100%) and other oral medications (89.2%)), but this did not influence the success rate of sildenafil citrate. But patients previously treated with prostaglandin-e intracavernosal injections were less successful on sildenafil citrate (77.3%). In the total cohort, 50 mg sildenafil citrate was an effective dose in 49% of patients and 46.5% patients needed 100 mg sildenafil citrate, while 4.1% of the total cohort needed only 25mg sildenafil citrate. Conclusion: Oral sildenafil citrate has been shown to be an effective, safe and well tolerated drug in Singaporean men with ED, as in men from other parts of the world. diabetes mellitus, erectile dysfunction, hypertension, ischemic heart disease, Viagra. Introduction Correspondence: Professor Peter HC Lim, Chief, Department of Urology, Changi General Hospital, 2 Simei Street 3, Singapore tphphcl@pacific.net.sg Received 16 May 2001; accepted 27 August Erectile dysfunction (ED) troubles many aging men. Almost all studies of healthy men and men with a disease show that age is a very important factor in its

2 Efficacy of Viagra in Singaporean male patients 309 occurrence. The prevalence of ED rises strongly after age A recent study from the USA (Massachusetts Male Aging Study) assessed the incidence of ED in men aged between 40 and 69 years. 2 The risk of ED in this cohort of men was 26 cases per 1000 men annually. The annual incidence rate increased with each decade: from 12.4 cases per 1000-years in men between 40 and 50 years to 46.4 cases in men between 60 and 69 years. In confirmation of other studies, age, diabetes mellitus (DM), heart disease and hypertension emerged as major risk factors for ED. 2 In Singapore, ED is proclaimed to influence the quality of life in a large number of men. 3 Worldwide, only 5 10% of men with these problems choose to undergo treatment even though major advancements in treatment have been made over the last decade, with presently a wide range of treatment options available. Sildenafil citrate is a selective phosphodiesterase-5 inhibitor and it has been shown to be highly efficacious in men with ED originating from a wide variety of etiologies. 4 6 In these studies, side-effects were noted by 25 33% of patients, mostly flushing, headache, dizziness, nasal congestion and heartburn. Drop out of treatment (because of intolerability of side-effects) varies between 0 6 and 6.1%. 5 Several studies have assessed the use and safety of sildenafil citrate in men with a diagnosis of diabetes, cardiovascular disease and hypertension and its efficacy has been reported. 7 9 However, data of this kind in similarly large groups of Asian men with ED are rare. This report presents our findings in a large cohort of patients (n = 1520) in Singapore who sought medical help for erectile difficulties. The present report provides a quantitative description of the diagnostic categories among the 1520 men seeking help, and whether the disease category and other characteristics were factors in the decision to accept treatment with sildenafil citrate and how successful the treatment was. The question of whether the use of sildenafil citrate impacted on the disease will be addressed. Quality of life is an important consideration for those men seeking help for ED, and this aspect was also analysed. Singapore is a multi-racial society and the present report also assessed whether ethnic background played a role in the abovementioned issues. These three hospitals serve the full range of patients coming from the three predominant racial groups of Singapore (Chinese, Malay and Indian). Of these 1520 men, 912 patients were able to be followed up. The remaining patients failed to present for their further appointment, and were unreachable by telephone and for various other reasons. Among the non-followed-up patients or those who failed to return to the clinic, Malaysian men constituted the highest percentage (47.4%), followed by Indian men (45%) and Chinese men (39%). However, these differences were not statistically significant. Thus, the data on the clinical efficacy of sildenafil citrate refer to only 912 patients. The mean age of the ED patients was 54.6 ± 10.6 years, with an age range of years. The mean duration of the ED was 31.5 ± 41.9 months. Nearly half of the cohort (52.2%) had ED for a minimum period of 1 year. Racially, the group of 912 patients who were followed up while using sildenafil citrate consisted of Chinese men (81%), Indian men (7.2%), Malay men (6.5%) and other (4.4%) (Fig. 1). With regard to the population trend of Singapore, the Chinese (71% of total) were overrepresented and the Malay (18% of total) were underrepresented. Based on the history and clinical examination, the prevalence of ED has been estimated to be 85.7%, 72.8%, 74.7% and 80%, respectively, in Chinese, Malay, Indian men and others. Among the various etiological factors of ED, evidence of vasculogenic, neurogenic and psychogenic causes were found in 29.3, 25.3 and 41.2%, respectively. The diagnosis of ED was essentially based on medical history. In every patient, physical examination, laboratory testing (including Efficacy (%) Methods Between April 1999 and May 2000, of those patients presenting with erectile difficulties, a total of 1520 patients were deemed to be eligible for treatment with sildenafil citrate. These patients had been examined in three hospitals located in different parts of Singapore. Chinese Malay Indian Others Fig. 1 Efficacy of sildenafil citrate in patients from different races (groups labelled with the same letters are not statistically significant).

3 310 PHC Lim et al. hormonal profiles) and selectively other procedures such as intracavernosal prostaglandin-e (PGE) injections were performed. However, these tests were done only in 17% of the total cohort and in other cases the causes were established based on medical history. With respect to the comorbidity profile, hypertension (32%) was the major associated disorder, followed by DM (29.7%) and ischemic heart disease (IHD; 4.8%). Besides these, benign prostatic hyperplasia (BPH) was diagnosed in 21.8% of patients. The comorbid profiles were obtained from direct interview with the patients as well as by documented medical history. Lifestyle factors such as alcoholism and smoking were noticed in a significant proportion of the patients: 12.9 and 14.8%, respectively (Table 1). The mean duration of the use of sildenafil citrate in these patients was 3.96 ± 3.53 months. The clinical outcome of the drug was assessed subjectively in terms of improved erection and sexual satisfaction based on a single global efficacy question (GEQ). Results were analysed using standard statistical package (SPSS, version 10.0), including descriptive statistics and Pearson chi-squared tests. Results The efficacy of sildenafil citrate in different racial groups is shown in Fig. 1. The highest efficacy was noted in Chinese men (86%), followed by the other Table 1 Demographic and comorbid characteristics and other medical conditions of Singaporean men on sildenafil citrate for ED Characteristics % patients (n = 912) Mean age (years) 54.6 Range (years) Mean duration of ED (months) 30.3 Cause of ED (% of total)* Vascular 29.3 Neurogenic 25.3 Psychogenic 41.2 Mixed 3.9 Concomitant conditions (% of total) IHD 4.8 Hypertension 32.0 DM 29.7 BPH 21.8 Alcoholism 12.9 Smoking 14.8 *In evaluable patients. BPH, benign prostatic hyperplasia; DM, diabetes mellitus; ED, erectile dysfunction; IHD, ischemic heart disease. groups: the Indian men and the Malay men in 80.0, 74.2 and 72.8%, respectively. The efficacy rate was statistically significant between Chinese men and those of other races, whereas the difference between Malay and Indian men was not statistically significant at P < The analysis of comorbid profile revealed low comorbidity percentages (in particular DM) in Chinese patients compared to Malay and Indian patients. In the Chinese group, IHD, DM, and hypertension were noted in 4.7%, 26.9%, and 32.6% of patients, respectively. Whereas the same comorbid profiles in Malay and Indian patients were 5.1%, 47.4%, 40.6%; and 7.6%, 43.9%, 18.2%, respectively. We presume that this could be a probable reason for the higher efficacy rate in Chinese patients. Taking all racial groups together, subjective analysis revealed an 83% efficacy in the 912 of the 1520 patients who were available for follow-up evaluation of their treatment, and in 17% of the population sildenafil citrate was ineffective. Efficacy with reference to differential comorbid conditions and lifestyle characteristics are shown in Table 2. The highest efficacy of 86.3% was recorded in IHD patients (n = 44), followed by patients with hypertension and diabetic patients (83.9% and 77.8% efficacy, respectively; Table 2). The efficacy rate was not statistically significant between the IHD and hypertension patients, but there was a statistically significant lower efficacy in DM patients than in other patients with IHD and hypertension. Nevertheless, Table 2 Efficacy of sildenafil citrate in patients with different comorbidity and other medical conditions, lifestyle characters, previous therapies for ED and overall effective dose Comorbid characters Efficacy (%) Hypertension (n = 292) 83.9 DM (n = 271) 77.8 IHD (n = 44) 86.3 BPH (untreated, n = 112) 83.9 BPH (treated, n = 87) 82.7 Smoking (n = 135) 80.0 Alcoholism (n = 118) 80.5 Previous treatments Oral forms 89.2 Intracavernosal injections 77.3 Urethral suppositories 84.9 Vacuum constriction devices 86.8 Others 85.0 Overall effective dose of sildenafil citrate 25mg mg mg 46.5 BPH, benign prostatic hyperplasia; DM, diabetes mellitus; ED, erectile dysfunction; IHD, ischemic heart disease.

4 Efficacy of Viagra in Singaporean male patients 311 sildenafil citrate had a positive effect on the erections in DM patients. 10 There was no significant difference in efficacy in the BPH treated and untreated condition. Patients with smoking and alcoholic habits were found to have the same efficacy rate of 80% (Table 2). With reference to previous treatments for ED, in the present cohort almost all patients had used some other form of treatment. Treatment with oral drugs such as yohimbine, arcalion, swiss oats, testosterone undecanoate, or methyltestosterone were the most frequently used modalities followed by PGE intracavernous injections and MUSE. In general, the efficacy of sildenafil citrate was greater than 75% in these patients. The highest efficacy of sildenafil citrate was recorded in patients with previous oral treatments (89.2%). Side-effects due to sildenafil citrate were reported by 13.9% of the patients. Facial flushing, headache, blurred vision, giddiness and warmth were the major side-effects comprising 3.5%, 2.0%, 1.3%, 1.2% and 1.1% of the patient population, respectively. In the present cohort, the effective dose of sildenafil citrate for satisfactory outcome was 50 mg in 49% and 100 mg in 46.5% of the patient population. For nearly 4.1% of the total cohort, 25mg was an effective dose (Table 2). Efficacy of sildenafil citrate in patients with hypertension In the total study group of 920 men, there were 292 hypertensive patients. Of these patients, 245 patients (84%) were satisfactorily treated with sildenafil citrate for ED (Table 3). Side-effects were noticed in 29 patients (9.9%). If the patients with hypertension had lifestyle characteristics such as smoking or alcohol consumption, a lower efficacy was noted: the additional effects of smoking and alcohol resulted in a lower efficacy of 74% and 76%, respectively. The hormonal status had no significant impact on efficacy; the results were similar in patients with normal and abnormal hormonal levels (Table 3). But it is of note that no major hormonal abnormalities were noted among the present patients. Hypertensive patients with previous ED treatments had an efficacy of more than 75% with sildenafil citrate; the lowest efficacy was found after previous treatment with PGE intracavernosal injections. The efficacy of sildenafil citrate with reference to the number of hypertensive drugs being taken concurrently revealed that patients who were taking a single drug had an efficacy of 90%, while in patients who were taking two or more Table 3 Efficacy profile of sildenafil citrate in patients with hypertension No. patients No. successful patients Efficacy (%) Improved erections Side-effects Efficacy with reference to previous ED treatments Oral forms Intracavernosal injections Urethral suppositories Traditional Chinese medicine Others Effective dose 25mg mg mg Efficacy with reference to no. hypertensive drugs Single drug Two drugs Three or more drugs Efficacy with reference to type of hypertensive drug Amylodipine ACE β-blockers Calcium antagonists Diuretic Others ACE, angiotensin-converting enzyme; ED, erectile dysfunction.

5 312 PHC Lim et al. drugs the efficacy was 84%. With regard to the type of drugs, patients treated with diuretics (63.3%) were less responsive to sildenafil citrate than patients on other drugs such as amylodipine (80%), angiotensinconverting enzyme (ACE) inhibitors (83%), β-blockers (86%), calcium antagonists (85%) and other forms (89%). In patients with hypertension, 50 mg sildenafil citrate was efficacious in 55% of the men while 41% needed 100 mg and 25mg was sufficient for 3.9% of the patients (Table 3). This compares favorably with the group as a whole. Efficacy of sildenafil citrate in patients with diabetes mellitus The prevalence of ED is much higher in patients with diabetes. 11,12 In the present cohort, there were 271 patients with DM. Of these 271 men, 211 patients (77.8%) reported satisfactory erections on sildenafil citrate. Side-effects were noticed in 32 patients (11.8%; Table 4). Diabetic patients with alcoholism had the lowest efficacy of 75%. There was no significant difference in efficacy of sildenafil citrate in patients with normal and abnormal hormonal profiles. In the diabetic patients who had previous ED treatments an efficacy of over 70% with sildenafil citrate was recorded; the lowest efficacy was observed in men with previous use of PGE intracavernosal injections. The type of diabetic treatment had an impact on the efficacy of sildenafil citrate: patients with insulin had a lower efficacy (57%) compared to patients treated with diet and oral antidiabetic drugs. Of the diabetic patients, a higher percentage of patients (59%) required 100-mg sildenafil citrate for a satisfactory outcome; 38.4% were satisfactorily treated with 50 mg and 2.2% were satisfactorily treated with 25mg (Table 4). Efficacy of sildenafil citrate in patients with ischemic heart disease In the present cohort, there were 44 patients with diagnosed IHD. Of these, 38 patients (86.3%) were satisfactorily treated with sildenafil citrate for ED. Side-effects were noticed in seven patients (15.9%; Table 5). Among the comorbid profile and other lifestyle charactersistics, lowest efficacy was noted if patients suffered from both IHD and DM. Similarly to the other subgroups, in the IHD patients there was no significant difference in efficacy in patients with normal and abnormal hormonal levels. In IHD patients with previous ED treatments, an efficacy of over 75% was observed and the lowest efficacy was found in patients earlier treated with PGE. Similar to the diabetic cohort, the IHD patients needed the maximum dose of 100 mg of sildenafil citrate in 59% of men for satisfactory outcome; for 36.4% of the patients treatment with 50 mg of sildenafil citrate was satisfactory and in 4.5% of the patients 25 mg was sufficient (Table 5). Discussion Since the approval of sildenafil citrate (Viagra) as a firstline treatment for ED, several studies have been carried Table 4 Efficacy profile of sildenafil citrate in patients with DM No. patients No. successful patients Efficacy (%) Improved erections Side-effects Efficacy with reference to previous ED treatments Oral forms Intracavernosal injections Urethral suppositories Vacuum constriction devices Traditional Chinese medicine Others Effective dose 25mg mg mg Efficacy with reference to diabetic treatments Diet OHGA Insulin DM, diabetes mellitus; ED, erectile dysfunction; OHGA, oral hypoglycemic acid.

6 Efficacy of Viagra in Singaporean male patients 313 Table 5 Efficacy profile of sildenafil citrate in patients with IHD No. patients No. successful patients Efficacy (%) Improved erections Side-effects Efficacy in patients with previous ED treatments Oral forms Intracavernosal injections Urethral suppositories Vacuum constriction devices Others Effective dose 25mg mg mg ED, erectile dysfunction; IHD, ischemic heart disease. out in regard to its efficacy and also safety. In the present study, sildenafil citrate was found to be effective in 83% of the total evaluable patients. The obtained clinical efficacy is very similar to that found in studies of American populations, 13,14 in which sildenafil citrate improved erections in 74% and 77.8% of the patients studied. Similarly, Meuleman et al. have reported improved erections in 79% and 82% of men treated with sildenafil citrate in a European population after 12 and 26 weeks of treatment, respectively. 4 However, the present efficacy rate is significantly lower than that obtained in the reports of Christiansen et al., 15 Fekete and Fabian 16 and Magoha, 17 which showed 93%, 90% and 91.2% efficacy in Norwegian, Hungarian and African patients, respectively. These results suggest that, compared to European and African patients, the efficacy is lower for Asian men presenting with ED. The efficacy of ED treatments relies entirely upon the comorbid profiles, differing medical conditions and their associated treatments. Erectile dysfunction is often associated with cardiovascular diseases and DM requiring drug treatment. The medications for these conditions are reported to cause or contribute to ED at a rate of 25%. 18,19 Also medications such as antidepressants and luteinizing-releasing hormone analogs may be responsible for ED. Similarly, alcoholism, smoking and use of drugs such as cocaine and heroin impair erectile function but this has not been quantified in the present study. With regard to diabetic patients, the efficacy was comparatively less. Nevertheless, sildenafil citrate had a positive effect on the erections in diabetic patients. 10 Hormonal changes such as the age-related decline in total and free testosterone and other hormonal disorders, namely, hypo- and hyperthyroidism, are reported to result in ED. 20,21 In the present study, there was no significant difference in efficacy of sildenafil citrate in patients with normal and abnormal baseline hormonal levels of luteinizing hormone, follicle stimulating hormone, testosterone, and prolactin. But it is of note that there were no major abnormalities in any of the hormones measured. In the present series, 13.9% of patients reported sideeffects. Goldstein et al. found a similar percentage of side-effects and profile in their series of 316 patients. 13 McMahon et al. recorded a severe side-effect profile in 5.3% of Australian patients. 5 Multiple side-effects (more than one form of side-effect) were noticed in 2.4% of the total cohort in the present study (Fig. 2). In contrast to these observations, Magoha reported a sideeffect rate of only 3.2% in African patients. 17 Over 75% efficacy was noted in patients with previous ED treatments. Jarow et al. also found that prior therapies did not affect the efficacy of sildenafil citrate. 22 In contrast, patients who had previously received PGE injection treatment were found to have a somewhat lower efficacy (77.8%) on sildenafil citrate compared to patients with other modes of previous treatments (Table 2). Patients with venous leakage have been reported to respond poorly to sildenafil citrate monotherapy; and in addition, the response is also dosedependent. 23 This could be the reason for low efficacy in PGE-treated patients compared to the efficacy in those who underwent other previous forms of treatment in the present series. In general, it is widely believed that patients with diabetes have a poor response to ED treatments. Viagra is not an exception in this scenario. Earlier studies in diabetic men treated with sildenafil citrate have shown an efficacy of 52% and 56%. 7,10 In the present study, a higher rate of efficacy was noticed in diabetic patients. This difference in efficacy rate could be due to the higher number of type II diabetic patients as well as their treatment. However, there was no significant difference in side-effects due to sildenafil citrate in diabetic

7 314 PHC Lim et al. Patients (%) Flushing Headache Blurred vision Side effects Giddiness Warmth Fig. 2 Side-effects profile of patients treated with sildenafil citrate. patients between the present study and that of Rendell et al. 10 Hypogonadism and diabetes have a cumulative effect on the erectile functions through their role in changing the ability of endothelial cells to produce neurotransmitters and thus cause ED. A recent Italian study assessed the prevalence of ED in 1383 men with type I DM and in 8373 men with type II DM, between the ages of years. 24 Not unexpectedly, age was a factor in the prevalence but, taking aging into account, 37/100 men with type II, and 51/100 men with type I DM had erectile problems. Poor metabolic control and smoking were additional risk factors. Romeo et al. found that rather than age, glycemic control and peripheral neuropathy were independent predictors of ED. 25 Erectile dysfunction is a common condition in men with cardiovascular disease. Some patients realize that there is a degree of cardiac risk associated with sexual activity, which subsequently becomes a concern for many patients with cardiovascular disease, particularly those who have experienced acute cardiac events in the past. The risks of triggering a myocardial infarction with sexual activity was assessed before sildenafil citrate was introduced and only 0.9% of myocardial infarctions could be linked to sexual activity. 26 The relative risk of an incidence of myocardial infarction following sexual activity was no different in patients with a previous history of myocardial infarction or angina pectoris compared with patients with no history of cardiovascular disease. 26,27 But many cardiac patients are hesitant to consider treatment with sildenafil citrate particularly because the underlying pharmacological mechanism of sildenafil citrate (to increase smooth muscle relaxation of the vasculature of the penis) impacts on the cardiovascular system. Also the absolute contraindication of combined use of sildenafil citrate with nitrates in cardiac patients is alarming for many patients. Meanwhile, several studies have assessed the use and safety of sildenafil citrate in men with a diagnosis of cardiovascular disease. 8,9 Experience shows that patients with pre-existing cardiovascular disease using sildenafil citrate have no higher risk of developing an acute cardiovascular event compared to the patients of similar age. 9 The same has also been observed in the present study. No adverse cardiovascular events were noted during the present study period. Also the fact that the combination of sildenafil citrate with a number of antihypertensive drugs (βblockers, diuretics, angiotensin-converting enzyme inhibitors or calcium antagonists) did not produce an additional cardiovascular risk is in agreement with an earlier report. 28 Conclusions The results of the present analysis in terms of improved erections; failure rate and side-effects are very similar to the findings of studies in the Western world. In general, 83% of patients reported that sildenafil citrate had improved their erections. Seventeen percent of the total cohort felt that sildenafil citrate was ineffective. Sideeffects were found in 13.9% of patients. Taking comorbidity into consideration, the highest efficacy was found in patients with IHD, followed by hypertension and then diabetes. Racially the efficacy was higher in Chinese men (statistically significant at P < 0.005) compared to Indian and Malay men. In the present cohort, no major hormonal abnormalities were found and there appeared to be no significant difference between hormonal profiles and efficacy of sildenafil citrate. The clinical efficacy of sildenafil was similar in patients with previous use of other forms of treatment for ED compared to those for whom sildenafil was the first form of treatment. But patients who had been treated with PGE intracavernosal injections exhibited lower efficacy compared to other forms of previous ED treatments. The majority of the ED patients were well served with 50 mg of sildenafil citrate. The success rate and side-effects of sildenafil citrate in the Singapore population consisting of Chinese, Malay and Indian men are very similar to reported data from the Western world. References 1 Kaiser FE. Erectile dysfunction in the aging man. In: Kaiser FE (ed.). The Medical Clinics of North America:

8 Efficacy of Viagra in Singaporean male patients 315 The Aging Male Patient. WB Saunders Co., Philadelphia, 1999; 83: Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J. Urol. 1994; 151: Lim PHC, Ng FC. Erectile dysfunction in Singaporean men: Presentation, diagnosis, treatment and results. Ann. Acad. Med. Singapore 1992; 21: Meuleman E, Cuzin B, Opsomer RJ et al. A dose escalation study to assess the efficacy and safety of sildenafil citrate in men with erectile dysfunction. Br. J. Urol. 2001; 87: McMahon CG, Samali R, Johnson H. Efficacy, safety and patient acceptance of sildenafil citrate as treatment for erectile dysfunction. J. Urol. 2000; 164: Moreira SG, Branningan RE, Spitz A, Orejuela FJ, Lipshultz LI, Kim ED. Side-effect profile of sildenafil citrate (Viagra) in clinical practice. Urology 2000; 56: Price DE, Gingell JC, Gepi-Attee S, Wareham K, Yates P, Boolell M. Sildenafil: Study of a novel oral treatment for erectile dysfunction in diabetic men. Diabet. Med. 1998; 15: Cheitlin MD, Hutter AM, Brindis RG et al. Use of sildenafil (Viagra) in patients with cardiovascular disease. J. Am. Coll. Cardiol. 1999; 33: Conti CR, Pepine CJ, Sweeney M. Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischaemic heart disease. J. Am. Coll. Cardiol. 1999; 83: 29C 34C. 10 Rendell MS, Rajfer J, Wicker PA, Smith MD. Sildenafil for treatment of erectile dysfunction in men with diabetes: A randomised controlled trial. JAMA 1999; 281: Rubin A, Babbott D. Impotence in diabetes mellitus. JAMA 1958; 168: McCulloch DK, Campbell IW, Wu FC, Prescott RJ, Clarke BF. The prevalence of diabetic impotence. Diabetologia 1980; 18: Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. N. Engl. J. Med. 1998; 338: Padma-Nathan H, Steers WD, Wicker PA. Efficacy and safety of oral sildenafil in the treatment of erectile dysfunction: A double-blind, placebo controlled study of 329 patients. Sildenafil Study Group. Int. J. Clin. Pract. 1998; 52: Christiansen E, Guirguis WR, Osterloh IH. Long-term efficacy and safety of oral Viagra (sildenafil citrate) in men with erectile dysfunction and the effect of randomised treatment withdrawal. Sildenafil Multicentre Study group. Int. J. Impot. Res. 2000; 12: Fekete F, Fabian E. Effectiveness and adverse effects of sildenafil in erectile dysfunction. Orv. Hetil. 2000; 141: Magoha GA. Sildenafil (Viagra) in the treatment of male erectile dysfunction in Nairobi. East Afr. Med. J. 2000; 77: Buffum J. Prescription drugs and sexual function. Psychol. Med. 1992; 10: Johnson L, Kaiser FE, Morley JE. Reproductive hormones and the aging male. In: Cassell CJ, Coihen HJ, Larson SB (eds). Geriatric Medicine, 3rd edn. Springer- Verlag, New York, Blackman MR, Kowatch MA, Wehmann RE, Harmann SM. Basal serum prolactin levels and prolactin responses to constant infusions of thyrotropin releasing hormone in healthy aging men. J. Gerontol. 1986; 41: Foster RS, Mulcahy JJ, Callagher JT, Crabtree R, Brashear D. Role of serum prolactin determination in evaluation of impotent patient. Urology 1990; 36: Jarow JP, Burnett AL, Geringer AM. Clinical efficacy of sildenafil citrate based on etiology and response to prior treatment. J. Urol. 1999; 162: McMahon CG, Samali R, Johnson H. Treatment of intracorporeal injection nonresponse with sildenafil alone or in combination with triple agent intracorporeal injection therapy. J. Urol. 1999; 162: Fedele D, Bortlotti A, Coscelli C et al. Erectile dysfunction in type I and type 2 diabetics in Italy. Int. J. Epidemiol. 2000; 29: Romeo JH, Seftel AD, Madhun ZT, Aron DC. Sexual function in men with diabetes type 2: Association with glycaemic control. J. Urol. 2000; 163: Muller JE, Mittleman A, Maclure M, Sherwood JB, Tofler GH. Triggering myocardial infarction by sexual activity. Low absolute risk and prevention by regular physical exertion. JAMA 1996; 275: De Busk RF. Sexual activity triggering myocardial infarction. One less thing to worry about. JAMA 1996; 275: Zusman RM, Morales A, Glasser DB, Osterloh IH. Overall cardiovascular profile of sildenafil citrate. J. Am. Coll. Cardiol. 1999; 83: 35C 44C.