Phosphodiesterase inhibitors efficacy

Alprostadil is approved as monotherapy for the management of ED. It is generally prescribed after failure of VEDs and phosphodiesterase inhibitors and for patients who cannot use these therapies. Of the available routes, the intracavern os al route is preferred over the intraurethral route because of better efficacy. 

THEOPHYLLINE PHOSPHODIESTERASE INHIBITORS-ENOXIMONE Theophylline may i efficacy of enoximone Possibly competitive inhibition of phosphodiesterases Be aware watch for poor response to enoximone... 

Tetrahydropyrazolo[3,4-f]pyridines have been prepared as cannabinoid modulators <2007W0112399>. The pyra-zolo[3,4-4pyridine, Apixaban (BMS-562247), has been found to be a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor xa <2007JMC5339>. Several pyrazolo[3,4-f]pyridines have been found to be potent inhibitors of human eosinophil phosphodiesterase <2007JMC344>. 

Administration of a cocktail containing eicosapentenoic acid and docosahexenoic acid to volunteers for up to 6 weeks, resulted in a significant depression in IL-1J3 (61%), IL-1 a (39%), and TNF (40%) synthesis. These levels returned to normal after a few weeks [99]. In vitro studies indicate that Pentoxifylline can block the effects of IL-1 and TNF on neutrophils [100]. It is a phosphodiesterase (PDE) inhibitor that causes increased capillary blood flow by decreasing blood viscocity and is used clinically in chronic occlusive arterial disease of the limbs with intermittent claudication. Denbufylline, a closely related xanthine, has been patented as a functional inhibitor of cytokines and exhibits a similar profile to Pentoxifylline [101]. Romazarit (Ro-31-3948) derived from oxazole and isoxazole propionic acids has been shown to block IL- 1-induced activation of human fibroblasts in vitro and in animal models reduces inflammation [102,103,104]. By using a spontaneous autoimmune MRL/lpr mouse model, a significant efficacy was shown [105]. Two-dimensional structures of some of these molecules are shown in Figure 14. 

Porst H, Rosen R, Padma-Nathan H, et al. Efficacy and tolerability of vardenafil, a new selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction the first at home clinical trial. IntJ Impot Res 2001 13 192-199. 

Another recent example is provided by the discovery of the use of sildenafil (Viagra Fig. 1.15), a phosphodiesterase type 5 (PDE5) inhibitor, as an efficacious, orally active agent for the treatment of erectile dysfunction [25,26]. Initially, this compound was brought to the clinic as an hypotensive and cardiotonic substance, but its usefulness in erectile dysfunction resulted unexpectedly from clinical observations made during a 10-day toleration study in Wales [27]. 

CIMETIDINE PHOSPHODIESTERASE TYPE 5 INHIBITORS -SILDENAFIL t efficacy and adverse effects of sildenafil Inhibition of metabolism via CYP3A4 Consider a starting dose of 25 mg of sildenafil... 

PHOSPHODIESTERASE TYPE 5 INHIBITORS (e.g. sildenafil, tadalafil, vardenafil) GRAPEFRUIT JUICE Possibly t efficacy and t adverse effects, e.g. hypotension Small t in bioavailability, t variability in pharmacokinetics, i.e. interindividual variations in metabolism Safest to advise against intake of grapefruit juice for at least 48 hours prior to intending to take any of these preparations. When necessaiy, the starting dose of sildenafil should not exceed 25-50 mg and that of tadalafil 10 mg. Avoid co-administration with vardenafil... 

The interaction of the macrolides with the phosphodiesterase type-5 inhibitors is established, although most of the studies concern the use of erythromycin. These interactions are expected to result in both increased efficacy and increased incidence of adverse effects. 

Comparative studies The efficacy and safety of the three main inhibitors of phosphodiesterase type 5, sildenafil, tadala-fil, and vardenafil have been extensively investigated in clinical trials. However, there is little information about potential... 

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