Sildenafil: study of a novel oral treatment for erectile dysfunction in diabetic men

The efficacy and safety of oral sildenafil, a potent inhibitor of phosphodiesterase type 5, were evaluated in men with diabetes mellitus and erectile dysfunction (ED). Twenty-one men (aged 42–65 years) were enrolled in a double-blind, placebo-controlled, three-way crossover study conducted in two parts. In part I, the effect of a single dose (25 mg or 50 mg) of sildenafil or placebo on penile rigidity was assessed by penile plethysmography during visual sexual stimulation. In part II, daily diary records of erectile activity and a global efficacy question were used to evaluate once-daily dosing with 25 mg or 50 mg of sildenafil or placebo for 10 days. After a single 50 mg dose of sildenafil, the adjusted geometric mean duration (min) of penile rigidity >60 % at the base of the penis during visual sexual stimulation was significantly increased (10.1 min) compared with placebo (2.8 min; p = 0.0053). In part II, sildenafil significantly increased the number of erections considered sufficiently hard for vaginal penetration compared with placebo (p = 0.0005). Improved erections were reported by 50 % and 52 % of patients treated with 25 mg and 50 mg of sildenafil, respectively, compared with 10 % of those receiving placebo (p values < 0.05). Adverse events were mostly mild or moderate in nature and included muscular pains, headache, and dyspepsia. Sildenafil is a well-tolerated and potentially efficacious oral treatment for ED in men with diabetes mellitus. © 1998 John Wiley & Sons, Ltd.     

Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: analysis of data from tadalafil clinical trials

Aims/hypothesis A retrospective analysis of pooled data from twelve placebo-controlled trials was conducted to characterise the efficacy and safety of tadalafil for the treatment of erectile dysfunction in men with diabetes compared with that in men without diabetes.Methods Patients were randomly allocated to tadalafil 10 mg, 20 mg, or placebo, taken as needed for 12 weeks. The study population comprised 637 men with diabetes (mean age 57 years) and 1681 men without diabetes (mean age 56 years).Results At baseline, patients with diabetes had more severe erectile dysfunction than patients without diabetes, with mean International Index of Erectile Function (IIEF) erectile function domain scores of 12.6 and 15.0 respectively (p<0.001). Compared with placebo, tadalafil 10 mg and 20 mg improved all primary efficacy outcomes in both patient groups (p<0.001). Men with diabetes receiving tadalafil 20 mg experienced a mean improvement of 7.4 in their IIEF erectile function domain score against baseline versus 0.9 for placebo (p<0.001). This group reported on average that 53% of their attempts at intercourse were successful, compared with 22% for placebo (p<0.001 for the change from baseline). Baseline IIEF erectile function domain scores correlated inversely with baseline HbA₁c levels. The responses to tadalafil were similar regardless of levels of baseline glycaemic control, diabetic therapy received, or previous use of sildenafil.Conclusions/interpretation Despite more severe baseline erectile dysfunction in men with diabetes, tadalafil was efficacious and well tolerated in this population. As reported for other phosphodiesterase 5 inhibitors, the response to tadalafil was slightly lower in men with diabetes than in men without diabetes.Conflict of interest statement: Funding for the studies and these analyses was provided by Lilly ICOS LLC. Drs Fonseca and Seftel did not receive any compensation from the sponsor for this analysis and the writing of this paper. Dr Fonseca does not have any conflicts of interest to declare. Dr Seftel is a consultant to Auxilium, Bayer, ICOS, LillyICOS LLC and Pfizer.     

Chronic administration of Sildenafil improves markers of endothelial function in men with Type 2 diabetes

Objective 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). Methods 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. Results 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. Conclusions 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. Diabet. Med. 25, 37–44 (2008)     

Erectile and endothelial dysfunction in Type II diabetes: a possible link

Aims/hypothesis: The aim of this study was to evaluate the relation between erectile dysfunction and endothelial functions, coagulation activation, peripheral and autonomic neuropathy in men with Type II (non-insulin-dependent) diabetes mellitus. Methods: We studied 30 Type II diabetic patients with symptomatic erectile dysfunction and 30 potent diabetic patients matched for age and disease. Endothelial functions were assessed with the l-arginine test, plasma thrombomodulin and cell adhesion molecules circulating concentrations. Haemostasis was evaluated with markers of thrombin activation and fibrinolysis. Quantitative sensory testing (vibratory, warming, and heat-pain thresholds), cardiovascular reflex tests and 24-h blood pressure monitoring were used to assess peripheral or autonomic neuropathy. Results: Mean erectile score and HbA_{1 c} were 10.5 ± 5.8 and 8.3 ± 1.6 % in patients with erectile dysfunction, and 24.0 ± 0.7 and 6.8 ± 1.4 % in those without erectile dysfunction, respectively (p < 0.001); there was a significant relation between HbA_{1 c} and erectile function score in patients with erectile dysfunction (r = –0.45, p = 0.02). The decrease in blood pressure and platelet aggregation in response to l-arginine was lower (p < 0.05–0.02) in patients with erectile dysfunction, whereas soluble thrombomodulin, P-selectin and intercellular cell ahhesion molecule-1 concentrations were higher (p < 0.05–0.02). Indices of coagulation activation (F1 + 2 and d-dimers) and reduced fibrinolysis (PAI-1) were also found to be higher in erectile dysfunction patients. Heat-pain and warm perception thresholds, as well as cardiovascular reflex tests, were most commonly abnormal in patients with erectile dysfunction (p < 0.05). In multivariate analysis, HbA_{1 c}, MBP response to l-arginine, P-selectin, indices of coagulation, and quantitative sensory testing were independent predictors of erectile function score. Conclusion/interpretation: Erectile dysfunction in diabetic men correlates with endothelial dysfunction. A reduced nitric oxide activity might provide a unifying explanation. [Diabetologia (2001) 44: 1155–1160] Received: 18 April 2001 and in revised form: 21 April 2001     

Erectile dysfunction in cirrhosis is impacted by liver dysfunction,portal hypertension,diabetes and arterial hypertension

Background

Although several risk factors for erectile dysfunction may be present in patients with cirrhosis, data on the actual prevalence and cause of erectile dysfunction is limited. The International Index of Erectile Function‐5 (IIEF‐5) is a well‐validated survey to determine the presence and severity of erectile dysfunction in men. We assessed (i) the prevalence and severity of erectile dysfunction, and (ii) risk factors for erectile dysfunction in patients with cirrhosis.

Methods

In this prospective study, erectile dysfunction was defined as: absent (>21 IIEF‐5‐points), mild (12‐21) and severe (5‐11). Patients with overt hepatic encephalopathy, active alcohol abuse, extrahepatic malignancy, previous urologic surgery, previous liver transplantation and severe cardiac conditions were excluded.

Results

Among n = 151 screened patients, n = 41 met exclusion criteria and n = 30 were sexually inactive. Thus, a final number of n = 80 male patients with cirrhosis were included. Patient characteristics: age: 53 ± 9 years; model for end‐stage liver disease score (MELD): 12.7 ± 3.9; Child‐Pugh score (CPS) A: 30 (37.5%), B: 35 (43.8%), C: 15 (18.7%); alcohol: 38 (47.5%), viral: 25 (31.3%), alcohol/viral: 7 (8.8%) and others: 10 (12.5%). The presence of erectile dysfunction was found in 51 (63.8%) patients with 44 (55%) and 7 (8.8%) suffering from mild‐to‐moderate and moderate‐to‐severe erectile dysfunction. Mean MELD and hepatic venous pressure gradient (HVPG) were significantly higher in patients with erectile dysfunction (P = .021; P = .028). Child‐Pugh score C, MELD, creatinine, age, arterial hypertension, diabetes, low libido, low testosterone and high HVPG were associated with the presence of erectile dysfunction. Interestingly, beta‐blocker therapy was not associated with an increased risk. In multivariate models, arterial hypertension (OR: 6.36 [1.16‐34.85]; P = .033), diabetes (OR: 7.40 [1.31‐41.75]; P = .023), MELD (OR: 1.19 [1.03‐1.36]; P = .015) and increasing HVPG (n = 48; OR: 1.11 [1.002‐1.23]; P = .045) were independent risk factors for the presence of erectile dysfunction.

Conclusion

About two‐thirds of male patients with cirrhosis show erectile dysfunction. Severity of liver dysfunction, portal hypertension, arterial hypertension and diabetes were identified as risk factors for erectile dysfunction.     

From aspiration to achievement: assessment and noninvasive treatment of erectile dysfunction in aging men

More than 70% of elderly men (>or=65) remain sexually active, and more than 40%, according to one estimate, are dissatisfied with their sex lives. Declining sexual function and a reluctance to seek medical attention with advancing age are cross-cultural observations. Normal erection is largely dependent on intact function of the central and peripheral nervous systems and the penile vascular endothelium. Consequently, chronic conditions (e.g., cardiovascular disease, diabetes mellitus) and lifestyle factors (e.g., smoking) that have adverse effects on the vascular endothelium and central and peripheral nervous systems, as well as on endocrine function or connective tissues within the corpus cavernosum of the penis, can attenuate erectile function. Because of these associations, assessment of sexual function in elderly men often reveals not only erectile dysfunction (ED) but also other reversible conditions. An expanding array of noninvasive options is available to assist the clinician in individualizing ED therapy to the unique health and lifestyle needs of each elderly ED patient and his partner. These treatment alternatives include the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil, as well as other oral medications, such as alpha-adrenoceptor antagonists and topical vasoactive or testosterone therapy.     

The role of endothelial dysfunction in the pathophysiology of erectile dysfunction in diabetes and in determining response to treatment.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction

Aims Erectile dysfunction (ED) is a common comorbidity in men with diabetes mellitus. Tadalafil 10 or 20 mg taken on demand is efficacious and safe for men with diabetes and ED. Recently, continuous treatment with tadalafil has been proposed, addressing ED management as any other chronic condition. This study examined whether once‐daily tadalafil 2.5 and 5 mg is efficacious for men with diabetes and ED. Methods This randomized, double‐blind, placebo‐controlled, multicentre, 12‐week study enrolled 298 men with diabetes and ED to once‐daily treatment with placebo, tadalafil 2.5 mg or tadalafil 5 mg. Primary efficacy measures were International Index of Erectile Function Erectile Function (IIEF EF) Domain score, and patient success rates for vaginal penetration and completion of intercourse. Patient satisfaction, endothelial function biomarkers, and safety were also assessed. Results Patients receiving either dose of tadalafil had clinically and statistically significant improvements in IIEF EF and statistically significant improvements in mean success rates for vaginal penetration, completion of intercourse, and overall treatment satisfaction (P ≤ 0.005 tadalafil vs. placebo, all measures). Endothelial dysfunction biomarkers were unchanged. The most common adverse events were headache, back pain and dyspepsia. Conclusions In this first study of men with diabetes and ED, once‐daily tadalafil 2.5 and 5 mg was efficacious and well tolerated, suggesting this may be an alternative to on‐demand treatment for some men, eliminating the need to plan sex within a limited timeframe.     

Sildenafil citrate (VIAGRA) improves erectile function in elderly patients with erectile dysfunction: a subgroup analysis

BACKGROUND: The prevalence of erectile dysfunction (ED) increases with advancing age, with a particularly high prevalence of ED in elderly patients with diabetes. In the United States it is estimated that approximately 45% of men aged 65 to 69 years have moderate or complete ED. The efficacy and safety of oral sildenafil (VIAGRA) for treating ED in elderly men (aged > or = 65 years or older) were assessed. METHODS: We analyzed data obtained from five double-blind, placebo-controlled studies of the efficacy and tolerability of oral sildenafil taken as required (but not more than once daily) over a 12-week to 6-month period. Two subgroups were evaluated: (i) elderly patients with ED of broad-spectrum etiology (n = 411), and (ii) elderly patients with ED and diabetes (n = 71). Efficacy was assessed using a global efficacy question, questions 3 and 4 of the International Index of Erectile Function (IIEF). and the five sexual function domains of the IIEF. RESULTS: All efficacy assessments indicated that sildenafil significantly improved erectile function both in elderly patients with ED of broad-spectrum etiology and in elderly patients with ED and diabetes. The most common adverse events were mild-to-moderate headache, flushing, and dyspepsia. The rates of discontinuation due to adverse events were low and were comparable to the rates with placebo. CONCLUSIONS: Sildenafil is an efficacious and well-tolerated treatment for ED in elderly men.     

Self-esteem, confidence, and relationships in men treated with sildenafil citrate for erectile dysfunction

BACKGROUND: Men with erectile dysfunction (ED) often have low self-esteem, confidence, and sexual relationship satisfaction. OBJECTIVE: We evaluated the impact of sildenafil citrate and its generalizability across cultures on self-esteem, confidence, and sexual relationship satisfaction in men with ED using the Self-Esteem And Relationship (SEAR) questionnaire. DESIGN: Pooled analysis of 2 double-blind, placebo-controlled, flexible-dose trials of sildenafil with identical protocols: 1 was conducted in the United States and the other in Mexico, Brazil, Australia, and Japan. PATIENTS: Men > or = 18 years old with ED. MEASUREMENTS: The impact of treatment on psychosocial factors associated with ED was determined by patient responses to the SEAR questionnaire. Erectile function was determined using the International Index of Erectile Function (IIEF) and a global efficacy question. Successful sexual intercourse attempts were derived from event logs of sexual activity. Treatment effect sizes were calculated for all study outcomes. RESULTS: Compared with patients who received placebo (n = 274), patients who received sildenafil (n = 279) reported significantly greater improvements (P < .0001) in self-esteem, confidence, sexual relationship satisfaction, and in all sexual function domains of the IIEF. Treatment effect sizes were large (range, 0.7 to 1.2) for all SEAR components, and improvement in psychosocial measures showed moderate to high correlations (range, 0.50 to 0.83, P < .0001) with improvement in erectile function, percentage of successful intercourse attempts, and global efficacy. CONCLUSIONS: In men with ED from 5 different nations, sildenafil produced substantial improvements in self-esteem, confidence, and sexual relationship satisfaction. Improvements in these psychosocial factors were observed crossculturally and correlated significantly and tangibly with improvements in erectile function.     

Endothelium-dependent and independent vasodilation studied at normoglycaemia in Type I diabetes mellitus with and without microalbuminuria

Aims/hypothesis. We examined whether endothelial function is impaired in patients with Type I (insulin-dependent) diabetes mellitus under conditions of near-normoglycaemia compared with age-matched healthy control subjects. Our aim was to determine whether microalbuminuria is associated with endothelial dysfunction in Type I diabetes. Methods. Endothelial function, measured as post-ischaemic flow-mediated dilatation of the brachial artery using ultrasound, was compared among 17 microalbuminuric and 17 normoalbuminuric diabetic patients, and 17 control subjects. Glyceryl trinitrate-mediated dilatation of the brachial artery was used to measure endothelium-independent function. All diabetic patients were studied at near-normoglycaemia, using insulin and 5 % dextrose infusions to maintain blood glucose between 3.5 and 8.0 mmol/l. Results. Flow-mediated dilatation was significantly lower in microalbuminuric diabetic patients (3.2 ± 0.3 %) compared with normoalbuminuric diabetic patients (5.4 ± 0.6 %) and control subjects (7.9 ± 0.6 %, p < 0.001). Normoalbuminuric diabetic patients also had significantly lower flow-mediated dilatation than control subjects (p = 0.01). Glyceryl trinitrate mediated dilatation was significantly lower in the microalbuminuric patients compared with the control subjects (11.9 ± 1.1 % vs 20.0 ± 1.2 %, p = 0.001). Albumin excretion rate and glycated haemoglobin showed a significant negative independent correlation with flow-mediated dilatation (both p < 0.05). Conclusion/interpretation. Type I diabetic patients show endothelial dysfunction at near-normoglycaemia compared with the control subjects, and this abnormality is more marked in diabetic patients with microalbuminuria. Endothelial dysfunction in Type I diabetes is related to the albumin excretion rate and glycaemic control. The presence of endothelial dysfunction in normoalbuminuric diabetic patients suggests it could precede microalbuminuria as an early risk marker for cardiovascular disease. [Diabetologia (2001) 44: 593–601] Received: 6 November 2000 and in revised form: 11 January 2001     

枸橼酸爱地那非治疗勃起功能障碍的疗效和安全性观察

目的评价临床枸橼酸爱地那非治疗男性勃起功能障碍（ED）的安全性和疗效。方法32例ED患者,其中24例予枸橼酸爱地那非60mg口服（观察组）,8例仅予安慰剂（对照组）。采用国际勃起功能指数表（IIEF-5）量表评价治疗效果,同时记录观察患者自签署知情同意书开始至最后一次随访之间,所发生的任何与治疗目的无关的事件。结果观察组治疗后IIEF-5量表总得分为（24．09±5．05）分,与治疗前的（14．75±3．61）分相比,P〈0．05;与对照组治疗后的（19．86±4．56）分相比,P〈0．05。与药物相关的主要不良事件有头晕、头痛、面部潮红和恶心,严重程度为轻至中度,呈一过性,无需处理。结论口服枸橼酸爱地那非60mg治疗ED安全、有效。     

Sildenafil in the treatment of erectile dysfunction: an overview of the clinical evidence

Erectile dysfunction (ED) is a highly prevalent disease associated with aging as well as with several risk factors including hypertension, heart disease, obesity, dyslipidemia, diabetes, hypogonadism, drugs-related, and pelvic surgery. Many of these factors are components of the metabolic syndrome, a multiplex risk factor for cardiovascular disease (CVD). ED shares common risk factors with CVD. Endothelial dysfunction seems to be the early underlying pathophysiology across both conditions. The efficacy, tolerability and cardiovascular safety of sildenafil has been evaluated in numerous large, randomized, double-blind, placebo-controlled clinical studies in the broad population of men with ED including men with several co-morbid conditions. Sildenafil is effective in several specific patient populations including the difficult-to-treat subpopulations such as diabetes mellitus and after radical prostatectomy. It is associated with rapid onset of action – within 14 minutes for some men – and an extended duration of action for up to 12 hours. Sildenafil improves quality of life and satisfaction for treated men and is well tolerated with a favorable safety profile. New data suggest that sildenafil has beneficial effects in several chronic conditions. It has been approved for the treatment of idiopathic pulmonary hypertension. Numerous articles have suggested that it improves endothelial function and a possible role on premature ejaculation or treatment of lower urinary tract symptoms has been suggested.     

Finger and penile tactile sensitivity in sexually functional and dysfunctional diabetic men

Summary Tactile sensitivity of the penis is related to sexual functioning, however its role in diabetic erectile problems is unclear. We evaluated penile sensitivity in 10 diabetic men with erectile dysfunction, 17 sexually functional diabetic men and 14 control subjects. Finger and penile thresholds and ratings of intensity and pleasantness for finger and penis were assessed using vibrotactile stimulation. Glycosylated haemoglobin and total and bioavailable testosterone measurements were determined and subjects completed self-reports on sexual function. Diabetic men with erectile problems had higher values of glycosylated haemoglobin than sexually functional diabetic men (p = 0.02) and both groups had lower bioavailable testosterone than control subjects (p K 0.05). Sexually dysfunctional diabetic men had a higher finger threshold than the other two groups (p < 0.01). Penile threshold for the sexually dysfunctional group was also marginally higher compared with the functional diabetic group (p < 0.052) but did not differ from control subjects (p = 0.09). Diabetic men with erectile dysfunction exhibited different response patterns than sexually functional men on dimensions of intensity and pleasantness to penile stimulation. Although these data do not directly implicate subjective response to penile stimulation in diabetic erectile problems, they suggest such anomalous response could be one contributing factor. [Diabetologia (1999) 42: 336–342] Received: 28 April 1998 and in final revised form: 30 October 1998     

Oral sildenafil in the treatment of erectile dysfunction in diabetic men: a randomized double-blind and placebo-controlled study

PURPOSE: To determine the efficacy and safety of oral sildenafil citrate in the treatment of erectile dysfunction (ED) in diabetic men. MATERIALS AND METHODS: In a randomized, double-blind, placebo-controlled, and fixed-dose study, a total of 282 men (mean age, 46.4 years) with ED (mean duration, 3.6 years) and diabetes (mean duration, 11 years) were randomly assigned to receive 100 mg sildenafil (n=144) or placebo (n=138) approximately 1 h before planned sexual activity, but not more than once daily, for 16 weeks. The efficacy of two treatments was assessed using responses to the International Index of Erectile Function (IIEF) questionnaire. RESULTS: Two hundred sixty-two (93%) of men completed the study (134/144 in the sildenafil group, 128/138 in the placebo group). Positive clinical results were obtained in 68 (51%) of 134 patients in the sildenafil group compared with 14 (11%) of 128 patients in the placebo group (P<.003). Fifty-nine percent of the patients reported at least one successful attempt at sexual intercourse in the sildenafil group as compared with 21% successful attempts for the placebo group (P<.002). Drug-related adverse effects occurred in 32 (22%) of 144 patients taking sildenafil and 4 (3%) of 138 patients receiving placebo. The most common adverse events were headache (20% sildenafil, 2% placebo), flushing (19% sildenafil, 0% placebo), dyspnea (9% sildenafil, 2% placebo), rhinitis (6% sildenafil, 0% placebo), and cardiovascular effects (7% sildenafil, 0% placebo). Of patients taking sildenafil, four (2.7%) developed new chest pains, with documented myocardial infarction in two. CONCLUSION: Oral sildenafil is a moderately effective treatment for ED in men with diabetes. The response rate was lower and cardiovascular events were higher than previously reported in nondiabetic patients.     

The Difference of Heart Rate Recovery between Males with and without Erectile Dysfunction

Aim: In this study, we aimed to investigate the relationship between heart rate recovery (HRR) time and Chronotropic Index (CHIND) parameters, which also reflect autonomic function, after exercise stress test (EST) in males with or without erectile dysfunction (ED), and we investigated the relationship between HRR and CHIND and serum steroid hormone levels. Material and Methods: A total of 135 participants (mean age: 45.0 ± 11.8 years) were enrolled into the study. Detailed biochemical and hormonal analyses, 12‐lead electrocardiography and EST (Treadmill) were performed in all participants. Erectile function was assessed using the International Index of Erectile Function (IIEF) questionnaire form. Patients were categorized into two groups according to their IIEF scores as ED (+) (IIEF < 26) and ED (?) (IIEF ≥ 26). Afterward, statistical analyses were performed to evaluate the correlations between ED and HRR and CHIND. Results: A total of 65 patients were ED (+) (mean age 44.9 ± 6.4 years), while 70 patients (mean age 43.7 ± 7.7 years) had normal erectile status. There were statistically significant differences in CHIND (P = 0.015) and HRR time (P = 0.037) between ED (+) and ED (?) patients. In correlation analysis, IIEF score was found positively correlated with HRR and metabolic equivalent (MET) values (r_HRR= 0.293, P = 0.037; r_METs= 0.388, P = 0.011, respectively). Linear regression analysis revealed that METs value and total exercise time had a more linear relationship with IIEF score compared to the other EST parameters (p_METs= 0.002 and p_TET= 0.015, respectively). Conclusion: Chronotropic incompetence and dynamic postexercise autonomic dysfunction are present in ED patients. This condition may reflect decreased functional capacity and exercise intolerance in these patients. Ann Noninvasive Electrocardiol 2010;15(3):223–229     

Cardiovascular risk factors determine erectile and arterial function response to sildenafil

BACKGROUND: Erectile dysfunction is related to endothelial function. Cardiovascular risk factors determine endothelial function. Sildenafil is effective in treatment of erectile dysfunction but shows variable results. This study investigated the relationship of cardiovascular risk factors to acute and chronic responses to sildenafil. METHODS: Cardiovascular risk factors and acute and chronic pulse wave responses to a single 50-mg dose of sildenafil were assessed in 45 patients with erectile dysfunction confirmed by low international index of erectile function (IIEF) score before and after chronic therapy with sildenafil. RESULTS: On recruitment all patients showed evidence of erectile dysfunction with an IIEF score of 5 points (1 to 20 points). Chronic sildenafil therapy resulted in an increase of IIEF score of 13 points (range -1 to +24 points) and 24 patients (53%) achieved an IIEF score>or=21 points. Improvement in erectile function in response to sildenafil (rn=0.79; P<.001) was dependent on initial erectile function (P=.002) and baseline apolipoprotein B (P=.01). Vascular responses to acute treatment with sildenafil were assessed using pulse wave analysis. Acute changes in stiffness index induced by sildenafil (rn=0.65; P<.001) were related to apolipoprotein A-1 (P=.006), B (P=.02), and lipoprotein(a) (P=.008) concentrations, whereas reflection index (rn=0.69; P<.001) was related to pulse pressure (P<.001), albumin-to-creatinine ratio (P=.007), and lipoprotein(a) (P=.02). CONCLUSIONS: The extent of acute and chronic effects of sildenafil on erectile function and pulse wave profiles is determined by metabolic cardiovascular risk factors. Improved cardiovascular risk factor control is likely to increase the efficacy of phosphodiesterase-5 inhibitor therapy in the treatment of erectile dysfunction.     

Genetic variability of the SUR1 promoter in relation to beta-cell function and Type II diabetes mellitus

Aims/hypothesis: We aimed to examine the promoter of SUR1 for genetic variation and to determine if variants were associated with Type II (non-insulin-dependent) diabetes mellitus or measures of beta-cell function. Methods: We examined 465 bp upstream of the ATG site in 46 Type II diabetic patients and 15 glucose tolerant control subjects by SSCP-heteroduplex analysis. Results: We identified an a → t substitution 437 bp upstream of the ATG site. The allelic frequency was similar in 455 unrelated Type II diabetic patients and in 203 glucose tolerant control subjects matched for age (0.036, [95 % CI 0.019–0.053] vs 0.034 [95 % CI 0.009–0.059]; p = 0.92). Among the glucose tolerant subjects there were no differences between non-carriers (n = 189) and carriers (n = 14) of the variant in fasting values or 30 min values of plasma glucose and serum insulin during an oral glucose tolerance test. In a study of 233 glucose tolerant offspring of and spouses to Danish Caucasian Type II diabetic patients, non-carriers (n = 193) and carriers (n = 37) of the –437 a/t polymorphism did not differ in glucose or tolbutamide stimulated insulin response during an intravenous glucose tolerance test with intravenous tolbutamide injection [AUCs-insulin (0–8) min, 2290 ± 1660 vs 2308 ± 1935 pmol/l · min and AUCs-insulin(20–30 min), 3113 ± 2033 vs. 3393 ± 2830 pmol/l · min, respectively]. Conclusion/interpretation: We have identified a novel a/t polymorphism of the SUR1 gene promoter which is not associated with Type II diabetes mellitus or measures of beta-cell function. Previous reported non-functional variants of SUR1 associated with Type II diabetes mellitus still need to be accounted for. [Diabetologia (2001) 44: 1330–1334] Received: 24 April 2001 and in revised form: 26 June 2001     

Oral treatment with an antioxidant (raxofelast) reduces oxidative stress and improves endothelial function in men with Type II diabetes

Aims/hypothesis. To determine whether raxofelast, a new water soluble antioxidant decreases oxidative stress and improves endothelial function in men with Type II (non-insulin dependent) diabetes mellitus. Methods. We treated ten normotensive, normocholesterolaemic men with Type II diabetes and as controls ten healthy men matched with them for age with raxofelast (600 mg twice daily) for 1 week. Plasma 8-epi-PGF₂α, a non-enzymic oxidation product of arachidonic acid was measured by gas chromatography/mass spectrometry as an index of oxidative stress. Forearm vasodilator responses to brachial artery infusion of acetylcholine (7.5, 15 and 30 μg min^–1) and of the nitric oxide donor nitroprusside (1, 3 and 10 μg min^–1) were measured by strain gauge plethysmography. Results. Plasma concentrations of 8-epi-PGF₂α were greater in diabetic than in control men (0.99 ± 0.20 vs 0.18 ± 0.01 nmol l^–1, means ± SEM, p < 0.001) and fell after raxofelast (from 0.99 ± 0.20 to 0.47 ± 0.07 nmol l^–1, p < 0.05) in diabetic men but not in control men. Blood flow responses to acetylcholine were lower (p < 0.05) in diabetic than in control men (7.4 ± 1.0 vs 12.9 ± 2.3 ml · min^–1· 100 ml^–1 for the highest dose). In diabetic men, but not in control men, raxofelast increased (p < 0.05) blood flow responses to acetylcholine (from 7.4 ± 1.0 ml · min^–1· 100 ml^–1 to 11.3 ± 2.3 ml · min^–1· 100 ml^–1 at highest dose). Blood flow responses to nitroprusside were similar in control and diabetic men and in both groups were similar before and after raxofelast. Conclusion/interpretation. Oral treatment with raxofelast for 1 week reduces oxidative stress and improves endothelial function in men with Type II diabetes. [Diabetologia (2000) 43: 974–977] Received: 14 October 1999 and in revised form: 28 May 2000