Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Jan 2015
ReviewSoluble guanylate cyclase: a new therapeutic target for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.
Nitric oxide (NO) activates soluble guanylate cyclase (sGC) by binding its prosthetic heme group, thereby catalyzing cyclic guanosine monophosphate (cGMP) synthesis. cGMP causes vasodilation and may inhibit smooth muscle cell proliferation and platelet aggregation. The NO-sGC-cGMP pathway is disordered in pulmonary arterial hypertension (PAH), a syndrome in which pulmonary vascular obstruction, inflammation, thrombosis, and constriction ultimately lead to death from right heart failure. Expression of sGC is increased in PAH but its function is reduced by decreased NO bioavailability, sGC oxidation and the related loss of sGC's heme group. ⋯ Riociguat is approved for PAH and yields functional and hemodynamic benefits similar to other therapies. Its main serious adverse effect is dose-dependent hypotension. Riociguat is also approved for inoperable chronic thromboembolic pulmonary hypertension.
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Clin. Pharmacol. Ther. · Jan 2015
ReviewTargeting leukocyte trafficking for the treatment of inflammatory bowel disease.
Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disease of the intestine that includes both Crohn's disease and ulcerative colitis, and afflicts nearly 1 million people throughout North America. As our understanding of IBD pathogenesis grows, several new therapies have been developed that use monoclonal antibodies to specifically target key mediators and biological pathways implicated in IBD immune dysfunction. One important pathway involves leukocyte trafficking and infiltration into the affected intestinal tissues. This review provides a summary of the different therapies that have been developed to inhibit leukocyte trafficking to the inflamed gut, and evaluates the relative safety and efficacy of these novel drugs within the context of existing medical therapies for IBD.