Phosphodiesterase type 5 inhibitors restore nitric oxide signaling, that plays a significant role in erectile function, and appears to counteract insulin resistance in animal and human models. This study was aimed to evaluate the glycemic and metabolic effects of low-dose tadalafil once daily in patients with type 2 diabetes and erectile dysfunction.
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This prospective pilot study showed that low-dose tadalafil administered once a day was effective in improving glycemic control and erectile function in patients with type 2 diabetes and erectile dysfunction.
Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin sensitivity, or both [9]. Insulin resistance (IR) is associated with the development of endothelial dysfunction and a reduction in NO bioavailability [10]. In humans, endothelial dysfunction is linked with diabetes mellitus via a mechanism that interrupts intracellular signaling pathways of insulin and NO production [11]. Endothelial NO mediates the insulin-induced effects by increasing intracellular levels of cGMP in human vascular smooth muscle cells [12]. The increase in glucose transport is stimulated by insulin via the endothelium-derived NO/cGMP pathway [13]. Reduced NO synthesis in endothelial cells contributes to impaired insulin action in patients with T2D [14]. Therefore, treatments that amplify NO/cGMP signaling could improve microvascular recruitment and muscle glucose uptake [15]. Moreover, recent evidence from animal models and in men with ED suggests that PDE-5 inhibition may have metabolic benefits [16]. Nevertheless, a meta-analysis of PDE-5 inhibitors studies showed little benefit in improving glycemic control [17].
We conducted a randomized clinical trial to evaluate the effect of the chronic use of low-dose tadalafil OAD on glycemic control, assessed its effect according to glycated hemoglobin (HbA1c) levels and other metabolic effects in patients with T2D and ED. Additionally, we assessed the long-term efficacy and safety of tadalafil in treating erectile function.
Tadalafil was first approved for low-dose daily administration at 2.5 or 5 mg for treating ED, and it has a longer duration of action than other PDE-5 inhibitors [29]. Chronic low-dose tadalafil therapy has favorable effects on systemic endothelial dysfunction [30]. Although we did not examine the effect of tadalafil on biomarkers of endothelial dysfunction, tadalafil was found to improve the levels of circulating inflammatory cytokines and chemokines in a diabetic animal model, while improving FPG levels [31]. Moreover, tadalafil improves insulin action on muscle glucose uptake by prolonging NO/cGMP signaling in women with obesity-linked IR [32]. Tadalafil administration was shown to improve β-cell function in metabolic syndrome independent of insulin sensitivity [33]. A pilot study has reported improvements in β-cell function with tadalafil treatment in individuals with severe obesity [34]. However, the participants in the present study were not severely obese and had good metabolic control, including BMI, WC, and HbA1c values. Therefore, it is difficult to generalize the findings of the present study. Future studies need to evaluate the glycemic effect of daily low-dose tadalafil treatment in obesity.
In the present study, we observed that ALT levels were lower in the tadalafil group at 6 months than in the placebo group. In a previous study, ALT levels were associated with T2D, and glucose-lowering drugs decreased ALT levels as tighter blood glucose levels were achieved [35]. Herein, daily administration of low-dose tadalafil improved erectile function, and there was a statistical difference in IIEF-5 scores between tadalafil and placebo groups. Diabetes-associated ED is predominantly attributed to endothelial dysfunction; however, the precise mechanisms remain poorly understood. Daily therapy with low-dose tadalafil has been approved by the Food and Drug Administration to treat LUTS, which is suggestive of clinical benign prostatic hyperplasia. However, the efficacy of tadalafil for LUTS did not significantly differ from that of the placebo, as reported in other studies [36], which might be due to the small sample size. In the safety assessment, tadalafil was well-tolerated, and no subject discontinued the study due to AEs. The AEs reported were mild in severity.
This prospective clinical study found that the daily use of tadalafil 5 mg resulted in more favorable HbA1c and FPG levels than the daily use of placebo after 6 months of treatment. Low-dose tadalafil may be used effectively and safely to improve glycemic control and erectile function in patients with T2D and ED. Nevertheless, future randomized controlled studies with large sample sizes are required to elucidate the underlying mechanisms that could clarify the effects of tadalafil on glycemic control.
This paper reviews laboratory and clinical data concerning oral phentolamine mesylate, Vasomax, an alpha-1, alpha-2 adrenergic receptor antagonist developed specifically for treatment of erectile dysfunction. A contemporary view of the neurovascular mechanisms in penile erection includes the effects of both smooth muscle relaxation and contraction. Contraction of the cavernosal arteries and trabecular smooth muscle appears to be predominantly under the control of alpha-adrenergic innervation. Conversely, adrenergic blockade of alpha-1 and alpha-2 receptors has been shown to facilitate penile erection in both animal and human models. The pharmacokinetic profile of Vasomax appears well suited for an oral erectogenic agent. Vasomax is rapidly absorbed and eliminated in normal males. Peak plasma concentrations are achieved in 30-60 min, and the half-life approximates 5-7 h. Food decreases the rate, but not the extent of bioavailability. Vasomax has low protein binding and is excreted primarily via urine and feces. There is a strong dose-response relationship in maximum plasma concentration (Cmax) and area under the curve (AUC), and there are no clear age-related differences in absorption or elimination rates. Efficacy of Vasomax has been systematically evaluated in two (ZON300, ZON301) large-scale, placebo-controlled trials, in addition to two long-term open-label studies. In both studies, Vasomax was associated with significant improvements in the erectile function domain scores of the International Index of Erectile Function (IIEF). Further improvements were noted as the duration of treatment and dose level were increased. The percentage of successful penetration attempts was also significantly improved with Vasomax compared to placebo. For patients who continued in open-label treatment with Vasomax, efficacy was generally well maintained. Vasomax was well tolerated by the majority of patients. The most common side effects observed were nasal congestion (10%), headache (3%), dizziness (3%), tachycardia (3%) and nausea (1%). Side effects were generally dose-related and in the mild-to-moderate range in all three studies. Furthermore, side effects seldom resulted in treatment discontinuation. Very few serious adverse events were observed in these trials. In summary, Vasomax appears to be effective in the treatment of male erectile dysfunction and well-tolerated by the majority of patients. The drug has a satisfactory side effect profile, without significant risk of cardiovascular effects. Results of clinical trials with Vasomax support the concept of adrenergic-blockade as a clinically relevant mechanism in the control of penile erection.
Erectile dysfunction (ED) is a common sexual-arousal disorder primarily affecting men over the age of 40 years. ED is clinically defined as the inability to attain or maintain a penile erection sufficient for sexual intercourse. In patients without trauma or surgery, a 3-month duration of this symptom is usually accepted as grounds for diagnosis.1 The landmark population-based Massachusetts Male Aging Study reported that up to 52% of men aged 40 to 69 years may experience ED to varying degrees. Although age does not directly precipitate ED, a correlation exists.2 Men with ED exhibit decreased quality of life in both physical and psychological dimensions, including self-esteem, compared with men without ED.3 ED impacts not only the patient with ED; partners of men with ED may experience poorer quality of life and report their own sexual dysfunction more than those whose partners do not have ED.4 An emerging field of evidence has suggested that ED is also a marker for cardiovascular disease and may be correlated with general male health status regardless of etiology.5 Compounding the significant prevalence of ED and the reduced quality of life that accompanies it, studies have suggested that men often underreport ED because of embarrassment or lack of awareness of medical causes.6 Therefore, optimal nonpharmacologic and/or pharmacologic treatment for ED is necessary.
Based on the 2007 American Urological Association Update for the Management of Erectile Dysfunction, first-line standard management of ED includes identifying and treating organic comorbidities and psychogenic dysfunction. Oral PDE5 inhibitors remain a first-line pharmacologic treatment.11
Most men who undergo treatment for prostate cancer will experience some erectile dysfunction for the first several months after treatment, even despite nerve sparing surgery or precision radiation. This is because the blood vessels that control an erection are easily affected by any trauma to the area.
Knowing that this is a potential and common side effect, be sure to discuss your management strategy for erectile dysfunction with your doctor. Erectile dysfunction can be a difficult topic to discuss, but being open and honest about the problems you are having will allow your doctor to make the best treatment recommendation for you. Side effects from prostate cancer treatments are often different from one man to the next. 2ff7e9595c
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