Levamisole

Levamisole

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Legal status	withdrawn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 Y
ATC code	P02CE01 QP52AE01
PubChem	CID 26879
DrugBank	DB00848
ChemSpider	25037 Y
UNII	2880D3468G Y
KEGG	D08114 Y
ChEMBL	CHEMBL1454 Y
Chemical data
Formula	C11H12N2S
Mol. mass	204.292 g/mol
SMILES N\2=C1/SCCN1C[C@@H]/2c3ccccc3
InChI 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 Y Key:HLFSDGLLUJUHTE-SNVBAGLBSA-N Y
Physical data
Density	1.31 g/cm³
Melt. point	60 °C (140 °F)
Y (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 In some of the leukemic cell line studies, both levamisole and tetramisole showed similar effect.^[3] The drug was withdrawn from the U.S. and Canadian markets in 1999 and 2003, respectively, due to the risk of serious side effects and the availability of more effective replacement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

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

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 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

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

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

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

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

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.^[33][34]

References