Levamisole

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Levamisole
Levamisole.svg
Levamisole molecule ball.png
Clinical data
Trade names Decaris, Ergamisol
AHFS/Drugs.com Micromedex Detailed Consumer Information
MedlinePlus a697011
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver
Elimination half-life 3–4 hours
Excretion Kidney (70%)
Identifiers
  • (S)-6-Phenyl-2,3,5,6-tetrahydroimidazo[2,1-b] [1,3]thiazole
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.035.290 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H12N2S
Molar mass 204.29 g·mol−1
3D model (JSmol)
Density 1.31 g/cm3
Melting point 60 °C (140 °F)
Solubility in water hydrochloride: 210 mg/mL (20 °C)
  • N\2=C1/SCCN1C[C@@H]/2c3ccccc3
  • InChI=1S/C11H12N2S/c1-2-4-9(5-3-1)10-8-13-6-7-14-11(13)12-10/h1-5,10H,6-8H2/t10-/m1/s1 Yes check.svgY
  • Key:HLFSDGLLUJUHTE-SNVBAGLBSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (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]

Contents

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] 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]

Other

Levamisole has been used to treat a variety of dermatologic conditions, including skin infections, leprosy, warts, lichen planus, and aphthous ulcers. [15]

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]

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. [19] [20] [21]

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. [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 ]

Toxicity

The LD50 (intravenous, mouse) is 22 mg/kg. [39]

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. [40] [41] 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. [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]

Related Research Articles

Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count and thus causing neutropenia in the circulating blood. It is a severe lack of one major class of infection-fighting white blood cells. People with this condition are at very high risk of serious infections due to their suppressed immune system.

<span class="mw-page-title-main">Ascariasis</span> Disease caused by the parasitic roundworm Ascaris lumbricoides

Ascariasis is a disease caused by the parasitic roundworm Ascaris lumbricoides. Infections have no symptoms in more than 85% of cases, especially if the number of worms is small. Symptoms increase with the number of worms present and may include shortness of breath and fever in the beginning of the disease. These may be followed by symptoms of abdominal swelling, abdominal pain, and diarrhea. Children are most commonly affected, and in this age group the infection may also cause poor weight gain, malnutrition, and learning problems.

<span class="mw-page-title-main">Praziquantel</span> Medication

Praziquantel (PZQ), sold under the brandname Biltricide among others, is a medication used to treat a number of types of parasitic worm infections in mammals, birds, amphibians, reptiles, and fish. In humans specifically, it is used to treat schistosomiasis, clonorchiasis, opisthorchiasis, tapeworm infections, cysticercosis, echinococcosis, paragonimiasis, fasciolopsiasis, and fasciolosis. It should not be used for worm infections of the eye. It is taken by mouth.

<span class="mw-page-title-main">Ivermectin</span> Medication for parasite infestations

Ivermectin is an antiparasitic drug. After its discovery in 1975, its first uses were in veterinary medicine to prevent and treat heartworm and acariasis. Approved for human use in 1987, it is used to treat infestations including head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, ascariasis and lymphatic filariasis. It works through many mechanisms to kill the targeted parasites, and can be taken by mouth, or applied to the skin for external infestations. It belongs to the avermectin family of medications.

<i>Haemonchus contortus</i> Species of roundworm

Haemonchus contortus, also known as the barber's pole worm, is a very common parasite and one of the most pathogenic nematodes of ruminants. Adult worms attach to abomasal mucosa and feed on the blood. This parasite is responsible for anemia, oedema, and death of infected sheep and goats, mainly during summer in warm, humid climates.

<i>Ascaridia galli</i> Species of roundworm

Ascaridia galli is a parasitic roundworm belonging to the phylum Nematoda. Nematodes of the genus Ascaridia are essentially intestinal parasites of birds. A. galli is the most prevalent and pathogenic species, especially in domestic fowl, Gallus domesticus. It causes ascaridiasis, a disease of poultry due to heavy worm infection, particularly in chickens and turkeys. It inhabits the small intestine, and can be occasionally seen in commercial eggs.

<span class="mw-page-title-main">4-Methylaminorex</span> Group of stereoisomers

4-Methylaminorex is a stimulant drug of the 2-amino-5-aryloxazoline class that was first synthesized in 1960 by McNeil Laboratories. It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as a stimulant.

<span class="mw-page-title-main">Aminorex</span> Chemical compound

Aminorex is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension. In the U.S., it is an illegal Schedule I drug, meaning it has high abuse potential, no accepted medical use, and a poor safety profile.

<span class="mw-page-title-main">Emodepside</span> Chemical compound

Emodepside is an anthelmintic drug that is effective against a number of gastrointestinal nematodes, is licensed for use in cats and belongs to the class of drugs known as the octadepsipeptides, a relatively new class of anthelmintic, which are suspected to achieve their anti-parasitic effect by a novel mechanism of action due to their ability to kill nematodes resistant to other anthelmintics.

Capillaria plica is a parasitic nematode which is most often found in the urinary bladder, and occasionally in the kidneys, of dogs and foxes. It has also been found in the domestic cat, and various wild mammals. Its presence usually produces no clinical symptoms, but in some cases, it leads to hematuria, cystitis, or difficulty in urination.

<span class="mw-page-title-main">Thelaziasis</span> Medical condition

Thelaziasis is the term for infestation with parasitic nematodes of the genus Thelazia. The adults of all Thelazia species discovered so far inhabit the eyes and associated tissues of various mammal and bird hosts, including humans. Thelazia nematodes are often referred to as "eyeworms".

<span class="mw-page-title-main">Anthelmintic</span> Antiparasitic drugs that expel parasitic worms (helminths) from the body

Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the host. They may also be called vermifuges or vermicides. Anthelmintics are used to treat people who are infected by helminths, a condition called helminthiasis. These drugs are also used to treat infected animals, particularly small ruminants such as goats and sheep.

<span class="mw-page-title-main">Oxfendazole</span> Chemical compound

Oxfendazole is a broad spectrum benzimidazole anthelmintic. Its main use is for protecting livestock against roundworm, strongyles and pinworms. Oxfendazole is the sulfoxide metabolite of fenbendazole.

<i>Teladorsagia circumcincta</i> Species of roundworm

Teladorsagia circumcincta is a nematode that is one of the most important parasites of sheep and goats. It was previously known as Ostertagia circumcincta and is colloquially known as the brown stomach worm. It is common in cool, temperate areas, such as south-eastern and south-western Australia and the United Kingdom. There is considerable variation among lambs and kids in susceptibility to infection. Much of the variation is genetic and influences the immune response. The parasite induces a type I hypersensitivity response which is responsible for the relative protein deficiency which is characteristic of severely infected animals. There are mechanistic mathematical models which can predict the course of infection. There are a variety of ways to control the infection and a combination of control measures is likely to provide the most effective and sustainable control.

Levamisole induced necrosis syndrome (LINES) is a complication of adulterated cocaine recognized in 2011, caused by the use of levamisole as a cutting agent for cocaine. Spontaneous bruising of the earlobes is considered characteristic of this condition, but lesions can present anywhere on the body.

Amphistomiasis is a parasitic disease of livestock animals, more commonly of cattle and sheep, and humans caused by immature helminthic flatworms belonging to the order Echinostomida. The term amphistomiasis is used for broader connotation implying the disease inflicted by members of Echinostomida including the family Paramphistomidae/Gastrodiscidae ; whereas paramphistomiasis is restricted to that of the members of the family Paramphistomidae only. G. discoides and Watsonius watsoni are responsible for the disease in humans, while most paramphistomes are responsible in livestock animals, and some wild mammals. In livestock industry the disease causes heavy economic backlashes due to poor production of milk, meat and wool.

Setaria cervi is a species of parasitic roundworms belonging to the genus Setaria. It infects cattle, bison, yak, reindeer, buffalo, moose, and sheep all over the world. It is most prevalent in Europe and Asia. Different species of Aedes mosquito can transmit the filarial worm. Stable fly Haematobia stimulans is the major vector. The mature roundworms are primarily present in the abdominal (peritoneal) cavity, but are capable of migrating to central nervous system causing serious neurological disease.

<i>Cooperia oncophora</i> Species of roundworm

Cooperia oncophora is one of the most common intestinal parasitic nematodes in cattle in temperate regions. Infections with C. oncophora may result in mild clinical symptoms, but can lead to weight loss and damage of the small intestine, especially when co-infections with other nematodes such as O. ostertagi occur. Infections are usually treated with broad-spectrum anthelmintics such as benzimidazole, but resistance to these drugs has developed in the last decades and is now very common. C. oncophora has a direct life cycle. Infective larvae are ingested by the host. The larvae grow to adults, which reproduce in the small intestines. Eggs are shed onto the pasture with the faeces, which leads to new infections. Co-infections with other gastro-intestinal nematodes such as O. ostertagi and H. contortus are common.

The fecal egg count reduction test was suggested in the World Association for the Advancement of Veterinary Parasitology guideline for estimating the reduction in fecal egg counts and its corresponding confidence interval. The results of this test can be used to determine the anthelmintic resistance status of the animals.

<span class="mw-page-title-main">Carlos Lanusse</span> Argentinean pharmacology researcher

Carlos E. Lanusse is an Argentine scientist and a professor of Pharmacology. He is the Director of the Veterinary Research Center and the Science and Technology Center of the Argentina National Council of Research in Tandil.

References

  1. ↑ 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. PMID   18430913.
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  3. 1 2 "Levamisole Advanced Patient Information - Drugs.com". www.drugs.com. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  4. ↑ Prevenier W, Howelland M (2001). From reliable sources : an introduction to historical methods (1st ed.). Ithaca: Cornell university press. p. 77. ISBN   9780801485602. Archived from the original on 10 September 2017.
  5. ↑ 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.
  6. 1 2 3 "Animal Drugs @ FDA". animaldrugsatfda.fda.gov. Retrieved 25 January 2023.
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  8. ↑ "Levamisole". Martindale: The Complete Drug Reference. Lexicomp. Archived from the original on 21 December 2016. Retrieved 21 April 2014.
  9. ↑ Sanford S (2007). "Levamisole Hydrochloride: Its application and usage in freshwater aquariums". Loaches Online. Archived from the original on 1 March 2009. Retrieved 27 February 2009.
  10. ↑ 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. PMID   11954915.
  11. ↑ 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. PMID   17151724.{{cite journal}}: CS1 maint: overridden setting (link)
  12. ↑ 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. PMID   8686167.
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  28. ↑ 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. PMID   23436169. S2CID   2222462.
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  31. ↑ Moisse K (23 June 2011). "Cocaine Laced With Veterinary Drug Levamisole Eats Away at Flesh". ABC News. Archived from the original on 25 June 2011. Retrieved 23 June 2011.
  32. ↑ Doheny K (1 June 2010). "Contaminated Cocaine Can Cause Flesh to Rot". Yahoo! . Archived from the original on 7 June 2010. Retrieved 8 June 2010.
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  36. ↑ Menni S, Pistritto G, Gianotti R, Ghio L, Edefonti A (1997). "Ear lobe bilateral necrosis by levamisole-induced occlusive vasculitis in a pediatric patient". Pediatric Dermatology. 14 (6): 477–479. doi:10.1111/j.1525-1470.1997.tb00695.x. PMID   9436850. S2CID   26527277.
  37. ↑ Bradford M, Rosenberg B, Moreno J, Dumyati G (June 2010). "Bilateral necrosis of earlobes and cheeks: another complication of cocaine contaminated with levamisole". Annals of Internal Medicine. 152 (11): 758–759. doi: 10.7326/0003-4819-152-11-201006010-00026 . PMID   20513844.
  38. ↑ Johnston D (31 August 2009). "Tainted cocaine kills 3, sickens dozens". msnbc.com. Retrieved 31 August 2020.
  39. ↑ 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. OCLC   1106595378.
  40. ↑ Van Belle H (July 1976). "Alkaline phosphatase. I. Kinetics and inhibition by levamisole of purified isoenzymes from humans". Clinical Chemistry. 22 (7): 972–6. doi: 10.1093/clinchem/22.7.972 . PMID   6169.
  41. ↑ Khodaparast-Sharifi SH, Snow LD (1989). "Levamisole inhibition of alkaline phosphatase and 5'-nucleotidase of bovine milk fat globule membranes". International Journal of Biochemistry. 21 (4): 401–405. doi:10.1016/0020-711X(89)90364-9. PMID   2545478.
  42. ↑ "Gonad Dissections | Schedl Lab". Archived from the original on 17 May 2014. Retrieved 15 May 2014. Schedl Lab Protocol for gonad dissections
  43. ↑ Rand JB (January 2007). "Acetylcholine". WormBook: 1–21. doi:10.1895/wormbook.1.131.1. PMC   4781110 . PMID   18050502.
  44. ↑ Dillman RO (February 2011). "Cancer immunotherapy". Cancer Biotherapy & Radiopharmaceuticals. 26 (1): 1–64. doi:10.1089/cbr.2010.0902. PMID   21355777.
  45. ↑ 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. PMID   29146214.
  46. ↑ (Chirigos et al. (1969, 1973, 1975)).
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