Ultrastructural effect of sildenafil citrate on corpus cavernosum and other genital organs in female rats.

Kilinc K, Gunduz MI, Gumus BH, Vatansever S, Kaymaz F.

Department of Urology, Medical Faculty, Celal Bayar University, 45010 Manisa, Turkey.

AIM: To determine the ultrastructural effects of sildenafil on the female genital organs. METHODS: Twenty female cycling Wistar albino rats weighing 250+/-20 g were randomly divided into two groups of 10 each. Rats of one group were gavaged with 0.5 mg.kg(-1).d(-1) of sildenafil 3 days in a week for 4 weeks and the other served as the controls. After cessation of treatment animals were sacrificed by cervical dislocation under methoxyflurane anaesthesia. The clitoris, vagina, uterus and bartholin glands were taken at the estrous and were fixed with 10% formalin solution for light microscopy and 2.5% glutaraldehyde and osmic acid for electron microscopy. RESULTS: Under the light microscope, the fibrocollageous tissue was found increased, the capillaries enlarged and the connecting tissue elements increased in the corpus cavernosum in the treated group. On electron microscopy, increased connective tissue, fibroblasts with notched nucleus, shorten immature collagen fibers without striation were seen. Abundant foldings and penetration with collagen bundles were observed in the basal membrane. Large connection complexes, especially gap junctions among the wide capillary endothelial cells were observed. CONCLUSION: There are evident histological changes due to sildenafil citrate in female rat corpus cavernosum. The clitoris and bartholin glands were the most effected organs. While the histopathological changes of clitoral tissue could be expected, an increase in the mass of bartholin gland was surprising.

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HPLC-MS for the determination of sildenafil citrate (Viagra) in biological fluids. Application to the salivary excretion of sildenafil after oral intake.

Tracqui A, Ludes B.

Institut de Medecine Legale, Faculte de Medecine de Strasbourg, 11 rue Humann, 67085 Strasbourg, France. atracqui mageos.com

An original high-performance liquid chromatography-mass spectrometry (HPLC-MS) procedure was developed for the determination of sildenafil in biological fluids. Liquid-liquid extraction was performed by chloroform/2-propanol/n-heptane (25:10:65, v/v) at pH 9.5 with 300 ng of buprenorphine-d4 as the internal standard (IS). After agitation (10 min) and centrifugation (3500 x g, 10 min), the organic phase was evaporated and the dry extract resuspended in 25 microL methanol, from which 2 microL was injected onto a NovaPak C18 (Waters) HPLC column. Separation was carried out by a gradient of (acetonitrile + 10 microg/mL trimethylamine) in 2mM NH4COOH pH 3.0 buffer (35-70% in 9 min). Detection was done by a PerkinElmer Sciex API-100 single-quadrupole mass analyzer with an ionspray interface operated in positive-ion mode. MS data were collected as either TIC or SIM at m/z (475 + 534) or (475 + 283) for sildenafil, depending on the potential applied at the ion sampling orifice (0 V or + 100 V). The retention times of sildenafil and the IS were 4.20 and 5.07 min, respectively. Extraction recoveries were always > 87%. LOD and LOQ were 0.2 and 0.5 ng/mL whatever the biological fluid tested. The method appears specific, extremely sensitive, and relatively simple in both equipment and sample preparation. As an example, we present the results of a preliminary study on the salivary excretion of sildenafil following the oral intake (T0) of 25 mg Viagra in a 38-year-old volunteer. Sildenafil was detectable in oral fluid at T0 + 0.5 h (1.2 ng/mL) and peaked at T0 + 1.5 h (8.3 ng/mL), whereas at the same time its plasma concentration was 72.4 ng/mL. Salivary concentrations then rapidly decreased, and the last detectable value (0.9 ng/mL) was at T0 + 5.5 h. It is suggested that the salivary excretion pattern of sildenafil resembles that of benzodiazepines (high plasma protein binding, low saliva-to-plasma ratio).

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Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure.

Chen Y, Traverse JH, Hou M, Li Y, Du R, Bache RJ.

Department of Medicine, Division of Cardiology, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA.

Inhibition of phosphodiesterase type 5 (PDE5) can relax systemic and coronary vessels by causing accumulation of cGMP. Both the endothelial dysfunction with decreased nitric oxide production and increased natriuretic peptide levels in congestive heart failure (CHF) have the potential to alter cGMP production, thereby influencing the response to PDE5 inhibition. Consequently, this study examined the effects of PDE5 inhibition with sildenafil in dogs with CHF produced by rapid ventricular pacing. CHF resulted in decreases of left ventricular (LV) systolic pressure, coronary blood flow, and the maximal first time derivative of LV pressure (LV dP/dt(max)) at rest and during treadmill exercise compared with normal, whereas resting LV end-diastolic pressure increased from 10 +/- 1.4 to 23 +/- 1.4 mmHg. Sildenafil (2 and 10 mg/kg per os) caused a 5- to 6-mmHg decrease of aortic pressure (P < 0.05), with no change of heart rate, LV systolic pressure, or LV dP/dt(max). Sildenafil caused no change in coronary flow or myocardial oxygen consumption in animals with CHF at rest or during exercise. In contrast to findings in normal animals, sildenafil did not augment endothelium-dependent coronary vasodilation in response to acetylcholine in animals with CHF. Furthermore, Western blotting showed decreased PDE5 protein expression in myocardium from failing hearts. These findings demonstrate that PDE5 contributes little to regulation of coronary hemodynamics in CHF.

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Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension.

Ghofrani HA, Schermuly RT, Rose F, Wiedemann R, Kohstall MG, Kreckel A, Olschewski H, Weissmann N, Enke B, Ghofrani S, Seeger W, Grimminger F.

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

Only a small percentage of patients with chronic thromboembolic pulmonary hypertension are eligible for pulmonary thrombendarterectomy. We investigated the effects of oral sildenafil on hemodynamics and exercise capacity in 12 nonoperable chronic thromboembolic pulmonary hypertension patients. All patients were in disease progression despite sufficient long-term anticoagulation and the best supportive care and suffered from severe pulmonary hypertension (pulmonary vascular resistance index 1,935 +/- 228 dyn. s. cm-5. m2, cardiac index 2.0 l. min-1. m-2, 6-minute walking distance 312 +/- 30 m). After approximately 6 months of sildenafil treatment, pulmonary hemodynamics and exercise capacity improved significantly (pulmonary vascular resistance index 1,361 +/- 177 L. min-1. m2, p = 0.004, cardiac index 2.4 +/- 0.2 L. min-1. m-2, p = 0.009, 6-minute walking distance 366 +/- 28 m, p = 0.02). Therefore, oral sildenafil may offer a new option for medical treatment of this devastating disease.

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Effects of phosphodiesterase 3,4,5 inhibitors on hepatocyte cAMP levels, glycogenolysis, gluconeogenesis and susceptibility to a mitochondrial toxin.

Abdollahi M, Chan TS, Subrahmanyam V, O'Brien PJ.

Graduate Department of Pharmaceutics, Faculty of Pharmacy, University of Toronto, Toronto, Canada.

Various phosphodiesterase (PDE) 3,4 and 5 inhibitors have been compared with glucagon for their effectiveness at increasing hepatocyte cAMP, glycogenolysis and gluconeogenesis. Preincubation of isolated hepatocytes with PDE 3 and 4 inhibitors (50 microM) for 2 h induced significant increases in cellular cAMP level. The order of effectiveness was: glucagon (78%), V11294A (42%), rolipram (40%), milrinone (36%), CDP-840 (33%), R(0) 20-1724 (31%), papaverine (27%), isobutylmethylxanthine (28%), isoliquiritigenin (25%), theophylline (22%), and amrinone (22%). The PDE 5 inhibitors dipyridamol and sildenafil had only a slight effect on cAMP levels. Glucose formation was increased as a result of increased glycogenolysis in the following order of effectiveness: glucagon (89%), V11294A (63%), rolipram (61%), milrinone (50%), CDP-840 (46%), R(0) 20-1724 (45%), sildenafil (34%), dipyridamol (31%), papaverine (30%), isobutylmethylxanthine (29%), theophylline (20%), amrinone (20%), and isoliquiritigenin (20%). Rolipram and milrinone, selective PDE 4 and PDE 3 inhibitors respectively, stimulated the gluconeogenesis of alanine, lactate + pyruvate, or fructose in hepatocytes isolated from fasted rats. On the other hand, selective cGMP specific phospodiesterase inhibitors, sildenafil and dipyridamol inhibited alanine-induced gluconeogenesis. All PDE inhibitors increased hepatocyte susceptibility to cyanide toxicity (3-4 fold) which was prevented by fructose whereas PDE 5 inhibitors did not significantly increase hepatocyte susceptibility.

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Effect of sildenafil (Viagra) on cerebral blood flow velocity: a pilot study.

Arnavaz A, Aurich A, Weissenborn K, Hartmann U, Emrich HM, Schneider U.

Department of Clinical Psychiatry and Psychotherapy, Medical School Hannover, 30625 Hannover, Germany.

Sildenafil (Viagra) is a selective inhibitor of the cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5 (PDE5) used for the oral treatment of male erectile dysfunction due to vasodilation. However, assessment of direct effects of sildenafil on cerebral arteries is unknown. The aim of this present experiment is to measure the possible changes in blood flow velocity of the middle cerebral artery after the administration of sildenafil and a placebo. Blood-flow velocity changes of the middle cerebral artery were measured before and 1 to 2 h after the administration of the drug. Neither the intake of sildenafil nor the application of placebo resulted in any significant changes in blood flow velocity of the right middle cerebral artery. The next step for future experiments will be in vitro measurement of the diameters of the cerebral arteries under the influence of sildenafil and in vivo measurement of carbon dioxide and cerebral blood flow velocity during sexual stimulation after sildenafil intake instead of under resting conditions.

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[Erectile dysfunction after radial prostatectomy. Response to treatment with sildenafil citrate]

[Article in Spanish]

Cruz Gimeno JL, Martinez-Pineiro L, Ramon de Fata F, Garcia Mediero JM, de la Pena Barthel J.

Servicio de Urologia, Hospital Universitario La Paz, Universidad Autonoma de Madrid, Madrid, Espana. jlcruz clubole.com

OBJECTIVES: Erectile dysfunction is one of the sequelae after radical prostatectomy most concerning for the patient, its appearance being influenced by factors such as surgical technique, or patient's age. Thus, around 40% of the patients younger than 70 years and over 90% of the patients older than 70 present with erectile dysfunction after prostatectomy. We studied the response to sildenafil citrate in patients who underwent non nerve sparing radical prostatectomy. METHODS: Medical records of 100 patients who underwent radical prostatectomy at our department between 1985 and 1998 were retrospectively reviewed and telephone interviews were done to investigate the degree of erectile dysfunction following surgery. All patients were offered to start a two-month therapeutic trial with sildenafil citrate, in dose escalation up to a maximum of 100 mg. Therapeutic response was evaluated by personal interviews. RESULTS: 5 out of 100 patients interviewed showed similar potency than preoperatively. Among 95 patients with erectile dysfunction 63 (66.3%) did not wish treatment for erectile dysfunction. 22 of the remainder 32 patients initiated treatment with sildenafil citrate, whereas 10 preferred trying intracavernous PGE1 injections only. In the intracavernous injections group 5 patients abandoned because of pain with injections and refused any further treatment with oral drugs; 5 patients are satisfied with intracavernous therapy and they do not want to try sildenafil. In the sildenafil group form 22 patients starting treatment 14 (63.6%) are satisfied, with a subjective improvement. Only 5 patients (22%) show an erectile response enough to have sexual intercourse with penetration. 8 (36.5%) abandon treatment because of lack of efficiency. CONCLUSIONS: 5% of the patients who undergo non nerve sparing radical prostatectomy maintain sexual potency without treatment postoperatively. Most patients with postoperative erectile dysfunction (63/95 = 66.3%) do not want any treatment. From 22 patients initiating treatment with sildenafil 5 can have sexual intercourse with penetration (5/22 = 22%), all of them with 100 mg doses of sildenafil.

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Effects of sildenafil citrate (Viagra) on hemodynamic parameters during exercise testing and occurrence of ventricular arrhythmias in patients with erectile dysfunction and cardiovascular disease.

Vardi Y, Bulus M, Reisner S, Nassar S, Aboud L, Sprecher E, Gruenwald I.

Department of Neuro-Urology, Rambam Medical Center, Haifa, Israel. yvardi rambam.health.gov.il

BACKGROUND: Erectile dysfunction (ED) is frequently observed in male cardiovascular disease (CVD) patients, creating concern about cardiac risk of their sexual activity, and their therapeutic use of sildenafil. Relatively little information exists about sildenafil effects on exercise testing, hemodynamic parameters or on occurrence of ventricular arrhythmias during normal activities in CVD patients. HYPOTHESIS: Single, oral doses of sildenafil do not significantly affect exercise-induced changes in hemodynamic parameters or occurrence of arrhythmias in ED/CVD patients. METHODS: ED patients, with or without CVD, were enrolled in one of two studies. In the first, patients underwent standard (Bruce Protocol) treadmill tests; an initial control test was followed 1 hour later by administration of 100mg oral sildenafil. After another hour, they underwent a second treadmill test. Systolic and diastolic blood pressure (SBP and DBP), heart rate, and double product were determined for each evaluation at pretest, maximum stress, and recovery. In the second, Holter ambulatory ECGs were recorded 5 hours before and 6 hours after 100mg oral sildenafil administration. RESULTS: Sildenafil had no clinically significant effects on exercise-induced changes in hemodynamic parameters in cardiac patients and only slight, clinically insignificant effects in noncardiac patients. ECG showed sildenafil did not affect incidence of ventricular arrhythmias. CONCLUSIONS: Sildenafil does not alter hemodynamic response to exercise or change incidence of ventricular arrhythmias in men with CVD and ED. These results suggest that, when used in accordance with prescribing information and current treatment guidelines, sildenafil should be safe for most patients with both these conditions.

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