In vitro biotransformation of sildenafil (Viagra): identification of human cytochromes and potential drug interactions.

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

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

The in vitro biotransformation of sildenafil to its major circulating metabolite, UK-103,320, was studied in human liver microsomes and in microsomes containing heterologously expressed human cytochromes. In human liver microsomes, the mean K(m) (+/-S.E. ) was 14.4 +/- 2.0 microM. A screen of the chemical inhibitors omeprazole (10 microM), quinidine (10 microM), sulfaphenazole (10 microM), and ketoconazole (2.5 microM) only revealed detectable inhibition with ketoconazole. Sildenafil biotransformation (36 microM) was inhibited by increasing concentrations of ketoconazole and ritonavir (IC(50) values less than 0.02 microM), which are established cytochrome P450 (CYP) 3A4 inhibitors. Using microsomes containing cDNA-expressed cytochromes, UK-103,320 formation was found to be mediated by four cytochromes: CYP3A4, -2C9, -2C19, and -2D6. Estimated relative contributions to net intrinsic clearance were 79% for CYP3A4 and 20% for CYP2C9; for CYP2C19 and -2D6, estimated contributions were less than 2%. These results demonstrate that CYP3A4 is the primary cytochrome mediating UK-103,320 formation and that drugs that inhibit CYP3A4 are likely to impair sildenafil biotransformation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10725306&dopt=Abstract sildenafil Viagra online



Comparative effects of sildenafil, phentolamine, yohimbine and L-arginine on the rabbit corpus cavernosum.

Sharabi FM, Daabees TT, El-Metwally MA, Senbel AM.

Department of Pharmacology, Faculty of Pharmacy, University of Alexandria, El-Khartoom Square, Alexandria, Egypt. fmsharabi hotmail.com

Penile erection involves relaxation of smooth muscle of corpus cavernosum and associated arterioles. Sildenafil, a highly selective inhibitor of phosphodiesterase type 5, is effective in the treatment of erectile dysfunction. The aim of this study is to investigate the effect of sildenafil on smooth muscle of the rabbit corpus cavernosum (RCC) and to compare its effect with those of phentolamine, yohimbine and L-arginine. The effects of sildenafil, phentolamine, yohimbine and L-arginine were studied on the response of the RCC to electrical field stimulation (EFS) as well as on the phenylephrine (PE, 3 x 10(-6) M)-induced tone. EFS caused transient, frequency-dependent relaxation of the RCC that was inhibited by the nitric oxide synthase inhibitor NG-nitro-L-arginine (3 x 10(-5) M). Sildenafil (1 x 10(-9)-1 x 10(-6) M) and phentolamine (1 x 10(-9)-1 x 10(-6) M) enhanced the EFS-induced relaxation in a concentration-dependent manner with ED50 of 0.056 +/- 0.004 and 0.572 +/-0.035 microM at 8 Hz, respectively, yohimbine (3 x 10(-7)-3 x 10(-5) M) and L-arginine (3 x 10(-6)-3 x 10(-4) M) did not show significant effects (ED50 at 8 Hz = 35.84 +/-2.24 and 2.164 +/- 0.174 microM, respectively). Sildenafil (1 x 10(-9) and 1 x 10(-8) M) potentiated the EFS-induced relaxation caused by L-arginine (3 x 10(-5) m). Sildenafil, phentolamine, yohimbine and L-arginine reduced the PE-induced tone to different extents; the ED50 values were 0.81 +/- 0.097, 0.49 +/- 0.025 and 13.97 +/- 1.10 microM, respectively. Maximum concentration of L-arginine used failed to produce 50% relaxation (ED20 = 221.82 +/- 15.71 microM). The muscle relaxant effects of different combinations of sildenafil and L-arginine on PE-induced tone did not differ significantly from the sum of the individual effects. The results demonstrate that sildenafil, when compared to other drugs used in penile erection dysfunction, shows the highest potency on the nitrergic transmission in the RCC. On the other hand, phentolamine was found to possess the highest potency in inducing relaxation of RCC proving that its action is independent on the stimulated neurogenic system. In addition, the combination of less effective doses of sildenafil and L-arginine has a potential advantage on erectile functions. The importance of this combination remains to be solved clinically.

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Interaction of L-arginine and phosphodiesterase inhibitors in vasodilation of the porcine internal mammary artery.

Wallace AW, Tom WL.

Department of Anesthesiology, San Francisco Veterans Administration Medical Center and Department of Anesthesiology, University of California-San Francisco, San Francisco, California, USA. awallace best.com

We tested the hypothesis that L-arginine (the substrate for nitric oxide production)-combined with amrinone, milrinone (Type III phosphodiesterase [PDE] inhibitors), zaprinast, or sildenafil (Type V PDE inhibitors)-would vasodilate synergistically. Internal mammary artery segments were excised from anesthetized swine, divided into rings, and suspended in a tissue bath at 37 degrees C. Force of contraction was measured during dose-response testing of combinations of L-arginine and amrinone, milrinone, zaprinast, or sildenafil. Amrinone and milrinone were additive to L-arginine. N(G)-methyl-L-arginine (L-NMA) inhibited the effects of milrinone but not amrinone. The effective concentration of amrinone eliciting 50% relaxation (EC(50)) was 3.8E-05M (n = 6) when given alone and 4. 4E-05M (n = 6) with L-NMA. Milrinone had EC(50) = 6.0E-06M alone (n = 6) and 2.8E-05M (n = 6) with L-NMA. Zaprinast (EC(50) = 6.5E-05M, n = 6) and sildenafil (EC(30) = 1.8E-05M, n = 6) were synergistic with L-arginine. L-NMA blocked their effects, increasing the EC(50) for zaprinast to 9.9E-03M and the EC(30) for sildenafil to 6.1E+02M. In conclusion, L-arginine is additive to the vasodilation of the type III PDE inhibitors, amrinone and milrinone, but synergistic with the type V PDE inhibitors, zaprinast and sildenafil. Implications: Amrinone and milrinone, Type III cAMP-dependent phosphodiesterase inhibitors, are additive to L-arginine-dependent vasodilation. Zaprinast and sildenafil, Type V cGMP-dependent phosphodiesterase inhibitors, are synergistic with L-arginine.

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Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF.

Sher G, Fisch JD.

Sher Institute for Reproductive Medicine, 3121 S. Maryland Parkway, Suite 300, Las Vegas, Nevada 89109, USA.

Endometrial growth is thought to depend on uterine artery blood flow and the importance of endometrial development on in-vitro fertilization (IVF) outcome has been previously reported. Nitric oxide (NO) relaxes vascular smooth muscle through a cGMP-mediated pathway and NO synthase isoforms have been identified in the uterus. Sildenafil citrate (Viagra), a type 5-specific phosphodiesterase inhibitor, augments the vasodilatory effects of NO by preventing the degradation of cGMP. In this preliminary report we describe the use of vaginal sildenafil to improve uterine artery blood flow and sonographic endometrial appearance in four patients with prior failed assisted reproductive cycles due to poor endometrial response. The uterine artery pulsatility index (PI) was measured in a mock cycle after pituitary down-regulation with Lupron. The PI was decreased after 7 days of sildenafil (indicating increased blood flow) and returned to baseline following treatment with placebo. The combination of sildenafil and oestradiol valerate improved blood flow and endometrial thickness in all patients. These findings were reproduced in an ensuing gonadotrophin-stimulated cycle. Three of the four patients conceived. Although greater numbers of patients and randomized evaluation are needed to validate this treatment, vaginal sildenafil may be effective for improving uterine artery blood flow and endometrial development in IVF patients with prior poor endometrial response.

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Sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men with Parkinson's disease.

Zesiewicz TA, Helal M, Hauser RA.

Parkinson's Disease and Movement Disorders Center, Department of Neurology, University of South Florida, Tampa, USA.

Sildenafil citrate (Viagra) is a phosphodiesterase type V inhibitor used to treat erectile dysfunction. Ten men with idiopathic Parkinson's disease (PD) and erectile dysfunction were prescribed 50-100 mg sildenafil citrate to use in eight sexual encounters over a 2-month period. Patients underwent Unified Parkinson's Disease Rating Scale (UPDRS) evaluations and completed a Beck's Depression Inventory (BDI) and a Sexual Health Inventory-M version (SHI-M) at baseline and after 8 weeks. There was statistically significant improvement in total SHI-M scores (23.8 +/- 2.0 vs 16.6 +/- 2.8; p = 0.01), overall sexual satisfaction (p = 0.03), satisfaction with sexual desire (p = 0.04), ability to achieve erection (p = 0.02), ability to maintain erection (p = 0.03), and ability to reach orgasm (p = 0.04) with use of sildenafil citrate. UPDRS and BDI scores were not significantly changed. Side effects included headache in one patient during three sexual encounters. In this open-label study, sildenafil citrate significantly improved sexual function in men with PD and erectile dysfunction.

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Effects of sildenafil on long-term retention of an inhibitory avoidance response in mice.

Baratti CM, Boccia MM.

Laboratorio de Neurofarmacologia de Procesos de Memoria, Catedra de Farmacologia, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Argentina. cbaratti ffyb.uba.ar

Sildenafil (1, 3, 10, and 30mg/kg, intraperitoneally (i.p.)), a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitor, facilitated retention performance of a one-trial step-through inhibitor avoidance task, when administered to male Swiss mice immediately after training, as indicated by performance on a retention test 48 h later. The dose-response curve was an inverted U in this dose range, although only the dose of 3 mg/kg of sildenafil produced significant effects. Sildenafil did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of sildenafil on retention were not due to non-specific proactive effects on retention performance. The effects of sildenafil (3 mg/kg, i.p.) were time-dependent, and the administration of sildenafil (3 mg/kg, i.p.) 30 min prior to the retention test did not affect retention in mice given post-training injections of vehicle or sildenafil (3 mg/kg, i.p.). However, the administration of sildenafil (3mg/kg, i.p.) 30 min before training also enhanced retention performace. Further, when mice were trained and received immediate post-training sildenafil (3 mg/kg) and were tested for retention either 1 week or 1 month later, at each retention interval the performance was comparable to that found with a 48-h retention interval. Finally, an enhancement of retention was also observed in female Swiss mice that received sildenafil (3 mg/kg, i.p.) immediately, but not 180min, after training. These findings could indicate that the actions of sildenafil on retention are not sex-dependent. The results suggest that sildenafil influences retention by modulating time-dependent mechanisms involved in memory storage and that the effects are long lasting. A possible participation of the nitric oxide (NO)-guanylyl cyclase-cGMP system also is suggested.

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Sildenafil for psychotropic-induced sexual dysfunction in 31 women and 61 men.

Salerian AJ, Deibler WE, Vittone BJ, Geyer SP, Drell L, Mirmirani N, Mirczak JA, Byrd W, Tunick SB, Wax M, Fleisher S.

Washington Psychiatric Center, Psychiatric Institute of Washington, DC 20016, USA. piwpsych erols.com

Ninety-two outpatients (31 women, 61 men) who were treated with oral sildenafil for psychotropic-induced sexual dysfunction (PISD) completed ratings of their sexual functioning pre- and posttreatment. Both women and men reported significant improvements (p = .001) in all domains of sexual functioning, with 88% reporting improvement in overall sexual satisfaction. Significant improvements were reported regardless of psychotropic medication type. However, patients taking selective serotonin re-uptake inhibitors reported less improvement in arousal, libido, and overall sexual satisfaction than did other patients, whereas patients taking benzodiazepines reported significantly more improvement in libido and overall sexual satisfaction. Oral sildenafil may be an effective treatment for PISD.

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Cost utility analysis of sildenafil compared with papaverine-phentolamine injections.

Stolk EA, Busschbach JJ, Caffa M, Meuleman EJ, Rutten FF.

Institute for Medical Technology Assessment, Erasmus University Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands. stolk bmg.eur.nl

OBJECTIVE: To compare the cost effectiveness of sildenafil and papaverine-phentolamine injections for treating erectile dysfunction. DESIGN: Cost utility analysis comparing treatment with sildenafil (allowing a switch to injection therapy) and treatment with papaverine-phentolamine (no switch allowed). Costs and effects were estimated from the societal perspective. Using time trade-off, a sample of the general public (n=169) valued health states relating to erectile dysfunction. These values were used to estimated health related quality of life by converting the clinical outcomes of a trial into quality adjusted life years (QALYs). PARTICIPANTS: 169 residents of Rotterdam. MAIN OUTCOME MEASURES: Cost per quality adjusted life year. RESULTS: Participants thought that erectile dysfunction limits quality of life considerably: the mean utility gain attributable to sildenafil is 0.11. Overall, treatment with sildenafil gained more QALYs, but the total costs were higher. The incremental cost effectiveness ratio for the introduction of sildenafil was pound sterling 3639 in the first year and fell in following years. Doubling the frequency of use of sildenafil almost doubled the cost per additional QALY. CONCLUSIONS: Treatment with sildenafil is cost effective. When considering funding sildenafil, healthcare systems should take into account that the frequency of use affects cost effectiveness.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10784537&dopt=Abstract sildenafil Viagra online