Long-term efficacy and safety of sildenafil for patients with erectile dysfunction.

Sheu JY, Chen KK, Lin AT, Chang YH, Wu HH, Huang WJ, Hsu YS, Kuo JY, Chung HJ, Chang LS.

Division of Urology, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

BACKGROUND: To investigate the long-term efficacy and safety of sildenafil for patients with erectile dysfunction (ED). METHODS: Between March 1999 and February 2001, a total of 3168 patients visited Taipei Veterans General Hospital for prescription of sildenafil. The follow-up period was 1-3 years. A questionnaire was designed for evaluation of efficacy and safety of sildenafil via telephone survey. RESULTS: Of the 3168 patients, 1414 were interviewed by telephone. Data from telephone questionnaires were successfully obtained in 1074 cases. Achievement of the first penile erection after sildenafil was reported in 58.8% of our patients. The distribution of the first doses was 0.6%, 8.5%, 81.9% and 90% for 12.5 mg, 25 mg, 50 mg and 100 mg, respectively. After administration of sildenafil, 72.1% men had successful intercourses "sometimes" or "always achieving vaginal penetration", and 72.3% had "slight difficulty" or "no difficulty" in maintaining of sexual intercourses. The "sometimes/most times/always" satisfaction accounted 63.9% and 62.8%, respectively for patients and partners. The global assessment of penile erection was improved in 58.6% of the patients. The sexual confidence of the patients was moderate, high and very high in 72.4% of the patients. Of the 434 patients who failed first penile erections, 400 (92.2%) were related to improper administration of sildenafil. Discontinuation of sildenafil in the last 3 months before telephone survey was found in 852 patients (80.2%). The causes of discontinuation were loss of efficacy in 51.6% of patients, lack of sexual desire in 8.8%, and chronic diseases in 8.2%. Spontaneous erection without sildenafil was claimed in 21.5% of the patients (most times in 9.5% and always in 12.0%). The rate of adverse events after taking sildenafil were 16.6%, and the most common adverse event was facial flushing (9.2%). CONCLUSIONS: The results of this study demonstrated that the efficacy of sildenafil was similar to the previous clinical trials. The adverse events after sildenafil were mild and tolerable. Recovery of complete or partial spontaneous erection was noted in some patients (21.5% in our study) after long-term usage of sildenafil.

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Why do patients with erectile dysfunction abandon effective therapy with sildenafil (Viagra((R)))?

Klotz T, Mathers M, Klotz R, Sommer F.

1Department of Urology, Weiden, Germany.

This prospective study determined the rate of abandonment of sildenafil therapy and assessed the reasons for abandonment. Between January 2001 and December 2002, 234 patients with erectile dysfunction (ED) at three independent centers successfully began therapy with sildenafil 50 or 100 mg. The rate of noncompliance was 31%. A telephone survey of these patients was conducted to determine the reasons for abandonment. The majority reported that they had had no opportunity or desire for sexual intercourse or that their partners had shown no sexual interest. Few patients stated that the high cost of the medication or that adverse events were the cause.International Journal of Impotence Research (2005) 17, 2-4. doi:10.1038/sj.ijir.3901252 Published online 17 June 2004.

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Increasing incidence and importance of HIV/AIDS and gonorrhea among men aged >/= 50 years in the US in the era of erectile dysfunction therapy.

Karlovsky M, Lebed B, Mydlo JH.

Department of Urology, Temple University School of Medicine, Philadelphia, PA 19140, USA.

OBJECTIVE: With the advent of effective pharmacotherapy for erectile dysfunction, the risk of sexually transmitted diseases is a possible consequence, especially in the older population. We wanted to review the incidence of sexually transmitted diseases in the older population in an attempt to correlate this with the advent of these new drugs. MATERIAL AND METHODS: Publicly available information on the incidence of HIV, AIDS and gonorrhea was retrieved from the websites of the Centers for Disease Control (CDC), the State of Florida Department of Health, the Senior HIV Intervention Project and the National Association on HIV Over Fifty. National case incidences of HIV and AIDS in men between 1996 and 2000 were examined for trends. National and Florida state trends were compared and, in Florida, Palm Beach, Broward and Dade counties in particular were selected because of their traditionally large retiree population. In addition, the national and Florida state incidences of gonorrheal infection were examined for trends. Statistics on national sildenafil (Viagra) prescriptions were obtained via a personal communication with a regional healthcare representative from Pfizer. RESULTS: According to the CDC, at the end of 1998 >10% of new AIDS cases nationally were in individuals aged >50 years. In the late 1990s, new AIDS cases rose faster in middle-aged and older adults than in people aged >40 years. Many of the newly diagnosed cases of AIDS may have contracted HIV before the age of 50 years; however, many individuals are newly becoming infected above the age of 50 years. Of the reported AIDS cases in 1996 in individuals aged >/= 50 years, 48% were aged 50-54 years, 26% were aged 55-59 years, 14% were aged 60-64 years and 12% were aged >/= 65 years; 84% of these cases were male, and blacks accounted for the greatest proportion of cases (43%). In the US, 7.5 million prescriptions for sildenafil were written in 1998, 9.5 million in 1999, 12 million in 2000 and 15.5 million in 2001. The age breakdown for these prescriptions was as follows: 40-49 years, 23%; 50-59 years, 35%; and 60-69 years, 25%. CONCLUSIONS: The past decade saw rises in heterosexual transmission of HIV and i.v. drug use, especially in the population aged >50 years. The CDC reports that the incidence of new HIV infection is stabilizing in men aged 30-39 years and even falling in men aged 20-29 years. Gonorrhea is well known to increase infectivity for HIV and other STDs. Although the rates of gonorrhea infection fell throughout the early 1990s, they increased by 9% between 1997 and 1999. The number of sildenafil prescriptions has increased by almost 80% over the last few years. Although there may be multiple contributory factors for these findings, to our knowledge this is the first paper in the urologic literature to examine such trends in the older male population, especially in the light of newly available medications for erectile dysfunction.

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Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation.

Blount MA, Beasley A, Zoraghi R, Sekhar KR, Bessay EP, Francis SH, Corbin JD.

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA.

Sildenafil, tadalafil, and vardenafil each competitively inhibit cGMP hydrolysis by phosphodiesterase-5 (PDE5), thereby fostering cGMP accumulation and relaxation of vascular smooth muscle. Biochemical potencies (affinities) of these compounds for PDE5 determined by IC(50), K(D) (isotherm), K(D) (dissociation rate), and K(D) ((1/2) EC(50)), respectively, were the following: sildenafil (3.7 +/- 1.4, 4.8 +/- 0.80, 3.7 +/- 0.29, and 11.7 +/- 0.70 nM), tadalafil (1.8 +/- 0.40, 2.4 +/- 0.60, 1.9 +/- 0.37, and 2.7 +/- 0.25 nM); and vardenafil (0.091 +/- 0.031, 0.38 +/- 0.07, 0.27 +/- 0.01, and 0.42 +/- 0.10 nM). Thus, absolute potency values were similar for each inhibitor, and relative potencies were vardenafil >> tadalafil > sildenafil. Binding of each (3)H inhibitor to PDE5 was specific as determined by effects of unlabeled compounds. (3)H Inhibitors did not bind to isolated PDE5 regulatory domain. Close correlation of EC(50) values using all three (3)H inhibitors competing against one another indicated that each occupies the same site on PDE5. Studies of sildenafil and vardenafil analogs demonstrated that higher potency of vardenafil is caused by differences in its double ring. Exchange-dissociation studies revealed two binding components for each inhibitor. Excess unlabeled inhibitor did not significantly affect (3)H inhibitor dissociation after infinite dilution, suggesting the absence of subunit-subunit cooperativity. cGMP addition increased binding affinity of [(3)H]tadalafil or [(3)H]vardenafil, an effect presumably mediated by cGMP binding to PDE5 allosteric sites, implying that either inhibitor potentiates its own binding to PDE5 in intact cells by elevating cGMP. Without inhibitor present, cGMP accumulation would stimulate cGMP degradation, but with inhibitor present, this negative feedback process would be blocked.

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Effect of sildenafil on anxiety in the plus-maze test in mice.

Kurt M, Bilge SS, Aksoz E, Kukula O, Celik S, Kesim Y.

Department of Pharmacology, University of Ondokuz Mayis, Samsun, 55139, Turkey.

Several studies have shown a role of nitric oxide/cyclic guanosine monophosphate signaling pathway in the regulation of anxiety. The effects of the phosphodiesterase (PDE) 5 inhibitors on anxiety are not fully understood. The aim of present study was to investigate the possible role of sildenafil, an inhibitor of cyclic GMP-specific phosphodiesterase, on anxiety in the plus-maze test in mice. Sildenafil at a dose of 0.5 mg/kg had no significant effect on the behavior in the plus-maze test but at doses of 1 and 3 mg/kg induced an anxiogenic effect. The combination of sildenafil (1 mg/kg, i.p.) and methylene blue (1 mg/kg, i.p.) abolished the anxiogenic-like effect of sildenafil. The combination of sildenafil (1 mg/kg, i.p.) and L-arginine (50 mg/kg, i.p.) decreased the percentage of time spent in open arms compared to saline-treated group. Diazepam at a dose of 2 mg/kg significantly increased the percentage of time spent in open arms (p < 0.05). Sildenafil at a dose of 3 mg/kg and the combination of L-arginine (50 mg/kg, i.p.) and sildenafil (1 mg/kg, i.p.) significantly decreased the locomotor activity (p < 0.05). These results suggest that a nitric oxide-cGMP pathway seems to play an important role in sildenafil-induced anxiogenic-like effect.

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Cardiovascular parameter changes in patients with erectile dysfunction using pde-5 inhibitors: a study with sildenafil and vardenafil.

Pomara G, Morelli G, Pomara S, Taddei S, Ghiadoni L, Dinelli N, Travaglini F, Dicuio M, Mondaini N, Salvetti A, Selli C.

Department of Urology, Pisa University, Pisa, Italy. g.pomara libero.it

Sildenafil is the most prescribed oral agent for patients with erectile dysfunction (ED). Vardenafil is a new phosphodiesterase type 5 (Pde-5) inhibitor that was approved by the US Food and Drug Administration last year to treat patients with ED of various causes. Both of these Pde-5 inhibitors have vasodilating properties and effects on blood pressure (BP), and like nitrates, they work through the nitric oxide cyclic guanosine monophosphate pathway. The aim of this study was to investigate the influence of these Pde-5 inhibitors on BP and heart rate (HR) in normotensive men with ED by a crossover comparison. Thirty-five patients with ED were enrolled to evaluate and compare the effect of sildenafil (50 mg) and vardenafil (10 mg) on BP and HR. At the screening (baseline [B]) visit, sitting systolic blood pressure (B-SBP), diastolic blood pressure (B-DBP), and HR were measured. We performed a multiple administration for both drugs and, therefore, multiple measurements of BP and HR changes, 3 doses a week, on alternate days, late in the afternoon, and on an empty stomach. B-SBP, B-DBP, and HR were recorded before each 50-mg sildenafil dosing and after 30, 60, 120, and 240 minutes. Data were averaged over the 4 time points and compared with the baseline values obtained before each dosing. After a 3-week wash-out period, patients were crossed over to vardenafil (10 mg) with the same study design. After administration of both drugs, we observed a statistically significant decrease of BP and an increase of HR. On average, sildenafil caused a decrease of SBP ranging from 5.1 +/- 3.9 mm Hg during the first dosing to 4.7 +/- 4.2 mm Hg during the third dosing, DBP ranged from 4.4 +/- 4.9 to 4 +/- 4.1 mm Hg, and HR increased 1.8 +/- 2.0 bpm (first dose) and 1.2 +/- 0.9 bpm (third dose). With vardenafil, we recorded a greater variation for SBP and DBP. SBP decreased from 8.02 +/- 8.0 mm Hg during the first dosing to 5.4 +/- 5.5 mm Hg during the third dosing, whereas DBP decreased from 6.6 +/- 7.2 to 5.0 +/- 5.3 mm Hg, respectively. Recorded HR showed an increase of 3.1 +/- 3.2 bpm (first dose) and 2.4 +/- 2.3 bpm (third dose). After the first vardenafil administration, we recorded fainting episodes in 3 patients because of a decrease in BP greater than 20 mm Hg. Two of the patients were in therapy with doxazosin for benign prostatic hyperplasia (BPH). Cardiovascular response was not significantly different after the first dose between the 2 treatments. Vardenafil demonstrated clinically significant differences (fainting) with respect to sildenafil only during the first doses. We suggest that before starting therapies with Pde-5 inhibitors, particularly with the newer ones, that baseline cardiovascular parameters are measured and monitored, especially during the first dose, because of the presence of a "first dose effect." Moreover, it is necessary to pay particular attention to those patients in treatment with other drugs that could have a synergistic hypotensive effect as a result of vasodilation potentiation.

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Impact of introduction of sildenafil on other treatment modalities for erectile dysfunction: a study of nationwide and local hospital sales.

Jiann BP, Yu CC, Su CC.

Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

We assess the impact of introduction of sildenafil on alprostadil injection and penile implant surgery for the treatment of erectile dysfunction (ED) at our institution and in Taiwan. The data of national sales of sildenafil, alprostadil injection and penile implant were provided by industry companies. In the meanwhile, we analyzed the users of the above-mentioned three treatments at our institution. The national sales of sildenafil grew 136% from 0.8 million tablets in 1999 to 1.6 million tablets in 2002, while those of alprostadil injection dropped 33% after the marketing of sildenafil and of penile implant dropped 40% after the marketing of alprostadil injection and sildenafil. The market share of drugstores for sildenafil rose from 41% in 1999 to 72% in 2002. The trend of sales of sildenafil at our institution was similar to that of national sales from hospitals. Mean age of the sildenafil new users was becoming younger in the past 4 y (P<0.001). Of the new users of alprostadil injection and the recipients of penile implant, the commonest age group shifted from the range of 60-69 y before the launch of sildenafil to that of over 70 y after (P<0.05). In conclusion, the introduction of sildenafil has prompted more men as well as younger men with ED to seek treatment. Part of the roles of alprostadil injection and penile implants in this field are substituted by sildenafil and the commonest age group of their users becomes older than before.

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Histopathologic effect of chronic use of sildenafil citrate on the choroid & retina in male rats.

Vatansever HS, Kayikcioglu O, Gumus B.

Department of Histology & Embryology, Faculty of Medicine, Celal Bayar University, Manisa-Turkey. hsedav yahoo.com

BACKGROUND & OBJECTIVES: Sildenafil citrate is an oral medication used to treat male impotence by the inhibition of phosphodiesterase-5 in the corpus cavernosum and subsequent facilitation of penile erection. Though the ocular side effects of sildenafil have been reported, no information is available on the histopathologic effects of chronic use of sildenafil citrate on the ocular vasculature. The present study was undertaken to study the histopathologic effects of chronic use of sildenafil on the retina and choroid of male rats. METHODS: Twelve adult male Wistar rats were used in the study. Six of them were given 8 mg/kg/day sildenafil citrate orally on alternate days, the other six rats were used as control. The animals were sacrificed after 4 wk of treatment, and the eyes were fixed in 10 per cent formalin solution and sectioned after embedding in paraffin. Sections were cut, stained with haematoxylin-eosin (HE) or periodic acid Schiff (PAS) and examined under light microscope. The choroidal capillary diameter was also measured. RESULTS: The choroidal capillaries were more dilated in the sildenafil citrate treated group (mean capillary diameter 3.44 +/- 1.68 microm versus the control of 1.78 +/- 1.36 microm, P < 0.001). The retinal layers and their configuration were unchanged in both the groups. INTERPRETATION & CONCLUSION: Chronic use of sildenafil citrate can cause dilatation and congestion in the choroidal vasculature of male rats.

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