Thiabendazole

Physical properties

MW 201, pKa not known. Practically insoluble in water.

Pharmacology and mechanism of action

Thiabendazole is a benzimidazole derivative introduced as a veterinary drug during the 1960s and later as a human anthelminthic drug. It has a broad spectrum anthelminthic activity being effective against various types of nematode infections. It is both ovicidal and larvicidal. It is also highly effective against many saprophytic and pathogenic fungi in vitro and has also shown anti-inflammatory, antipyretic and analgesic properties in laboratory animals^[1]. Clinically, it is primarily used against Strongyloides stercoralis and cutaneous larva migrans.
The mechanism of action is not clearly understood. It has been shown to inhibit the mitochondrial fumurate reductase, which is specific for helminths^[2]. Thiabendazole may also affect parasite microtubules, by a mechanism similar to that described for mebendazole (see Mebendazole).
 

Indications

Thiabendazole is primarily indicated in infections with Strongyloides stercoralis and cutaneous larva migrans. It may also prove useful against Capillaria philippinensis, Trichostrongylus species and alleviate symptoms during the invasion stage of trichinosis.
 

Interactions

In a single patient, thiabendazole has been reported to have increased the plasma half-life of theophylline by three-fold because of decreased plasma clearance^[3].
 

Side effects

Common side effects include nausea, vomiting, headache, dizziness, and abdominal pain. In one clinical study around 40% of the patients treated experienced side effects including vomiting (25%), headache (11%) and dizziness (11%) ^[4]. In another study ^[5], 43 patients treated with the recommended doses of the drug, 34 (89%) suffered side effects. Majorcomplaints included nausea (67%), smelly urine (26%), neuropsychiatric symptoms (23%), malaise (16%), dizziness (16%), anorexia (7%), vomiting (7%), abdominal pain (7%), ‘thought going to die’ (7%), and headache (5%). The patients in the study were largely elderly. Side effects occurred 1–4 hours after drug ingestion and lasted for up to 8–12 hours.
Occasionally cholestatic jaundice, skin reactions, crystalluria, diarrhoea, headache, fatigue, drowsiness and drying of mucous membranes may occur. Hyperglycaemia, disturbances in colour vision, bradycardia and hypotension are uncommon. Hypersensitivity reactions such as fever, oedema, and lymphoadenopathy are also rare ^[4,6]. Single cases of StevensJohnsons syndrome and toxic epidermal necrosis have been reported ^[6]. The urine of some patients may have an odour much like that observed after eating asparagus; it is attributed to the presence of a metabolite ^[1,7].
 

Contraindications and precautions

Thiabendazole should be given with caution to patients with a history of drug hypersensitivity. Dosage reductions must be made in patients with kidney or hepatic failure. Thiabendazole is a potent inhibitor of cytochrome P450, and it is likely to increase the plasma concentrations of drugs metabolized by this route.
 

Preparations

• Mintesol® (Merck Sharp & Dohme). Oral suspension 100 mg/ml. Tablets 500 mg.
 

Description

Thiabendazole is a kind of fungicide and parasiticide. As a fungicide, it can be used for the treatment of mold, blight and many other fungal diseases occurring in fruits and vegetable. As an antiparasitic, it is capable of treating roundworms, hookworms, and other kinds of helminth species that can attack wild animals, livestock and humans. It also has effects of inhibiting the angiogenesis of cells. The mechanism of action is still not fully understood. It has found that Thiabendazole is capable of suppressing the helminth-specific mitochondrial enzyme fumarate reductase, further inhibiting the citric acid cycle, mitochondrial respiration and ATP production, leading to helminth’s death. It may also inhibit the microtubule polymerization processes.

References

1. Robinson HJ, Phases HF, Graessle DE (1969). Thiabendazole: lexicological, pharmacological and antifungal properties. Texas Rep Biol Med, 27, 537–560.
2. Sheth UK (1975). Thiabendazole inhibited the fumarate reductase metabolism of helminths. Prog Drug Res, 19, 147.
3. Schneider D, GannonR, Sweeney K, Shore E (1990). Theophylline and antiparasitic drug interactions. A case report and study of the influence of thiabendazole and mebendazole on theophylline pharmacokinetics in adults. Chest, 97, 84–87.
4. Farahmandian I, Arfaa F, Jalali H, Reza M (1977). Comparative studies on the evaluation of the effect of new anthelminthics on various intestinal helminthiasis in Iran. Chemotherapy, 23, 98.
5. Grove DI (1982). Treatment of strongyloidiasis with thiabendazole: an analysis of toxicity and effectiveness. Trans R Soc Trop Med Hyg, 76, 114–118.
6. Robinson HM, Samorodin CS (1976). Thiabendazole-induced toxic epidermal necrolysis. Arch Dermatol, 112, 1757–1760.
7. Robinson HJ, Phases HF, Graessle DE (1978). The lexicological and antifungal properties of thiabendazole. Ecotoxicol Environ Safety, 1, 471–476.
 

Description

Thiabendazole is a broad-spectrum anthelmintic that is active against a variety of helminths. In sheep, thiabendazole (50 mg/kg) kills greater than 95% of adult worms from ten genera, including Trichostrongylus, Cooperia, Nematodirus, Ostertagia, Haemonchus, Oesophagostomum, Bunostomum, Strongyloides, Chabertia, and Trichuris. It also inhibits production of eggs and disrupts larval development. Thiabendazole inhibits fumarate reductase in helminths, which inhibits succinate formation, and therefore energy production through the citric acid cycle. It also inhibits methionine aminopeptidase in E. coli (K_i = 40 nM; IC₅₀ = 47.2 nM). Formulations containing thiabendazole have been used in the control of parasitic infections in livestock.

Description

Thiabendazole is also a broad-spectrum systemic fungicide against many fungal pathogens, although this compound was originally introduced as an anthelminthic (25).

Chemical Properties

Light yellow powder

Originator

Mintezol,MSD,US,1967

Uses

anticoagulant, rodenticide

Uses

A drug used in the treatment of helminthiases

Uses

Thiabendazole is widely used as a post-harvest systemic fungicide on citrus and bananas. It is active against fruit rots in bananas, citrus, apples and pears; bulb and corm rots in ornamentals; storage rots in sweet potato and potato and is also used to control Dutch elm disease. It is the original benzimidazole anthelmintic for both human and animal health usages.

Uses

Systemic fungicide used for diseases of fruits and vegetables and for control of Dutch elm disease.

Definition

ChEBI: A member of the class of benzimidazoles carrying a 1,3-thiazol-4-yl substituent at position 2. A mainly post-harvest fungicide used to control a wide range of diseases including Aspergillus, Botrytis, Cladosporium and Fusarium.

Indications

Thiabendazole is used against nematodes and nematode larvae: Enterobius, Ascaris, Strongyloides, Necator, Trichinella, Ancylostoma, Capillaria, Dracunculus, and Trichostrongylus. It is also effective against intestinal flukes.

Manufacturing Process

6.5 grams of thiazole-4-carboxylic acid is stirred with 5.9 grams of thionyl chloride in 20 ml xylene for 10 hours at room temperature to form 4-thiazolyl acid chloride. 1.3 grams of 4-thiazolyl acid chloride and 1.3 grams of onitroaniline are then stirred together in 3.5 ml of pyridine at room temperature for about 12 hours. At the end of this time, the mixture is quenched in ice water and the solid nitroanilide recovered by filtration and washed with dilute sodium carbonate solution. The solid is suspended in 15 ml of glacial acetic acid, and 8 ml of 6 N hydrochloric acid added to the suspension. 6 grams of zinc dust is added in small portions to the acetic mixture. After the zinc addition is complete, and the reaction is essentially finished (by visual observation), the reaction mixture is filtered and the filtrate neutralized with concentrated ammonium hydroxide to precipitate 2-(4'- thiazolyl)-benzimidazole. The product is purified by recrystallization from ethyl acetate, according to US Patent 3,274,207.

Therapeutic Function

Anthelmintic

Synthesis Reference(s)

The Journal of Organic Chemistry, 30, p. 259, 1965 DOI: 10.1021/jo01012a061

General Description

White or cream-colored odorless, tasteless powder. Sublimes above 590°F. Fluoresces in acidic solution. Formulated as a dust, flowable powder or wettable powder for use as a systemic fungicide and anthelmintic.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Thiabendazole is incompatible with a number of pesticides, including copper-containing fungicides, and with highly alkaline materials. Thiabendazole is a chelating agent, binding many metals including iron, but not calcium

Fire Hazard

Flash point data for Thiabendazole are not available; however, Thiabendazole is probably combustible.

Agricultural Uses

Fungicide: Thiabendazole is a fungicide used to control blight, mold, stain and rot that are found on fruit and vegetables; Dutch elm disease; and diseases found in food storage and other diseases. It is also used to treat roundworms and similar conditions in livestock and humans. Registered for use in EU countries. A U.S. EPA restricted use Pesticide (RUP). U.S. Maximum Allowable Residue Levels for Thiabendazole and its metabolite benzimidazole (free and conjugated) in or on the following food commodities:[40CFR 180.242(a) (1)]: apple, wet pomace 12.0 ppm; Avocado (There are no U.S. registrations on the indicated commodity) 10.0 ppm; banana, post harvest 3.0 ppm; bean, dry, seed 0.1 ppm; beet, sugar, dried pulp 3.5 ppm; beet, sugar, roots 0.25 ppm; beet, sugar, tops 10.0 ppm; cantaloupe (There are no U.S. registrations on the indicated commodity) 15.0 ppm; carrot, roots, postharvest 10.0 ppm; citrus, oil 15.0 ppm; fruit, citrus, group 10, postharvest 10.0 ppm; fruit, pome, group 11, postharvest 5.0 ppm; mango 10.0 ppm; mushroom 40.0 ppm; papaya, postharvest 5.0 ppm; potato, postharvest 10.0 ppm; soybean 0.1 ppm; strawberry (There are no U.S. registrations on the indicated commodity) 5.0 ppm; sweet potato (postharvest to sweet potato intended only for use as seed) 0.05 ppm; wheat, grain 1.0 ppm; wheat, straw 1.0 ppm. [40CFR 180.242(a)(2)]: cattle, meat 0.1 ppm; cattle, meat byproducts 0.4 ppm; goat, meat byproducts 0.4 ppm; Hog, meat byproducts 0.3 ppm; horse, meat byproducts 0.4 ppm; milk 0.1 ppm; sheep, meat byproducts 0.4 ppm. [40CFR 180.2010]: Use/Limits: As a seed treatment for dry pea (including field pea, pigeon pea, chickpea or lentil), using a maximum application rate of 0.075 pounds of active ingredient per 100 pounds of seed. Vines or hay grown from treated seed may not be fed to livestock.

Pharmaceutical Applications

Thiabendazole; a thiazolyl benzimidazole available for oral administration. It is active against most common intestinal nematodes. As a result of its larvicidal and ovicidal activity, it is effective in strongyloidiasis, trichinosis, visceral larva migrans and cutaneous larva migrans.
It is well absorbed from the small intestine. Peak plasma levels are reached about 1–2 h after a single oral dose of the suspension. It is extensively metabolized in the liver to the 5-hydroxy derivative, which is inactive. Most of the drug is excreted within 24 h. About 90% is excreted in the urine, chiefly as glucuronide or sulfate conjugates; the remainder is passed in the feces.
A wide range of unpleasant side effects occur, including nausea and other gastrointestinal upsets, fever and neurological effects. It has been largely replaced by the less toxic benzimidazole carbamates. Although active against Ascaris lumbricoides, E. vermicularis and hookworms, it should not be used as primary therapy for these infections.

Trade name

AGROSOL AGROSOLT, (with thiram); APL-LUSTER ARBOTECT BOVIZOLE BRODEX CHEM-TEK CITRUS LUSTR DECCO SALT NO.19 E-Z-EX EPROFIL EQUIVET TZ EQUIZOLE FRESHGARD FUNGICIDE 4 T GRANOX IRGAGUARD LOMBRISTOP MERTEC MERTECT 160 METASOL TK-100 MINTEZOL MINZOLUM MK-360 MYCOZOL NEMAPAN NSC 525040 OMNIZOLE POLIVAL RIVAL (captan + PCNB + thiabendazole); RPH RTU-VITAVAX-EXTRA STA-FRESH TBZ 6 TECTO TECTO RPH TECTO 10P TECTO 40 F TESTO THIABEN THIABENDAZOLUM THIABENZAZOLE THIABENZOLE THIBENZOL THIBENZOLE THIBENZOLE 200 THIBENZOLE ATT TIABENDAZOLE TOBAZ TOP FORM WORMER VITAVAXThiabendazole Chemical class: Benzimidazole

Contact allergens

This fungicide and vermifuge agent is widely used in agriculture (for example, forcitrus fruits), and in medical and veterinary practice as an anthelmintic drug.

Mechanism of action

Thiabendazole is an antihelmintic drug with a broad spectrum of action. Although the details of its mechanism of action are not conclusively known, it seems likely that its action is mediated by the inhibition of a specific enzyme of helminthes—fumarate reductase. Thiabendazole is active with respect to most nematode infections, including Angyostrongylus cantonesis, Strongyloides stercoralis, Trichinella spiralis, Toxocara canis, Toxocara cati, Ancylostoma caninum, A. braziliense
, A. duodenale, Dracunculus medinesis, Capillaria philippinesis, as well as for treating Acaris cantonesis and Shistosoma stercoralis. Synonyms of this drug are mintezol, minzolum, and others.

Clinical Use

2-(4-Thiazolyl)benzimidazole (Mintezol) occurs as a whitecrystalline substance that is only slightly soluble in waterbut is soluble in strong mineral acids. Thiabendazole is abasic compound with a pKa of 4.7 that forms complexeswith metal ions.
Thiabendazole inhibits the helminth-specific enzymefumarate reductase. It is not known whether metal ionsare involved or if the inhibition of the enzyme is related tothiabendazole’s anthelmintic effect. Benzimidazole anthelminticdrugs such as thiabendazole and mebendazolealso arrest nematode cell division in metaphase by interferingwith microtubule assembly. They exhibit a highaffinity for tubulin, the precursor protein for microtubulesynthesis.
Thiabendazole has broad-spectrum anthelmintic activity.It is used to treat enterobiasis, strongyloidiasis (threadworminfection), ascariasis, uncinariasis (hookworm infection), andtrichuriasis (whipworm infection). It has also been used torelieve symptoms associated with cutaneous larva migrans(creeping eruption) and the invasive phase of trichinosis. Inaddition to its use in human medicine, thiabendazole iswidely used in veterinary practice to control intestinalhelminths in livestock.

Side effects

Frequent adverse reactions are dizziness, anorexia, vomiting, and epigastric distress. Diarrhea, fever, headache, skin rashes, hallucinations, and olfactory disturbances occur occasionally. Tinnitus, hypotension, and syncope are rare complications.

Safety Profile

Moderately toxic by ingestion. An experimental teratogen. A questionable carcinogen. Experimental reproductive effects. Mutation data reported. When heated to decomposition it emits toxic fumes of SOX and NOX. See also SULFIDES.

Synthesis

Thiabendazole, 2-(4
-thiazolyl)benzimidazole (38.1.9), is also made in the same manneraheterocyclization which occurs upon reacting o-phenylendiamine with 1,3-thiazol-4-carboxylic acid.

Veterinary Drugs and Treatments

Thiabendazole has been used for the removal of the following parasites in dogs: ascarids (Toxocara canis, T. leonina), Strongyloides stercoralis, and Filaroides. It has been used systemically as an anti-fungal agent in the treatment of nasal aspergillosis and penicillinosis. Topical and otic use of thiabendazole for the treatment of various fungi is also commonly employed.
Thiabendazole is indicated (labeled) for the removal of the following parasites in cattle: Haemonchus spp., Ostertagia spp., Trichostrongylus spp., Nematodirus spp., Cooperia spp. and Oesophagostomum radiatum.
Thiabendazole is indicated (labeled) for the removal of the following parasites in sheep and goats: Haemonchus spp., Ostertagia spp., Trichostrongylus spp., Nematodirus spp., Cooperia spp., Chabertia spp., Bunostomum spp. and Oesophagostomum spp.
Thiabendazole is indicated (labeled) for the removal of the following parasites in horses: Strongylus spp., craterstomum spp., Oesphagodontus spp., Posteriostomum spp., Cyathostomum spp., Cylicocylus spp., Cylicostephanus spp., Oxyuris spp., and Parasacaris spp.
Thiabendazole is indicated (labeled) for the removal or prevention of the following parasites in swine: large roundworms (Ascaris suum) (prevention), and in baby pigs infested with Strongyloides ransomi.
Although not approved, thiabendazole has been used in pet birds and llamas. See the Dosage section for more information.
In many geographic areas, significant thiabendazole resistance problems have developed and, for many parasites, other anthelmintics would be a better choice for treatment.
When used topically, thiabendazole has antidermatophytic properties.

Environmental Fate

Thiabendazole does not hydrolyze readily, nor it is metabolized in soil under aerobic or anaerobic conditions. While it photodecomposes in minutes in aqueous solutions, photodecomposition of thiabendazole in soil did not cause more than 40% reduction. Thiabendazole is also only slightly water soluble, and does not migrate in soil. Thus, it is unlikely to contaminate groundwater. If released into the atmosphere, it exists primarily in the particulate phase. In the vapor phase, it will degrade in the atmosphere by reacting with photochemically produced hydroxyl radicals with an estimated half-life of 6 h.

Metabolic pathway

The primary photolytic degradation of thiabendazole involves the cleavage of the thiazole-benzimidazole ring linkage. In animals, thiabendazole is extensively oxidised in bluegill sunfish, hens, goats, sheep, cattle, mice, rats and humans, followed by conjugation. When foliarly applied to plants, degradation to benzimidazole and its conjugates occurred. Benzimidazole formed in plants is mainly due to photolytic action. The primary degradation/metabolic pathways of thiabendazole in water, soil, plants and animals are depicted in Scheme 1.

Degradation

Thiabendazole (1) is quite stable in aqueous suspension and in acidic media, and it is stable to heat (PM).
Opening and/or the cleavage of the thiazole-benzimidazole ring linkage appeared to be the primary photolytic degradation pathway. Thiabendazole was photolysed to (benzimidazol-2-yl)carboxamide (2) and benzimidazole (3) under natural sunlight exposure on sugar beet leaf surfaces or on glass plates (Jacob et al., 1975). Thiabendazole was also photolysed in aqueous solution when exposed to a Pyrex glass filtered high pressure mercury lamp (≥290 nm). In addition to 2 and 3, photoproducts included degradates 4-8 (Murthy et al., 1996). Compound 2 was proposed to result from hydrolysis of (benzimidazol-2-yl)nitrile (7). The rate constant for photolysis was not affected sigruficantly by the presence of either fulvic or humic acids, indicating that indirect photolysis does not play a large role in the degradation of thiabendazole.

References

[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3774 - 3780
[2] Journal of the American Chemical Society,
[3] Journal of the American Chemical Society, 2010, vol. 132, p. 1230 - 1231
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 5, p. 1985 - 1988
[5] Molecules, 2017, vol. 22, # 2,

Pesticide Type

Fungicide; Veterinary substance