sildenafil-citrate and Diabetic-Angiopathies

Erectile dysfunction is a common multi-factorial complication of diabetes mellitus. Numerous strategies have been tried to overcome this diabetic complication. In recent years, phosphodiesterase type 5 (PDE-5) inhibitors have been introduced in the management of erectile dysfunction.. The objective of this review was to assess the effect of PDE-5 inhibitors on the management of erectile dysfunction in diabetic men.. Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library.. Randomised controlled trials, in which treatment with PDE-5 inhibitors was compared to control, in diabetic patients with erectile dysfunction.. Two reviewers independently extracted data and assessed trial quality.. Eight randomised controlled trials were identified. A total 976 men were allocated to receive a PDE-5 inhibitor and 741 were randomised to the control groups. Overall, 80% of the participants suffered from type 2 diabetes mellitus. The weighted mean difference (WMD) for the International Index of Erectile Function (IIEF) questions 3 and 4 (frequency of penetration during and maintaining erection to completion of intercourse) was 0.9 (95% CI 0.8 to 1.1) and 1.1 (95% CI 1.0 to 1.2) at the end of the study period, in favour of the intervention group. The WMD for the IIEF erectile dysfunction domain at the end of the study period was 6.6 (95% CI 5.2 to 7.9) in favour of the PDE-5 inhibitors arm. The relative risk (RR) for answering "yes" to a global efficacy question ( "did the treatment improve your erections?") was 3.8 (CI 95% 3.1 to 4.5) in the PDE-5 inhibitors compared with the control arm. The WMD between the percentage of successful attempts in the PDE-5 inhibitors and in the control arm was 26.7 (95% CI 23.1 to 30.3). Mortality was not reported in any of the included trials. Adverse cardiovascular effects were reported in one study. Headache was the most frequent adverse event reported, flushing was the second most common event, with upper respiratory tract complaints and flu like syndromes, dyspepsia, myalgia, abnormal vision and back pain also reported in a descending order of frequency. The overall risk ratio for developing any adverse reaction was 4.8 (CI 95% 3.74 to 6.16) in the PDE-5 inhibitors arm as compared to the control.. Sufficient evidence exists that PDE-5 inhibitors form a care that improves erectile dysfunction in diabetic men.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetic Angiopathies; Erectile Dysfunction; Humans; Imidazoles; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

Risk factors for erectile dysfunction (ED) (hypertension, diabetes, smoking, lipid abnormality) are also risk factors for coronary artery disease. However, most cardiologists do not routinely ask about ED and patients often are reluctant or embarrassed to discuss it. We determined how common ED was in a group of patients with chronic stable coronary artery disease.. We administered the validated Sexual Health Inventory for Men (SHIM) 5-item questionnaire, based on the International Index of Erectile Function questionnaire, to 76 men with chronic stable coronary artery disease during routine outpatient cardiology visits. Most of these men had not previously discussed ED with their cardiologist.. The mean patient age was 64 years (range 40 to 82). The questionnaire took about 5 minutes to complete. Of the patients 47% were on beta blockers, 92% statins, 28% diuretics. SHIM score was 21 or less in 53 men (70%), which is indicative of ED. Of the patients 75% had some difficulty achieving erections (question 2) and 67% had some difficulty maintaining an erection after penetration (question 3). The questionnaire reflected successful sildenafil treatment in 4 patients (SHIM scores 23 to 25). If these 4 men are included as having had ED then 57 of 76 (75%) had ED or recent history of ED.. ED is extremely common in men with chronic coronary artery disease (affecting approximately 75%) yet most cardiologists do not ask about it. The SHIM is a useful, quick and inexpensive tool for discussion and diagnosis of ED in this population. Although it is well established that cardiovascular risk factors are associated with erectile dysfunction, once it is present there is mixed information on whether treating the risk factors will treat the ED. Problems appear to be that lifestyle modification in midlife may simply be too late to effect a change, and some antihypertensive and lipid lowering drugs may actually exacerbate ED. Oral therapy for ED, namely the PDE5 inhibitors, is effective and safe in most cardiac and hypertensive patients. Organic nitrates such as nitroglycerin remain a contraindication to the concomitant use of these drugs. Guidelines for treatment of ED in the cardiac patient issued by the American College of Cardiology/American Heart Association and Princeton Guidelines may be useful in the approach to the cardiac patient with ED.

Topics: Comorbidity; Coronary Disease; Diabetic Angiopathies; Erectile Dysfunction; Heart Diseases; Humans; Hypertension; Imidazoles; Life Style; Male; Penile Erection; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Smoking; Sulfones; Triazines; Vardenafil Dihydrochloride

Diabetes can induce sexual disorders by different mechanisms. These troubles are more frequent in diabetics subjects. Thus, management of sexual impotence is an important aspect of diabetes care. However, most diabetologists are not trained to treat sexual disorders. The recent availability of oral drugs, i. e. Sildenafil (Viagra), has partly simplified the treatment of sexual impotence, particularly in diabetic patients. However, Viagra is efficient in only 60% cases in diabetic subjects. In the remaining cases, intracavernosal injections or vacuum can be used. Since Viagra has been available, more diabetic patients complained with sexual disorders, and ask for treatment of impotence. Cardio-vascular diseases must retain more attention in diabetic patients who are exposed to silencious myocardial ischemia. In such subjects, Viagra is not contra-indicated, but must be used after myocardial explorations, especially if the patients have cardio-vascular risk factors. However, patients and their doctors have been threatened by death cases reported with Viagra in United States. The lack of detailed informations has restrained Viagra's prescription. The following explains how to manage sexual disorders as part of diabetes care, and suggests rules for Viagra's prescription in diabetic patients.

Topics: Cardiovascular Diseases; Contraindications; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Erectile Dysfunction; Humans; Male; Myocardial Ischemia; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Diabetic patients have a reduced endothelial response to phosphodiesterase-5 inhibitors. The aim of this study was to determine the effects of chronic therapy with sildenafil on endothelial function in patients with Type 2 diabetes mellitus (DM2).. In a double-blind, placebo-controlled parallel design, 20 patients without erectile dysfunction randomly received a loading dose of sildenafil (100 mg) for 3 days, followed by either sildenafil 25 mg three times a day (t.d.s.) for 4 weeks or sildenafil 25 mg t.d.s. for 4 days followed by placebo t.d.s. for 3 weeks.. After 1 week, flow-mediated dilatation (FMD) improved significantly (> 50% compared with baseline) in patients allocated to both sildenafil arms (62 and 64%, respectively). In patients allocated to chronic sildenafil, a progressive increase in percentage of patients with FMD improvement was noted (78, 86 and 94% at 2, 3 and 4 weeks, respectively) while a progressive decrease in the placebo group occurred (45, 18 and 6% at 2, 3 and 4 weeks, respectively). At the end of the study, a significant improvement in FMD compared with baseline was noted after chronic sildenafil (FMD from 6.8 +/- 0.5 to 12.5 +/- 0.7%, P = 0.01 vs. baseline). A decrease in endothelin-1 levels and an increase in nitrite/nitrate levels were found after chronic sildenafil; significant changes from baseline in C-reactive protein, interleukin 6, intercellular adhesion molecule and vascular adhesion molecule levels were also found.. In DM2 patients, daily sildenafil administration improves endothelial function and reduces markers of vascular inflammation, suggesting that the diabetes-induced impairment of endothelial function may be improved by prolonged phosphodiesterase-5 inhibition.

Topics: Adult; Aged; Biomarkers; Brachial Artery; C-Reactive Protein; Cell Adhesion Molecules; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; Humans; Interleukin-6; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilation; Vasodilator Agents

In the 5-10% of diabetic men with type 1 diabetes, erectile dysfunction (ED) may be a particularly common and unwanted complication. This is the first study focusing exclusively on the effects of sildenafil in men with type 1 diabetes and ED.. A total of 188 patients were entered into a double-blind, placebo-controlled, parallel-group, flexible-dose study and were randomized to receive sildenafil (25-100 mg; n = 95) or placebo (n = 93) for 12 weeks. Efficacy was evaluated using questions three (Q3; achieving an erection) and four (Q4; maintaining an erection) from the International Index of Erectile Function (IIEF), a global efficacy question (GEQ; "Did treatment improve your erections?"), and a patient event log of sexual activity.. Improvements in mean scores from baseline to end-of-treatment for IIEF Q3 (35.7 vs. 19.9%) and Q4 (68.4 vs. 26.5%) were significant in patients receiving sildenafil compared with those receiving placebo (P = 0.0001). Moreover, the percent of improved erections (GEQ, 66.6 vs. 28.6%) and successful intercourse attempts (63 vs. 33%) was significantly increased with sildenafil compared with placebo. Improvements in sexual function were seen irrespective of the degree of ED severity. Adverse events were generally mild to moderate in severity, with headache (20 vs. 8%), flushing (18 vs. 3%), and dyspepsia (8 vs. 1%) reported more often in the sildenafil than in placebo-treated patients.. Treatment with sildenafil for ED was effective, resulting in an increased percentage of successful attempts at intercourse, and was well tolerated among men with type 1 diabetes.

Topics: Adult; Aged; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Double-Blind Method; Erectile Dysfunction; Humans; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Impaired nitric oxide (NO), soluble guanylyl cyclase (sGC), and cyclic guanosine monophosphate (cGMP) signaling (NO-sGC-cGMP) has been implicated in the pathogenesis of diabetic vascular dysfunction. Efforts to directly target this signaling have led to the development of sGC agonists that activate the heme group of sGC (stimulators) or preferentially activate sGC when the heme is oxidized (activators). In this study, we hypothesized that resistance arteries from female rats with spontaneous type 2 diabetes (Goto-Kakizaki rats, GK) would have reduced vasodilatory responses to heme-dependent sGC activation and increased responses to heme-independent sGC activation compared with control rats (Wistar). Endothelium-dependent and -independent relaxation was assessed in isolated segments from mesenteric resistance arteries (MA) mounted in a wire myograph. GK MA had reduced responses to acetylcholine (pEC50: 7.96 ± 0.06 vs. 7.66 ± 0.05, P < 0.05) and sodium nitroprusside (pEC50: 8.34 ± 0.05 vs. 7.77 ± 0.04, P < 0.05). There were no group differences in 8-bromoguanosine cGMP-induced relaxation and protein kinase G1 expression (P > 0.05). GK MA had attenuated responses to BAY 41-2272 (heme-dependent sGC stimulator; pEC50: 7.56 ± 0.05 vs. 6.93 ± 0.06, P < 0.05) and BAY 58-2667 (heme-independent sGC activator; pEC50: 10.82 ± 0.07 vs. 10.27 ± 0.08, P < 0.05) and increased sensitivity to sildenafil [phosphodiesterase 5 (PDE5) inhibitor; pEC50: 7.89 ± 0.14 vs. 8.25 ± 0.13, P < 0.05]. Isolated resistance arteries from female rats of reproductive age that spontaneously develop type 2 diabetes have increased sensitivity to PDE5 inhibition and reduced responsiveness to sGC activators and stimulators.

Topics: Animals; Arterial Pressure; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Activators; Female; Guanylate Cyclase; Mesenteric Arteries; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Receptors, Cytoplasmic and Nuclear; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfonamides; Vasodilation; Vasodilator Agents

The low pharmacological response to phosphodiesterase type 5 inhibitors represents an expression of higher endothelial damage in certain categories of patients with erectile dysfunction and high cardiovascular risk. The present study evaluated this objective in type 2 diabetic patients with erectile dysfunction, classified as "non responders" to Sildenafil.. Eighteen "responder" and twelve "non responder" type 2 diabetic patients were evaluated, relatively to different levels of endothelial damage, through the diagnostic use of a new immunophenotype of circulating endothelial progenitor cells (CD45neg/CD34pos/CD144pos) and endothelial microparticles (CD45neg/CD144pos/Annexin Vpos), recently developed and published by our group.. "Non responder" patients showed a significant higher severity [8.0±3.0 (International Index of Erectile Function-abbreviated version with 5 questions) vs 14.0±3.0] and duration (10.0±2.0 vs 7.0±2.0 years) of erectile dysfunction, higher level of penile arterial insufficiency (peak systolic velocity=13.0±16.0 vs 28.0±26.0cm/s; acceleration time=153±148 vs 125±128 mm/s) and finally a significant higher level of endothelial apoptosis [0.15±0.13 vs 0.05±.0.03% (serum concentrations of endothelial microparticles)] associated with higher serum concentrations of circulating late immunophenotype of endothelial progenitor cells (0.40±0.35 vs 0.12±.0.10%).. The results of this study corroborate the clinical value of the low clinical response to phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction in the patients with high cardiovascular risk profile, such as diabetics. In addition, the markers used in this study confirm their potential application in clinical practice as useful indicators of endothelial alteration. However, in the future we will have to assess a larger number of patients and for a longer period of observation in order to better understand the causal and temporal relations.

Topics: Aged; Apoptosis; Arteries; Cardiovascular Diseases; Cell-Derived Microparticles; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Resistance; Endothelium, Vascular; Flow Cytometry; Humans; Impotence, Vasculogenic; Italy; Male; Middle Aged; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Risk Factors; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome

Abnormal vascular activity in diabetes is related not only to impaired nitric oxide bioavailability but also to inflammatory cytokines, endothelin A receptor (ET(A) ) activation and NADPH oxidase in the vasculature. The potential role of sildenafil in improving vascular function was investigated. Its action was likely blocking upregulated ET(A) and NADPH oxidase, and was compared with the endothelin receptor antagonist CPU0213.. Diabetes was induced by single-dose administration of streptozotocin (65 mg/kg, i.p.) to rats and the vascular activity of the thoracic aorta was measured.. An increase in contractile tone to phenylephrine and a decrease in relaxant tone to acetylcholine was found in the thoracic aorta. Oxidative stress was evident by increased malondialdehyde and reduced glutathione peroxidase levels in serum and upregulation of ET(A), MMP-9 (matrix metalloproteinase-9), inducible nitric oxide synthase and NADPH oxidase p67(phox) were found in the vascular wall. The vascular abnormalities and abnormal biomarkers were attenuated significantly by either sildenafil or CPU0213 along with an improvement of nitric oxide bioavailability and vascular activity.. Improvement of diabetic vascular abnormal activity by sildenafil results from its suppression of activation of ET(A) and NADPH oxidase in the vasculature, and these actions are comparable with those of the endothelin receptor antagonist CPU0213.

Topics: Animals; Aorta, Thoracic; Biomarkers; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelin Receptor Antagonists; Gene Expression Regulation; In Vitro Techniques; Male; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrazoles; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger; Sildenafil Citrate; Sulfones

Erectile dysfunction (ED) in diabetes is related to autonomic neuropathy and endothelial dysfunction. We studied the relative importance of these factors in diabetic and non-diabetic men with ED and determined if they predict responses to treatment with sildenafil.. Thirty-three men, aged 35-65 years, with ED (20 diabetic, 13 non-diabetic), 15 of whom were sildenafil responders and 18 non-responders, were compared with 30 age and risk-matched control subjects (15 diabetic, 15 non-diabetic). Subjects with ED completed the International Index of Erectile Function (IIEF) questionnaire. Endothelial function was assessed by changes in brachio-radial and femoro-tibial arterial pulse-wave velocity (pulse-wave velocity) during reactive hyperaemia, expressed as percentage endothelium-dependent dilatation. Autonomic function was assessed by heart rate variation during expiration and inspiration (E/I ratio) and during the valsalva manoeuvre.. The respective changes in pulse-wave velocity, in the arm and leg [mean (sd)] were 0.71 (6.5)% and 3.5 (6.4)% in the impotent diabetic men, 0.7 (7.6)% and 2.4 (5.9)% in the non-diabetic impotent men, -0.68 (5.7)% and -1.31 (7.2)% in the non-impotent diabetic men and 7.7 (3.7)% and 7.6 (3.4)% in the control subjects. There was a significant interaction between ED and diabetic status such that there was significantly impaired vascular response in the diabetic group (both with and without ED) and in the non-diabetic group with ED compared with the non-diabetic control group (P = 0.01 and P = 0.001 for brachio-radial and femoro-tibial measures, respectively). The E/I ratios of the diabetic men were significantly lower than those of the control subjects [1.17 (0.14) vs. 1.33 (0.16), P < 0.02), but there were no differences in the measures of autonomic neuropathy between the groups with ED and those with normal erectile function. Amongst diabetic men, the initial IIEF scores (maximum score 30, low score indicates more severe ED) were significantly higher in sildenafil-responders than non-responders [16.3 (8.4), vs. 6.8 (7 1), P < 0.02]. The rate of sildenafil response was not significantly affected by the measures of endothelial or autonomic function.. ED in both diabetic and non-diabetic men is characterized by marked endothelial dysfunction in comparison with non-diabetic control subjects. Response to sildenafil is not predicted by either endothelial function or autonomic function, but in diabetic men appears to be related to the initial degree of erectile dysfunction.

Topics: Adult; Aged; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Neuropathies; Endothelium, Vascular; Erectile Dysfunction; Humans; Male; Middle Aged; Penile Erection; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Brachial Artery; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Piperazines; Purines; Regional Blood Flow; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil citrate is a potent donor of nitric oxide that has been proved to be effective for the treatment of male erectile dysfunction, but it has been contraindicated in patients with cardiovascular diseases, because of sudden death occurred to some of them. Based on the known vasodilator effect of nitrix oxide, effect that should be beneficial for some cardiomyopathies, this work was carried out in order to prove the cardiovascular effects of sildenafil citrate on: 1) heart rate, rhythm and repolarization changes on the ecg; 2) systolic and diastolic arterial blood pressure; 3) left ventricular systolic function and 4) right and left ventricular diastolic function in 26 patients suffering from the following cardiomyopathies: chronic Chagas's and diabetic cardioneuromyopathies, hypertensive and/or hypertrophic cardiomyopathies with or without chronic congestive heart failure.. sildenafil citrate 50 mgr after a single oral dose: 1) improved the ecg findings in some patients, worsening the basal ecg in none of the studied patients; 2) significantly reduced systolic and diastolic arterial blood pressure being such reduction very strong in those with basal high level 3) significantly improved left ventricular systolic function in those patients with basal reduced function and 4) Right ventricular diastolic function evaluation: Sildenafil citrate 50 mgr significantly modified to normal pattern the E/A basal altered ratio in those patients with the inverted pattern as well as in those with restrictive pattern of tricupid diastolic influx to the right ventricle during the echo-duplex interrogation (p < 0.0001) 5) Left ventricular diastolic function evaluation: Sildenafil citrate 50 mgr significantly modified to normal pattern the E/A basal altered ratio in those patients with the inverted pattern as well as in those with restrictive pattern of mitral diastolic influx to the left ventricle, during the echo-duplex interrogation (p 0 <.0001).. Based on the above findings it is feasible to propose the use of sildenafil citrate to treat patients with cardiovascular diseases, with exclusion of severe obstructive coronary artery disease, hypertrophic subaortic stenosis and patients with funduscopic alterations that may be affected by a significant and acute increase of flow within the ophthalmic arteries. The right ventricular diastolic changes observed with Sildenafil Citrate may be useful in patients with abnormal right ventricular compliance such as pulmonary stenosis or hypertension.

Topics: Blood Pressure; Cardiovascular Diseases; Chagas Disease; Diabetic Angiopathies; Electrocardiography; Female; Heart Failure; Heart Rate; Humans; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents; Ventricular Function

Topics: Diabetic Angiopathies; Erectile Dysfunction; Humans; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Treatment Outcome