Latest News - Part 38

The clinical evidence: efficacy of tadalafil in ED

Published in Main
Tags: ED, tadalafil

clinical evidence

The most important outcome for an ED therapy is the patient’s perception of success. When patients with ED experience a successful intercourse after treatment, they feel cured of their problem. Furthermore, they express the desire of unplanned, unpremeditated or spontaneous sexual intercourse. In this sense, one possible use of the self-administered questionnaire International Index of Erectile Function – Erectile Function domain (IIEF-EF) score is to ascertain whether patients return to normal erectile function after treatment, with scores of 26–30 representing the normal ranges. Integrated analysis of data from phase III trials demonstrated that tadalafil, at doses from 5 mg to 20 mg versus placebo, significantly improved erectile function (EF) by all measures. In particular, 50%–65% of patients, regardless of ED severity at baseline, returned to normal erectile function with almost 60%–90% of success rate at intercourse attempts during active treatment.

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A clinical pharmacological approach to the effective and safe use of tadalafil

Published in Main
Tags: cGMP, tadalafil

clinical pharmacologicalThe mechanism of action leading to penile erection involves inhibition of PDE5, the major cyclic guanosine monophospate (cGMP) hydrolyzing enzyme located in the vascular smooth muscle cells of corpus cavernosum. Sexual stimulation triggers the release of the endothelium dependent relaxing factor nitric oxide (NO), stimulating through the protein kinase G the release of guanylyl cyclase with an increase of intracellular cGMP, thus causing a decrease in intracellular calcium and, ultimately, the relaxation of trabecular erectile tissues and the dilatation of the helicine artery of the penis. The increase in blood flow causes the engorgement of the sinusoidal spaces of the corpora cavernosa, the tunica albuginea compresses the subtunical venules that drain the corpora and reduces the venous outflow increasing penile blood pressure and causing erection. This mechanism acts primarily to maintain the tumescence phase, whereas neuronal-derived NO is mainly active in the induction of erectile function. Inhibiting PDE5 prolongs the effects of nerve stimulation. Tadalafil, like the PDE5 inhibitors sildenafil and vardenafil, competitively blocks the cGMP hydrolysis by PDE5, thereby fostering cGMP accumulation and the relaxation of vascular smooth muscle. Increased concentrations of cGMP produce higher PDE5 promoter activities. cGMP accumulation stimulates cGMP degradation, but the pharmacological PDE5 inhibition blocks this negative feedback process. Thus, with PDE5 inhibitors, erection develops in a physiologic manner and only with sexual stimulation.

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Medical treatment of erectile dysfunction: Other treatments

ORAL AGENTS

Trazodone
The antidepressant trazodone was noted to occasionally induce priapism and therefore interest developed in its possible role in treatment of erectile dysfunction. There are reports of good erectogenic activity with trazodone, although no significant benefit was found in a placebo-controlled trial. There are also troublesome side-effects, including drowsiness, orthostatic hypotension, nausea and vomiting.

Sildenafil (Viagra®)
Sildenafil is a novel oral therapy currently under active investigation. It is a specific inhibitor of type 5 cGMP phosphodiesterase, which is the predominate isoenzyme in the cavernosal tissue of the penis. Its inhibition leads to increased local levels of the secondary messenger cGMP, leading to relaxation of smooth muscle in the cavernosal tissue. This in turn increases blood flow into the corpora cavernosa, an essential stage in the erectile process. In a double-blind cross-over study of 12 patients with erectile dysfunction of no established organic cause, an objective dose-dependent increase in erectile activity as determined by plethysmography (RigiScan, Dacomed Corporation, MN, USA) was demonstrated. Ten of 12 patients reported improved erectile activity in the sildenafil group compared with two of 12 taking placebo. In another double-blind placebo-controlled study of 351 men with erectile dysfunction, outcome by patient and partner questionnaire confirmed a significant dose-dependent improvement on erectile activity. Side-effects such as facial flushing, headaches and dyspepsia were rare and mild. Sildenafil seems to be efficacious and safe and will undoubtedly play a major role in the treatment of erectile dysfunction in the future. Buy Viagra Professional

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External vacuum devices

For patients with erectile dysfunction who cannot tolerate or do not respond to intracavernosal injections, there is a choice between a penile prosthesis or a vacuum device. A vacuum device works by creating penile congestion and enough rigidity to allow penetration (figure l). There are no comparative controlled studies and most of the questionnaire reviews are carried out by the manufacturers themselves. However, a satisfaction rate of 70% was reported by Price in diabetics, who also emphasized the importance of a stable relationship for success. One major disadvantage to the patient is that these devices are not available on the National Health Service and cost £200 or more. Of the 60% who were able to get an adequate erection, only one third purchased a device, claiming price as the limiting factor. There are few side-effects; some complained of pain and bruising at the site of the constricting rubber ring at the base of the penis and in a minority the partner found it an unacceptable method.

Although not universally popular, for some patients who cannot tolerate intracavernosal injections or are too elderly or unfit to be offered a penile prosthesis, a vacuum device may be a very effective treatment and it does not carry the risk of priapism.

Testosterone replacement and supplementation

Testosterone can be given orally, by injection or implant, and now by a transdermal route (patch). Oral administration of testosterone is an unreliable route for increasing testosterone levels and injections or implants, both invasive techniques, are needed to sustain increased levels. The testosterone patch is a convenient and noninvasive method of obtaining controlled and sustained increases in testosterone levels. However, the use of the testosterone patch has been limited to date, probably because of problems with skin irritation.

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INTRACAVERNOSAL AGENTS

Vasoactive intestinal polypeptide and phentolamine
Vasoactive intestinal polypeptide (VIP) is a postganglionic neurotransmitter which seems to have a role in the erectile process. VIP is described as a ‘facilitator’ of erections because intracavernosal injection leads to tumescence only. A combination of VIP and phentolamine can be very effective. In a study of 52 men with erectile dysfunction of mixed aetiology but full response to papaverine, intracorporeal injection of 30 ug of VIP and 0.5-2 mg of phentolamine led to a functionally rigiderection in 100% of cases. At 6 months follow-up no patient had complained of pain or suffered a complication such as corporeal fibrosis or priapism. VIP and phentolamine would seem to be a very promising, safe and efficacious treatment for erectile dysfunction and maybe an especially important alternative for patients who suffer PGEl-induced pain. At present this combina tion is currently only available on a named-patient basis in hospitals.

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PROSTAGLANDIN El (PGEl)

Effectiveness
There are a multitude of publications on the use of PGEl. One large multicentre trial of 187 patients with erectile dysfunction reported good or very good patient satisfaction in 91% of patients. In a study by Stackl of 550 sufferers, 70% reported a full erection lasting for more than 30 minutes and all were adequate for vaginal penetration. More recently, in an open flexible-dose study of 683 men with erectile dysfunction, 11 924 of 13 762 PGEl injections given (87%) resulted in a satisfactory sexual performance. Satisfaction rates of between 77% and 86% amongst partners was also reported.

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About Cialis
myimg Tadalafil is an orally administered drug for treating impotence (erectile dysfunction), that initially was developed by the biotechnology company ICOS, and then developed and marketed world-wide as Cialis, by Lilly ICOS, LLC, the joint venture of ICOS Corporation and Eli Lilly and Company. Cialis tablets, in 5mg, 10mg, and 20mg doses, are yellow, film-coated, and almond-shaped.