Nonresponders to PDE5 inhibitors

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Of course there are real non-responders to PDE-5 inhibitors. Real non-responders mostly have a severe end-organ failure, which means that the cavernosal tissue has lost a considerable portion of its functional smooth musculature [99]. In the clinical setting these PDE-5 inhibitor non-responders show severe veno-occlusive dysfunction, with many of them also non-responding to intracavernosal injection of va-soactive drugs such as alprostadil or the trimix combination. Quite frequently this veno-occlusive dysfunction (syn: venous leak or cavernous insufficiency) is associated with severe impairment of the penile arterial blood supply in the penile color Doppler findings. But many so-called non-respon-ders may be rescued by appropriate counseling, by treatment of concomitant diseases or change in medication use. The definition of a real non-responder is justified if no success is seen under the following conditions: use of at least four tablets with the highest dose of the respective PDE-5 inhibitor, at four different occasions, under optimal conditions (appropriate sexual stimulation, appropriate interval between tablet intake and sexual activity, with sildenafil and vardenafil—fasting conditions for two hours, and with tadalafil—keeping an interval of at least two hours between intake and sexual activity) (personal experience).

In the literature the following measures resulted in convincing salvage rates from previously defined PDE-5 non-responders:

1 Re-counseling of the patients/couples in the proper use of PDE-5 inhibitors, including especially the use of the highest doses, with salvage rates of up to 60% depending on the study population under investigation [100-103].

2 Optimal treatment of concomitant diseases, such as optimal diabetes control (elevated gycosylated hemoglobin can directly impair the relaxant capacity of the cavernosal smooth musculature [104]) or hypertension control. In addition, treatment of hypercho-lesterolemia with statins such as atorvastatin were able to improve erectile function per se, due to the fact that statins decrease low density lipoprotein (LDL) levels and subsequently the negative effect of oxidized LDL on endothelial function [105].

3 Treatment of concomitant hypogonadism. As it is proven that testosterone regulates the expression of PDE-5 and the responsiveness to PDE-5 inhibitors in the corpus cavernosum [106], and that androgens per se improve the cavernous vasodilation [107], hy-pogonadal men with ED show principally a poorer responsiveness to PDE-5 inhibitors and also other erectogenic drugs. In this regard many authors have provided evidence that hypogonadal ED patients, originally unresponsive to PDE-5 inhibitors, may be rescued by testosterone replacement therapy [108-110].

4 "High dose" (overdosing) PDE-5 inhibitor therapy i.e. doubling the maximum dose, resulted in a 24% salvage rate of ED patients (n = 54) previously unresponsive to 100mg sildenafil [111]. According to personal experience, this concept may also apply for vardenafil and tadalafil in suitable patients— especially in unresponsive diabetics.

5 Shifting patients to another PDE-5 inhibitor: Shifting of real non-responders from sildenafil to vardenafil resulted in a rescue success rate of 12% [112]. According to personal experience with more than 7000 patients on PDE-5 inhibitors, only a small minority (5-8%) of real non-responders (vaginal penetration not possible after four attempts with the highest dose) to one PDE-5 may be rescued by another one.

6 Daily dosing with PDE-5 inhibitors for several months in patients, previously unresponsive, is able to rescue more than 50% of failures [113,114]. Although this was proven for sildenafil and tadalafil, it can be assumed that this also holds true for all PDE-5

inhibitors, in particular in patients with severe organic ED.

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