Levamisole

Absorption

Levamisole is rapidly absorbed (2 hours) from the gastrointestinal tract.

Toxicity

LD50 = 40 mg/kg (Pigs, subcutaneous); LD50 = 180 mg/kg (rat, oral)

Originator

Solaskil,Specia,France,1971

The Uses of Levamisole

Levamisole is used for initial and secondary immunodeficient conditions, autoimmune diseases, chronic and reoccurring infections, large intestine adenocarcinoma, helmintosis, and rheumatoid arthritis. Synonyms of this drug are decaris, tetramizole, and others.
Levimasole is also a drug of choice for ascardiasis. Numerous investigations show that a single dose of levamisole heals from 90 to 100% of patients with ascardiasis, in particular those infected with A. duodenale. It is less effective against ancylostomiasis and strongyloidiasis. However, it is not effective against N. americanus. It seems likely that it has a gangliostimulating effect on parasite tissues in both the parasympathetic and sympathetic regions. Moreover, it is presumed that this drug has an immunomodulatory effect on the host organism. Synonyms of this drug are decaris, solacil, ergamisol, tramisol, immunol, and others.

The Uses of Levamisole

Biological response modifier.

Background

Levamisole is an antihelminthic drug that was commonly used for the treatment of parasitic, viral, and bacterial infections. It was manufactured by Janssen and first used in 1969 as an agent to treat worm infestations Levamisole was approved by the FDA in 1990 as an adjuvant treatment for colon cancer. Prior to this, levamisole was used as an antirheumatic therapy in the 1970s and 1980s for patients with rheumatoid arthritis.
Because of its immunomodulatory effects, this drug has been studied in the treatment of various immune-mediated diseases, with some studies showing positive results. This drug has also been used in combination with other drugs for the treatment of various cancers.
Levamisole was withdrawn from the American market in 2000 due to its ability to cause serious adverse effects, including agranulocytosis. Interestingly, levamisole has been found as an adulterant in cocaine and can lead to a variety of adverse effects in individuals using this drug.

Indications

For adjuvant treatment in combination with fluorouracil after surgical resection in patients with Dukes' stage C colon cancer. Also used to treat malignant melanoma and head/neck cancer.

Definition

ChEBI: Levamisole is a 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole that has S configuration. It is used (generally as the monohydrochloride salt) to treat parasitic worm infections in pigs, sheep and cattle and was formerly used in humans as an adjuvant to chemotherapy for the treatment of various cancers. It is also widely used as an adulterant to coccaine. It has a role as an antinematodal drug, an antirheumatic drug, an immunomodulator, an immunological adjuvant and an EC 3.1.3.1 (alkaline phosphatase) inhibitor. It is an enantiomer of a dexamisole.

Indications

Levamisole (Ergamisol) is an antiparasitic drug that has been found to enhance T-cell function and cellular immunity. The drug improves survival of patients with resected colorectal cancers when combined with 5-fluorouracil; the mechanism of this interaction is not known. Levamisole does not have antitumor activity against established or metastatic cancer and has not been found useful in the adjuvant therapy of cancers other than colorectal cancer.
The major adverse effects of levamisole are nausea and anorexia. Skin rashes, itching, flulike symptoms, and fevers also have been observed.

Indications

Levamisole (Ergamisol) was originally developed as an antihelminthic drug. It potentiates the stimulatory effects of antigens, mitogens, lymphokines, and chemotactic factors on lymphocytes, granulocytes, and macrophages. It has been shown to increase T cell–mediated immunity.
Levamisole has been used successfully in treating chronic infections. It also has been approved for use in combination with fluorouracil in the treatment of colorectal cancer.

brand name

Ergamisol (Janssen).

Therapeutic Function

Antiinflammatory

Antimicrobial activity

Its principal activity is against Asc. lumbricoides and hookworms. Worms are paralyzed and passed out in the feces within a few hours.

Pharmaceutical Applications

The l-isomer of tetramisole, available as the monohydrochloride. The d-isomer has no anthelmintic activity. It is very soluble in water and is stable in the dry state.

Mechanism of action

Levamisole has immunomodulating activity. It is believed that it regulates cellular mechanisms of the immune system, and the mechanism of its action may be associated with activation and proliferative growth of T-lymphocytes, increased numbers of monocytes and activation of macrophages, and also with increased activity and hemotaxis of neutrophylic granulocytes. Levamisole also exhibits anthelmint action. It also increases the body’s overall resistivity and restores altered T-lymphocyte and phagocyte function. It can also fulfill an immunomodulatory function by strengthening the weak reaction of cellular immunity, weakening strong reaction, and having no effect on normal reaction.

Pharmacokinetics

Levamisole is a synthetic imidazothiazole derivative that has been widely used in treatment of worm infestations in both humans and animals. As an anthelmintic, it probably works by targeting the nematode nicotinergic acetylcholine receptor. As an immunomodulator, it appears that Levamisole is an immunostimulant which has been shown to increase NK cells and activated T-cells in patients receiving this adjuvantly along with 5FU for Stage III colon cancer.

Pharmacokinetics

Oral absorption: c. 90%
C_max 150 mg oral: 0.5 mg/L after c. 2 h
Plasma half-life: c. 4 h
Volume of distribution: 100–120 L
Levamisole is rapidly absorbed from the gut and extensively metabolized in the liver. It is excreted chiefly in the urine.

Clinical Use

Ascariasis
Hookworm infection
Levamisole has been used in rheumatoid arthritis and some other conditions that are said to respond to its immunomodulatory activity.

Side Effects

Nausea, gastrointestinal upsets and very mild neurological problems have been reported.

Synthesis

Levamisole, 2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole (31.1.4), is synthesized in various ways. One of them begins with α-bromoacetophenone, the reaction of which with 2-imino-1,3-thiazolidine gives 3-phenacyl-2-imino-1,3-thiazolidine (31.1.1). Reacting this product with acetic anhydride gives 3-phenacyl-2-acetylimino-1,3- thiazolidine (31.1.2). The ketone group in the resulting compound is reduced to an alcohol using sodium borohydride, and the resulting hydroxyl group in (31.1.3) is replaced with chlorine using thionyl chloride. Heating the product in acetic anhydride, the imidazole cycle closes, forming the product (31.1.4).

A somewhat different approach was realized when using styrene oxide as the initial starting material. Reacting it with 2-imino-1,3-thiazolidine gives 3-(2-phenyl-2-hydroxyethyl)- 2-imino-1,3-thiazolidine (31.1.5), which is subsequently treated with thionyl chloride and then acetic anhydride to give the desired levamisole (31.1.4).
Finally, the following scheme of making the product has been proposed using the same styrene oxide. Styrene oxide is reacted with aziridine, forming 2-aziridion-1- phenylethanol-1 (31.1.6). Treating this with potassium isothiocyanate or thiourea gives 3- (2-phenyl-2-hydroxyethyl)-2-amino-1,3-thiazolidine (31.1.5), and subsequent treatment with thionyl chloride (such as described above) and then with acetic anhydride gives the desired levamisole (31.1.4).

Veterinary Drugs and Treatments

Depending on the product licensed, levamisole is indicated for the treatment of many nematodes in cattle, sheep and goats, swine, poultry. In sheep and cattle, levamisole has relatively good activity against abomasal nematodes, small intestinal nematodes (not particularly good against Strongyloides spp.), large intestinal nematodes (not Trichuris spp.), and lungworms. Adult forms of species that are usually covered by levamisole, include: Haemonchus spp., Trichostrongylus spp., Osteragia spp., Cooperia spp., Nematodirus spp., Bunostomum spp., Oesophagostomum spp., Chabertia spp., and Dictyocaulus vivapurus. Levamisole is less effective against the immature forms of these parasites, and is generally ineffective in cattle (but not sheep) against arrested larval forms. Resistance of parasites to levamisole is a growing concern.
In swine, levamisole is indicated for the treatment of Ascaris suum, Oesophagostomum spp., Strongyloides, Stephanurus, and Metastrongylus.
Levamisole has been used in dogs as a microfilaricide to treat Dirofilaria immitis infection in the past, but is rarely used today. It has also garnered some interest as an immunostimulant in the adjunctive therapy of various neoplasms.
Because of its narrow margin for safety and limited efficacy against many equine parasites, levamisole is not generally used in horses as an antiparasitic agent. It has been tried as an immune stimulant, however.

Metabolism

Primarily hepatic (extensive) with both active and inactive metabolites.