Levamisole, Aminorex, and Pulmonary Arterial Hypertension: A Review

Abstract

Context: An epidemic of aminorex-associated pulmonary arterial hypertension (PAH), resulting in multiple fatalities, occurred in the 1970s ending only after the drug was removed from the market. In 2009, when it was found that horses de-wormed with the anthelmintic levamisole, metabolized that drug to aminorex, the same drug that caused the 1970s outbreak of PAH. The discovery would not have been cause for concern except to horseracing enthusiasts, who feared horse doping. However, at about the same time the relationship between levamisole and aminorex was discovered, cocaine cartels began adulterating cocaine with levamisole. The rationale for adulterating cocaine with levamisole remains to be established. The purpose of this short review article is to discuss possible reasons for levamisole contamination, new discoveries about the human pharmacokinetics of aminorex, and the possible relationship between aminorex and pulmonary arterial hypertension in man. Evidence acquisition: Medline contents, as well as estimates published by the U.S. drug enforcement agency (DEA), US state department, and the European monitoring center for drugs and drug abuse (EMCDDA) were reviewed and relevant articles retrieved. There is uniform agreement among the various monitoring agencies analyzed.Results: Approximately 70 percent of the U.S. cocaine supply and 40 percent of the European cocaine supply is contaminated with levamisole. Aminorex has the same binding affinities for serotonin and other neurotransmitters as amphetamine. As serotonin is considered to be an important factor in the development of PAH, the possibility of another epidemic of aminorex-induced PAH, this time among cocaine abusers, seems real, and threatening. Conclusions:The results of the first human pharmacokinetic studies of aminorex were first characterized in 2013. The results suggest that while humans could produce aminorex from levamisole, they probably do not convert very much. Even though cases of PAH have been reported in cocaine users, the latest pharmacokinetic studies suggest that very little aminorex is actually produced from the ingested levamisole, probably not enough to cause PAH. However, since both cocaine and aminorex can cause PAH the situation remains unclear. the lack of a clear answer is partially the development of an insidious pulmonary hypertension, producing subtle and non-specific symptoms in its early stages.

DARK Classics in Chemical Neuroscience: Aminorex Analogues

“…In healthy individuals who ingested high doses of pure levamisole, comparatively small amounts of aminorex were found in plasma and urine118,119. It seems to be the case that the conversion rate from levamisole to aminorex might be quite low121,122. Still, Karch et al .…”

“…Eiden et al found levamisole in 75% of all analyzed urine samples yet aminorex could not be detected . In healthy individuals who ingested high doses of pure levamisole, comparatively small amounts of aminorex were found in plasma and urine. , It seems to be the case that the conversion rate from levamisole to aminorex might be quite low. , Still, Karch et al describe the case of a deceased long-term poly drug user with systemically detectable levamisole and aminorex levels who might have suffered from idiopathic pulmonary arterial hypertension, and it has been shown that levamisole accumulates in lung tissue. − Deaths due to levamisole or aminorex toxicity associated with the consumption of cocaine have rarely been reported. , At this point, it is known that only a small fraction of levamisole is metabolized into aminorex and its (side) effects seem negligible when compared to those observed with levamisole. Future studies should explore the prevalence of pulmonary arterial hypertension in long-term, high-dose users of levamisole-adulterated cocaine.…”

“…118,119 It seems to be the case that the conversion rate from levamisole to aminorex might be quite low. 121,122 Still, Karch et al describe the case of a deceased long-term poly drug user with systemically detectable levamisole and aminorex levels who might have suffered from idiopathic pulmonary arterial hypertension, and it has been shown that levamisole accumulates in lung tissue. 123−126 Deaths due to levamisole or aminorex toxicity associated with the consumption of cocaine have rarely been reported.…”

Analysis of tetramisole metabolites – Is “Aminorex” found in forensic samples of cocaine users actually 4‐phenyl‐2‐imidazolidinone?

“…15 Soon afterwards, aminorex was found in human urine after controlled oral intake of levamisole. 17 From then on, it is often cited as a human metabolite of PTHIT [18][19][20] even though data relating to the analytical proof of aminorex in forensic samples is still quite rare and contradictory in the literature. 10,21 Moreover, there are further less known putative metabolites of PTHIT sharing the same sum formula (C 9 H 10 N 2 O).…”