Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats.

Schermuly RT, Kreisselmeier KP, Ghofrani HA, Yilmaz H, Butrous G, Ermert L, Ermert M, Weissmann N, Rose F, Guenther A, Walmrath D, Seeger W, Grimminger F.

Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany.

Sildenafil, a phosphodiesterase 5 inhibitor, is currently under investigation for therapy of pulmonary hypertension. This study was designed to investigate chronic effects of sildenafil in monocrotaline (MCT)-induced pulmonary hypertension in rats. Four weeks after a single subcutaneous injection of MCT, the animals displayed nearly threefold elevated pulmonary artery pressure and vascular resistance values, with a concomitant decline in central venous oxygen saturation and arterial oxygenation. Marked right heart hypertrophy was evident, and massive thickening of the precapillary artery smooth muscle layer was histologically apparent. Further deterioration of pulmonary hypertension occurred 6 weeks after MCT injection, with some animals dying during this period because of right heart failure. When chronically administered from Days 14-28, sildenafil significantly increased plasma cyclic guanosine monophosphate and inhibited the development of pulmonary hypertension and right heart hypertrophy, with preservation of gas exchange and systemic arterial pressure. A corresponding efficacy profile was also noted for long-term feeding with sildenafil from Days 28-42. Moreover, the death rate significantly decreased in those animals treated with sildenafil. We conclude that sildenafil attenuates MCT-induced pulmonary hypertension and cor pulmonale in rats.

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Quality control in the urologist's practice Erectile dysfunction as an example of a multi-centered approach to documenting treatment results in urologist practices.

Junemann KP, Cassens S, Lippert H, Burkart M.

Klinik fur Urologie und Kinderurologie, Universitatsklinikum Schleswig-Holstein, Campus Kiel, Kiel.

Of 517 urologist practices approached, 93% participated in a pilot study on the quality of care in the treatment of erectile dysfunction (ED). Treatment modalities and satisfaction were documented for 10,750 ED patients in 2002-at a time when vardenafil and tadalafil had not yet been officially approved. Psychological factors (55%), BPH (42%), and hypertension (33%) were given as the most prevalent ED risk factors; 82% of the patients received sildenafil, 20% apomorphine, 12% yohimbine, and 10% intracavernous alprostadil. Of the patients, 81% were satisfied or very satisfied with one of the treatment options offered and 85% and more were satisfied or very satisfied with sildenafil's onset of action, duration of action, efficacy, and tolerability. Of the physicians, 97% rated the opportunity to compare their own treatment results with other urologists' results as important or very important.

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Stimulation by theophylline and sildenafil of rat submandibular secretion of protein, epidermal growth factor and flow rate.

Abdollahi M, Simaiee B.

Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran University of Medical Science, Tehran 14155 6451, Iran. mohammad.abdollahi utoronto.ca

In the present study, the effects of cAMP- and cGMP-phosphodiesterase (PDE) inhibitors, theophylline, and sildenafil on secretion of protein, amylase and epidermal growth factor (EGF) and the flow rate from rat submandibular saliva were examined in an acute experiment. Theophylline at doses of 25, 50, 85mgkg(-1) and sildenafil at doses of 1, 2, 5mgkg(-1) were administered intraperitoneally 2h before saliva collection. Pure submandibular saliva was collected intraorally by microployethylene tubes under anesthesia using dissecting microscope.Theophylline at doses of 25, 50, 85mgkg(-1) increased salivary flow rate to 197% (P<0.01), 186% (P<0.01), and 209% of control, respectively. Sildenafil at doses of 1, 2, 5mgkg(-1) also increased flow rate to 232% (P<0.01), 182% (P<0.01), and 197% of control, respectively. Theophylline at doses of 25, 50, 85mgkg(-1) increased total protein concentration to 98% (P<0.01), 84% (P<0.01), and 210% of control, respectively. Sildenafil at doses of 2 and 5mgkg(-1) increased total protein concentration to 75% (P<0.01), and 240% of control, respectively. Theophylline at dose of 85mgkg(-1) increased EGF concentration to 60% (P<0.01) of control. Sildenafil at doses of 2 and 5mgkg(-1) increased EGF concentration to 44% (P<0.05) and 90% (P<0.01) of control, respectively. No statistically significant change was observed in amylase activity by administration of theophylline or sildenafil. The present results indicate that increasing intracellular levels of cAMP and cGMP have stimulatory effects on salivary functions. Regarding beneficiary effects of increased salivary flow rate and secretion of EGF in maintaining oral health, theophylline and sildenafil may find good places in some oral diseases.

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[Combined treatment with intravenous prostacyclin and sildenafil in patients with pulmonary hypertension: report of 4 cases]

[Article in Spanish]

Garcia Hernandez FJ, Ocana Medina C, Mateos Romero L, Martinez Martinez A, Bautista Lorite A, Santos Ramos B, Sanchez Roman J.

Unidad de Colagenosis. Hospital Universitario Virgen del Rocio. Sevilla. Spain.

BACKGROUND AND OBJECTIVE: Here we report the experience obtained from a combined treatment with intravenous (i.v) prostacyclin and oral sildenafil in patients with severe pulmonary hypertension (PHT) who had a poor response to prior treatment with prostacyclin alone. PATIENTS AND METHOD: Sildenafil was added to the treatment in four patients with PHT (primary in two patients and secondary to collagenosis in the other two) with no adequate response to i.v. prostacyclin treatment. The clinical course, 6minutes walking test and echocardiogram were evaluated. RESULTS: Initial sildenafil dose was 12.5 mg three times daily, which was increased up to 50 mg three times daily in one patient and up to 50 mg four times daily in the other three. The symptoms of right heart failure were controlled in all cases. Before the start of sildenafil administration, two patients had class III dyspnea and two patients had class IV dyspnea. Two patients converted to class I (previously class III and IV), and the other two converted to class II. The distance walked within 6 minutes increased (average increase 55%) and systolic pulmonary artery pressure decreased in all patients (average reduction 27%). Effects of sildenafil were substained. The only side effect seen was mild headache. CONCLUSIONS: Our experience supports the value of sildenafil in the treatment of PHT and suggests that combined treatment is useful for rescuing patients who fail to respond to initial treatment with i.v. prostacyclin.

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Sildenafil citrate for the management of antidepressant-associated erectile dysfunction.

Nurnberg HG, Hensley PL.

Department of Psychiatry, Health Sciences Center, University of New Mexico School of Medicine, Albuquerque, NM 87131-52886, USA. geon unm.edu

Sexual side effects of serotonin reuptake inhibitors, such as antidepressant-associated erectile dysfunction, are common and negatively impact treatment compliance. Current management approaches have important limitations, and most lack clear and meaningful efficacy in double-blind, placebo-controlled trials. A MEDLINE search (English language, 1966-2003) was performed using the terms antidepressive agents, erectile dysfunction, and sildenafil. Emphasis was placed on studies that used specific sexual function measurements and were placebo controlled. Sildenafil citrate, a selective and competitive inhibitor of phosphodiesterase type 5, enhances the cyclic guanosine monophosphate-mediated relaxation of cavernosal smooth muscles in response to sexual stimulation, permitting vascular engorgement and penile erection. The efficacy and tolerability of sildenafil in the treatment of antidepressant-associated erectile dysfunction have been confirmed in double-blind, placebo-controlled trials.

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Sildenafil: a new oral therapy for erectile dysfunction.

Noss MB, Christ GJ, Melman A.

Department of Urology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York 10467, USA.

Sildenafil citrate (Viagra) is a relatively selective 5-phosphodiesterase (PDE) inhibitor. It is the first oral medication approved for the treatment of erectile dysfunction (ED). The neuronal release of NO which binds to the heme-containing region of guanylate cyclase increases levels of cGMP. This leads to a cascade of reaction which results in corporal smooth muscle relaxation and penile erection. Sildenafil causes an erection by inhibiting PDE5, which in turn causes an increase in the intracellular levels of cGMP. Sildenafil is well absorbed after a single oral administration with a t(1/2) of approximately 4 h. The mode of onset varies from 0.5-4 h. The drug has been used in millions of men since first approved by the U.S. FDA 1 year ago and has revolutionized the approach to, and therapy of, erectile dysfunction. (c) 1999 Prous Science. All rights reserved.

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Identification of a new analogue of sildenafil added illegally to a functional food marketed for penile erectile dysfunction.

Shin MH, Hong MK, Kim WS, Lee YJ, Jeoung YC.

Busan Regional Food and Drug Administration, Busan 608-829, Korea.

A new analogue of sildenafil was discovered to have been added illegally to a functional food marketed for penile erectile dysfunction. The structure of the analogue was established by various NMR spectroscopic techniques (including DEPT, COSY, TOCSY, HMQC, HMBC). Because of the addition of a methylene group to sildenafil, the main ingredient of Viagra(R), it was given the name homosildenafil, and this has never been reported previously. An analytical method using HPLC was proposed. Homosildenafil was added as a new inspection item and other foods have since been discovered to contain it.

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Physicochemical properties of sildenafil citrate (Viagra) and sildenafil base.

Melnikov P, Corbi PP, Cuin A, Cavicchioli M, Guimaraes WR.

CCET, Department of Physics, UFMS, Cidade Universitaria s/n, CEP 79070-900, Campo Grande, MS, Brazil. petrmelnikov yahoo.com

Sildenafil citrate (Viagra) [I] and sildenafil base [II] are easily and unequivocally characterized by a set of physicochemical methods that include X-ray diffractometry, infrared spectroscopy, and thermal analysis. Monoclinic lattice constants: [I]: a = 26.98 A; b = 11.95 A; c = 16.68 A; beta = 106.97 degrees. [II]: a = 8.66 A; b = 34.27 A; c = 8.93 A; beta = 96.63 degrees. Both compounds decompose at 189.4 degrees C [I] and 251.9 degrees C [II]. Densities and refractive indices are given. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association

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Sildenafil for selective serotonin reuptake inhibitor-induced erectile dysfunction in elderly male depressed patients.

Aizenberg D, Weizman A, Barak Y.

Geha Mental Health Center, Petah-Tiqva, Israel. daizenberg clalit.org.il

Treatment with antidepressants, especially agents with potent serotonergic effects, is frequently associated with sexual side effects. In the present study, we examined the efficacy of sildenafil, a potent phosphodiesterase inhibitor, in the treatment of elderly men (n = 10; 70-81 years) with erectile dysfunction induced by antidepressant treatment for major depressive disorder. Eligible subjects were instructed to add sildenafil (25-50 mg/day) to their current drug treatment. Clinical assessment of erectile function was performed at beginning of treatment with sildenafil and at follow up, 4 weeks later. All patients reported an improvement of their erectile capacity, and in 7 out of 10 subjects, erectile function returned to a normal level. Sildenafil appears to be a safe and well-tolerated agent in elderly subjects. We noted side effects in 2 patients (flashes), but the side-effects were bothersome only to one patient (headache). It appears that sildenafil coadministration improves erectile dysfunction associated with selective serotonin reuptake inhibitor ongoing treatment in elderly patients.

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