Bemoradan

An early event associated with neutrophil-dependent tissue damage involves the adhesion of neutrophils to the vascular endothelium and the subsequent release of oxygen-derived free radicals and granule constituents. Elevations in intracellular cAMP are known to inhibit free radical release but not lysosomal enzyme release. The role of cAMP in FMLP-induced neutrophil adhesion was examined in this study by using an in vitro model of neutrophil-endothelial cell adhesion. FMLP stimulated a time- and concentration-dependent increase in human neutrophil adhesion to HUVEC. FMLP-mediated adhesion was inhibited by a diverse group of cAMP modulators: forskolin, isoproterenol, phosphodiesterase IV inhibitors (rolipram and Ro 20-1724), but not phosphodiesterase III inhibitors (milrinone and bemoradan). Endogenous adenosine has previously been shown to mediate FMLP-induced increases in cAMP enhanced in the presence of Ro 20-1724. In this study, adenosine deaminase prevented the inhibitory effects observed with rolipram and Ro 20-1724, implicating endogenous adenosine as a co-modulator of inhibition. FMLP stimulated neutrophil shape change and the surface expression of the beta 2 integrins CD11b/CD18 and CD11a/CD18. Both these responses were inhibited by rolipram but not bemoradan. With the use of 4,4'-diisothiocyanostilbene-2,2'disulfonic acid, we showed that mobilization of the intracellular pool of CD11b/CD18 paralleled adhesion. We conclude that neutrophil-endothelial cell adhesion is attenuated by elevating neutrophil intracellular cAMP and that inhibition of neutrophil CD11b/CD18 surface expression by cAMP accounts for this observed inhibition of adhesion.

Bemoradan is a potent, long-acting orally active inodilator. The pharmacokinetics and bioavailability of bemoradan were studied in twelve normal males following oral administration of single, ascending doses of the bemoradan HCL salt in capsules. Plasma and urine levels of bemoradan were determined by HPLC (detection limits: approximately 0.5 ng/ml for plasma and 5 ng/ml for urine). Bemoradan was rapidly absorbed from the capsule formulation at all doses (Cmax occurred at 2.1-2.4 hours). Bemoradan was slowly eliminated from the body (harmonic mean t1/2 16-23 hours). There was a dose-proportional increase in the AUC (0-48) values of bemoradan in humans following the administration of 0.5, 1, 1.5 and 2 mg of bemoradan. The AUC (0-48) values increased to 2.3, 3.4 and 4.0 times when the dose was increased to 2, 3 and 4 times. Urinary excretion of unchanged bemoradan accounted for approximately 5-12% of the dose. Results from this study and previous studies in rats and dogs indicate that bemoradan is well and rapidly absorbed after oral dosing, has linear pharmacokinetics and long elimination half-lives across species.