Side effects may include abdominal pain, vomiting, headache, and dizziness.[2] Use is not recommended during breastfeeding or the third trimester of pregnancy.[2] Serious side effects may include an increased risk of infection.[3] It belongs to the anthelmintic class of medications.[3]
Levamisole was originally used as an anthelmintic to treat worm infestations in both humans and animals. Levamisole works as a nicotinic acetylcholine receptoragonist that causes continued stimulation of the parasitic worm muscles, leading to paralysis.[8] Levamisole has gained prominence among aquarists as an effective treatment for Camallanusroundworm infestations in freshwatertropical fish.[9] Levamisole has been used to treat small ruminant animals since the late 1960s.[10] Levamisole-resistant parasitic worms are common in sheep farms in New Zealand,[11] Uruguay,[12] Paraguay,[13] and Brazil.[14]
An interesting 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, although this was never a marketed use of the drug.[16][17]
Adverse effects
One of the more serious side effects of levamisole is agranulocytosis, or the depletion of the white blood cells. In particular, neutrophils appear to be affected the most. This occurs in 0.08–5% of the studied populations.[18]
Levamisole is readily absorbed from the gastrointestinal tract and metabolized in the liver. Its time to peak plasma concentration is 1.5–2 hours. The plasma elimination half-life is fairly quick at 3–4 hours which can contribute to not detecting levamisole intoxication. The metabolite half-life is 16 hours. Levamisole's excretion is primarily through the kidneys, with about 70% being excreted over 3 days. Only about 5% is excreted as unchanged levamisole.[22][23]
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.[24][25][26] Further testing confirmed aminorex in human and canine urine, meaning that both humans and dogs also metabolize levamisole into aminorex,[27] though it is unclear whether plasma aminorex is present at any appreciable level. Blood samples following oral administration of levamisole out to 172 hr post-dose did not demonstrate any plasma aminorex levels above that of the limit of quantification (LoQ). Additionally, in cocaine-positive plasma samples, of which 42% contained levamisole, aminorex was never reported at concentrations higher than LoQ.[28]
Detection in body fluids
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.[29][30]
Adulterant in illegal drugs
Levamisole has increasingly been used as a cutting agent in cocaine sold around the globe with the highest incidence being in the United States. In 2008–2009, levamisole was found in 69% of cocaine samples seized by the Drug Enforcement Administration (DEA).[19] By April 2011, the DEA reported the adulterant was found in 82% of seizures.[31]
Levamisole adds bulk and weight to powdered cocaine (whereas other adulterants produce smaller "rocks" of cocaine) and makes the drug appear purer.[32] 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.[33]
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.[19][34][35] Levamisole has also been linked to a risk of vasculitis,[36] and two cases of vasculitic skin necrosis have been reported in users of cocaine adulterated with levamisole.[37]
Levamisole-tainted cocaine has caused three deaths and sickened over 100 in US and Canada, as of 2009.[38]
Chemistry
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. The racemic mixture is referred to as "tetramisole" - levamisole refers only to the levorotatory enantiomer of tetramisole.[citation needed]
It is used to immobilize the nematode C. elegans on glass slides for imaging and dissection.[42]
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.[43]
Research
It has been studied as a method to stimulate the immune system as part of the treatment of cancer.[44] It has also shown some efficacy in the treatment of nephrotic syndrome in children.[45]
After being pulled from the market in the US and Canada in 1999 and 2003, respectively, 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. In some of the leukemic cell line studies, both levamisole and tetramisole showed similar effect.[46]
Veterinary uses
The combination doramectin/levamisole, sold under the brand name Valcor, is indicated for the treatment and control of gastrointestinal roundworms, lungworms, grubs, sucking lice, and mange mites in cattle.[6] It is given by subcutaneous injection.[6]
References
^Keiser J, Utzinger J (April 2008). "Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis". JAMA. 299 (16): 1937–48. doi:10.1001/jama.299.16.1937. PMID18430913.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Harder A (March 2002). "Chemotherapeutic approaches to nematodes: current knowledge and outlook". Parasitology Research. 88 (3): 272–277. doi:10.1007/s00436-001-0535-x. PMID11954915.
^Waghorn TS, Leathwick DM, Rhodes AP, Lawrence KE, Jackson R, Pomroy WE, et al. (December 2006). "Prevalence of anthelmintic resistance on sheep farms in New Zealand". New Zealand Veterinary Journal. 54 (6): 271–277. doi:10.1080/00480169.2006.36710. PMID17151724.
^Nari A, Salles J, Gil A, Waller PJ, Hansen JW (April 1996). "The prevalence of anthelmintic resistance in nematode parasites of sheep in southern Latin America: Uruguay". Veterinary Parasitology. 62 (3–4): 213–222. doi:10.1016/0304-4017(95)00908-6. PMID8686167.
^Maciel S, Giménez AM, Gaona C, Waller PJ, Hansen JW (April 1996). "The prevalence of anthelmintic resistance in nematode parasites of sheep in southern Latin America: Paraguay". Veterinary Parasitology. 62 (3–4): 207–212. doi:10.1016/0304-4017(95)00907-8. PMID8686166.
^Echevarria F, Borba MF, Pinheiro AC, Waller PJ, Hansen JW (April 1996). "The prevalence of anthelmintic resistance in nematode parasites of sheep in southern Latin America: Brazil". Veterinary Parasitology. 62 (3–4): 199–206. doi:10.1016/0304-4017(95)00906-x. PMID8686165.
^Chang A, Osterloh J, Thomas J (September 2010). "Levamisole: a dangerous new cocaine adulterant". Clinical Pharmacology and Therapeutics. 88 (3): 408–11. doi:10.1038/clpt.2010.156. PMID20668440. S2CID31414939.
^Kouassi E, Caillé G, Léry L, Larivière L, Vézina M (1986). "Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine". Biopharmaceutics & Drug Disposition. 7 (1): 71–89. doi:10.1002/bdd.2510070110. PMID3754161.
^Luyckx M, Rousseau F, Cazin M, Brunet C, Cazin JC, Haguenoer JM, et al. (1982). "Pharmacokinetics of levamisole in healthy subjects and cancer patients". European Journal of Drug Metabolism and Pharmacokinetics. 7 (4): 247–54. doi:10.1007/bf03189626. PMID7166176. S2CID13206196.
^Scarth, et al. (2012). "The use of in vitro drug metabolism studies to complement, reduce and refine in vivo administrations in medication and doping control.". In Beresford GD, Howitt RG (eds.). Proceedings of the 18th International Conference of Racing analysts and Veterinarians (ICRAV), Queenstown, New Zealand. Auckland: Dumnor Publishing, Limited. pp. 213–222. ISBN978-0-473-22084-6.
^Bertol E, Mari F, Milia MG, Politi L, Furlanetto S, Karch SB (July 2011). "Determination of aminorex in human urine samples by GC-MS after use of levamisole". Journal of Pharmaceutical and Biomedical Analysis. 55 (5): 1186–1189. doi:10.1016/j.jpba.2011.03.039. PMID21531521.
^Hess C, Ritke N, Broecker S, Madea B, Musshoff F (May 2013). "Metabolism of levamisole and kinetics of levamisole and aminorex in urine by means of LC-QTOF-HRMS and LC-QqQ-MS". Analytical and Bioanalytical Chemistry. 405 (12): 4077–4088. doi:10.1007/s00216-013-6829-x. PMID23436169. S2CID2222462.
^Vandamme TF, Demoustier M, Rollmann B (1995). "Quantitation of levamisole in plasma using high performance liquid chromatography". European Journal of Drug Metabolism and Pharmacokinetics. 20 (2): 145–9. doi:10.1007/bf03226369. PMID8582440. S2CID9258640.
^Zhu NY, Legatt DF, Turner AR (February 2009). "Agranulocytosis after consumption of cocaine adulterated with levamisole". Annals of Internal Medicine. 150 (4): 287–289. doi:10.7326/0003-4819-150-4-200902170-00102. PMID19153405.
^Symoens J, DeCree J, Bever WV, Janssen PA (1979). "Levamisole". In Goldberg ME (ed.). Pharmacological and Biochemical Properties of Drug Substances. Vol. 2. Washington: American Pharmaceutical Association. pp. 407–464. OCLC1106595378.
^Couderc A, Bérard E, Guigonis V, Vrillon I, Hogan J, Audard V, et al. (December 2017). "[Treatments of steroid-dependent nephrotic syndrome in children]". Archives de Pédiatrie. 24 (12): 1312–1320. doi:10.1016/j.arcped.2017.09.002. PMID29146214.
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