Levamisole, Aminorex, and Pulmonary Arterial Hypertension: A Review

Authors

1 Consultant Pathologist/Toxicologist, Berkeley, California, USA

2 Department of Health Sciences, Forensic Toxicology Division, University of Florence, Florence, Italy

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.

Keywords

Open Access Policy: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/

References

1. Hoendermis ES. Pulmonary arterial hypertension: an update. Neth Heart J. 2011;19(12):514-22.
https://doi.org/10.1007/s12471-011-0222-1
PMid:22083429 PMCid:PMC3221752
 
2. Colvin KL, Yeager ME. Animal Models of Pulmonary Hypertension: Matching Disease Mechanisms to Etiology of the Human Disease. J Pulm Respir Med. 2014;4(4)
 
3. Ryan J, Dasgupta A, Huston J, Chen KH, Archer SL. Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med (Berl). 2015;93(3):229-42.
https://doi.org/10.1007/s00109-015-1263-5
PMid:25672499 PMCid:PMC4339102
 
4. Liou CM, Tsai SC, Kuo CH, Williams T, Ting H, Lee SD. Chronic methamphetamine exposure induces cardiac fas-dependent and mitochondria-dependent apoptosis. Cardiovasc Toxicol. 2014;14(2):134-44.
https://doi.org/10.1007/s12012-013-9237-8
PMid:24307234
 
5. Barbosa DJ, Serrat R, Mirra S, Quevedo M, de Barreda EG, Avila J, et al. The mixture of "ecstasy" and its metabolites impairs mitochondrial fusion/fission equilibrium and trafficking in hippocampal neurons, at in vivo relevant concentrations. Toxicol Sci. 2014;139(2):407-20.
https://doi.org/10.1093/toxsci/kfu042
PMid:24595818
 
6. Collazos J, Martinez E, Fernandez A, Mayo J. Acute, reversible pulmonary hypertension associated with cocaine use. Respir Med. 1996;90(3):171-4.
https://doi.org/10.1016/S0954-6111(96)90160-2
PMid:8736210
 
7. Yakel DJ, Eisenberg MJ. Pulmonary artery hypertension in chronic intravenous cocaine users. Am Heart J. 1995;130(2):398-9.
https://doi.org/10.1016/0002-8703(95)90459-X
PMid:7631626
 
8. Cogswell R, Kobashigawa E, McGlothlin D, Shaw R, De Marco T. Validation of the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) pulmonary hypertension prediction model in a unique population and utility in the prediction of long-term survival. J Heart Lung Transplant. 2012;31(11):1165-70.
https://doi.org/10.1016/j.healun.2012.08.009
PMid:23062726
 
9. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493-537.
https://doi.org/10.1093/eurheartj/ehp297
PMid:19713419
 
10. Rothman RB, Ayestas MA, Dersch CM, Baumann MH. Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension. Circulation. 1999;100(8):869-75.
https://doi.org/10.1161/01.CIR.100.8.869
PMid:10458725
 
11. Ho EN, Leung DK, Leung GN, Wan TS, Wong AS, Wong CH, et al. Aminorex and rexamino as metabolites of levamisole in the horse. Anal Chim Acta. 2009;638(1):58-68.
https://doi.org/10.1016/j.aca.2009.02.033
PMid:19298880
 
12. Gaine SP, Rubin LJ, Kmetzo JJ, Palevsky HI, Traill TA. Recreational use of aminorex and pulmonary hypertension. Chest. 2000;118(5):1496-7.
https://doi.org/10.1378/chest.118.5.1496
PMid:11083709
 
13. Karch SB, Mari F, Bartolini V, Bertol E. Aminorex poisoning in cocaine abusers. Int J Cardiol. 2012;158(3):344-6.
https://doi.org/10.1016/j.ijcard.2011.06.105
PMid:21764154
 
14. van Riel AC, Schuuring MJ, van Hessen ID, Zwinderman AH, Cozijnsen L, Reichert CL, et al. Contemporary prevalence of pulmonary arterial hypertension in adult congenital heart disease following the updated clinical classification. Int J Cardiol. 2014;174(2):299-305.
https://doi.org/10.1016/j.ijcard.2014.04.072
PMid:24794056
 
15. Hess C, Ritke N, Broecker S, Madea B, Musshoff F. Metabolism of levamisole and kinetics of levamisole and aminorex in urine by means of LC-QTOF-HRMS and LC-QqQ-MS. Anal Bioanal Chem. 2013;405(12):4077-88.
https://doi.org/10.1007/s00216-013-6829-x
PMid:23436169
 
16. Karch SB, Defraia B, Messerini L, Mari F, Vaiano F, Bertol E. Aminorex associated with possible idiopathic pulmonary hypertension in a cocaine user. Forensic Sci Int. 2014;240:e7-10.
https://doi.org/10.1016/j.forsciint.2014.03.028
PMid:24794740
 
17. Anon LO. National Early Warning System of the Council of Ministers of Italy. 2009.
 
18. Casale J, Corbeil E, Hays P. Identification of Levamisole Impurities Found in Illicit Cocaine Exhibits Microgram. 2006;6(3-4):2.
 
19. Bertucci C, Tedesco D, Fabini E, Di Pietra AM, Rossi F, Garagnani M, et al. Determination of levamisole and tetramisole in seized cocaine samples by enantioselective high-performance liquid chromatography and circular dichroism detection. J Chromatogr A. 2014;1363:150-4.
https://doi.org/10.1016/j.chroma.2014.07.069
PMid:25124228
 
20. Lapachinske SF, Okai GG, dos Santos A, de Bairros AV, Yonamine M. Analysis of cocaine and its adulterants in drugs for international trafficking seized by the Brazilian Federal Police. Forensic Sci Int. 2015;247:48-53.
https://doi.org/10.1016/j.forsciint.2014.11.028
PMid:25544694
 
21. US Department of Justice. National Drug Threat Assessment: 2010. Washington, DC: National Drug Intelligence Center; 2010.
 
22. Raymon LP, Isenschmid DS. Letter to the editor: The possible role of levamisole in illicit cocaine preparations. J Anal Toxicol. 2009;33(9):620-2.
https://doi.org/10.1093/jat/33.9.620
PMid:20040138
 
23. Hofmaier T, Luf A, Seddik A, Stockner T, Holy M, Freissmuth M, et al. Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters. Neurochem Int. 2014;73:32-41. Karch SB et al. Razavi Int J Med. 2015;3(3):e28277 7
https://doi.org/10.1016/j.neuint.2013.11.010
PMid:24296074 PMCid:PMC4077236
 
24. Picazo ML, Martinez Ara J, Diaz C, Perez-Mies B. [Nephropathy with occlusive intracapillary IgA thrombi and necrotizing vasculitis, manifesting as rapidly progressive renal insufficiency]. Nefrologia. 2003;23(1):27-36.
 
25. Buchanan JA, Vogel JA, Eberhardt AM. Levamisole-induced occlusive necrotizing vasculitis of the ears after use of cocaine contaminated with levamisole. J Med Toxicol. 2011;7(1):83-4.
https://doi.org/10.1007/s13181-010-0097-3
PMid:20549422 PMCid:PMC3614109
 
26. Buchanan JA, Oyer RJ, Patel NR, Jacquet GA, Bornikova L, Thienelt C, et al. A confirmed case of agranulocytosis after use of cocaine contaminated with levamisole. J Med Toxicol. 2010
https://doi.org/10.1007/s13181-010-0060-3
PMid:20358411 PMCid:PMC3550277
 
6(2):160-4. 27. Kew MC. Aminorex fumarate: a double-blind trial and examination for signs of pulmonary arterial hypertension. S Afr Med J. 1970;44(14):421-3.
 
27. Follath F, Burkart F, Schweizer W. Drug-induced pulmonary hypertension? BMJ. 1971;1(5743):265-6. 29. Blaho K, Logan B, Winbery S, Park L, Schwilke E. Blood cocaine and metabolite concentrations, clinical findings, and outcome of patients presenting to an ED. Am J Emerg Med. 2000;18(5):593-8.
https://doi.org/10.1053/ajem.2000.9282
PMid:10999576
 
28. Shimoda LA, Laurie SS. Vascular remodeling in pulmonary hypertension. J Mol Med (Berl). 2013;91(3):297-309.
https://doi.org/10.1007/s00109-013-0998-0
PMid:23334338 PMCid:PMC3584237
 
29. Herve P, Humbert M, Sitbon O, Parent F, Nunes H, Legal C, et al. Pathobiology of pulmonary hypertension. The role of platelets and thrombosis. Clin Chest Med. 2001;22(3):451-8.
https://doi.org/10.1016/S0272-5231(05)70283-5
PMid:11590840
 
30. Shannon R, Chaudhry M. Effect of alpha1-adrenergic receptors in cardiac pathophysiology. Am Heart J. 2006;152(5):842-50.
https://doi.org/10.1016/j.ahj.2006.05.017
PMid:17070143
 
31. Grant JS, White K, MacLean MR, Baker AH. MicroRNAs in pulmonary arterial remodeling. Cell Mol Life Sci. 2013;70(23):4479-94.
https://doi.org/10.1007/s00018-013-1382-5
PMid:23739951 PMCid:PMC3827895
 
32. Friedman RC, Burge CB. MicroRNA target finding by comparative genomics. Methods Mol Biol. 2014;1097:457-76.
https://doi.org/10.1007/978-1-62703-709-9_21
PMid:24639172
 
33. Gurtner HP. Pulmonary hypertension, "plexogenic pulmonary arteriopathy" and the appetite depressant drug aminorex: post or propter? Bull Eur Physiopathol Respir. 1979;15(5):897-923.
 
34. Rivier JL. [Primary arterial pulmonary hypertension. Preliminary statistical results under the sponsorship of the Swiss Cardiological Society and with the aid the Swiss Foundation f Cardiology]. Schweiz Med Wochenschr. 1970;100(4):143-5.
 
35. Hess C, Ritke N, Sydow K, Mehling LM, Ruehs H, Madea B, et al. Determination of levamisole, aminorex, and pemoline in plasma by means of liquid chromatography-mass spectrometry and application to a pharmacokinetic study of levamisole. Drug Test Anal. 2014;6(10):1049-54.
https://doi.org/10.1002/dta.1619
PMid:24574157
Razavi International Journal of Medicine
Volume 3, Issue 3
July 2015
Pages 1-5

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