Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation.

Prickaerts J, Sik A, Van Der Staay FJ, De Vente J, Blokland A.

Department of Psychiatry and Neuropsychology, Brain and Behavior Institute, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.

RATIONALE. Phosphodiesterase enzyme type 5 (PDE5) inhibitors and acetylcholinesterase (AChE) inhibitors have cognition-enhancing properties. However, it is not known whether these drug classes affect the same memory processes. OBJECTIVE. We investigated the memory-enhancing effects of the PDE5 inhibitor sildenafil and AChE inhibitors metrifonate and donepezil in the object recognition task to find out whether acquisition or consolidation processes were affected by these drugs. METHODS. The object recognition task measures whether rats remembered an object they have explored in a previous learning trial. All drugs were given orally 30 min before or immediately after learning to study acquisition and consolidation, respectively. RESULTS. Sildenafil given immediately after the first trial improved the memory performance after 24 h and resulted in an inverted U-shaped dose-effect curve with the peak dose at 3 mg/kg. When given before the first trial, sildenafil also improved the memory performance. However, the dose needed for the best performance under this condition was 10 mg/kg, suggesting that the dose-effect curve shifted to the right. This can be explained by the metabolic clearance of the high dose of sildenafil. Donepezil had no memory improving effect when given after the first trial. However, when given before the first trial, a gradually increasing dose-effect curve was found which had its maximum effect at the highest dose tested (1 mg/kg). Likewise, only when metrifonate (30 mg/kg) was given before the first trial did rats show an improved memory performance. CONCLUSION. Our data strongly suggest that PDE5 inhibitors improve processes of consolidation of object information, whereas AChE inhibitors improve processes of acquisition of object information.

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Acute effects of sildenafil on Humphrey visual field and intraocular pressure.

Ermis SS, Inan UU, Samli M, Ozturk F.

Department of Ophthalmology, School of Medicine, University of Afyon Kocatepe, Afyon, Turkey. sametermis hotmail.com

PURPOSE: To evaluate the effects of sildenafil on visual field and intraocular pressure in a group of healthy subjects. METHODS: Twenty-eight healthy male volunteers with normal eyes were included in the study. Visual field examinations were performed using FASTPAC 30-2 program (white-on-white and blue-on-yellow) with the Humphrey field analyzer before and one hour after receiving oral 50 and 100 mg sildenafil citrate. RESULTS: The mean age was 51.1 +/- 8.9 years. Mean deviation, pattern standard deviation, short-term fluctuation and corrected pattern standard deviation did not differ significantly among tests both in white-on-white and blue-on-yellow visual field examinations. Changes in intraocular pressure were not statistically significant. CONCLUSIONS: No significant effect of sildenafil was seen on visual field and intraocular pressure in healthy subjects.

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Oxidative stress and antioxidant therapy: their impact in diabetes-associated erectile dysfunction.

De Young L, Yu D, Bateman RM, Brock GB.

Department of Urology, St Joseph's Health Care, London, Canada N6A 4V2.

Oxidative stress is believed to affect the development of diabetic-associated vasculopathy, endothelial dysfunction, and neuropathy within erectile tissue. Our hypothesis is that, given adequate concentrations of the oxygen free radical scavenger vitamin E, enhanced levels of circulating nitric oxide (NO) should improve erectile function with the potential for a synergistic effect with a phosphodiesterase type 5 (PDE5) inhibitor. Twenty adult male Sprague-Dawley streptozotocin-induced (60 mg/kg intraperitoneally) diabetic rats were placed in 4 therapeutic groups (n = 5 per group) as follows: 1) peanut oil only (diabetic control), 2) 20 IU of vitamin E per day, 3) 5 mg/kg of sildenafil per day, and 4) vitamin E plus sildenafil using oral gavage for 3 weeks. In addition, 5 age-matched rats served as normal nondiabetic controls (normal). Erectile function was assessed by measuring the rise in intracavernous pressure (ICP) following cavernous nerve electrostimulation. Penile tissue was evaluated for neuronal NO synthase (nNOS), smooth muscle alpha-actin, nitrotyrosine, and endothelial cell integrity. Urine nitrite and nitrate (NOx) concentration was quantified, and electrolytes were tested by a serum biochemistry panel. A significant decrease in ICP was recorded in the diabetic animals, with improvement measured in the animals receiving PDE5 inhibitors either with or without vitamin E; the controls had a pressure of 54.8 +/- 5.3 cm H2O, the vitamin E group had a pressure of 73.5 +/- 6.6 cm H2O, the sildenafil group had a pressure of 78.4 +/- 10.77 cm H2O, and the vitamin E plus sildenafil group had a pressure of 87.9 +/- 5.5 cm H2O (P <.05), compared with the normal cohorts at 103.0 +/- 4.8 cm H2O. Histoexaminations showed improved nNOS, endothelial cell, and smooth muscle cell staining in the vitamin E plus sildenafil group compared to the control animals. Urine NOx increased significantly in all the diabetic groups but was blunted in the vitamin E and vitamin E plus sildenafil groups. A significant increase in positive staining for nitrotyrosine was observed in the vitamin E plus sildenafil group. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in this study, supporting the potential use of oxygen free radical scavengers in salvaging erectile function in diabetic patients.

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Erectile dysfunction in kidney transplanted patients: efficacy of sildenafil.

Russo D, Musone D, Alteri V, Cindolo L, Lanzillo B, Federico S, Andreucci VE.

Departments of Nephrology, School of Medicine, University Federico II Naples, Naples, Italy. gigi.russo libero.it

BACKGROUND: Erectile dysfunction (ED) is the inability to achieve and/or maintain an erection for satisfactory sexual performance. The effects of kidney transplantation on pre-existing ED are poorly understood, as well as the onset of new ED cases after kidney transplantation. This study aimed to evaluate the effects of kidney transplantation on pre-existing ED, to assess the onset of new ED cases after renal transplantation and to assess both the efficacy and safety of sildenafil. METHODS: Erectile function was assessed using the self-administered International Index of Erectile Function (IIEF) to kidney transplanted patients. A 50 mg dose of sildenafil was prescribed. Sildenafil efficacy was assessed by re-administering the questionnaire after 4 weeks of therapy. Blood chemistry and serum cyclosporine concentration were evaluated at the beginning of the study and, in patients treated with sildenafil, after 4 weeks of treatment. RESULTS: One hundred and thirteen patients (87.5%) completed the questionnaire. Fifty-three patients (47%) did not complain of ED, the remaining 60 patients (53%) reported ED. ED was already present during dialysis in 40 patients; it appeared ex novo in 20 patients after transplantation. Pre-existing ED disappeared in 8 patients (20%), ameliorated in 13 patients (32.5%), worsened in 2 patients (5%), and remained unchanged in 17 patients (42.5%) after transplantation. The IIEF score significantly improved in sildenafil-treated patients (n=20); there were no observed changes in blood chemistry, blood pressure (BP), renal function and cyclosporine concentration. The side-effects were minimal. CONCLUSIONS: ED was still present in a large cohort of kidney transplanted men. Renal transplantation cures few ED cases. ED can appear ex novo after transplantation. Sildenafil is an effective ED treatment in kidney transplanted men.

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Screening for potentially transmitting sexual risk behaviors, urethral sexually transmitted infection, and sildenafil use among males entering care for HIV infection.

Cachay E, Mar-Tang M, Mathews WC.

Owen Clinic, Department of Medicine, University of California at San Diego, San Diego, California 92103-8681, USA.

The study aims were to evaluate the prevalence and predictors of sexual risk behaviors and urethral sexually transmitted disease (STD) among males entering care for HIV infection and to examine if sildenafil prescriptions are associated with potentially transmitting sexual risk behavior (PTSRB). The research design included (1) self-administered questionnaire of symptoms of sexually transmitted infection (STI), number of recent sex partners, unprotected sexual risk behaviors, use of drugs/alcohol during sex, and HIV disclosure; (2) urine gonorrhea/chlamydia polymerase chain reaction (PCR); and (3) record review for sildenafil prescriptions. A PTSRB was defined as insertive anal, vaginal, or oral sex without a condom. Between March 2001 and March 2002, 413 entrants were surveyed. The prevalence of positive urine PCR among those with and without urethral symptoms was 16.7% and 2.4%, respectively. Fifty-one percent met criteria for PTSRB during the preceding month. Those reporting PTSRB were more likely to report multiple partners. In a multiple logistic regression model, the following were significant (p < 0.05) predictors of PTSRB: drug or alcohol use during sex; white race; only male partners, and sildenafil use. Drug use during sex was associated both with more sex partners and more sexual risk behaviors. Always disclosing HIV status was associated with fewer partners. There was a high prevalence of PTSRB among HIV-infected males entering care. Men who have sex with men (MSM), white race, drug/alcohol use during sex, and sildenafil use were independent risk factors. PTSRB was associated with having multiple partners. Physicians should discuss risk behaviors before prescribing sildenafil.

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Relaxant action of sildenafil citrate (Viagra) on human myometrium of pregnancy.

Khan RN, Hamoud H, Warren A, Wong LF, Arulkumaran S.

Academic Division of Obstetrics and Gynaecology, University of Nottingham, The Medical School, Derby City General Hospital, Derby, United Kingdom. raheela.khan nottingham.ac.uk

OBJECTIVE: The purpose of this study was to investigate the effect of the cyclic guanosine monophosphate phosphodiesterase 5-specific inhibitor, sildenafil citrate, on the contractions of isolated pregnant human myometrium. STUDY DESIGN: Myometrial samples were obtained from women who underwent elective cesarean delivery. Myometrial contractions that were recorded in response to sildenafil in the absence and presence of the potassium channel blocker, tetraethylammonium or the guanylate cyclase inhibitor, methylene blue (10 micromol/L) were studied. One-way analysis of variance with post-hoc analysis was used to test differences among groups. RESULTS: Sildenafil caused relaxation of myometrium in a concentration-dependent manner. The log(10) EC(50) value for this relaxation in the presence of 20 mmol/L tetraethylammonium was significantly different (P<.01) than values that were obtained with sildenafil alone or sildenafil in the presence of either methylene blue or 5 and 10 mmol/L tetraethylammonium. CONCLUSION: Myometrial relaxation that is evoked by the direct application of sildenafil occurs independently of cyclic guanosine monophosphate. Potassium channels appear to be the likely candidates in mediating this response.

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Pilot assessment of the response of several pulmonary hemodynamic variables to sublingual sildenafil in candidates for heart transplantation.

Angel Gomez-Sanchez M, Saenz De La Calzada C, Escribano Subias P, Francisco Delgado Jimenez J, Lazaro Salvador M, Albarran Gonzalez A, Cea Calvo L.

Heart Failure and Pulmonary Hypertension Unit, Cardiology Department, Hospital Universitario Doce de Octubre, Avda de Cordoba s/n, Madrid, Spain.

OBJECTIVE: To determine the acute vasodilator effect of sublingual sildenafil in heart transplant candidates with severe pulmonary hypertension due to severe left ventricular dysfunction (LVD). BACKGROUND: Pulmonary hypertension confers an increased risk of early graft failure. PATIENTS AND METHODS: Seven patients, (mean age of 53+/-8) with severe LVD (mean EF: 19+/-1.7%, functional class III-IV) due to coronary artery disease, dilated cardiomyopathy and valvulopathy were evaluated for heart transplant. All patients presented a mean transpulmonary gradient >12 mmHg and pulmonary vascular resistances >2.5 W.U., despite full treatment for advanced heart failure. The following hemodynamic data were obtained at basal state and then 15, 30 and 45 min after administration of 100 mg of sublingual sildenafil: right atrial, mean pulmonary artery pressure (mPAP), mean pulmonary capillary wedge pressures, mean transpulmonary gradient (mTPG), blood pressure, cardiac output, pulmonary vascular resistances (PVR) and systemic vascular resistances. Sublingual sildenafil was given without changing the previous treatment of heart failure. RESULTS: After 30 min of sublingual sildenafil, mPAP decreased from 37 (28-61) to 30 (16-42) mmHg and PVR decreased from 5.2 (1.9-13.8) to 2.5 (1.4-3.9) W.U. after 45 min. Mean TPG decreased from 19 (16-33) to 12 (8-14) mmHg at 45 min. Mean pulmonary capillary wedge pressure, cardiac output, systemic vascular resistances and mean blood pressure were unchanged. Sublingual sildenafil was well tolerated, with only transient facial flushing in 4 patients and mild headache in 2. CONCLUSIONS: Based on this initial study, sublingual sildenafil may be a useful alternative drug to perform acute vasodilator test in heart transplant candidates with significant pulmonary hypertension due to severe LVD. Nevertheless, further studies are warranted to confirm our results.

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Vardenafil: structural basis for higher potency over sildenafil in inhibiting cGMP-specific phosphodiesterase-5 (PDE5).

Corbin JD, Beasley A, Blount MA, Francis SH.

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 702 Light Hall, Nashville, TN 37232-0615, USA.

Phosphodiesterase-5 (PDE5) inhibitors act by competing with the substrate, cGMP, for the catalytic site of the enzyme. Two commercialized PDE5 inhibitors, sildenafil and vardenafil, are being used to treat erectile dysfunction. These two compounds differ in the heterocyclic ring system used to mimic the purine ring of cGMP. They also differ in the substituent (ethyl/methyl) of a piperazine side chain. Although these are the only two structural differences, vardenafil has more than 20-fold greater potency than sildenafil for inhibiting purified PDE5. The molecular structural basis for the difference in potency of the two compounds was investigated by synthesizing an analog of sildenafil ("methyl-sildenafil") that contained the sildenafil ring system but with the appended ethyl group found in vardenafil, and an analog of vardenafil ("demethyl-vardenafil") that contained the vardenafil ring system but with the appended methyl group found in sildenafil. The IC50 of methyl-sildenafil for inhibiting PDE5 indicated that it was 64 times less potent than demethyl-vardenafil, which was similar to the finding that, based on IC50, sildenafil was 40 times less potent than vardenafil. Similarly, the EC50 of methyl-sildenafil for inhibiting [3H]vardenafil binding to PDE5 indicated that it was 84 times less potent than demethyl-vardenafil, while the EC50 for sildenafil indicated that it was 31 times less potent than vardenafil. It is concluded that the methyl/ethyl appended group on the piperazine moiety plays very little role in the difference in potency between sildenafil and vardenafil for inhibiting PDE5, whereas the differences in the ring systems play a critical role in higher potency of vardenafil over sildenafil.

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