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Phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction in patients with diabetes mellitus.

Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has become a first-line therapy for diabetic patients with erectile dysfunction (ED). The efficacy in this subgroup, based on the Global Efficacy Question, is 56% vs 84% in a selected group of non-diabetic men with ED. Two novel PDE5 inhibitors, tadalafil (Lilly ICOS) and vardenafil (Bayer), have recently completed efficacy and safety clinical trials in 'general' and diabetic study populations and are now candidates for US FDA approval. A summary analysis of the phase three clinical trials of sildenafil, tadalafil and vardenafil in both study populations is presented to provide a foundation on which the evaluation of the role of the individual PDE5 inhibitors for the treatment of patients with ED and DM can be built.

3',5'-Cyclic-GMP Phosphodiesterases↗

Vardenafil improves sexual function and treatment satisfaction in couples affected by erectile dysfunction (ED): a randomized, double-blind, placebo-controlled trial in PDE5 inhibitor-naïve men with ED and their partners.

INTRODUCTION: Erectile dysfunction (ED) is a common condition with diverse sequelae affecting men and their women partners. AIM: The FINDER study aimed to evaluate the efficacy and tolerability of the phosphodiesterase type-5 (PDE5) inhibitor, vardenafil, in a broad population of PDE5-naïve men with ED of different etiologies and severity and included their partners' assessments of treatment with vardenafil. METHODS: Men with ED (N = 260) were randomized to receive either vardenafil or placebo in a multicenter, flexible-dose study. MAIN OUTCOME MEASURES: Primary efficacy variables were patients' responses to the Global Assessment Question (GAQ), and Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3). RESULTS: Compared with placebo, vardenafil significantly improved rates of successful "Yes" responses to SEP3 ("Did your erection last long enough for you to have successful intercourse?") (49% placebo vs. 78% vardenafil at last period carried forward [LPCF]; P < 0.0001), SEP2 ("Were you able to insert your penis into your partner's vagina?") (65% placebo vs. 85% vardenafil at LPCF; P < 0.0001), and GAQ (36% placebo vs. 83% vardenafil at last observation carried forward; P < 0.0001). In addition, patients' and their partners' Treatment Satisfaction Scale (TSS) scores were statistically significantly improved across each of the TSS domains (satisfaction with orgasm, ease with erection, confidence, pleasure, erectile function satisfaction, and satisfaction with medication) in the vardenafil group compared with the placebo group. CONCLUSIONS: Vardenafil improved sexual function to the extent that both patients and their partners expressed a considerable and agreed level of satisfaction with treatment.

Adult↗

Phosphodiesterase type 5 inhibitors' extended duration of response as a variable in the treatment of erectile dysfunction.

The phosphodiesterase type 5 (PDE5) inhibitors, sildenafil, tadalafil and vardenafil, are a class of medications that are safe and effective in treating erectile dysfunction (ED). Yet, resuming sexual activity following a period of abstinence in response to ED may be anxiety-provoking for the man, his partner and their relationship, causing the sexual encounter to become a stressful event. The differences between PDE5 inhibitors in terms of duration of action can be successfully utilized by healthcare professionals to mitigate some of the psychosocial barriers that interfere with treating ED. PDE5 inhibitors with a longer duration of responsiveness provide some men with ED and their partners, a treatment option that may offer greater flexibility and potentially less anxiety surrounding the resumption of sexual activity. Shorter-acting PDE5s may be preferred by men/couples with predictable sexual scripts, excellent communication strategies and concerns regarding the duration of side effects.

3',5'-Cyclic-GMP Phosphodiesterases↗

Novel pyrazolopyrimidopyridazinones with potent and selective phosphodiesterase 5 (PDE5) inhibitory activity as potential agents for treatment of erectile dysfunction.

Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones and their analogues, potentially useful for the treatment of erectile dysfunction, were synthesized and evaluated as inhibitors of phosphodiesterase 5 (PDE5). Several compounds showed IC50 values in the low nanomolar range, and in particular, compound 5r, displaying high potency toward PDE5 (IC50 = 8.3 nM) and high selectivity versus PDE6 (240-fold) appeared to be a very promising new lead both in comparison with the potent but not selective sildenafil and in comparison with some analogues previously reported by us. SAR studies in this triheterocyclic scaffold led us to conclude that the best arranged groups are a methyl in position 1, a benzyl in position 3, a phenyl in position 9, and a linear four-carbon chain in position 6.

3',5'-Cyclic-GMP Phosphodiesterases↗

Erectile dysfunction after transurethral prostatectomy for lower urinary tract symptoms: results from a center with over 500 patients.

AIM: To identify possible risk factors for erectile dysfunction (ED) after transurethral resection of prostate (TURP) for benign prostatic hyperplasia (BPH). METHODS: Between March 1999 and March 2004, 629 patients underwent TURP in our department for the treatment of symptomatic BPH. All patients underwent transrectal ultrasound examination. In addition, the flow rate, urine residue, International Prostate Symptom Score (IPSS) and quality of life (QOL) were recorded for those who presented without a catheter. Finally, the erectile function of the patient was evaluated according to the International Index of Erectile Function Instrument (IIEF-5) questionnaire. It was determined that ED existed where there was a total score of less than 21. The flow rate, IPSS and QOL assessment were performed at 3 and 6 months post-treatment. The IIEF-5 assessment was repeated at a 6-month follow-up. A logistic regression analysis was used to identify potential risk factors for ED. RESULTS: At baseline, 522 (83%) patients answered the IIEF-5 questionnaire. The mean patient age was (63.7+/-9.7) years. The ED rate was 65%. After 6 months, 459 (88%) out of the 522 patients returned the IIEF questionnaire. The rest of the group was excluded from the statistical analysis. Six months after TURP, the rate of patients reporting ED increased to 77%. Statistical analysis revealed that the only important factors associated with newly reported ED after TURP were diabetes mellitus (P = 0.003, r = 3.67) and observed intraoperative capsular perforation (P = 0.02, r = 1.12). CONCLUSION: The incidence of postoperative, newly reported ED after TURP was 12%. Risk factors for its occurrence were diabetes mellitus and intraoperative capsular perforation.

Aged↗

Prevalence of erectile dysfunction in Colombia, Ecuador, and Venezuela: a population-based study (DENSA).

The purpose of this study was to estimate the prevalence of erectile dysfunction (ED) in Colombia, Ecuador, and Venezuela. A 49-item questionnaire was completed by 1946 men aged 40 years and older. The age-adjusted combined prevalence of minimal, moderate, and complete ED for all three countries was 53.4%, with 19.8% of all men reporting moderate to complete ED. Age was the variable most strongly linked to ED; the prevalence of complete ED increased markedly in men older than 79 y of age (31.9%) and 70-79 y (17.2%) compared with men aged 40-49 y (<3%). Several medical conditions, such as hypertension, benign prostatic hyperplasia, and diabetes, and the use of medications to treat these conditions were correlated with the prevalence of ED. This study corroborates earlier studies demonstrating that ED is very common, increases dramatically with age, and has multiple correlates, including some that are also risk factors for cardiovascular disease.

Adult↗

Factors predicting efficacy of phentolamine-papaverine intracorporeal injection for treatment of erectile dysfunction in diabetic male.

Thirty-three diabetic men were instructed in the use of phentolamine-papaverine injections for the treatment of erectile dysfunction over a two-year period. Of these, 12 reported a satisfactory response and 21 reported a nonsatisfactory response. The responders and the nonresponders were retrospectively studied to identify characteristics that would predict a satisfactory response. No difference was found between the two groups in the duration of diabetes, the presence of retinopathy, neuropathy, nephropathy, peripheral vascular disease, or ischemic heart disease. The utilization of insulin, the prevalence of type II diabetes, or the use of drugs which would cause impotence, did not differ between the two groups. There was no difference in the serum testosterone levels between the two groups. Age was the only predictive factor. Only 1 of 14 patients over age sixty had a satisfactory response to treatment while 11 of 19 patients under age sixty had a satisfactory response. Five of the responders and 2 of the nonresponders proceeded to penile implant surgery and reported satisfactory results. While older diabetic men may choose a trial of intracorporeal injections, they should be counselled regarding the high failure rate and alternative forms of therapy.

Age Factors↗

Screening for erectile dysfunction in the primary care practice: results of a survey.

To evaluate the screening patterns of primary care physicians (PCP) with regards to erectile dysfunction, a study was performed using an Institution Review Board Approved SHIM (Sexual Health Inventory for Men) questionnaire of 131 male patients presenting to the Family Practice Clinic at West Virginia University School of Medicine in Morgantown. A total of 109 surveys were completed and the data were compiled and analyzed with descriptive statistics using SPSS version 10.0 software. Of these patients, over 92% were Caucasian. The average age bracket for the study population was 40-50, and the average number of risk factors for ED, not including age, was 1.65. Forty-one percent of patients had a SHIM score less than or equal to 21, indicative of an element of ED. A total of 84% had primary care physicians, 22% of patients with a PCP were screened for ED. Of those who were screened by their PCP over half were initiated by the patient. As a result of this study, we believe the SHIM instrument should be performed on patients with any identifiable risk factor since effective treatment of ED is available, and ED can be associated with occult cardiac disease.

Adult↗

Intracavernous injection during diagnostic screening for erectile dysfunction; five-year experience with over 600 patients.

Psychophysiological diagnostic screening (PDS) was carried out on just over 1000 consecutive patients with erectile dysfunction (ED) during 1995 through 1999. Roughly one-third did not require an intracavernous injection (ICI) because of optimal penile response during visual and tactile penile sexual stimulation. The present article deals with those other patients (n = 609) who required an ICI and completed a 24-hour-postinvestigation questionnaire (PIQ). The two ICI preparations used, prostaglandin and papaverine + fentolamine, were virtually equally effective in the doses applied, with very low and similar percentages of unwanted side effects, for example, prolonged erection. Somatic ED patients displayed the lowest penile responses to ICI, whereas psychogenic ED patients had the highest penile responses. ED patients who also suffered from premature ejaculation (PE) ejaculated significantly more readily during PDS that those without PE. An ICI following an ejaculation/orgasm could lead to an erection presumably sufficient for intromission, which indicates ICI as a therapeutic option for rapid ejaculators. Our elaborate and lengthy PDS procedure, particularly the use of penile vibration as an addition to the visual sexual stimulation, obviates the diagnostic use of the PIQ.

Adjuvants, Immunologic↗

A meta-regression analysis of treatment effect modifiers in trials with flexible-dose oral sildenafil for erectile dysfunction in broad-spectrum populations.

Several trials and reviews provide evidence for the efficacy of phosphodiesterase-5 inhibitors in the treatment of erectile dysfunction (ED). However, little is known about the impact of treatment effect modifiers other than concomitant diseases. Our objective was to identify patient and trial characteristics as well as methodological and publication-related issues that are associated with the treatment effect measured in flexible-dose randomized controlled trials of oral sildenafil for ED. The MEDLINE and the Cochrane Central databases were searched for efficacy trials of sildenafil. Thirteen trials fulfilled all inclusion criteria. A series of meta-regression and graphical analyses were performed to test the impact of possible effect modifiers. Treatment effect was influenced by mean baseline disease severity and mean duration of the disease. These associations were at least partly mediated by placebo response. Trial duration, age of patients and etiology of ED in patients did not have any significant influence on the treatment effect. The year of publication of primary trials was also related to trial findings. Our analysis adds important data to enable the control of confounding variables in future trials and meta-analyses. It might also help the individual to assess the unbiased efficacy and true innovative potential of available and forthcoming pharmacological agents.

Administration, Oral↗

Practice patterns in the diagnosis and treatment of erectile dysfunction among family practice physicians.

OBJECTIVES: To examine the philosophies and practices of the family practitioner (FP) regarding the diagnosis and treatment of erectile dysfunction (ED). METHODS: A prospective study by questionnaire of a group of FPs was performed. The Spearman correlation coefficient and proportional odds regression analysis were used to measure the relationship between the continuous variable and ordinal-scale variables. The Goodman-Kruskal gamma test was used to measure the strength of the association between the ordinal-scale variables. RESULTS: Eighty-five FPs completed the questionnaire. All respondents had at least occasional discussions with their patients about ED. History taking, physical examination, and laboratory data were the most common tools used for diagnosis. Eighty-two percent of the FPs reported being either comfortable or somewhat comfortable in making a diagnosis of ED; 93% believed that only selected patients required more extensive diagnostic workups for ED. Sildenafil was the most commonly used agent. All physicians referred patients with ED to urologists at least occasionally. Most referred only after unsuccessful trials with sildenafil. The relationship between the degree of managed care penetration and the percentage of patients with ED referred for evaluation to a urologist was not statistically significant (P = 0.402). The relationship between the number of years in practice and the percentage of patients referred to a urologist for treatment or evaluation was found to be a negative, but statistically significant, relationship (P = 0.003). CONCLUSIONS: FPs are now diagnosing and treating ED on a routine basis. Referrals to urologists are likely to be made when they are no longer comfortable treating the problem.

Adult↗

A comparative, crossover study of the efficacy and safety of sildenafil and apomorphine in men with evidence of arteriogenic erectile dysfunction.

The aim of the study was to establish and compare the efficacy and safety of sildenafil and apomorphine in men with arteriogenic erectile dysfunction (ED). In all, 43 men with ED and postinjection max penile systolic velocity <25 cm/s in repeated Doppler ultrasonography were included. Of these, 24 men started on apomorphine 2 mg and 19 on sildenafil 50 mg, the doses titrated up to 3 and 100 mg according to effectiveness and tolerability. Safety was evaluated according to adverse events (AEs) and patient withdrawal. Efficacy was the percentage of attempts resulting in erections firm enough for intercourse, based on event log data. The incidence of AEs with apomorphine 3 mg was higher than with sildenafil 100 mg. Two men on apomorphine 3 mg discontinued treatment due to AEs. The overall success rate of sildenafil was 63.7% compared to 32.1% of apomorphine (Pearson chi(2), P<0.01). Of all men, 25 (58.1%) responded to sildenafil 50 mg without the need for dose increase, while only one responded to apomorphine 2 mg. The response to sildenafil 50 mg was age related (analysis of variance, p=0.04). Satisfaction was reported by 76.75 and 13.95% of patients for sildenafil and apomorphine, respectively, but 20.9% were not satisfied with any of the two drugs. In conclusion, this study provides clear evidence that sildenafil, even at 50 mg dose, is more effective than apomorphine 3 mg in men with arteriogenic ED. The fact that one out of five patients is not satisfied with the above-studied drugs shows that new oral agents need to be evaluated for the treatment of this disorder.

Apomorphine↗

Efficacy and safety of sildenafil citrate (Viagra) in men with erectile dysfunction and spinal cord injury: a review.

Spinal cord injury (SCI) affects a substantial number of men who are young, active, and otherwise healthy. Erectile dysfunction (ED) is a common consequence of SCI. Since its approval, sildenafil citrate (Viagra) has been shown to effectively treat ED of various etiologies. We review the evidence for the efficacy and safety of sildenafil treatment of ED in men with SCI. A literature search identified 2 randomized controlled trials and 4 prospective case series that evaluated sildenafil treatment for ED from SCI. Efficacy was evaluated using an assessment of global efficacy and a more specific assessment of erectile function. For general efficacy, the proportion of patients who reported improved erections and ability to have intercourse was as high as 94%. Up to 72% of intercourse attempts were successful. For measures of erectile function, 5 of the 6 studies showed statistically significant improvements among sildenafil-treated versus placebo-treated patients. Erectile response rates were generally higher in patients with incomplete versus complete SCI and in patients with upper versus lower motor neuron lesions. Nevertheless, a substantial proportion of patients with complete lesions, regardless of level or lower motor neuron lesions, also benefited from sildenafil. Sildenafil was well tolerated. Incidence rates and types of adverse events that occurred in these studies were similar to those published previously. Symptoms of autonomic dysreflexia were not reported in any study. Existing evidence suggests that oral sildenafil is a highly effective and well-tolerated treatment for ED associated with SCI.

Coitus↗

Evaluating the effects of an alpha-2 adrenoceptor antagonist on erectile function in the human male. 2. The erectile response to erotic stimuli in men with erectile dysfunction, in relation to age and in comparison with normal volunteers.

The effect of a new alpha-2 adrenoceptor antagonist on erectile function was assessed in 24 men with probable psychogenic erectile dysfunction. The drug was given in two dosages, together with placebo, by intravenous infusion in a balanced cross over design. Once plasma levels were established, erectile, subjective and haemodynamic responses to erotic fantasy and films were measured. Subjects were divided into two age groups, "Younger" (i.e. less than 45 years) and "Older" (greater than 45 years). There was a significant though modest increase in the duration of erectile response with the high dose of the drug, but only in the younger men. There were also drug effects on haemodynamic responses confined to the younger men, who showed markedly reduced responses during placebo administration when compared with the older dysfunctional men and with young "functional" volunteers. The findings raise the possibility that in younger men with psychogenic erectile failure, there is an inhibition of general arousal responses to erotic stimuli which is partially reversed by this drug. In the older men, the different pattern of response suggests that a) there may be a decline in response to the drug with age and b) other age-related factors are playing an important part in the aetiology of their erectile failure.

Adrenergic alpha-2 Receptor Antagonists↗

An oral yohimbine/L-arginine combination (NMI 861) for the treatment of male erectile dysfunction: a pharmacokinetic, pharmacodynamic and interaction study with intravenous nitroglycerine in healthy male subjects.

AIMS: Interaction of phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction with organic nitrates could lead to severe hypotension. NMI 861 is a combination of 7.7 mg yohimbine tartrate and 6 g l-arginine glutamate. A similar oral combination, which contains the same amount of yohimbine and L-arginine, has been shown to improve erectile function in previous studies. METHODS: In two placebo-controlled, randomized, double-blind, two-way crossover design studies we aimed to assess first the pharmacokinetics and pharmacodynamics of a single oral dose of NMI 861 administered in 16 healthy male subjects, and then the pharmacodynamics of orally administered NMI 861 in combination with intravenous nitroglycerine (GTN) in 12 healthy male subjects. Systolic (SBP) and diastolic (DBP) blood pressures, pulse rate and adverse events were measured in each study. RESULTS: NMI 861 was well tolerated by all subjects with no significant adverse reactions reported. For L-arginine, mean C(max) +/- SEM (range) was 42 +/- 2.2 (28-63) microg ml(-1) and t(max) (range) was 0.88 (0.50-1.5) h. AUC and t(1/2) were not calculated for L-arginine because of the presence of endogenous concentrations and the contribution from food sources. For yohimbine, mean C(max) was 42 +/- 11 (2.8-128) ng ml(-1); t(max) was 0.57 (0.25-1.0) h; mean AUC(0,8 h) was 65 +/- 24 (5.4-332), ng ml(-1) h and t(1/2) was 1.0 +/- 0.34 (0.40-6.0) h. There was a small but significant difference in the mean change from baseline for SBP from 0 to 6 h after NMI 861 treatment compared with placebo (0.8 +/- 1.4 vs-4.1 +/- 2.1 mmHg, respectively; 95% CI 0.0, 9.8 mmHg (P = 0.047)). There was no significant difference in SBP between treatments for the studied periods 6-12 h and 12-24 h. There was no significant difference in DBP or pulse between NMI 861 and placebo treatments for the three studied time periods. In the study designed to investigate the interaction of organic nitrate with NMI 861, subjects were infused intravenously with increasing doses of GTN (15 min each dose) at 2.5, 5, 10, 20 and 40 microg min(-1) starting 40 min after a single oral dose of either NMI 861 or placebo. There was no significant difference in the hypotensive response induced by GTN between the NMI 861 and placebo treatments. The mean maximum changes from baseline during GTN infusion for subjects administered with either NMI 861 or placebo were a decrease of 16.9 +/- 3.4 vs 13.6 +/- 2.4 mmHg (mean difference between treatments -3.3 mmHg, 95% CI -12.7, 6.0 mmHg (P = 0.460)) for SBP, a decrease of 14.7 +/- 2.0 vs 14.0 +/- 2.0 mmHg for DBP (mean difference -0.7 mmHg, 95% CI -8.2, 6.8 mmHg (P = 0.835)), and an increase of 11.8 +/- 1.9 vs 14.1 +/- 2.4 beats min(-1) for pulse, respectively (mean difference -2.3 beats min(-1), 95% CI -9.3, 4.5 beats min(-1) (P = 0.464)). CONCLUSIONS: Acute oral administration of NMI 861 was found to be well tolerated and bioavailable in healthy male subjects and no significant hypotensive interaction with intravenous GTN was detected at the doses investigated.

Administration, Oral↗

Achieving treatment optimization with sildenafil citrate (Viagra) in patients with erectile dysfunction.

Since its approval in 1998, sildenafil citrate (Viagra) has been shown to be efficacious in >100 clinical trials involving >8000 men with erectile dysfunction (ED). In clinical practice, however, many men do not continue long-term use of sildenafil for a variety of reasons; thus, 6 different aspects of optimizing treatment with sildenafil are described here. (1) Intercourse success rates, considered a reflection of real-world effectiveness, were assessed in 1276 patients with ED. Results indicated that the cumulative probability of achieving intercourse success with sildenafil increased with the number of attempts, reaching a plateau after approximately 8 attempts. (2) A comprehensive disease management approach that included a medical history, physical examination, educational material about ED, modifications of risk factors/lifestyle changes, and counseling resulted in successful intercourse in 74% of 111 patients taking sildenafil. (3) A survey conducted among primary care physicians revealed that almost 50% did not routinely question their patients about ED symptoms, although it is known that most patients would prefer their physician to take the initiative. (4) Overall, 55% of 137 men who were previously not successful with sildenafil became successful after reeducation and counseling, which included information on patient and partner expectations, how to properly take the drug, titration to maximum dose, and a minimum trial of 8 attempts for efficacy assessment. (5) Many men with ED have underlying comorbidities or take multiple medications that are risk factors for ED. Controlling these risk factors in 521 men from a multispecialty clinic led to an overall intercourse success rate of 82%; patients with multiple risk factors were less likely to have intercourse success than men with only 1 risk factor. (6) Finally, treatment satisfaction is a pivotal factor in maintaining long-term ED therapy. In an open-label trial, 82% of 443 subjects reported treatment satisfaction with sildenafil. In summary, these findings highlight how important it is for physicians to take a more comprehensive, proactive approach when treating men with ED, including control of risk factors, instructions on how to properly take the drug, partner involvement, and follow-up visits. Using these recommended measures, most men with ED, including those whose treatment was previously unsuccessful, can be treated successfully with sildenafil.

Coitus↗

Free radical-scavenging activity of Korean red ginseng for erectile dysfunction in non-insulin-dependent diabetes mellitus rats.

OBJECTIVES: To investigate the antioxidant activity of Korean red ginseng (KRG) and its effect on erectile function in non-insulin-dependent diabetes mellitus (NIDDM) rats. Oxidative stress is an important factor in vascular complications of diabetes. METHODS: A total of 84 male Sprague-Dawley rats were included in this study. NIDDM was induced by an intraperitoneal injection of 90 mg/kg of streptozotocin on day 2 after birth. According to the diabetic period, they were classified as either short-term (22 weeks, n = 32) or long-term (38 weeks, n = 32) diabetics. Of those, 20 (10 short-term and 10 long-term) were fed 30 mg/kg of KRG three times weekly for 1 month. The remaining diabetic rats (22 short-term and 22 long-term) and their age-matched controls (n = 10 each for each group) were fed a normal diet. Erectile function was measured after electrostimulation of the cavernous nerve. The total cavernous malondialdehyde and glutathione levels were measured using a spectrophotometric assay. RESULTS: The intracavernous pressure after nerve stimulation and cavernous glutathione level were significantly lower in the long-term than the short-term diabetics with a normal diet and were markedly decreased compared with their age-matched controls (P <0.01 and P <0.05, respectively). The malondialdehyde content was markedly increased in the short-term diabetics compared with the controls (P <0.05). In contrast, erectile function was not impaired in the diabetic group treated with KRG. Furthermore, both glutathione and malondialdehyde levels in those treated with KRG were comparable to their age-matched controls. CONCLUSIONS: Oxidative stress to cavernous tissue may be a contributory factor in erectile dysfunction in diabetics. KRG may preserve potency in the NIDDM rats through its antioxidant activity.

Animals↗

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