Perspective Immune-Mediated Agranulocytosis Caused by the Cocaine Adulterant Levamisole: A Case for Reactive Metabolite(s) Involvement

The United States Public Health Service Administration is alerting medical professionals that a substantial percentage of cocaine imported into the United States is adulterated with levamisole, a veterinary pharmaceutical that can cause blood cell disorders such as severe neutropenia and agranulocytosis. Levamisole was previously approved in combination with fluorouracil for the treatment of colon cancer; however, the drug was withdrawn from the U.S. market in 2000 because of the frequent occurrence of agranulocytosis. The detection of autoantibodies such as antithrombin (lupus anticoagulant) and an increased risk of agranulocytosis in patients carrying the human leukocyte antigen B27 genotype suggest that toxicity is immune-mediated. In this perspective, we provide an historical account of the levamisole/cocaine story as it first surfaced in 2008, including a succinct review of levamisole pharmacology, pharmacokinetics, and preclinical/clinical evidence for levamisole-induced agranulocytosis. Based on the available information on levamisole metabolism in humans, we propose that reactive metabolite formation is the rate-limiting step in the etiology of agranulocytosis associated with levamisole, in a manner similar to other drugs (e.g., propylthiouracil, methimazole, captopril, etc.) associated with blood dyscrasias. Finally, considering the toxicity associated with levamisole, we propose that the 2,3,5,6-tetrahydroimidazo[2,1-b]thiazole scaffold found in levamisole be categorized as a new structural alert, which is to be avoided in drug design. Agranulocytosis Associated with Cocaine Use: Identification of the Cause In the summer of 2008, a man and woman, both in their twenties, were separately admitted to a Canadian hospital with unremitting fevers, flu-like symptoms, and dangerously low white blood cell counts. Their symptoms were consistent with a life-threatening disorder known as agranulocytosis (Chang et al., 2010). Agranulocytosis is an immune disorder, typically caused by chemotherapy or highly individualized and unexpected (idiosyncratic) reaction to certain nonchemotherapy drugs such as the antipsychotic clozapine and the antibiotic combination trimethoprim-sulfamethoxazole (Ibáñez et al., 2005). Neither of the Canadian patients fit that description, but they did have one thing in common—illegal use of cocaine. In April of that same year, a New Mexico laboratory in the United States had also identified a small number of unexplained cases of agranulocytosis in people who had snorted, injected, or smoked cocaine. In the following year, a few cocaine addicts in San Francisco, mostly crack (a solid smokable form of cocaine) smokers, began displaying even stranger symptoms such as dead, darkened skin. In the Canadian case, toxicological analysis of urine specimens from the two patients revealed the presence of cocaine and its metabolites and, surprisingly, the presence of levamisole (6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole; Fig. 1), a drug that was once used to treat colon cancer but is now reserved for veterinary use as an anthelmintic (Zhu et al., 2009). Since the 1970s, clinical use of levamisole has been associated with cases of agranulocytosis (Macfarlane and Bacon, 1978). There have now been several dozen cases of cocaine-related agranulocytosis (including one death) reported in Canada (British Columbia, Alberta) and the United States of America (Colorado, Arizona, New Mexico, and Washington) (Waller et al., 2010; Walsh et al., 2010). Similarities in the onset of symptoms in almost all cases included severe neutropenia (absolute neutrophil count 0.5 10 cells/l), symptoms of infectious illness (fever and malaise or sore throat), and a disproportionally high association with a positive test Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. http://dx.doi.org/10.1124/dmd.112.045021. ABBREVIATIONS: HLA, human leukocyte antigen; DEA, U.S. Drug Enforcement Agency; t1/2, plasma elimination half-life; F, oral bioavailability; P450, cytochrome P450; Tmax, time to attain maximal systemic exposure; MHC, major histocompatibility complex; RM, reactive metabolite; MPO, myeloperoxidase; ACE, angiotensin-converting enzyme. 1521-009X/12/4006-1067–1075$25.00 DRUG METABOLISM AND DISPOSITION Vol. 40, No. 6 Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics 45021/3769430 DMD 40:1067–1075, 2012 1067 at A PE T Jornals on O cber 9, 2017 dm d.aspurnals.org D ow nladed from