Cure Erectile Dysfunction

New Treatment of Erectile Dysfunction

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Fig. 3. Pharmacokinetics of PDE 5 inhibitors.

Fig. 3. Pharmacokinetics of PDE 5 inhibitors.

lower in men with diabetes than in men without diabetes (59). The pharmacokinetic profile of tadalafil differs from that of sildenafil and vardenafil in that it has a much longer half-life (Fig. 3). This means that the effect of tadalafil might last for more than 24 h or even longer, whereas the duration of action for the other two drugs is around 4-5 hours. Such a longer "window of opportunity" may be preferable by some men, but similarly possible side effects may also be prolonged.

Vardenafil (Levitra®). In a large 12-week multicenter trial including 439 men with diabetes (type 2: 88%) that excluded sildenafil nonresponders, the rates of men with improved erections were 72% with 20 mg vardenafil, 57% with 10 mg vardenafil, and 13% on placebo (60a). Both vardenafil 10 mg and 20 mg were superior to placebo in improving the IIEF erectile function domain score (questions 1-5, 15). In a recent study including 302 men with type 1 diabetes vardenafil given in a flexible dose of 5-20 mg effectively improved erectile function regardless of the level of glycemic control and as well as tolerated (60b). Similar to tadalafil, despite the exclusion of nonresponders to sildenafil the effect of vardenafil was comparable to that reported previously for sildenafil. Treatment-related adverse events (>5%) on 20 mg, 10 mg, and placebo were headache (10, 9, and 2%), flushing (10, 9, and <1%), and headache (6, 3, and 0%).

Phentolamine (Vasomax®). The nonselective a-blocking agent phentolamine was evaluated for a possible beneficial effect on the erectile behavior. In prospective, randomized, double blind studies, a beneficial effect of orally administered fast-resolving phentolamine on the erectile capacity of men with erectile dysfunction was shown. These beneficial effects were more pronounced in elderly men. The side effect profile of this drug introduced decades ago for other indications seems to be safe with stuffy nose and some hypotension being the most frequent complaints. However, published data are minimal so that a thorough evaluation is not possible for the moment (61).

Vacuum Devices

These have the merit of being noninvasive and may be effective in all men. They create a vacuum around the penis and blood is drawn into the corporal spaces. A band is slipped off the plastic cylinder around the base of the penis to maintain penile tumescence without rigidity in the crura. The disadvantages are that they require some degree of dexterity in handling them, and some time spent in application of the device. They should only be used for 30 minutes at a time, and require the willing cooperation of the partner. There are few side effects although there is some degree of discomfort and the penis feels cold. Ejaculation is usually blocked and some men feel this makes orgasm less satisfactory. Bruising can occur in 10-15% of men. Vacuum devices are particularly useful in older men in stable relationships and when other treatment options are ineffective. They may also be used to augment the result of pharmacotherapy. Some men find that the constrictive ring is a useful aid in itself for maintaining the erection without the use of a vacuum device (33). However, the long-term drop-out rates among users of vacuum constriction devices are relatively high. A recent study showed an overall drop-out rate of more than 3 years for the ErecAid® system of 65%, i.e., 100% in men with mild ED, 56% in those with moderate ED, and 70% in those with complete ED. The main reasons for stopping its use were that the device was ineffective (57%), too cumbersome (24%), and too painful (20%) (62).

Transurethral Alprostadil

Alprostadil was first licensed for the treatment of erectile dysfunction by intracavernous injection. Alprostadil, the synthetic preparation of the naturally occurring prostaglandin E1 acts by initiating the erection. In contrast to sildenafil it initiates the relaxation of cavernous smooth muscle to bring about erection. This drug has been incorporated into a pellet that can be given by intraurethral application medical urethral system for erection (MUSE). Patients need to be instructed in the use of MUSE which is introduced into the urethra with a disposable applicator. The patient first passes urine to act as a lubricant to facilitate the passage of the applicator and the absorption of the drug. Absorption of the drug is also facilitated by the patient rolling his penis between the palms of his hands. Some patients find that a constrictive ring around the base of the penis enhances the efficacy. The erection takes about 10 minutes to develop and the dose range varies between 125 and 1000 ^g although the majority of patients require 500 or 1000 ^g. The use of MUSE is contraindi-cated without a condom when the partner is pregnant or likely to conceive (33).

In the US and European multicenter trials about 65% of men with different causes of ED who tried MUSE had erections sufficient for intercourse during in-clinic testing (63,64). About half of the treatments at home were successful, but the drop-out rate after 15 months was 75%, the main reason being lack of efficacy (64). The most common side effects are penile pain (30%), urethral burning (12%), or minor urethral bleeding (5%) (65). Systemic side effects (such as hypotension or even syncope) were usually uncommon but helped to highlight the role of the physician in administering the first supervised dose. Disappointing results have been reported in a study conducted in a urology practice setting, in which an adequate rigidity score was achieved in only 13 and 30% of the patients using 500 and 1000 ^g, respectively. Pain, discomfort, or burning in the penis were observed in 18%, but orthostatic hypotension (defined as a decrease in systolic/diastolic blood pressure by

20/10 mmHg or orthostatic symptoms) was present in 41% of the patients. The discontinuation rate was very high, achieving 81% after 2-3 months (66).

Intracavernosal Injection Therapy

Intracavernosal therapy requires some specialist knowledge and the ability to treat priapism should it occur. Many specialists used to regard this as the standard treatment and use it for both diagnostic and therapeutic reasons although its role as first line therapy has been replaced by less invasive treatment modalities. Patients need to be taught how to perform selfinjection and the dose needs to be chosen carefully to avoid prolonged erections or priapism. Some patients find it helpful to use one of the many autoinjector devices available. The erection occurs after 10 minutes and may be enhanced by sexual stimulation. The incidence of complications varies with the different pharmacological agents. Some pain is not uncommon but long-term problems are limited to priapism or penile fibrosis.

Alprostadil is the most widely used agent (67,68). lt is effective in more than 80% of patients with different aetiologies of ED and has a low incidence of side effects. In a recent comparative study of intracavernosal vs intraurethral administration of alprostadil the rates of erections sufficient for sexual intercourse were 82.5 vs 53.0%, respectively (68). Patient and partner satisfaction was higher with intracavernosal injection, and more patients preferred this therapy. Penile pain occurs in 15-50% of patients but is often not troublesome. The dose range is 5-20 ^g but some physicians will increase it further or use a combination with papaverine and phentolamine. Priapism occurs in about 1% of patients. The cumulative incidence of penile fibrosis was 11.7% after a period of 4 years, and the risk of irreversible fibrotic alterations was 5% (69). About half of the cases with fibrosis resolved spontaneously. Other less frequently used agents include thymoxamine (moxisylyte hydrocholoride [Erecnos®]), papaverine/ phentolamine mixtures (Androskat®), papaverine/phentolamine/alprostadil mixtures (Trimix®), and VIP/Phentolamine (Invicorp®).

Penile Prostheses and Surgery

This type of treatment is carried out only after careful patient selection and a trial of the less invasive options. There are a number of different devices ranging from the simple malleable prosthesis to more complex hydraulic prostheses. The choice of prosthesis is very much dependent on the wishes of the patient and is often cost-related. A prosthesis does not restore a normal erection but makes the penis rigid enough for sexual intercourse. The hydraulic prostheses have the advantage of flaccidity and are now mechanically reliable with revision rates less than 5% per annum. Infection remains a major complication in approximately 3-5% of cases with different causes of ED and usually leads to removal of the device (33). Arterial reconstruction is associated with complication rates of more than 30% and remains an experimental procedure which cannot be generally recommended to patients with diabetes with ED.

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