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

Abstract

ABSTRACT: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was previously approved in combination with fluorouracil for the treatment of colon cancer; however, the drug was withdrawn from the U.S. market in 2000 because of the frequent occurrence of agranulocytosis.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.

Nasal septal and mucosal disease associated with pyoderma gangrenosum in a cocaine user

“…Levamisole-tainted cocaine use may result in PG lesions refractory to treatment and occurring in unusual sites such as the face, neck, and trunk 1 . Detection of serum levamisole is helpful, although the estimated mean half-life of levamisole in the blood is only 5.6 hours, 12 which can result in a negative test if the drug exposure occurred more than 24 hours before testing, as in our patient.…”

Drug-Induced Glomerular Disease

“…Levamisole has been detected with increased frequency in the illicit cocaine supply entering the United States and Europe over the last decade (17,18), with a 2011 Drug Enforcement Agency report noting contamination in 82% of the United States supply. Levamisole shares similar physical properties (appearance, smell, and taste) with cocaine, and it may mimic or potentiate the euphoric effects of cocaine through sympathetic nervous system stimulation.…”

Amperometric flow-injection determination of the anthelmintic drugs ivermectin and levamisole using electrochemically pretreated boron-doped diamond electrodes

“…Other properties of LVM have also been recognized and, thus, it has been used as an adjuvant drug in the treatment of colon cancer and as an immunomodulator; more recently, LVM has been identified as a cocaine adulterant that might have toxic effects [15,16].…”