Recreational Use of Aminorex and Pulmonary Hypertension

S, Gaine; Rubin, Lewis J.; Kmetzo, James J.; Palevsky, Harold I.; Traill, Thomas A.

doi:10.1378/chest.118.5.1496

Cited by 40 publications

(17 citation statements)

References 3 publications

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“…Recent findings from our laboratory also refute the role of 5‐HT 2B sites in anorectic‐associated IPAH 24 . Aminorex is a SERT substrate that caused an epidemic of IPAH in the 1960s, 82 and case reports implicate the related designer drug, 4‐methylaminorex, as a potential cause of the disease 83 . If 5‐HT 2B receptors are involved in the pathogenesis of aminorex‐associated IPAH, then aminorex should target 5‐HT 2B sites.…”

Section: Discussionmentioning

confidence: 72%

Serotonin (5‐HT) Transporter Ligands Affect Plasma 5‐HT in Rats

Rothman

Żółkowska

Baumann

2008

Annals of the New York Academy of Sciences

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Dual dopamine (DA)/serotonin (5-HT)-releasing agents are promising candidate medications for stimulant addiction and other disorders. However, certain 5-HT transporter (SERT) substrates are associated with development of idiopathic pulmonary arterial hypertension (IPAH) and valvular heart disease (VHD). According to the "5-HT hypothesis," SERT substrates increase the risk for developing IPAH and VHD by increasing plasma 5-HT. To test this hypothesis directly, we determined the effects of acute and chronic fenfluramine, and other SERT ligands, on plasma 5-HT in male rats. For acute treatments, rats received i.v. vehicle or test drug (0.3 and 1.0 mg/kg), and serial blood samples were withdrawn. For chronic treatments, vehicle or test drug was infused via osmotic minipump (3 and 10 mg/kg/d) for 2 weeks. On the last day of infusion, rats received i.v. fenfluramine challenge (1 mg/kg), and serial blood samples were withdrawn. Plasma 5-HT was measured using ex vivo microdialysis in whole-blood samples. Baseline plasma 5-HT was <1.0 nM. Acute injection of fenfluramine or other SERT substrates caused large (up to 24-fold) dose-dependent increases in plasma 5-HT. Chronic fenfluramine at 3 and 10 mg/kg/d produced 1.7- and 3.5-fold increases in baseline plasma 5-HT, while chronic fluoxetine had no effect. Chronic infusions of fenfluramine or fluoxetine diminished the ability of acute fenfluramine to elevate dialysate 5-HT, and both drugs markedly reduced whole-blood 5-HT. Acute fenfluramine increases plasma 5-HT to concentrations that are below the micromolar levels necessary to produce adverse cardiovascular effects. Chronic fenfluramine and fluoxetine have minimal effects on plasma 5-HT, suggesting that the increased risk for IPAH associated with fenfluramine does not depend upon elevations in plasma 5-HT.

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Section: Discussionmentioning

confidence: 72%

Serotonin (5‐HT) Transporter Ligands Affect Plasma 5‐HT in Rats

Rothman

Żółkowska

Baumann

2008

Annals of the New York Academy of Sciences

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“…Aminorex has the same reuptake blocking capabilities as any other amphetamine, and is sometimes used to dope horses. Humans also occasionally abuse aminorex (11) and an association between aminorex abuse and PAH has long been suspected (12). In 2012, our group published a case report demonstrating that humans are capable of the same conversion as horses (13), Although the kinetics of this conversion are only now being clarified (14,15).…”

Section: Contextmentioning

confidence: 99%

Levamisole, Aminorex, and Pulmonary Arterial Hypertension: A Review

Karch¹,

Vaiano²,

Bertol³

2015

Razavi Int J Med

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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.

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“…Alternatively, after levamisole administration to race horses, the identification of the stimulant aminorex as a circulating metabolite of levamisole (Fig. 1) suggests that a similar metabolic fate in humans would lead to enhanced hypertensive stimulation, a common sensation associated with cocaine use (Gaine et al, 2000). Studies in animals have shown that the pharmacodynamics of aminorex are similar to those of cocaine and amphetamines with respect to their stimulant effects and indirect sympathomimetic effects in the central nervous system (Young, 1992).…”

Section: Why Is Levamisole Used As a Cocaine Adulterant?mentioning

confidence: 99%

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

Wolford

McDonald²,

Eng³

et al. 2012

Drug Metabolism and Disposition

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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.

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Recreational Use of Aminorex and Pulmonary Hypertension

Cited by 40 publications

References 3 publications

Serotonin (5‐HT) Transporter Ligands Affect Plasma 5‐HT in Rats

Serotonin (5‐HT) Transporter Ligands Affect Plasma 5‐HT in Rats

Levamisole, Aminorex, and Pulmonary Arterial Hypertension: A Review

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

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