Levamisole

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Levamisole
Levamisole2.svg
Levamisole ball-and-stick animation.gif
Systematic (IUPAC) name
(S)-6-Phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
MedlinePlus a697011
Legal status withdrawn
Routes Oral
Pharmacokinetic data
Metabolism Hepatic
Half-life 4.4-5.6 hours (biphasic)
Identifiers
CAS number 14769-73-4 YesY
ATC code P02CE01 QP52AE01
PubChem CID 26879
DrugBank DB00848
ChemSpider 25037 YesY
UNII 2880D3468G YesY
KEGG D08114 YesY
ChEBI CHEBI:6432 N
ChEMBL CHEMBL1454 YesY
Chemical data
Formula C11H12N2S 
Mol. mass 204.292 g/mol
Physical data
Density 1.31 g/cm³
Melt. point 60 °C (140 °F)
 N (what is this?)  (verify)

Levamisole, marketed as the hydrochloride salt under the trade name Ergamisol (R12564), is an anthelmintic and immunomodulator belonging to a class of synthetic imidazothiazole derivatives. It was discovered in 1966 at Belgium's Janssen Pharmaceutica, where it was prepared initially in the form of its racemate called tetramisole.[1] The two stereoisomers of tetramisole were subsequently synthesized, and the levorotatory isomer was given the name levamisole.[2] Levamisole has been used in humans to treat parasitic worm infections, and has been studied in combination with other forms of chemotherapy for colon cancer, melanoma, and head and neck cancer. In some of the leukemic cell line studies, both levamisole and tetramisole showed similar effect.[3] The drug was withdrawn from the U.S. and Canadian markets in 1999 and 2003, respectively, due to the risk of serious side effects and the availability of more effective replacement medications.[4][5] The key toxic effect of the drug is agranulocytosis, a severe depletion of white blood cells that leaves patients vulnerable to infection.

Currently, levamisole remains in veterinary use as a dewormer for livestock. The medication has also been increasingly used as an adulterant in cocaine sold in the United States and Canada, resulting in serious side effects.[4][6]

Chemistry[edit]

The original synthesis at Janssen Pharmaceutica resulted in the preparation of a racemic mixture of two enantiomers, whose hydrochloride salt was reported to have a melting point of 264–265 °C; the free base of the racemate has a melting point of 87–89 °C. When the two enantiomers were made separately, the levorotatory (S-(−)-) enantiomer, subsequently called levamisole, was found to have a melting point of 227–229 °C as its hydrochloride salt, and 60–61.5 °C as the free base. Thus, 60 °C is entered as the value for melting point in the info box. The dextrorotatory (R-(+)-) enantiomer, subsequently called dexamisole, has a melting point of 227–227.5 °C as its hydrochloride salt, and 60–61.5 °C as the free base.[7]

Medical uses[edit]

Levamisole was originally used as an antihelminthic to treat worm infestations in both humans and animals. Most current commercial preparations are intended for veterinary use as a dewormer in cattle, pigs, and sheep. However, levamisole has also recently gained prominence among aquarists as an effective treatment for Camallanus roundworm infestations in freshwater tropical fish.[8]

Levamisole has been tested in combination with fluorouracil to treat colon cancer. Evidence from clinical trials support its addition to fluorouracil therapy to benefit patients with colon cancer, but it is no longer used for this. Levamisole is also used infrequently to treat melanoma and head and neck cancer.[medical citation needed] One study found it to have "immune-stimulating" properties in rats.[9]

A 1984 study on complicated influenza found levamisole to be an effective inducer of interferon, and recommended its use in combination therapy for influenza.[10] It is also used routinely in India to treat steroid-dependent childhood nephrotic syndrome cases, based on literature published in a few UK-based studies.[11] Levamisole has been used to treat a variety of dermatologic conditions, including skin infections, leprosy, warts, lichen planus, and aphthous ulcers.[12] Levamisole has been used[where?] in patients with steroid-sensitive and frequently relapsing nephrotic syndrome.[citation needed]

A comprehensive review of the pharmacology, toxicology and therapeutic applications of levamisole, thoroughly covering the literature through June 1978 (at which time over 1500 publications already existed) was published by Janssen and coworkers in 1979.[13]

An interesting adverse side effect these reviewers reported in passing was "neurologic excitement". Later papers, from the Janssen group and others, indicate levamisole and its enantiomer, dexamisole, have some mood-elevating or antidepressant properties.[14][15]

Metabolism[edit]

Drug testing of racehorse urine has led to the revelation that among Levamisole equine metabolites are both pemoline and aminorex, stimulants that are forbidden by racing authorities.[16][17][18] Further testing confirmed aminorex in human and canine urine, meaning that both humans and dogs also metabolize levamisole into aminorex.[19]

Laboratory use[edit]

Levamisole reversibly and noncompetitively inhibits most isoforms of alkaline phosphatase (e.g., human liver, bone, kidney, and spleen) except the intestinal and placental isoform.[20] It is thus used as an inhibitor along with substrate to reduce background alkaline phosphatase activity in biomedical assays involving detection signal amplification by intestinal alkaline phosphatase, for example in in situ hybridization or Western blot protocols.

It is used to immobilize the nematode C. elegans on glass slides for imaging.

In a C. elegans behavioral assay, analyzing the time course of paralysis provides information about the neuromuscular junction. Levamisole acts as an acetylcholine receptor agonist, which leads to muscle contraction. Continuing activation leads to paralysis. The time course of paralysis provides information about the acetylcholine receptors on the muscle. For example, mutants with fewer acetylcholine receptors may paralyze slower than wild type.[21]

Illicit use[edit]

Levamisole has increasingly been used as a cutting agent in cocaine sold in the United States and Canada. In 2008–2009, levamisole was found in 69% of cocaine samples seized by the Drug Enforcement Administration (DEA).[6] By April 2011, the DEA reported the adulterant was found in 82% of seizures.[22]

Levamisole adds bulk and weight to powdered cocaine (whereas other adulterants produce smaller "rocks" of cocaine) and makes the drug appear purer.[23] In a series of investigative articles for The Stranger, Brendan Kiley details other rationales for levamisole's rise as an adulterant: possible stimulant effects, a similar appearance to cocaine, and an ability to pass street purity tests.[24]

Levamisole suppresses the production of white blood cells, resulting in neutropenia and agranulocytosis. With the increasing use of levamisole as an adulterant, a number of these complications have been reported among cocaine users.[6][25][26] Levamisole has also been linked to a risk of vasculitis,[27] and two cases of vasculitic skin necrosis have been reported in users of cocaine adulterated with levamisole.[28]

Levamisole-tainted cocaine was linked to several high-profile deaths. Toxicology reports showed levamisole, along with cocaine, was present in DJ AM's body at the time of his death.[29] Andrew Koppel, son of newsman Ted Koppel, was also found with levamisole in his body after his death was ruled a drug overdose.[30] More recently it has also been suspected in the death of a Sydney teenager.[31]

In response to the dangers, The Stranger, People's Harm-Reduction Alliance and DanceSafe began producing tests to identify levamisole's presence in cocaine. The kits include a survey postcard, and one revealed its presence in a 1/4-kg block of cocaine, indicating both users and dealers were using the kits.[32]

Toxicity[edit]

The LD50 (intravenous, mouse) is 22 mg/kg.[13]

Detection in body fluids[edit]

Levamisole may be quantified in blood, plasma, or urine as a diagnostic tool in clinical poisoning situations or to aid in the medicolegal investigation of suspicious deaths involving adulterated street drugs. About 3% of an oral dose is eliminated unchanged in the 24-hour urine of humans. A post mortem blood levamisole concentration of 2.2 mg/l was present in a woman who died of a cocaine overdose.[33][34]

References[edit]

  1. ^ A. H. M. Raeymakers et al. (1966) J. Med. Pharm. Chem. 9 545-551.
  2. ^ A. H. M. Raeymakers, L. F. C. Roevens and P. A. J. Janssen (1967) Tet. Lett. 16 1467-1470.
  3. ^ (Chirigos et al. (1969, 1973, 1975)).
  4. ^ a b http://www.ncbi.nlm.nih.gov/pubmed/20668440
  5. ^ "Products Discontinued from the Market Since Publication of the 2000 CPS". Canadian Pharmacists Association. Retrieved 2009-08-13. 
  6. ^ a b c Centers for Disease Control and Prevention (CDC) (December 2009). "Agranulocytosis associated with cocaine use - four States, March 2008-November 2009". Morb. Mortal. Wkly. Rep. 58 (49): 1381–5. PMID 20019655. 
  7. ^ The Merck Index, 10th Ed. (1983) p. 1321, Rahway: Merck & Co.
  8. ^ Sanford, Shari (2007). "Levamisole Hydrochloride: Its application and usage in freshwater aquariums". Loaches Online. Retrieved 2009-02-27. 
  9. ^ Sadigh-Eteghad, S., khayat-Nuri, H., Abadi, N., Ghavami, S., Golabi, M., Shanebandi, D. (2011). "Synergetic effects of oral administration of levamisole and Echinacea purpurea on immune response in Wistar rat". Res Vet Sci. 91 (1): 82–5. doi:10.1016/j.rvsc.2010.07.027. PMID 20797737. 
  10. ^ Grishchenko SV, Lavrukhina LA, Ketiladze ES, Krylov VF, Ershov FI (1984). "[Results of combined therapy using levamisole for patients with influenza complicated by pneumonia]". Vopr. Virusol. (in Russian) 29 (2): 175–9. PMID 6203228. 
  11. ^ "Levamisole for corticosteroid-dependent nephrotic syndrome in childhood. British Association for Paediatric Nephrology". Lancet 337 (8757): 1555–7. 1991. PMID 1675705. 
  12. ^ Scheinfeld N, Rosenberg JD, Weinberg JM (2004). "Levamisole in dermatology: a review". Am J Clin Dermatol 5 (2): 97–104. doi:10.2165/00128071-200405020-00004. PMID 15109274. 
  13. ^ a b J. Symoens et al. (1979). In Pharmacological and Biochemical Properties of Drug Substances, Vol. 2, (M. E. Goldberg, Ed.), pp. 407-464, Washington: American Pharmaceutical Association.
  14. ^ P. M. Vanhoutte et al. (1977) J. Pharmacol. Exp. Ther. 200 127-140.
  15. ^ E. Przegalinski et al. (1980) Pol. J. Pharmacol. Pharm. Sci. 32 21-29.
  16. ^ J. Guiterrez et al. (2010) "Pemoline and tetramasole 'positives' in English racehorses following levamisole administration." Irish Veterinary Journal 63:8 498-500.
  17. ^ E.N. Ho et al. (2009) "Aminorex and rexamino as metabolites of levamisole in the horse." Anal Chem Acta. 638(1); 58-68.
  18. ^ J. Scarth et al. (2010) "The use of in vitro drug metabolism studies to complement, reduce and refine in vivo administrations in medication and doping control." Proceedings of the 18th International Conference of Racing Analyists and Veterinarians. pp 213-222
  19. ^ Bertol E, Mari F, Milia MG, Politi L, Furlanetto S, Karch SB. (2011). "[Determination of aminorex in human urine samples by GC-MS after use of levamisole.]". J Pharm Biomed Anal. 15 (55): 1186–9. PMID 21531521. 
  20. ^ Van Belle, H. (1976). "Alkaline phosphatase. I. Kinetics and inhibition by levamisole of purified isoenzymes from humans". Clin. Chem. 22 (7): 972–6. PMID 6169. 
  21. ^ http://www.wormbook.org/chapters/www_acetylcholine/acetylcholine.html
  22. ^ Moisse, Katie (2011-06-23). "Cocaine Laced With Veterinary Drug Levamisole Eats Away at Flesh". ABC News. Retrieved 2011-06-23. 
  23. ^ Doheny, Kathleen (Jun 1, 2010). "Contaminated Cocaine Can Cause Flesh to Rot". Yahoo!. Retrieved 8 June 2010. [dead link]
  24. ^ Kiley, Brendan (August 17, 2010). "The Mystery of the Tainted Cocaine". The Stranger. Retrieved December 21, 2010. 
  25. ^ Nancy Y Zhu, Donald F. LeGatt, A Robert Turner (February 2009). "Agranulocytosis After Consumption of Cocaine Adulterated With Levamisole". Annals of Internal Medicine 150 (4): 287–289. doi:10.1059/0003-4819-150-4-200902170-00102. PMID 19153405. Retrieved 2009-10-07. 
  26. ^ Kinzie, Erik (April 2009). "Levamisole Found in Patients Using Cocaine". Annals of Emergency Medicine 53 (4): 546–7. doi:10.1016/j.annemergmed.2008.10.017. PMID 19303517. Retrieved 2009-08-18. 
  27. ^ Menni S, Pistritto G, Gianotti R, Ghio L, Edefonti A (1997). "Ear lobe bilateral necrosis by levamisole-induced occlusive vasculitis in a pediatric patient". Pediatr Dermatol 14 (6): 477–9. doi:10.1111/j.1525-1470.1997.tb00695.x. PMID 9436850. 
  28. ^ Bradford, M., Rosenberg, B., Moreno, J., Dumyati, G. (June 2010). "Bilateral necrosis of earlobes and cheeks: another complication of cocaine contaminated with levamisole". Ann. Intern. Med. 152 (11): 758–9. doi:10.1059/0003-4819-152-11-201006010-00026. PMID 20513844. 
  29. ^ "'Kate Plus Eight' is enough". The San Francisco Chronicle. September 29, 2009. Retrieved January 21, 2014. 
  30. ^ Parascandola, Rocco (2010-06-18). "Ted Koppel's son, Andrew Koppel, overdosed on cocktail containing booze, heroin, cocaine and Valium". Daily News (New York). 
  31. ^ Olding, Rachel (2014-01-12). "Young man's death highlights the tragic reality of online illegal drug stores". Sydney Morning Herald (Sydney). 
  32. ^ Brendan Kiley (September 11, 2012). "Now Drug Dealers (Not Just Users) Are Testing Their Cocaine for Levamisole". The Stranger. Retrieved September 14, 2012. 
  33. ^ Vandamme TF, Demoustier M, Rollmann B. "Quantitation of levamisole in plasma using high performance liquid chromatography". Eur. J. Drug Metab. Pharmacokinet. 20: 145-149, 1995.
  34. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp.901-902. http://www.biomedicalpublications.com/levamisole.pdf.