Basic Introduction

Thiabendazole is an anthelmintic provided as 500 mg chewable tablets, and as a suspension, containing 500 mg thiabendazole per 5 mL. The suspension also contains sorbic acid 0.1% added as a preservative. Inactive ingredients in the tablets are acacia, calcium phosphate, flavors, lactose, magnesium stearate, mannitol, methylcellulose, and sodium saccharin. Inactive ingredients in the suspension are an antifoam agent, flavors, polysorbate, purified water, sorbitol solution, and tragacanth.Thiabendazole is a white to off-white odorless powder with a molecular weight of 201.26, which is practically insoluble in water but readily soluble in dilute acid and alkali. Its chemical name is 2-(4-thiazolyr)-1/-/-benzimidazole. The empirical formula is C10H7N3S and the structural formula is as following:[1]

Chemical Synthesis Route

General procedure: A solution of substituted o-phenyldiamine (1.0 equiv), thiazole-4-aldehyde or pyridine-2-aldehyde (1.0 equiv) with sodium pyrosulfite in DMF was stirred at 120° C overnight. On completion of the reaction monitored by TLC, the solvent was evaporated and the residue was purified by silica gel chromatography by DCM/MeOH system to afford the final product. If necessary, the crudeproduct could be recrystallized in DCM or dichloroethane to afford pure sample.[2]

Medical Applications

uses

Thiabendazole is indicated for the treatment of: Strongyloidiasis (threadworm) Cutaneous larva migrans (creeping eruption) Visceral larva migrans

Trichinosis: Relief of symptoms and fever and a reduction of eosinophilia have followed the use of MINTEZOL (thiabendazole) during the invasion stage of the disease.

Thiabendazole is usually inappropriate as first line therapy for enterobiasis (pinworm). However, when enterobiasis occurs with any of the conditions listed above, additional therapy is not required for most patients. MINTEZOL (thiabendazole) should be used only in the following infestations when more specific therapy is not available or cannot be used or when further therapy with a second agent is desirable: Uncinariasis (hookworm: Necator americanus and Ancylostoma duodenale); Trichuriasis (whipworm); Ascariasis (large roundworm).

How To Use

Take thiabendazole exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.Take each dose with a full glass of water. Chew the chewable tablets thoroughly before swallowing.

Shake the suspension well before measuring a dose. Measure each dose with a dose-measuring dropper, spoon or cup, not a regular table spoon, to ensure that you measure the correct amount of medicine. Ask your pharmacist where you can get a dose-measuring device if you do not have one. Take each dose with food to lessen stomach upset. Doses are usually taken twice a day. Follow your doctor's instructions. It may take 2 days or more for the treatment to remove the worm from the stomach andintestines. Repeat treatment is usually necessary in 7 days to prevent reinfection. Fasting, laxatives, or purging will not help to cure the infection. Treatment of family members and other close contacts may be necessary. Pinworm is spread very easily to others in close contact with the infected person. To prevent reinfection, toilets must be disinfected daily, and clothing, linens, towels, and pajamas must be changed and washed daily. Store thiabendazole at room temperature away from moisture and heat.

SIDE EFFECTS: 

Nausea, vomiting, loss of appetite, diarrhea, dizziness, drowsiness, or headache may occur. If any of these effects persist or worsen, notify your doctor promptly. Tell your doctor immediately if any of these unlikely but serious side effects occur: seizures, tingling of hands/feet, mental/mood changes. Tell your doctor immediately if any of these highly unlikely but very serious side effects occur: ringing in the ears, vision changes, stomach pain, yellowing eyes and skin, dark urine, fever, fatigue, increased thirst, change in the amount of urine. A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of an allergic reaction include: rash, itching, swelling, severe dizziness, trouble breathing. If you notice other effects not listed above, contact your doctor or pharmacist.

PRECAUTIONS: 

This medication should not be used as prophylactic treatment for pinworms or any other worm infections. This medication should not be used if you have a mixed infection with the Ascaris type of roundworm. This drug may cause the Ascaris worms to spread in your body, and possibly appear in your nose and mouth. Contact your doctor if this should occur. Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, kidney disease, anemia, dehydration, poor nutrition, any allergies. This drug may make you dizzy or drowsy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages. Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug. This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor. It is not known whether this drug passes into breast milk. Breast-feeding is not recommended while using this drug.

Toxicological Investigation

To date, the most commonly reported toxicities associated with Thiabendazole include general toxicity, reproductive toxicity, immunotoxicity, carcinogenicity, and mutagenicity. Recent studies have highlighted that Thiabendazole may induce cancer and liver injury. Among the reported adverse effects of Thiabendazole, there is more literature on induction of hepatic injury and less on tumor induction. Therefore, whether Thiabendazole is actually carcinogenic remains to be investigated. In addition, most studies have focused only on the toxic effects of Thiabendazole, the mechanisms of how Thiabendazole induces diseases remain to be clarified. The liver, as the largest detoxification organ in the body, is difficult to detect any potential problems due to its lack of sensory nerves. Cancer is an incurable disease, making prevention of both diseases crucial. Several studies have shown that Thiabendazole can remain in soil, domestic wastewater, bananas, apples, tea, flat mushrooms, etc, which has immeasurable impacts on the human and animal living environment, food safety and trade. Unfortunately, environmental pollution typically triggers complex toxicity networks by disrupting various biomolecules. Conventional toxicological detection methods struggle to comprehensively and systematically assess the interrelationships among toxicities.[3]

An emerging network-based assessment method, known as network toxicology and molecular docking, can reverse this situation. Network toxicology involves the interdisciplinary integration of various scientific fields such as bioinformatics, big data analysis, genomics, and other related technologies. It focuses on exploring the toxic pathways of compounds and understanding the molecular mechanisms associated with diseases. Using a network-based approach, it aims to elucidate how different molecules interact within biological systems and how these interactions contribute to toxicity. The field seeks to build networks of relationships between chemicals, biological targets, and adverse outcomes, providing insights into complex interactions and systems biology to better understand toxic effects. Compared to traditional toxicology discovery methods, network toxicology has changed the “one target, one drug” model and formed a new “multi-target, one drug” model. It elucidates the complex interactions between genes, proteins, and metabolites involved in diseases and drugs from a network perspective.

Scientists identified 29 potential targets associated with Thiabendazole-induced cancer and 30 potential targets associated with Thiabendazole-induced liver injury, findings that may have far-reaching implications for disease treatment and drug development. In addition, by enrichment analysis of the signaling pathways where these targets are located, the potential links between Thiabendazole and prostate cancer, gastric cancer are revealed, which provided new clues for the study of the pathogenic mechanisms of these diseases. This study is innovative in the existing literature because it is not limited to exploring a single disease, but comprehensively explores the mechanisms of Thiabendazole toxicity in multiple diseases. However, the findings are based on computational models and predictions, which require experimental validation to ensure their reliability and applicability. Despite these limitations, this research provides comprehensive evidence for understanding the potential mechanisms of Thiabendazoles in disease pathogenesis. Future investigations should emphasize experimental validation to confirm these hypotheses and delve deeper into the disease mechanisms induced by Thiabendazole. In addition, considering the use of Thiabendazole in food industry, it is particularly important to evaluate its safety in food materials, which is essential to protect public health and food safety. 

References：

[1] Zhang, Y., et al. Synthesis and biological evaluation of thiabendazole derivatives as anti-angiogenesis and vascular disrupting agents. *Eur. J. Med. Chem.* 2015; 96: 292-303.

[2] Zhang, Chao; Zhong, Bo; Yang, Simin; Pan, Liangkun; Yu, Siwang; Li, Zhongjun; Li, Shuchun; Su, Bin; Meng, Xiangbao[Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, art. no. 12211, p. 3774 - 3780]

[3] He, J., et al. Network toxicological and molecular docking to investigate the mechanisms of toxicity of agricultural chemical Thiabendazole. *Chemosphere* 2024; 240: 130595.