A genomic change associated with the development of resistance to hycanthone in Schistosoma mansoni.

Ribosomal gene probes were used to investigate the genetic basis of drug resistance in schistosomes in a model where resistance to the anthelmintic hycanthone (HC) is generated by exposing immature worms to the drug. Two strains of Schistosoma mansoni, JHU and NMRI, were used. Drug resistance could be produced in the JHU strain by treatment with HC, but was also found to occur spontaneously.

Effects of oltipraz, BHA, ADT and cabbage on glutathione metabolism, DNA damage and lipid peroxidation in old mice.

Eighteen-month-old female mice were fed defined diets for 2 weeks which contained 0.05% or 0.10% oltipraz, 0.

Clinical evaluation of amoscanate in healthy male volunteers.

Single oral doses of amoscanate (4-isothiocyanato-4'-nitrodiphenylamine), an experimental antiparasitic agent, are highly effective in animals against the four major species of schistosomes which infect humans. Two prospective, randomized, double blinded, placebo controlled Phase I studies were designed to evaluate the tolerance and safety of the 5% aqueous suspension of 2-mu particles of amoscanate administered to healthy male volunteers. In addition to routine safety monitoring, particular attention was directed toward detecting hepatic, neurological, cardiovascular or ocular toxicity.

Inhibitory effects of 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (Oltipraz) on carcinogenesis induced by benzo[a]pyrene, diethylnitrosamine and uracil mustard.

5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione (Oltipraz) was studied for its capacity to inhibit carcinogen-induced neoplasia in female ICR/Ha mice. When administered by oral intubation 48 h prior to benzo[a]pyrene (BP), also given by oral intubation, Oltipraz inhibited the occurrence of pulmonary adenomas and tumors of the forestomach. The ratio of the number of tumors occurring in the mice receiving Oltipraz to that of the corresponding controls was: lung, 0.

1,2-Dithiol-3-thione analogs: effects on NAD(P)H:quinone reductase and glutathione levels in murine hepatoma cells.

The 1,2-dithiol-3-thiones are a class of five-membered cyclic sulfur compounds which have chemotherapeutic and chemoprotective properties. The parent 1,2-dithiol-3-thione nucleus and a series of six substituted analogs all induced NAD(P)H: quinone reductase (EC 1.6.

Biochemical effects of dithiolthiones.

Administration of dithiolthiones to mice in single intragastric doses (2-4 mmol/kg body weight) or in the diet (0.5% for 14 days), and to rats in the diet (0.1% for 14 days) was found to increase glutathione levels and the activities of a number of enzymes in various tissues including the liver and lung.

Effects of anethole dithiolthione and 2(3)-tert-butyl-4-hydroxyanisole on schistosome granuloma formation.

Administration of the antioxidants 2(3)-tert-butyl-4-hydroxyanisole (BHA) or 5-(P-methoxyphenyl)-3H-1,2-dithiol-3-thione (ADT) to female CD-1 mice starting 4 weeks after infection with 70 cercariae of Schistosoma mansoni resulted in a decrease in the size of the inner fibrotic region of the hepatic granuloma. The cellular composition of the granuloma was not altered by treatment with these two compounds. The administration of the specific superoxide scavenger copper diisopropylsalicylate (CuDIPS) resulted in a similar decrease in granuloma size, suggesting a role of superoxide radicals in the granulomatous response.

Modification of aflatoxin B1 binding to DNA in vivo in rats fed phenolic antioxidants, ethoxyquin and a dithiothione.

The effects of dietary administration of 3,5-di-tert-butyl-4-hydroxytoluene (BHT), 2(3)-tert-butyl-4-hydroxyanisole (BHA), ethoxyquin (EQ) and 5-(2-pyrizinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) on aflatoxin B1 (AFB1) - DNA adduct formation in vivo in livers and kidneys of rats were investigated. Male F344 rats were treated with 1 mg/kg AFB1 by i.p.

Effects of multiple putative anticarcinogens on the carcinogenicity of trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]-1,2,4-oxadiazole.

In an attempt to dissociate the chemotherapeutic from the carcinogenic properties of the antischistosomal and antitrypanosomal nitrovinylfuran trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]1,2,4-oxadiazole [(SQ18506) CAS: 28754-68-9; (E)-5-amino-3-(2-(5-nitro-2-furyl)vinyl)-1,2,4-oxadiazole], potential inhibitors of carcinogenesis were administered to female outbred CD-1 mice before and during exposure to SQ18506. The compounds tested were ascorbic acid, etretinate, butylated hydroxyanisole (BHA), cysteamine hydrochloride, cysteine hydrochloride, dimercaprol, disulfiram, 1,4-dithiothreitol, reduced glutathione, and spermidine phosphate. The primary types of tumors observed were squamous cell carcinomas of the stomach and thymic and nonthymic lymphomas.

Carcinogenicity of the antischistosomal nitrofuran trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]-1,2,4-oxadiazole.

The antischistosomal and antitrypanosomal drug trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]-1,2,4-oxadiazole [(SQ18506) CAS: 28754-68-9; (E)-amino-3-(2-(5-nitro-2-furyl)-vinyl)-1,2,4-oxadiazole] was carcinogenic for both male and female CD-1 mice when it was administered either in the diet or by gastric intubation. Dose-dependent increases in tumors of the forestomach and lymphatic tissues were observed in all groups receiving SQ18506 including mice infected with Schistosoma mansoni. The predominant tumor observed was squamous cell carcinoma of the forestomach.

Chemoprotective effects of two dithiolthiones and of butylhydroxyanisole against carbon tetrachloride and acetaminophen toxicity.

Administration of tert-butyl-4-hydroxyanisole or of two dithiolthiones to female CD-1 mice protected against the acute toxic effects of two hepatotoxic agents, acetaminophen and carbon tetrachloride. Reduced mortality of mice was observed following pretreatment with tert-butyl-4-hydroxyanisole or dithiolthiones. Pretreatment reduced or prevented hepatic glutathione depletion produced by these two hepatotoxic agents.

Efficacy of amoscanate against experimental schistosomal infections in monkeys.

The antischistosomal activity of oral doses of amoscanate (4-isothiocyanato-4'-nitrodiphenylamine) was determined in infected Cebus apella (capuchin monkeys) and Macaca mulatta (rhesus monkeys). In C. apella infected with Schistosoma japonicum or S.

Identification and quantitation of a metabolite of anethol dithiolthione in rat and mouse urine using high-performance liquid chromatography.

Urine samples from rats and mice fed anethol dithiolthione (ADT) [3-(p-methoxyphenyl)-1,2-dithiol-3-thione] were analyzed using reversed-phase high-performance liquid chromatography. Urine was introduced directly on the liquid chromatograph which was modified by replacing the sample loop with a guard column. Highly polar urine components were washed off the guard column prior to chromatography.

Conversion of amoscanate to a mutagenic metabolite in gnotobiotic mice implanted with Streptococcus equinus.

Recent in vitro studies indicate that intestinal bacteria convert amoscanate (4-nitro-4'-isothiocyanodiphenylamine), an antischistosomal drug, to a potent mutagen. The present study indicates that the implantation of germfree mice with Streptococcus equinus, isolated from the small intestine of conventional mice, restores the mutagenic activation of amoscanate in vivo.

The antischistosomal activity of oltipraz.

Administration of a single oral dose of oltipraz (5-(2-pyrazinyl)-4 methyl-1,2 dithiol-3-thione) to mice infected with Schistosoma mansoni resulted in the elimination of the parasites. Oltipraz is a slow-acting drug and approximately 2 months are required until its full schistosomicidal effect becomes evident. One of the earliest effects of the drug is a reduction of the glutathione stores of the worms.

Granuloma formation around exogenous eggs of Schistosoma mansoni and Schistosoma japonicum in mice.

Hepatic granulomata which were qualitatively and quantitatively similar to those seen in infections established with cercariae were induced by surgical injection of exogenous eggs of Schistosoma mansoni and Schistosoma japonicum via the mesenteric veins of previously unexposed albino mice. Thereafter, their comparative histopathologic studies were made. The maximum mean sizes of granulomata were attained on Day 32 with viable eggs of these parasite species.

An evaluation of the host-mediated assay and body fluid analysis. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

The methodologies and status of the Host-Mediated Assay were reviewed using the published literature available up to June 1980. The Working Group reviewed 274 documents, including abstracts, research articles, review articles, and publicly available contracts and grant final reports. From this group, abstracts and reviews were rejected from critical evaluation.

Metabolic requirements of schistosomes.

In adult Schistosoma mansoni and S. japonicum carbohydrate utilization, formation of lactic acid and ATP levels were the same under aerobic and anaerobic conditions. Therefore, these parasites exhibited no pasteur effect.

Antischistosomal effects of cyclosporin A.

Administration of cyclosporin A, a new selective immunosuppressive agent, to mice infected with Schistosoma mansoni resulted in a significant reduction in the number of mature and immature male and, to a greater extent, female worms. With lower, subeffective, doses a reduction in hemoglobinase activity and protein content of female schistosomes is produced. Evidence available so far suggests that the antischistosomal effects of cyclosporin A are mediated through a stimulation of host mechanisms directed against the parasite.

Protection by antibiotics against experimental focal cholangitis produced in mice by a schistosomicidal isothiocyanate.

Oral administration to mice of high doses of 4-isothiocyano-4'nitrodiphenylamine (amoscanate), a potent antischistosomal drug, produced focal necrotizing lesions of the large intrahepatic and extrahepatic bile ducts and the gallbladder. Coadministration of erythromycin and, to a somewhat lesser degree, of paromomycin, markedly reduced the effects of amoscanate on the biliary tract. These results suggest that amoscanate may be converted to a cholangiotoxic product by one or several constituents of the enteric bacterial flora.

Effect of unisexual Schistosoma mansoni infections on hepatic drug metabolism of mice.

The effect of unisexual schistosome infection on the activities of several hepatic enzymes was studied in mice. The activities of hepatic drug-metabolizing enzymes in mice infected with either female or male schistosomes were not significantly different from those of noninfected control animals. However, the total amount of heme pigment in the liver of infected mice was 2.