Arsenicals

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Arsenicals

Important Compounds

Carbasone, Glycobiarsol, Melarsoprol, Thiacetarsamide, Mel PH, R7/45.

Synonyms

Carbasone: N-carbamoylarsanilic acid, Amebevan, Ameban, Amibiarson, Arsambide, Carb-O-Sep, Histocarb, Fenarsone, Leucarsone, Aminarsone, Amebarsone

Glycobiarsol: Bismuth glycoloylarsanilate, Broxolin, Dysentulin, Milibis, Viasept, Wintodon

Thiacetarsamide: Arsenamide, Thioarsenite, Caparsolate, Caparside, Arsphenamide, Filicide, Filaramide

Clinical Relevance

The great interest in arsenicals at the beginning of the 20th century relied on their antibacterial activities. Thus, 4-arsanilic acid sodium (Atoxyl) and Salvarsan were the first drugs to be active against syphilis. Carbasone as one of the antiprotozoal arsenicals was introduced in 1931 against infections with Trichomonas vaginalis and Entamoeba histolytica. Glycobiarsol introduced in 1938 exerts activities against Trichomonas vaginalis, E. histolytica and Giardia lamblia. Melarsoprol is still one of the drugs of choice for the treatment of late stage sleeping sickness caused by Trypanosoma brucei gambiense or T. b. rhodesiense. Arsanilic acid and roxarsone exhibit activity against E. tenella sporozoites. Acetarsone in combination with arecoline was used as an anticestodal drug in small animals. In addition, sodium arsanilic acid in combination with copper sulfate has antinematodal activities against nematodes in ruminants. The macrofilaricidal efficacy of arsenicals is also known for a long time. Interestingly, all arsenicals obtain almost exclusively adulticidal effects which is clinically proven in man. Thiacetarsamide potassium is a drug routinely used against Dirofilaria immitis in the dog (Inhibitory-Neurotransmission-Affecting Drugs/Table 1). Another arsenical is melarsomine used as adulticide against Dirofilaria immitis in dogs. The main disadvantage of the arsenicals are their severe side effects, such as the arsenical encephalopathy. In the meantime new and less toxic organic arsenicals such as Mel PH and R7/45 have been developed. In general, there are no marked reductions of microfilariaemia levels until day 7 p.i. and the adulticidal efficacy of drugs varies with the parasite species. Thus, thiacetarsamide is much more active against Brugia spp. than other arsenicals; Acanthocheilonema viteae is more resistant to Mel PH and R7/45 than Litomosoides carinii and B. malayi. Arsenicals exert better activity against female L. carinii and B. malayi than against males whereas both worm sexes of A. viteae are equally sensitive to arsenicals.

Molecular Interactions

The mechanism of action of antiprotozoal arsenicals is presumably due to an inhibition of glycolytic enzymes and/or protein kinases with SH-groups. Also trypanothione reductase may be a target of arsenical compounds (DNA-Synthesis-Affecting Drugs III/Fig. 1).

The antifilarial arsenicals lead to an in-vitro and in-vivo inhibition of glutathione reductase as shown in L. carinii adults. Thereby, the parasitic enzyme is more susceptible to inhibition than the corresponding mammalian enzyme.