title: Ritonavir and disulfiram may be synergistic in lowering active interleukin-18 levels in acute pancreatitis, and thereby hasten recovery.
abstract: Interleukin-18 (IL-18) is one of the mediators of both pancreas damage and systemic complications like hypotension and multi-organ dysfunction during acute pancreatitis. IL-18 is generated intracellularly from pro-IL-18 by caspase-1 mediated proteolysis. Active caspase-1 itself is generated intracellularly by the action of the inflammasome, autocatalysis and other stimuli. The anti-retroviral drug ritonavir inhibits conversion of inactive pro-caspase-1 to active caspase-1. Since ritonavir is well tolerated in short-term use it may therefore prove useful in treating acute pancreatitis by lowering caspase-1 mediated IL-18 formation and the many inflammatory mediators downstream from that. The alcoholism treatment drug disulfiram has been in continuous use since the 1950s. It likewise has a low risk profile. Disulfiram inhibits several human proteases, among them caspase-1. Given the current morbidity and mortality of pancreatitis, research should be directed to ritonavir and disulfiram as treatment options for illnesses like pancreatitis where excessive IL-18 contributes to pathology. The first clinically used angiotensin converting enzyme inhibitor, captopril, has shown potent caspase-1 inhibiting activity as well and should be investigated in rodent models of human pancreatitis.
authors.forename: Richard Eric
authors.initials: RE
authors.lastname: Kast
mesh_terms: D000208:Acute Disease; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D061945:Caspase Inhibitors; D004221:Disulfiram / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D020382:Interleukin-18 / Q000097:blood* / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D010195:Pancreatitis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D012074:Remission Induction; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000959:Antihypertensive Agents; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D020382:Interleukin-18; D002216:Captopril; D019438:Ritonavir; D004221:Disulfiram