Studies Of The Pharmacological Effects Of Benzoic Acid Analogs On Thrombosis And Inflammation

Previous work in this laboratory demonstrated that a series of benzoic acid analogs, with only minor structural variations compared to ASA, displayed a wide variation in biological effects compared to ASA. The compounds studied include 2-propionyloxybenzoic acid (2-PBA), 3-propionyloxybenzoic acid (3-PBA), 2-acetylbenzoic acid (ABA), 3-methylphthalide (3-MP) and 3-hydroperoxy-3-methylphthalide (3HMP). The purpose of this study was to extend our knowledge of the effects of these compounds and the processes they modify by assessing the in vivo antithrombotic and anti-inflammatory activities and the inhibition of prostaglandin (PG) synthesis (including PGI(,2)) in related in vitro systems. The ultimate aim of this work is the design of agents with more specific anti-inflammatory and antithrombotic activities.;The systems studied were (1) ADP and collagen-stimulated platelet aggregation and release of ATP; (2) platelet PG synthesis products; (3) platelet cyclic nucleotide phosphodiesterase activity (PDE); (4) aorta PGI(,2)-like activity production; (5) aorta arachidonic acid (AA) metabolism; (6) electrical injury-induced thrombosis in a rat model; (7) carrageenin-induced pleurisy in a rat model and; (8) polymorphonuclear neutrophil (PMN) AA metabolism.;ABA appears to be a unique agent with both anti-inflammatory and antithrombotic activity not accountable by PG synthesis or PDE inhibition. This agent appears a likely candidate as an anti-inflammatory agent without antiplatelet activity. The hydroperoxide, 3HMP, appears as a particularly useful tool for the study of the mechanisms of cyclo-oxygenation and lipoxygenation of AA and the activation and inhibition of the enzyme systems involved.;These studies point to unique mechanisms of action of antithrombotic and anti-inflammatory activities with a series of benzoic acid analogs and suggest that PG synthesis does not totally account for either antithrombotic or anti-inflammatory activity

Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial.

Maribavir is an oral benzimidazole riboside with potent in vitro activity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double-blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV-seronegative liver transplant recipients with CMV-seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC)-confirmed CMV disease within 6 months of transplantation. In a modified intent-to-treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: -0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC-confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non-CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well-tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field