Bithionol

Description

Bithionol (97-18-7) is an antihelmintic drug with bacteriostatic and fungicidal properties. Bithionol has also been found to be an inhibitor of glutamate dehydrogenase1,2?(IC50?= 4.8 μM bovine GDH1).

Chemical properties

off-white crystalline powder

Chemical properties

Bithionol is a white or grayish powder with a slight phenolic odor.

Physical properties

Bithionol is virtually insoluble in water, readily soluble in ethanol, diethyl ether, acetone, glacial acetic acid, and dilute alkalis.

The Uses of Bithionol

anthelmintic, antiseptic

The Uses of Bithionol

bactericide; antihelmintic; algicide; proposed as agricultural fungicide; food additive in feed and drinking water for foodproducing animals; permitted in food for human consumption; deodorant; in germicide pharmaceuticals, antibacterial agent in soaps, cosmetics, veterinary antiseptic and antihelminthic products, industrial cleansers, etc.

Background

Bithionol, formerly marketed as an active ingredient in various topical drug products, was shown to be a potent photosensitizer with the potential to cause serious skin disorders. Approvals of the NDA's for bithionol drug products were withdrawn on October 24, 1967 (see the Federal Register of October 31, 1967 (32 FR 15046)).

Definition

ChEBI: An aryl sulfide that is diphenyl sulfide in which each phenyl group is substituted at position 2 by hydroxy and at positions 3 and 5 by chlorine. A fungicide and anthelmintic, it was used in various topical drug products for the treatment of liver flukes, ut withdrawn after being shown to be a potent photosensitizer with the potential to cause serious skin disorders.

Indications

Bithionol (Actamer) is a phenolic derivative whose mode of action is related to uncoupling of parasitespecific fumarate reductase–mediated oxidative phosphorylation. The drug is administered orally and is absorbed from the intestinal tract. Peak blood levels are achieved in 4 to 8 hours. Excretion is mainly by the kidneys.
Bithionol is used in treatment of F. hepatica infections and as an alternative to praziquantel in the treatment of infestation by P. westermani. It is highly active against the adult worm but exerts no action against the migratory stages. A second course of treatment is required for complete cure in 20 to 30% of patients.
Side effects are generally mild and transient; they include nausea, vomiting, diarrhea, headache, dizziness, urticaria, and other skin rashes in 50% of patients.

Production Methods

Bithionol is prepared by reaction of 2,4-dichlorophenol with sulfur dichloride and AlCl3 in carbon disulfide or tetrachloromethane. It is used as a microbicide to protect aqueous functional fluids from biodeterioration and to control algae and slime formation in process water systems.

brand name

Lorothidol (Sterling Winthrop);Anafogene;Bacteriostat cs-1;Bidiphen;Lorothiodol;Neopellis;Nobacter;Prevenol;Tbp;Vancide bl.

World Health Organization (WHO)

Bithionol, which has bactericidal and anthelminthic activity, was formerly available in soaps. By the late 1960s use of such preparations had been associated with a risk of photosensitivity reactions and cross-sensitivity with other halogenated disinfectants. This resulted in their withdrawal in the USA. Oral preparations of bithionol remain available for the treatment of paragonimiasis and fascioliasis.

General Description

White or grayish white crystalline powder with a very faint aromatic or phenolic odor.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Bithionol is incompatible with acids, diazo and azo compounds, halocarbons, isocyanates, aldehydes, alkali metals, nitrides, hydrides, and other strong reducing agents. Reactions with these materials may generate heat and toxic or flammable gases.

Hazard

Toxic by ingestion.

Health Hazard

ACUTE/CHRONIC HAZARDS: Bithionol is a skin irritant. When heated to decomposition or upon contact with acid or acid fumes, toxic fumes are evolved.

Fire Hazard

Flash point data is not available for Bithionol, but Bithionol is probably combustible.

Mechanism of action

Biothionol is bis-dichlorophenol, and it is structurally similar to hexachlorophene. It is the antihelmintic drug of choice for treating humans infected with Fasciola hepatica. It is an alternative drug to praziquantel that is used for treating pulmonary and cerebral paragonimiasis. The exact mechanism of action is not known, although it seems likely that it inhibits oxidative phosphorylation in Paeagonumus westermani. Synonyms of this drug are actamer, bitin, prevenol, and others.

Clinical Use

2,2’-Thiobis(4,6-dichlorophenol), or bis(2-hydroxy-3,5-dichlorophenyl)sulfide (Lorothidol, Bithin), a chlorinatedbisphenol, was formerly used in soaps and cosmetics for itsantimicrobial properties but was removed from the marketfor topical use because of reports of contact photodermatitis.Bithionol has useful anthelmintic properties and hasbeen used as a fasciolicide and taeniacide. It is still consideredthe agent of choice for the treatment of infestationscaused by the liver fluke Fasciola hepatica and the lungfluke Paragonimus westermani. Niclosamide is believed tobe superior to it for the treatment of tapeworm infestations.

Synthesis

Bithionol, 2,2
-thiobis(4,6-dichlorophenol) (38.1.38), is made by reacting a solution of 2,4-dichlorophenol in carbon tetrachloride with sulfur chloride in the presence of aluminum chloride.

Potential Exposure

It is used as a surfactant-formulated antimicrobial against bacteria, molds and yeast. It is proposed as an agricultural fungicide. Other uses include deodorant, germicide, fungistat, and in the manufacture of pharmaceuticals. It is no longer allowed to be used in cosmetics. A food additive in feed and drinking water of animals. Also a food additive permitted in food for human consumption.

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts theskin, remove contaminated clothing and wash immediatelywith soap and water. Seek medical attention immediately. Ifthis chemical has been inhaled, remove from exposure,begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR ifheart action has stopped. Transfer promptly to a medicalfacility. When this chemical has been swallowed, get medical attention. Give large quantities of water and inducevomiting. Do not make an unconscious person vomit.

Metabolism

Not Available

storage

Color Code—Blue: Health Hazard/Poison: Storein a secure poison location. Store in a refrigerator or a cooldry place.

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1—Poisonous materials, Technical Name Required.

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides.

References

1) Li?et al. (2009),?Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics; J. Biol. Chem.,?284?22988 2) Zocher?et al. (2012),?Biochemical and structural characterization of Plasmodium falciparum glutamate dehydrogenase 2; Mol. Biochem. Parasitol.,?183?52