Chemistry:Levamisole

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Short description: Chemical compound
Levamisole
Skeletal formula of levamisole
Ball-and-stick model of the levamisole molecule
Clinical data
Trade namesDecaris, Ergamisol
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa697011
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • CA: Withdrawn drug
  • US: Withdrawn
  • Rx-only (Russia )
Pharmacokinetic data
MetabolismLiver
Elimination half-life3–4 hours
ExcretionUrine (70%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC11H12N2S
Molar mass204.29 g·mol−1
3D model (JSmol)
Density1.31 g/cm3
Melting point60 °C (140 °F)
Solubility in waterhydrochloride: 210 mg/mL (20 °C)
 ☒N☑Y (what is this?)  (verify)

Levamisole, sold under the brand name Ergamisol among others, is a medication used to treat parasitic worm infections, specifically ascariasis and hookworm infections.[1] It is taken by mouth.[2]

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 invented in 1966 in Belgium by Janssen Pharmaceuticals.[4] It is on the World Health Organization's List of Essential Medicines.[5] Levamisole is also used as a dewormer for cattle.[6][7]

Medical uses

Worms

Levamisole was originally used as an anthelmintic to treat worm infestations in both humans and animals. Levamisole works as a nicotinic acetylcholine receptor agonist that causes continued stimulation of the parasitic worm muscles, leading to paralysis.[8] Levamisole has gained prominence among aquarists as an effective treatment for Camallanus roundworm infestations in freshwater tropical fish.[9]

Other

Levamisole has been used to treat a variety of dermatologic conditions, including skin infections, leprosy, warts, lichen planus, and aphthous ulcers.[10]

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.[11][12]

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.[13]

It has been used as an adulterant in cocaine, resulting in serious side effects that present as levamisole induced necrosis syndrome, in which erythematous painful papules can appear almost anywhere on skin.[14][15][16]

Metabolism

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.[17][18]

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.[19][20][21] Further testing confirmed aminorex in human and canine urine, meaning that both humans and dogs also metabolize levamisole into aminorex.,[22] 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.[23]

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.[24][25]

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).[14] By April 2011, the DEA reported the adulterant was found in 82% of seizures.[26]

Levamisole adds bulk and weight to powdered cocaine (whereas other adulterants produce smaller "rocks" of cocaine) and makes the drug appear purer.[27] 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.[28]

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.[14][29][30] Levamisole has also been linked to a risk of vasculitis,[31] and two cases of vasculitic skin necrosis have been reported in users of cocaine adulterated with levamisole.[32]

Levamisole-tainted cocaine has caused three deaths and sickened over 100 in US and Canada, as of 2009.[33]

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]

Toxicity

The LD50 (intravenous, mouse) is 22 mg/kg.[34]

Laboratory use

Levamisole reversibly and uncompetitively inhibits most isoforms of alkaline phosphatase (e.g., human liver, bone, kidney, and spleen) except the intestinal and placental isoform.[35][36] 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.[citation needed]

It is used to immobilize the nematode C. elegans on glass slides for imaging and dissection.[37]

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.[38]

Research

It has been studied as a method to stimulate the immune system as part of the treatment of cancer.[39] It has also shown some efficacy in the treatment of nephrotic syndrome in children.[40]

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.[41]

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

  1. ↑ "Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis". JAMA 299 (16): 1937–48. April 2008. doi:10.1001/jama.299.16.1937. PMID 18430913. 
  2. ↑ 2.0 2.1 2.2 WHO Model Formulary 2008. World Health Organization. 2009. pp. 86, 590. ISBN 9789241547659. 
  3. ↑ 3.0 3.1 "Levamisole Advanced Patient Information - Drugs.com". https://www.drugs.com/cons/levamisole.html. 
  4. ↑ From reliable sources : an introduction to historical methods (1st ed.). Ithaca: Cornell university press. 2001. p. 77. ISBN 9780801485602. https://books.google.com/books?id=wSqgwOZPjJ4C&pg=PA77. 
  5. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  6. ↑ 6.0 6.1 6.2 "Animal Drugs @ FDA". https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/141-553. 
  7. ↑ (in en) Veterinary Parasitology. John Wiley & Sons. 2015. p. 329. ISBN 9781119073673. https://books.google.com/books?id=ta7YCgAAQBAJ&pg=PA329. 
  8. ↑ "Levamisole". Martindale: The Complete Drug Reference. Lexicomp. http://online.lexi.com/lco/action/doc/retrieve/docid/martindale_f/1351191. 
  9. ↑ "Levamisole Hydrochloride: Its application and usage in freshwater aquariums". Loaches Online. 2007. http://www.loaches.com/disease-treatment/levamisole-hydrochloride-1. 
  10. ↑ "Levamisole in dermatology : a review". American Journal of Clinical Dermatology 5 (2): 97–104. 2004. doi:10.2165/00128071-200405020-00004. PMID 15109274. 
  11. ↑ "Differential effects of the isomers of tetramisole on adrenergic neurotransmission in cutaneous veins of dog". The Journal of Pharmacology and Experimental Therapeutics 200 (1): 127–40. January 1977. PMID 189006. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=189006. 
  12. ↑ "Psychopharmacological profile of dexamisole". Polish Journal of Pharmacology and Pharmacy 32 (1): 21–9. 1980. PMID 7454609. 
  13. ↑ "Levamisole". DEA. http://www.deadiversion.usdoj.gov/drug_chem_info/levamisole.pdf. 
  14. ↑ 14.0 14.1 14.2 Centers for Disease Control Prevention (CDC) (December 2009). "Agranulocytosis associated with cocaine use - four States, March 2008-November 2009". MMWR. Morbidity and Mortality Weekly Report 58 (49): 1381–5. PMID 20019655. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5849a3.htm. 
  15. ↑ "Levamisole: a dangerous new cocaine adulterant". Clinical Pharmacology and Therapeutics 88 (3): 408–11. September 2010. doi:10.1038/clpt.2010.156. PMID 20668440. 
  16. ↑ "Cocaine powder: review of its prevalence, patterns of use and harm". Advisory Council on the Misuse of Drugs. 12 March 2015. https://www.gov.uk/government/publications/cocaine-powder-review-of-its-prevalence-patterns-of-use-and-harm. 
  17. ↑ "Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine". Biopharmaceutics & Drug Disposition 7 (1): 71–89. 1986. doi:10.1002/bdd.2510070110. PMID 3754161. 
  18. ↑ "Pharmacokinetics of levamisole in healthy subjects and cancer patients". European Journal of Drug Metabolism and Pharmacokinetics 7 (4): 247–54. 1982. doi:10.1007/bf03189626. PMID 7166176. 
  19. ↑ "Pemoline and tetramisole 'positives' in english racehorses following levamisole administration". Irish Veterinary Journal 63 (8): 498. August 2010. doi:10.1186/2046-0481-63-8-498. PMID 21777496. 
  20. ↑ "Aminorex and rexamino as metabolites of levamisole in the horse". Analytica Chimica Acta 638 (1): 58–68. April 2009. doi:10.1016/j.aca.2009.02.033. PMID 19298880. Bibcode: 2009AcAC..638...58H. 
  21. ↑ "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 analysts and Veterinarians (ICRAV), Queenstown, New Zealand. Auckland: Dumnor Publishing, Limited. 2012. pp. 213–222. ISBN 978-0-473-22084-6. 
  22. ↑ "Determination of aminorex in human urine samples by GC-MS after use of levamisole". Journal of Pharmaceutical and Biomedical Analysis 55 (5): 1186–1189. July 2011. doi:10.1016/j.jpba.2011.03.039. PMID 21531521. 
  23. ↑ "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. May 2013. doi:10.1007/s00216-013-6829-x. PMID 23436169. 
  24. ↑ "Quantitation of levamisole in plasma using high performance liquid chromatography". European Journal of Drug Metabolism and Pharmacokinetics 20 (2): 145–9. 1995. doi:10.1007/bf03226369. PMID 8582440. 
  25. ↑ Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. 2011. pp. 901–902. http://www.biomedicalpublications.com/levamisole.pdf. Retrieved 2011-01-22. 
  26. ↑ "Cocaine Laced With Veterinary Drug Levamisole Eats Away at Flesh". ABC News. 2011-06-23. https://abcnews.go.com/Health/Wellness/flesh-eating-cocaine-laced-veterinary-drug-levamisole/story?id=13902353. 
  27. ↑ "Contaminated Cocaine Can Cause Flesh to Rot". Yahoo!. Jun 1, 2010. https://news.yahoo.com/s/hsn/contaminatedcocainecancausefleshtorot;_ylt=Arpc.e2vZk4K0VyhIadneKes0NUE;_ylu=X3oDMTRhMzAybmR2BGFzc2V0A2hzbi8yMDEwMDYwMS9jb250YW1pbmF0ZWRjb2NhaW5lY2FuY2F1c2VmbGVzaHRvcm90BGNjb2RlA21vc3Rwb3B1bGFyBGNwb3MDOARwb3MDNQRwdANob21lX2Nva2UEc2VjA3luX2hlYWRsaW5lX2xpc3QEc2xrA2NvbnRhbWluYXRlZA--. 
  28. ↑ "The Mystery of the Tainted Cocaine". The Stranger. August 17, 2010. http://www.thestranger.com/seattle/the-mystery-of-the-tainted-cocaine/Content?oid=4683741. 
  29. ↑ "Agranulocytosis after consumption of cocaine adulterated with levamisole". Annals of Internal Medicine 150 (4): 287–289. February 2009. doi:10.7326/0003-4819-150-4-200902170-00102. PMID 19153405. 
  30. ↑ "Levamisole found in patients using cocaine". Annals of Emergency Medicine 53 (4): 546–547. April 2009. doi:10.1016/j.annemergmed.2008.10.017. PMID 19303517. 
  31. ↑ "Ear lobe bilateral necrosis by levamisole-induced occlusive vasculitis in a pediatric patient". Pediatric Dermatology 14 (6): 477–479. 1997. doi:10.1111/j.1525-1470.1997.tb00695.x. PMID 9436850. 
  32. ↑ "Bilateral necrosis of earlobes and cheeks: another complication of cocaine contaminated with levamisole". Annals of Internal Medicine 152 (11): 758–759. June 2010. doi:10.7326/0003-4819-152-11-201006010-00026. PMID 20513844. 
  33. ↑ "Tainted cocaine kills 3, sickens dozens" (in en). 2009-08-31. http://www.nbcnews.com/id/32633293/ns/us_news-crime_and_courts/t/tainted-cocaine-kills-sickens-dozens/. 
  34. ↑ "Levamisole". Pharmacological and Biochemical Properties of Drug Substances. 2. Washington: American Pharmaceutical Association. 1979. pp. 407–464. OCLC 1106595378. 
  35. ↑ "Alkaline phosphatase. I. Kinetics and inhibition by levamisole of purified isoenzymes from humans". Clinical Chemistry 22 (7): 972–6. July 1976. doi:10.1093/clinchem/22.7.972. PMID 6169. 
  36. ↑ "Levamisole inhibition of alkaline phosphatase and 5'-nucleotidase of bovine milk fat globule membranes". International Journal of Biochemistry 21 (4): 401–405. 1989. doi:10.1016/0020-711X(89)90364-9. PMID 2545478. 
  37. ↑ "Gonad Dissections | Schedl Lab". http://genetics.wustl.edu/tslab/protocols/dissection-staining-in-situ/gonad-dissections/.  Schedl Lab Protocol for gonad dissections
  38. ↑ "Acetylcholine". WormBook: 1–21. January 2007. doi:10.1895/wormbook.1.131.1. PMID 18050502. PMC 4781110. https://www.ncbi.nlm.nih.gov/books/NBK19736/. 
  39. ↑ "Cancer immunotherapy". Cancer Biotherapy & Radiopharmaceuticals 26 (1): 1–64. February 2011. doi:10.1089/cbr.2010.0902. PMID 21355777. 
  40. ↑ "[Treatments of steroid-dependent nephrotic syndrome in children]". Archives de Pédiatrie 24 (12): 1312–1320. December 2017. doi:10.1016/j.arcped.2017.09.002. PMID 29146214. 
  41. ↑ (Chirigos et al. (1969, 1973, 1975)).

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