Abstract

Sexual behaviour in rats can be used to predict putative effects on human sexual behaviour. Anecdotic reports exist, that the beta-lactamase inhibitor, clavulanic acid exerts sexual stimulating activities in monkeys. To characterize these pro-sexual activities, clavulanic acid was tested in three doses and compared to one dose of a sexually inhibitory dose of the selective serotonin reuptake inhibitor, paroxetine, in sexually-experienced male rats, selected for a moderate level of sexual performance in a standard 30-min test with an oestrus female. After acute administration, clavulanic acid had minor sexual stimulating effects at the highest dose in the number of intromissions and in the first ejaculation series. After sub-chronic 7-days treatment, clavulanic acid increased the number of ejaculations at all three doses and reduced the number of intromissions in the 1st series at the highest dose. After chronic 14 days treatment, a similar but stronger pro-sexual profile was observed. The sexual side effects of paroxetine were as expected, including slight sexual inhibitory effects after acute administration, but somewhat stronger overall inhibitory effects after 7 and 14-days pretreatment, particularly notable in the decreasing number of animals contributing to the 2nd ejaculation series, which was even stronger after 14-days treatment. One week after cessation of treatment, the paroxetine group had completely recovered, whereas the highest dose-group of clavulanic acid still showed some pro-sexual effects. This remarkable pro-sexual activity of clavulanic acid cannot readily be explained by its mechanism of action as a beta-lactamase inhibitor but could be due to unexpected central activity of the compound.

source: https://www.ncbi.nlm.nih.gov/pubmed/19285063

Abstract

The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.

source: https://www.ncbi.nlm.nih.gov/pubmed/17149874

Abstract

A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.

source: https://www.ncbi.nlm.nih.gov/pubmed/15239663

Abstract

Eleven patients with moderate to severe erectile dysfunction (ED) were given a single-dose corpus cavernosum injection of hMaxi-K, a “naked” DNA plasmid carrying the human cDNA encoding hSlo (for human slow-poke), the gene for the alpha, or pore-forming, subunit of the human smooth muscle Maxi-K channel. Three patients each were given 500, 1000, and 5000 microg, and two patients were given 7500 microg, of hMaxi-K and monitored for 24 weeks. The primary objectives of this phase I study were safety and tolerability of escalating hMaxi-K doses as assessed by clinical evaluations and laboratory tests. Secondary efficacy objectives were measured primarily by use of the International Index of Erectile Function (IIEF) scale. Patient responses were validated by partner responses. There were no serious adverse events and no dose-related adverse events attributed to gene transfer for any patient at any dose or study visit. No clinically significant changes from baseline were seen in physical evaluations (general and genitourinary), hematology, chemistry, and hormone analyses, or in cardiac events evaluated by repeated electrocardiograms. Importantly, no plasmid was detected in the semen of patients at any time after the injections. Patients given the two highest doses of hMaxi-K had apparent sustained improvements in erectile function (EF) as indicated by improved IIEF-EF domain scores over the length of the study. One patient given 5000 microg and one given 7500 microg reported EF category improvements that were highly clinically significant and were also maintained through the 24 weeks of study. Efficacy conclusions cannot be drawn from results of a phase I trial with no control group. However, the promising primary safety outcomes of the study and preliminary indications of effectiveness provide evidence that hMaxi-K gene transfer is a viable approach to the treatment of ED and that further studies investigating the efficacy of hMaxi-K in patients with ED should be performed.

source: https://www.ncbi.nlm.nih.gov/pubmed/17134370

Abstract

PURPOSE:

We evaluated the safety and efficacy of intranasal bremelanotide in men with erectile dysfunction who did not respond to sildenafil.

MATERIALS AND METHODS:

A total of 342 married men (28 to 59 years old) with erectile dysfunction who did not respond to sildenafil were randomly assigned to receive 10 mg bremelanotide as an intranasal spray (group 1, 172) 45 minutes to 2 hours prior to sexual stimulation, or a similar regimen of placebo (group 2, 170). Patients were asked to use at least 16 doses/attempts at home. They underwent preliminary assessment, including medical and sexual history, and self-administered International Index of Erectile Function. The efficacy of 2 treatments was assessed every 4 attempts during treatment and at the end of study, using responses to International Index of Erectile Function, and evaluation of mean intercourse satisfaction domain, mean weekly coitus episodes and adverse drug effects.

RESULTS:

Positive clinical results were seen in 51 (33.5%) patients in the bremelanotide group compared with 13 (8.5%) patients in the placebo group (p = 0.03). Patients in the bremelanotide group reported significantly greater intercourse satisfaction than those in placebo group (p = 0.03). More drug related adverse effects occurred in the bremelanotide group (p = 0.01).

CONCLUSIONS:

Bremelanotide can be an alternative treatment for erectile dysfunction with a potentially broad patient base. Further studies with different dosages and treatment regimens are necessary to draw final conclusions on the efficacy of this drug in erectile dysfunction.

source: https://www.ncbi.nlm.nih.gov/pubmed/11035391

Abstract

We review our experience with Melanotan II, a non-selective melanocortin receptor agonist, in human subjects with erectile dysfunction (ED). Melanotan II was administered to 20 men with psychogenic and organic ED using a double-blind placebo-controlled crossover design. Penile rigidity was monitored for 6 h using RigiScan. Level of sexual desire and side effects were reported with a questionnaire. In the absence of sexual stimulation, Melanotan II led to penile erection in 17 of 20 men. Subjects experienced a mean of 41 min Rigiscan tip rigidity>80%. Increased sexual desire was reported after 13/19 (68%) doses of Melanotan II vs 4/21 (19%) of placebo (P<0.01). Nausea and yawning were frequently reported side effects due to Melanotan II; at a dose of 0.025 mg/kg, 12.9% of subjects had severe nausea. We conclude that Melanotan II is a potent initiator of penile erection in men with erectile dysfunction. Our findings warrant further investigation of melanocortin agonists and antagonists on penile erection. International Journal of Impotence Research (2000) 12, Suppl 4, S74-S79.

source: https://www.ncbi.nlm.nih.gov/pubmed/11035391

Abstract

OBJECTIVE:

We sought to study the effects of a single oral dose of sildenafil citrate (50 mg) on blood pressure (BP) in men taking the nitric oxide (NO) donor drugs isosorbide mononitrate (ISMN) or glyceryl trinitrate (GTN) for stable angina.

BACKGROUND:

Sildenafil, a selective phosphodiesterase type 5 inhibitor, is an orally effective treatment for erectile dysfunction. The presence of phosphodiesterases in the vasculature suggests the possibility of an interaction between sildenafil and NO donor drugs.

METHODS:

Two double-blind, placebo-controlled, randomized, two-way crossover trials were undertaken. Sixteen male patients received oral ISMN (20 mg twice a day) for five to seven days before their dose of sildenafil or placebo and continued receiving ISMN daily until administration of the alternate drug seven days later. For the second study, 15 male patients received sublingual GTN (500 microg) 1 h after sildenafil or placebo on each of two study days, which were seven days apart. Sitting or standing BP was measured before and for 6 h after the administration of the study drug.

RESULTS:

The effects of sildenafil plus ISMN on BP (standing mean maximum reductions from baseline in systolic/diastolic BP, -52/-29 mm Hg) were greater than the effects of placebo plus ISMN on BP (-25/-15 mm Hg; p < 0.001). Sildenafil plus GTN also resulted in greater sitting mean maximum reductions from baseline in systolic/diastolic BP (-36/-21 mm Hg) compared with placebo plus GTN (-26/-12 mm Hg; p < 0.01).

CONCLUSIONS:

Coadministration of sildenafil with ISMN or GTN produced significantly greater reductions in BP than ISMN or GTN alone. Based on these data, sildenafil should not be administered to patients taking nitrates.

source: https://www.ncbi.nlm.nih.gov/pubmed/10898408

Abstract

INTRODUCTION:

Diabetic men with erectile dysfunction (ED) are less responsive to therapy with type 5 phosphodiesterase (PDE5) inhibitors. Although an impairment of the nitric oxide (NO)/cyclic guanosin-monophosphate (cGMP) pathway has been shown in diabetic ED vs. non-diabetic ED, the functionality of NO/cGMP pathway in non-diabetic and diabetic ED patients with respect to non-ED patients has not been established.

AIM:

The aim of this study is to evaluate the function of NO/cGMP signalling in human erectile tissues from ED patients exploring the added impact of diabetes.

METHODS:

Corpus cavernosum strips (human corpus cavernosum [HCC]) and penile resistance arteries (HPRA) were collected from penile specimens from organ donors (OD) and from diabetic and non-diabetic men with ED undergoing penile prosthesis implantation.

MAIN OUTCOME MEASURES:

Relaxations to acetylcholine, electrical field stimulation, sodium nitroprusside, and sildenafil were evaluated in phenylephrine-contracted HCC and norepinephrine-contracted HPRA. cGMP content in HCC was also determined.

RESULTS:

The impairment of endothelium-dependent relaxation in HCC and HPRA from ED patients was exacerbated by diabetes (E(max) 76.1, 62.9, and 49.3% in HCC and 73.1, 59.8, and 46.0% in HPRA from OD, non-diabetic and diabetic ED, respectively). Hypertension, hypercholesterolemia, or aging did not exert a further impairment of endothelial relaxation among ED patients. Diabetes also causes a further impairment of neurogenic relaxation in HCC and HPRA. The basal and stimulated content of cGMP in HCC was significantly decreased in patients with ED, but specially reduced in diabetic patients. Diabetes clearly impaired PDE5 inhibitor-induced vasodilation of HPRA from ED patients.

CONCLUSIONS:

ED is related to impaired vasodilation, reduced relaxant capacity, and diminished cGMP content in penile tissue. These alterations are more severe in diabetes and accompany reduced relaxant efficacy of PDE5 inhibition. Thus, an exacerbated reduction of nitric oxide/cGMP signaling could be responsible for ED in diabetic men and would explain their reduced response to treatment.

source: https://www.ncbi.nlm.nih.gov/pubmed/19912487

Abstract

Erectile dysfunction (ED) is highly prevalent in diabetes mellitus. Pathophysiological mechanisms underlying diabetes-associated ED are in large part due to endothelial dysfunction, which functionally refers to the inability of the endothelium to produce vasorelaxing messengers and to maintain vasodilation and vascular homeostasis. The precise mechanisms leading to endothelial dysfunction in the diabetic vasculature, including the penis, are not yet fully understood. Hyperglycemia affects endothelial nitric oxide synthase activity and nitric oxide production/bioavailability, nitric oxide-independent relaxing factors, oxidative stress, production and/or action of hormones, growth factors and/or cytokines, and generation and activity of opposing vasoconstrictors. Considering recent advances in the field of vascular biology and diabetes, the emphasis in this review is placed on the mechanisms of hyperglycemia-induced endothelial dysfunction in the pathophysiology of diabetes-associated ED.

source: https://www.ncbi.nlm.nih.gov/pubmed/16775612

Abstract

OBJECTIVE:

To assess the clinical efficacy of sildenafil as treatment for erectile dysfunction (ED) the factors associated with treatment failure were investigated.

METHODS:

Open, prospective study including 244 patients suffering from ED who were evaluated by anamnesis, physical exploration, blood test, dynamic penile color duplex ultrasonography and Sexual Health Inventory for Male (SHIM). The efficacy of sildenafil was assessed by repeating the SHIM 2 months after therapy, independent of the final dose used. Side effects were also recorded. Factors influencing treatment outcome were evaluated by univariate and multivariate statistical analysis.

RESULTS:

Overall, sildenafil was effective in 56.8% of 213 eligible patients. When the etiologic diagnosis was not included in the multivariate analysis, antecedents of diabetes mellitus, non-nerve-sparing radical prostatectomy and SHIM basal score were selected as predictors of a poor response. In a second analysis including etiologic diagnosis, only SHIM basal score and etiological diagnosis proved to be of prognostic value. Side effects were noticed by 24.4% of patients, none of them being severe.

CONCLUSIONS:

Sildenafil is a rather effective and well-tolerated treatment for ED. The basal severity of ED and etiological diagnosis are the prognostic factors most significantly associated with treatment outcome.

source: https://www.ncbi.nlm.nih.gov/pubmed/11805410