Phosphodiesterases clinical significance

CICLOSPORIN PHOSPHODIESTERASE TYPE S INHIBITORS-SILDENAFIL t plasma concentrations of cidosporin, with risk of adverse effects Competitive inhibition of CYP3A4-mediated metabolism of cidosporin Be aware. Sildenafil is taken intermittently and is unlikely to be of clinical significance unless concomitant therapy is long term... 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

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. 

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