4-Isothiocyanato-4′-nitrodiphenylamine (C9333-Go/CGP 4540) an anthelminthic with an unusual spectrum of activity against intestinal nematodes, filariae and schistosomes

Striebel, H.P.

doi:10.1007/bf01920794

Cited by 54 publications

(11 citation statements)

References 4 publications

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“…Although the synthesis of amoscanate was reported in the 1960s, the extent of its broad spectrum of activity against helminths, including the 3 major schistosomes, was not fully appreciated until at least 15 years later (Striebel 1976(Striebel , 1978.…”

Section: Amoscanatementioning

confidence: 99%

Clinical Pharmacokinetics of Anthelmintic Drugs

Edwards

Breckenridge

1988

Clinical Pharmacokinetics

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A rational strategy for chemotherapy demands that dosage schedules be based on an adequate knowledge of clinical and biochemical pharmacology. Many anthelmintic drugs (e.g. suramin, diethylcarbamazine, hycanthone) were introduced before modern techniques for drug evaluation (controlled clinical trials) and before the development of specific and sensitive analytical methods for the assay of drugs and metabolites in biological fluids. Thus, many of the regimens used today for the treatment of parasitic diseases are largely empirically derived. By means of specific analytical methodology (high performance liquid chromatography, gas chromatography and mass-spectrometry) introduced in the 1960s, it is now possible to measure drugs and their metabolites with specificity and sensitivity. Much of this review deals with compounds which are active against the major systemic helminths, i.e., filariae (diethylcarbamazine, ivermectin and suramin) and schistosomes (niridazole, metrifonate, oxamniquine and praziquantel), but recent advances in the treatment of hydatid disease involving the benzimidazole carbamates albendazole and mebendazole are also discussed. Among the imidazole derivatives, mebendazole, a broad-spectrum anthelmintic, is poorly absorbed from the gastrointestinal tract after a therapeutic dose, but that fraction which is absorbed and escapes hepatic first-pass extraction is pharmacologically active against systemic helminths. Albendazole is more completely absorbed, but is almost undetectable in plasma due to its rapid conversion to an active sulphoxide metabolite. This compound may well become the drug of choice for the chemotherapy of echinococcosis. Levamisole, the 1-isomer of tetramisole, is rapidly and completely absorbed, but has not been widely used in systemic helminthiases because of severe side effects associated with prolonged dosage. Diethylcarbamazine is microfilaricidal against Onchocerca volvulus, but its use has been associated with major adverse effects resulting from its action on the microfilariae. These effects are related to the concentration of the drug in the plasma which, in turn, is influenced by urinary pH. The elimination half-life of diethylcarbamazine is prolonged and renal clearance reduced in alkaline urine. Under these conditions the microfilaricidal effect is enhanced, but the adverse reactions to treatment are more severe. Suramin is the only available antifilarial agent with macrofilaricidal activity. It has a long elimination half-life (36 to 54 days), and is highly (99.7%) bound to plasma protein which limits its removal from the blood.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Amoscanatementioning

confidence: 99%

Clinical Pharmacokinetics of Anthelmintic Drugs

Edwards

Breckenridge

1988

Clinical Pharmacokinetics

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“…In the 1980s, aryl isothiocyanate derivatives such as amoscanate ( 6 ) were developed by Ciba Geigy AG. Amoscanate showed excellent activity after a single‐dose administration against S. japonicum , S. haematobium and S. mansoni in vitro and in vivo . Initially, it was assumed that the isothiocyanate moiety of 6 might be the target of a nucleophilic attack by amine residues of schistosomal plasma proteins to form a thiourea.…”

Section: Anthelmintic Drug Therapymentioning

confidence: 99%

“…Amoscanate showede xcellent activity after as ingle-dose administration against S. japonicum, S. haematobium and S. mansoni in vitro and in vivo. [51][52][53][54][55] Initially, it was assumed that the isothiocyanate moiety of 6 might be the target of an ucleophilic attack by amine residues of schistosomal plasma proteinst of orm a thiourea.B ecause derivatives such as CGP-6140 (7)o rp henithionate (8,F igure 2C)s howeds imilar antischistosomal activity despite lacking the isothiocyanate moiety,t he mechanism of action remained unclear. [56,57] Amoscanate, as well as 8,w ere extensively tested in China revealing > 90 %c ure rates in patients (administration of 7mgkg À1 over three days).…”

Section: Arylisothiocyanatesa Nd Derivativesmentioning

confidence: 99%

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

et al. 2018

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Chemotherapy based on repeated doses of praziquantel remains the most effective control strategy against schistosomiasis, a neglected tropical disease caused by platyhelminths of the genus Schistosoma spp. Its long-term use, however, raises serious concerns about drug resistance against praziquantel. Therefore, it is generally acknowledged that alternative treatment options are urgently needed. This Review summarizes data on relinquished drugs as well as recent advances in the area of antischistosomal compounds from a medicinal chemistry point of view. Furthermore, insights into the structure-activity relationships of each class of compounds are presented including in vitro and in vivo data, if available. Although many compounds have demonstrated good antischistosomal activity in vitro, they offer little promise to replace praziquantel. Nevertheless, the race to develop novel antischistosomal agents is ongoing.

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“…Preservation of structures such as the choroid plexus and the white matter within the necrotic zone indicate a high susceptibility to the compound of the ependymal cells and the underlying gray matter of the caudatoputamen. Amoscanate is available in two forms: the first, poorly absorbed from the gastrointestinal tract, is used against hookworm infection (Doshi et al 1977); the second, which is well absorbed, is highly effective against schistosomiasis even when administered as a single oral dose (Striebel 1976). Neuropathologic lesions in the rat brain have only been observed when the absorbable form was repeatedly administered at high dosages ; at least three consecutive daily (oral) doses of 125 mg/ kg or 500 mg/ kg were required to damage the ependymal cell lining, and periventricular necrosis occurred following a 1 0-day treatment (Krinke et al 1983).…”

Section: Biologic Featuresmentioning

confidence: 99%

Neurotoxic Effects of Amoscanate, Rat

Krinke¹

1988

Nervous System

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4-Isothiocyanato-4′-nitrodiphenylamine (C9333-Go/CGP 4540) an anthelminthic with an unusual spectrum of activity against intestinal nematodes, filariae and schistosomes

Cited by 54 publications

References 4 publications

Clinical Pharmacokinetics of Anthelmintic Drugs

Clinical Pharmacokinetics of Anthelmintic Drugs

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

Neurotoxic Effects of Amoscanate, Rat

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