SBIR-STTR Award

Human plasma butyrylcholinesterase (EC 3.1.1.8), also referred to as pseudocholinesterase, is an enzyme with no known biological function. However, it is clinically significant in that it is inhibited by a number of antiacetylcholinesterase toxins and drugs and is responsible for hydrolyzing and inactivating others. Butyrylcholinesterase is also the only enzyme yet identified that is capable of hydrolyzing cocaine to biologically inactive metabolites. Approximately 5% of the population carries any of several genetic defects that affect butyrylcholinesterase activity. This population is sensitive to succinylcholine, a muscle relaxant commonly used in surgical anaesthesia. Recently, it has been proposed that individuals deficient in butyrylcholinesterase should also be hypersensitive to cocaine, a possibility that could explain some of the small fraction of the cocaine-abusing population who experience acute, life-threatening reactions to cocaine. We propose that in these cases, and in others involving large overdoses, treatment with butyrylcholinesterase would accelerate the inactivation ofcocaine thereby providing a useful adjuvant therapy. We intend to develop a method for purifying large quantities of human plasma butyrylcholinesterase suitable for the production of pharmaceutical quality material. We will test its ability to detoxify cocaine in mice.Awardee's statement of the potential commercial applications of the research:Butrylcholinesterase would be a useful therapeutic for the treatment of acute cocaine toxicity. Other uses would include the relief or prevention of succinylcholine-induced apnea in cholinesterase-deficient surgical patients.National Institute on Drug Abuse (NIDA)

Each year approximately 100,000 people are admitted to hospitals for acute cocaine overdose, yet current treatments are merely palliative. We will develop butyrylcholinesterase from human plasma as a safe and effective treatment of cocaine overdose. In contrast to pharmacotherapies, which may have a benefit in treating one medical complication, but can have adverse effects on another, butyrylcholinesterase is an enzyme that hydrolyzes cocaine to inactive metabolites; thus, the enzyme reduces its toxicity. In preclinical studies, butyrylcholinesterase has been shown to be safe and well tolerated in doses up to 1000-fold normally present. Pretreatment with butyrylcholinesterase protected laboratory animals from the lethal cardiovascular effects of cocaine. Butyrylcholinesterase also reversed the neurotoxic effects of cocaine (hyperactivity and convulsions leading to death) when administered therapeutically after cocaine. This proposal is for the development of a commercially viable manufacturing process and for the continuation of preclinical studies of the effects of butyrylcholinesterase on cocaine metabolism. These studies will support the filing of an "Investigational New Drug" (IND) application for clinical development. The clinical program (outside the scope of this proposal) can be accomplished in less than one year, and approval may be expedited via the recent designation of butyrylcholinesterase as an Orphan Drug.Awardee's statement of the potential commercial applications of the research: Butyrylcholinesterase has the potential of being the first, and possibly the only safe and effective antidote for treating acute cocaine overdose. In contrast to current therapies aimed at symptomatic treatment, butyrylcholinesterase, found in human plasma, metabolizes cocaine and reduces its harmful potential.National Institute on Drug Abuse (NIDA)