Nuclear magnetic resonance investigation of the interaction of water vapor with Sildenafil Citrate (Viagra) in the solid state.

Solid-state carbon-13 ((13)C) and nitrogen-15 ((15)N) nuclear magnetic resonance (NMR) have been used to investigate how water interacts with Sildenafil Citrate (Viagra). When the humidity is altered, the water concentration in the solid compound changes in a reversible manner. The proportion of occupied sites depends on the humidity, but the water concentration never reaches a rational (e.g., 1:1) stoichiometric ratio to form a true hydrate. The NMR spectra were obtained under several humidity-controlled conditions to determine what changes occur as the water content is varied and where the water is located in the crystal structure. Only one set of (15)N and (13)C signals is observed for each humidity level. This shows that water incorporated into the crystal lattice of Sildenafil Citrate (Viagra) is very mobile and exchanges rapidly on the NMR time scale between various sites. The (13)C data are consistent with formation of a hydrogen bond between a water molecule and one carbonyl of the citrate anion. The spectra also show that the water content affects the environment (perhaps influencing the average conformation) of the propyl group. Additionally, (15)N dipolar dephasing experiments show that theSildenafil Citrate (Viagra) molecule is only protonated in the piperazine ring. The work is supported by solution-state NMR. (c) 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:516-523, 2005

Sildenafil: emerging cardiovascular indications.

The discovery in 1989 of sildenafil, a highly selective inhibitor of phosphodiesterase-5 (PDE-5), was the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Initial clinical studies onSildenafil Citrate (Viagra) in the early 1990s were not promising with respect to its antianginal potential. However, the incidental discovery of its antiimpotence effect led to its approval of for the treatment of Erectile Dysfunction. Thereafter, several reports of adverse cardiac events in patients onSildenafil Citrate (Viagra) raised concerns about its safety in cardiovascular disorders. Novel therapeutic indications are emerging forSildenafil Citrate (Viagra) with the recent discovery that PDE-5 is expressed in various other tissues such as the arterial vasculature, including pulmonary and coronary arteries, venous vasculature, skeletal muscles, platelets, and visceral and tracheobronchial muscles. In this review we briefly summarize the pharmacology ofSildenafil Citrate (Viagra) and the current available evidence on its potential therapeutic applications in cardiovascular disorders

Long-term efficacy ofSildenafil Citrate (Viagra) and tachyphylaxis effect.

PURPOSE: We observed that patients who initially responded toSildenafil Citrate (Viagra) frequently became resistant to it with time. We evaluated the long-term efficacy of sildenafil. MATERIALS AND METHODS: A telephone survey was conducted of patients during the first year ofSildenafil Citrate (Viagra) usage, and another one was completed 2 years later of the same group. RESULTS: During the first survey, the etiology of impotence included post radical prostatectomy in 25, arterial insufficiency in 26, diabetes in 19, neurogenic impotence in 12, suspected venous leak in 9, proved venous leak in 7, Peyronie's disease in 6 and unspecified in 47 patients. The overall improvement rate, which was defined as the ability to initiate and maintain erections for successful intercourse, was 74%. The dose necessary to achieve this response was 100 mg.Sildenafil Citrate (Viagra) in 15% of patients, 50 mg. in 83% and 25 mg. in 2%. During the second survey, information was collected on 82 patients and only 43 (52%) had continued treatment. Of the 69 patients who reported an initial good response 41 (59%) were still using sildenafil, and of the 43 who were still using it 16 (37%) had to increase the dose by 50 mg. to achieve an adequate result. There was no significant relationship between the need to increase the dose and frequency of treatment per month. Reduction in efficacy ranged from 15% to 50% (mean 36 +/- 12%) and the time to loss of efficacy ranged from 1 to 18 months (mean 11 +/- 5). Of the 82 patients in the second surgery, 39 (48%) stopped using sildenafil. A total of 28 (74%) patients reported a good initial response on the first survey, and 6 had spontaneous erections and no longer needed treatment. However, 14 (50%) patients discontinuedSildenafil Citrate (Viagra) because of the loss of efficacy. In this group 10 patients had side effects, mainly headache and flushing of the face and nose, and only 2 discontinued treatment because of them. CONCLUSIONS: Our data suggest that there is a possible tachyphylaxis effect with sildenafil. Of the patients who were followed for 2 years 20% had to increase theSildenafil Citrate (Viagra) dose to have the same effect and 17% discontinued use due to loss of efficacy

Sildenafil and Erectile Dysfunction: new preparation. Helpful.

(1) The clinical file is bulky, including 14 double-blind, placebo-controlled trials conducted in normal conditions of use. (2)Sildenafil Citrate (Viagra) effectively treats the symptoms of erection disorders, whatever their origin (psychogenic or organic, especially spinal injuries). Efficacy seems slightly lower in case of diabetes or total prostatectomy. (3) Overall,Sildenafil Citrate (Viagra) allows 80 to 90% of patients to have an erection adequate for sexual intercourse, but only one in two sexual acts on average were considered "satisfactory" by the clinical trial investigators. (4)Sildenafil Citrate (Viagra) does not affect sexual desire. It has not been studied in men without erection disorders. The results of ongoing trials in women are not yet known. (5) The adverse effects ofSildenafil Citrate (Viagra) seem infrequent and generally mild. However, the risk of sudden arterial hypotension if the drug is combined with nitrate derivatives calls for careful safety monitoring. This combination is contraindicated. (6) In our opinionSildenafil Citrate (Viagra) should not be prescribed to anyone with cardiovascular risk factors or a history of heart problems

Chronic ischemia increases prostatic smooth muscle contraction in the rabbit.

PURPOSE: We studied the effect of chronic ischemia on prostatic smooth muscle contraction in the rabbit. MATERIALS AND METHODS: New Zealand male rabbits weighing 3 to 3.5 kg were assigned to 2 groups. Group 1 (10 rabbits) underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet for 4 weeks and then a regular diet for 8 weeks. Control group 2 (10 rabbits) received a regular diet. After 12 weeks the animals were anesthetized. Iliac artery and prostate blood flow was recorded. Prostate tissues were prepared for isometric tension measurement, enzyme immunoassay to determine cyclic guanosine monophosphate (cGMP) release and histological examination. RESULTS: In group 1 atherosclerosis as well as a significant decrease in iliac artery and prostate blood flow were observed. Ischemia significantly increased prostatic tissue contraction, decreased cGMP release and led to capsular and stromal thickening, and epithelial atrophy. The alpha1-adrenoceptor blocker doxazosin and the phosphodiesterase-5 inhibitor Sildenafil Citrate (Viagra) significantly decreased the contraction of control and ischemic tissues. Doxazosin was more effective in decreasing contractions when it was combined withSildenafil Citrate (Viagra) or the nitric oxide (NO) precursor L-arginine. In contrast, doxazosin was less effective when it was combined with the NO synthase inhibitor N omega-nitro-L-arginine or with the guanylate cyclase inhibitor methylene blue. Doxazosin significantly increased cGMP release in control tissues but not in ischemic tissues.Sildenafil Citrate (Viagra) significantly increased cGMP release in control and ischemic tissues. CONCLUSIONS: Ischemia increased prostatic smooth muscle contraction and led to marked structural damage. Stimulators of NO synthesis and cGMP production enhanced the efficacy of doxazosin in decreasing prostatic tissue contraction.Sildenafil Citrate (Viagra) decreased contractility and increased cGMP release. Increased smooth muscle tone and structural changes in the ischemic prostate may suggest a role for prostate ischemia in resistance to urinary flow independent of prostate size

Sildenafil Citrate (Viagra) corrects DeltaF508-CFTR location in nasal epithelial cells from patients with cystic fibrosis.

BACKGROUND: Most patients with cystic fibrosis (CF) have a DeltaF508 mutation resulting in abnormal retention of mutant gene protein (DeltaF508-CFTR) within the cell. This study was undertaken to investigate DeltaF508-CFTR trafficking in native cells from patients with CF with the aim of discovering pharmacological agents that can move DeltaF508-CFTR to its correct location in the apical cell membrane. METHOD: Nasal epithelial cells were obtained by brushing from individuals with CF. CFTR location was determined using immunofluorescence and confocal imaging in untreated cells and cells treated with sildenafil. The effect ofSildenafil Citrate (Viagra) treatment on CFTR chloride transport function was measured in CF15 cells using an iodide efflux assay. RESULTS: In most untreated CF cells DeltaF508-CFTR was mislocalised within the cell at a site close to the nucleus. Exposure of cells toSildenafil Citrate (Viagra) (2 hours at 37 degrees C) resulted in recruitment of DeltaF508-CFTR to the apical membrane and the appearance of chloride transport activity.Sildenafil Citrate (Viagra) also increased DeltaF508-CFTR trafficking in cells from individuals with CF with a single copy DeltaF508 (DeltaF508/4016ins) or with a newly described CF trafficking mutation (R1283M). CONCLUSIONS: The findings provide proof of principle forSildenafil Citrate (Viagra) as a DeltaF508-CFTR trafficking drug and give encouragement for future testing ofSildenafil Citrate (Viagra) and related PDE5 inhibitors in patients with CF

Effects of Sildenafil Citrate (Viagra) on blood pressure in normotensive and hypertensive men.

OBJECTIVES: To determine the occurrence of clinically significant decreases in blood pressure (BP) withSildenafil Citrate (Viagra) use in normotensive and hypertensive men by means of ambulatory BP monitoring. METHODS: On 2 nights, 49 men (22 hypertensive, 27 normotensive) had their ambulatory systolic BP (SBP), diastolic BP (DBP), and heart rate monitored during the first 3 hours (waking period) and every 30 minutes after midnight for 3 additional hours (sleeping period). No medication was taken on one night;Sildenafil Citrate (Viagra) 100 mg was taken on the other. RESULTS:Sildenafil Citrate (Viagra) decreased SBP (-6.0 mm Hg; P = 0.0003), DBP (-4.5 mm Hg; P = 0.001), and mean arterial pressure (-5.3 mm Hg; P = 0.00008). The BP-lowering effects ofSildenafil Citrate (Viagra) did not differ significantly in the normotensive and hypertensive men. Age significantly affected the BP reductions; decreases in SBP, DBP, and mean arterial pressure were greater in men 49 years old and older than in those younger than 49 years old. According to readings averaged over the entire control and treatment periods, 22.7% of hypertensive men and 3.7% of normotensive men experienced SBP reductions of 20 mm Hg or greater (P = 0.08 for comparison of the two groups); the respective values for DBP were 9.1% and 3.7% (P not significant). These reductions were not associated with any hypotensive symptoms. All participants toleratedSildenafil Citrate (Viagra) well. CONCLUSIONS:Sildenafil Citrate (Viagra) caused small, clinically insignificant reductions in ambulatory BP in active and resting normotensive and hypertensive men. The results of this study suggest that, when used in accordance with the prescribing information and current treatment guidelines,Sildenafil Citrate (Viagra) should be safe in younger and older men with or without hypertension

Effects ofSildenafil Citrate (Viagra) on cardiac repolarization.

OBJECTIVES: Sudden death has occasionally been reported in patients taking sildenafil. The objective of this study was to investigate the effect ofSildenafil Citrate (Viagra) on cardiac repolarization. METHODS: We used conventional microelectrode recording technique in isolated guinea pig papillary muscles and canine Purkinje fibers, whole-cell patch clamp techniques in guinea pig ventricular myocytes, and in vivo ECG measurements in guinea pigs. RESULTS: Action potential duration at 90% repolarization (APD(90)) was not affected bySildenafil Citrate (Viagra) in the therapeutic ranges (< or =1 microM), but shortened by higher concentration (> or =10 microM) in both guinea pig papillary muscles and canine Purkinje fibers. D-Sotalol prolonged APD(90) in the same preparations with concentrations > or =1 microM in a reverse frequency-dependent manner. Co-administration ofSildenafil Citrate (Viagra) (10 and 30 microM) abolished the APD-prolonging effects of D-sotalol (30 microM) and amiodarone (100 microM). Sildenafil, with concentrations up to 30 microM, had no significant effect on both the rapid (I(Kr)) and the slow (I(Ks)) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes.Sildenafil Citrate (Viagra) dose-dependently blocked L-type Ca(2+) current (I(Ca,L)), but had no effect on persistent Na(+) current in guinea pig ventricular myocytes. ECG recordings in intact guinea pigs revealed significant shortening of QTc interval bySildenafil Citrate (Viagra) (10 and 30 mg/kg orally). The QT-prolonging effects by D,L-sotalol (50 mg/kg) and amiodarone (100 mg/kg) were abolished bySildenafil Citrate (Viagra) (30 mg/kg). CONCLUSIONS:Sildenafil Citrate (Viagra) does not prolong cardiac repolarization. Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably through its blocking effect on I(Ca,L)