14769-73-4

Pharmacology and mechanism of action

Levamisole is the L-isomer of tetramisole and is more active than the racemic mixture. It was introduced in 1966 as a veterinary drug and a little later as a human anthelminthic drug against ascariasis. The drug has also shown to be effective against hookworms (Ancylostoma duodenale and Necator americanus), but results of reported studies are inconsistent [1]. The mechanism of action of levamisole in helminthiasis is through its stimulation of autonomic ganglia (nicotinic receptors) of the worms. On exposure to the drug, immature and adult worms show spastic contraction followed by tonic paralysis. This mechanism seems to be common to other anthelminthics such as pyrantel and bephenium hydroxynaphthoate [2]. In higher doses, levamisole acts as an immunostimulant. It restores depressed cell-mediated immune mechanisms in peripheral T-lymphocytes, but may have marginal effects in immunologically competent individuals [3]. The clinical implication of this effect in the treatment of helminthiasis is unknown.

Indications

Monoinfections with Ascaris lumbricoides. In polyinfections, mebendazole is the drug of choice.

Side effects

During the treatment of nematode infections the drug produces minor side effects including nausea, vomiting, abdominal pain and headache [4, 5]. During prolonged treatment as an immunomodulator in rheumatic arthritis and in cancer patients, serious side effects such as blood disorders (agranulocytosis, neutropenia and thrombocytopenia), kidney damage, influenza-like reactions, vasculitis, photosensitivity and allergy to the drug have been reported [6, 7].

Contraindications and precautions

The drug should be avoided in patients allergic to the drug. Administration of levamisole may provoke a reaction similar to that seen after intake of alcohol together with disulfiram. During long-term treatment, patients with kidney damage or with blood disorders may experience exacerbation of their diseases.

Interactions

Levamisole has been reported to displace the protein binding of rifampicin in vitro [8]. The clinical significance of this is as yet unknown.

Preparations

Available as levamisole hydrochloride: 118 mg is equivalent to 100 mg base. ? Ketrax? (Zeneca). Oral solution 40 mg base per 5 ml. Tablets 40 mg base. ? Solaskil? (Rh?ne-Poulenc Rorer). Tablets 30 mg base, 150 mg base. ? Ergamisol? (Lederle). Tablets 50 mg base. ? Levamisol? (Janssen). Tablets 50 mg base.

Originator

Solaskil,Specia,France,1971

Uses

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

Definition

ChEBI: 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 huma s as an adjuvant to chemotherapy for the treatment of various cancers. It is also widely used as an adulterant to coccaine.

Manufacturing Process

To a stirred and refluxed suspension of 17 parts of 1,2-dibromoethane, 7.8 parts of sodium hydrogen carbonate and 50 parts of 2-propanol is added a mixture of 3.4 parts of dl-2-thio-1-phenyl-imidazolidine, 9 parts of a 20% potassium hydroxide solution in 40 parts of 2-propanol over a period of about 1 hour. After the addition is complete, the whole is stirred and refluxed for an additional 3 hours. The reaction mixture is evaporated. To the residue are added 18 parts of a 15% potassium hydroxide solution. The whole is extracted with toluene. The extract is dried and evaporated. The oily residue is dissolved in acetone and gaseous hydrogen chloride is introduced into the solution. The precipitated solid salt is filtered off and recrystallized from 2-propanol, yielding dl-2,3,5,6-tetrahydro-6-phenyl-imidazo[2,1-b]thiazole hydrochloride; melting point 264°C to 266°C.dl-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole hydrochloride, 188 g (0.785 mol), is suspended in a mixture of 500 ml of water and 500 ml of methylene chloride. The suspension is stirred mechanically while 20% sodium hydroxide solution is added until the solution is basic. Ice is added from time to time to keep the temperature below the boiling point of the methylene chloride. The methylene chloride layer is separated, washed with water, dried over potassium carbonate and evaporated. The oily residue crystallizes with the evolution of the heat when poured into a beaker containing 100 ml of ether. The free base is washed with ether. The yield of dl-6-phenyl-2,3,5,6- tetrahydroimidazo[2,-b]thiazole is 151.4 g (0.746 mol), 94%. The product has a melting point of 90°C.A solution of 204.3 g (1 mol) of dl-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1- b]thiazole and 232.3 g (1 mol) of d-10-camphorsulfonic acid in 1,750 ml of chloroform is allowed to crystallize overnight at -28°C. The solvate is recovered by filtration and washed with ice cold chloroform (400 ml). The solvate is dried (decomposed) under nitrogen 7 hours and then in air overnight. The yield of d(+)6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole d-10-camphorsulfonate is 202.5 g (0.464 mol) 92.8%, melting point 139°C to 140°C [α]D25+ 82.6 (C = 16, H2O).A solution of 150 g (0.344 mol) of d(+)6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole, d-10-camphorsulfonate in water is treated with 15.5 g (0.378 mol) of 98% sodium hydroxide and the liberated base extracted with chloroform. The chloroform solution is washed with water followed by sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent left 72.1 g of residue which crystallized shortly. The free base hereby obtained has a melting point of 60°C to 61.5°C and an optical rotation [α]D25+ 85.1 (C = 10, CHCl3).The free base d(+)6-phenyl-2,3,5.6-tetrahydroimidazo[2.1-b]thiazole is dissolved in 112 ml of acetone and 178 ml of isopropanolic hydrogen chloride is added all at once. The hydrochloride crystallizes at once. After cooling to below 0°C, the salt is recovered by filtration and washed with acetone. The product weighs 75.2 g (0.312 mol), 91%, from the camphorsulfonate, melting point 227°C to 227.5°C [α]D25+ 123.1 (C = 15, H2O).

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

Oral absorption: c. 90% Cmax 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.

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.

Who Evaluation

Evaluation year: 2012