Response of drug resistant isolates of Schistosoma mansoni to antischistosomal agents.

The susceptibility of four isolates of Schistosoma mansoni (BH, MAP, MPR-1 and K) to four multiple doses of anti-schistosomal agents (hycanthone, niridazole, oxamniquine, and praziquantel) were evaluated in infected female Swiss albino mice. These schistosomal isolates had been maintained in the laboratory without further drug pressure for 20 to 30 generations. Multiple dosage regimens were used for each drug against each isolate of S. mansoni to generate ED50 (effective dose 50%) values. Results demonstrated that the K isolate is resistant to niridazole, the MPR-1 isolate to oxamniquine, and the MAP isolate to both hycanthone and oxamniquine. The BH isolate was susceptible to all drugs and was used as the reference isolate. All isolates were susceptible to parziquantel. The significance of the difference in response of the MPR-1 and MAP isolates is discussed. These results confirm the resistance of these isolates of S. mansoni to three schistosomicides and demonstrate that the resistance of these isolates are stable over long periods of time without exposure to drugs.

Autoradiographic quantification of the efficacy of niridazole in mice infected with 75Se-labelled cercariae of Schistosoma mansoni.

The effects of the anti-schistosomal drug, niridazole, on the migration of Schistosoma mansoni larvae, biosynthetically radioisotope-labelled with 75[Se]-selenomethionine, was evaluated by autoradiography of compressed tissues of mice treated daily from Days 6 to 10 post-infection with 200 mg kg-1 niridazole. The results were compared with the migration of schistosomula in untreated controls. The distribution of schistosomula was altered in niridazole-treated mice, where there was a delayed migration from the lungs relative to the controls and significantly fewer schistosomula in total appeared to reach the liver. The total percentage of schistosomula detected as autoradiographic foci was significantly lower in treated mice than in the untreated controls. Niridazole-treated mice were free of any foci 10 days after the last treatment and no adult worms were recovered on perfusion of the hepatic portal system relative to control mice from which 5.8% of the infective cercariae were recovered as adult worms at Day 42 post-infection.

Studies of embryotoxic mechanisms of niridazole: evidence that oxygen depletion plays a role in dysmorphogenicity.

Previous study has shown that niridazole (NDZ) is dysmorphogenic to rat embryos between days 10 and 11 under culture conditions including 5% oxygen. Other studies have found that reductive embryonic biotransformation is required but that covalent binding is not a major basis of this embryotoxicity. In research presented here, NDZ exposure of homogenates prepared from day 10 rat embryos resulted in stimulation of oxygen uptake from incubation media. Further studies showed that a large percentage of this increased oxygen uptake was associated with the generation of superoxide anion radical and hydrogen peroxide. These findings led us to hypothesize that redox cycling forms the basis of the in vitro dysmorphogenicity of NDZ. The basic premise of this hypothesis is that as a result of redox cycling, oxygen is depleted from the sensitive tissues of embryos. In order to investigate it, we devised a technique for carefully controlling and monitoring oxygen tensions in embryo cultures. We found that when oxygen concentrations of 4% were established, a highly significant incidence of asymmetric defects resulted. These defects appeared analogous to those induced by NDZ exposure, consisting of asymmetric necrosis of mesenchymal tissue near the cephalic end of the neural tube and thinning of the neuroepithelium on the right. We concluded that the hypoxia induced by redox cycling of NDZ and related nitroheterocycles represents a major embryotoxic principle of action.

Modification of cytochrome P-450, NADPH-cytochrome c reductase and aryl hydrocarbon hydroxylase activities by schistosomicidal drugs.

This study was planned to investigate the modification of the mouse microsomal monooxygenase enzymes using various schistosomicidal drugs. Enzymes investigated were cytochrome P-450, NADPH-cytochrome c reductase and aryl hydrocarbon hydroxylase (AHH). Administration of oxamniquine and niridazole increased, whereas praziquantel and hycanthone lowered the cytochrome P-450 content. An apparent increase in the activity of NADPH-cytochrome c reductase was only observed with oxamniquine. The in vivo and in vitro effects of schistosomicidal drugs on the activity of AHH were investigated using benzo(a)pyrene (BP) as substrate. Oxamniquine and niridazole significantly increased the AHH activity in vivo and in vitro, while the antimonial drugs enhanced the enzyme activity only in vivo. On the other hand, praziquantel and hycanthone lowered the AHH activity only in vivo. Metrifonate did not show any effect either in vivo or in vitro. The mechanisms by which these drugs modify the AHH activity are discussed in the text.

Metabolite profile in milk of lactating rats after treatment with a carcinogen, N-2-fluorenylacetamide.

Metabolites were determined in milk and urine of lactating rats 4 to 5 hr after each of 3 to 6 ip injections of N-2-fluorenylacetamide (2-FAA) at 0.2 mmol/kg of body weight. Milk contained 2-FAA as the major free compound, variable amounts of N-2-fluorenamine (2-FA) and phenols (7- greater than 5- greater than 3-hydroxy-2-FAA) chiefly as glucuronides, and very small amounts of the glucuronide of N-hydroxy-2-FAA. Urine contained large amounts of the phenols and N-hydroxy-2-FAA as free and conjugated compounds, but in contrast to milk, only small amounts of 2-FAA and no 2-FA. Pretreatment of rats with beta-napthoflavone, an inducer of microsomal C- and N-hydroxylations of 2-FAA, increased the amounts of 3- and 5-hydroxy-2-FAA in milk and of 3-hydroxy-2-FAA in urine. However, the total amounts of the compounds excreted in 1 ml of milk or urine, i.e. 0.05 to 0.13% or 0.6% of the dose of 2-FAA, respectively, were similar in the uninduced and induced groups. Protein hydrolysates of milk of 2-FAA-treated rats and of milk interacted with 2-nitrosofluorene (2-NOF) in vitro both contained 2-FA and 9-oxo-2-FA. This suggested formation of 2-NOF in vivo possibly by peroxidative metabolism of N-OH-2-FAA. Since 2-NOF has been reported to form adducts with unsaturated lipids, the effect of treatment of lactating rats with 2-FAA on the fatty acid composition of milk lipids was examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of niridazole and chloroquine on arterial and myometrial prostacyclin synthesis.

1. The effects of niridazole and chloroquine on rat arterial and myometrial prostacyclin (PGI2) synthesis in vitro were investigated by use of a rat platelet antiaggregatory bioassay. Niridazole (233 microM) and chloroquine (97 microM) inhibited PGI2 synthesis in both tissues. 2. Niridazole-induced inhibition in the myometrium was not reversed by exogenous arachidonic acid (33 microM) indicating a direct effect of the compound on PGI2 synthesizing enzymes. 3. Chloroquine-induced inhibition in the myometrium was significantly reversed by exogenous arachidonic acid (33 microM) indicating a direct effect of the compound on arachidonic acid releasing enzymes (e.g. phospholipases A2 and C). 4. Niridazole and chloroquine also inhibited prostaglandin E2 synthesis in the myometrium. 5. Chloroquine- and niridazole-induced inhibition of prostaglandin synthesis may contribute towards a better understanding of some of their actions in vivo.

Comparison of in vitro activity of niridazole, metronidazole and tetracycline against subgingival bacteria in chronic periodontitis.

Niridazole, metronidazole and tetracycline were compared for their activity against subgingival bacteria from patients with chronic periodontitis. Niridazole was consistently more effective than the other drugs against obligate anaerobes and exhibited some activity against facultative organisms. It was concluded that niridazole has potential for topical use in chronic periodontitis.

Activities of metronidazole and niridazole against Trichomonas vaginalis clinical isolates.

The activities of niridazole and metronidazole against Trichomonas vaginalis C1-NIH and six isolates of clinical origin were compared using the in-vitro assay technique. Under the standard anaerobic assay conditions both metronidazole and niridazole were highly effective at low concentrations against all the strains used. However niridazole, in contrast to metronidazole, was equally effective in the aerobic assay, a feature which may be exploited in the chemotherapy of patients with refractory trichomoniasis.

Antimicrobial effects of niridazole on Gardnerella vaginalis.

Niridazole, a nitrothiazole derivative, demonstrated powerful antimicrobial activity against 510 clinical isolates of Gardnerella vaginalis tested. MIC's ranged from 0.002 to 1.0 mg/l with MIC50 and MIC90 values of 0.02 and 0.067 mg/l respectively.

Reduction of niridazole by metronidazole resistant and susceptible strains of Trichomonas vaginalis.

The inhibitory effect of niridazole on hydrogen production by metronidazole-resistant (CDC-85) and susceptible (C1-NIH) Trichomonas vaginalis strains was investigated. The results show that niridazole is more effective than metronidazole in inhibiting hydrogen production by the resistant isolate. In CDC-85 aerobic inhibition requires a 4-fold increase in metronidazole concentration compared with that required anaerobically, but the corresponding factor for niridazole is only 1.5-fold. Reduction of the drug by a hydrogenosome-enriched preparation gave rise to a multiline electron spin resonance detectable signal, which is due to a nitrogen-centred radical.

N-nitrosamine formation by microorganisms isolated from human gastric juice and urine: biochemical studies on bacteria-catalysed nitrosation.

Twelve out of 14 bacterial strains isolated from patients with urinary infections and nine out of 30 microorganisms isolated from gastric juice from patients with gastric achlorhydria were shown to catalyse the formation of N-nitrosomorpholine (NMOR) from nitrite and morpholine at neutral pH. The effects of various metal ions and cofactors on the bacterial nitrosation reaction was investigated. The presence of nitrate in the culture medium was required to induce nitrosating activity in bacteria, but low nitrate concentrations inhibited the nitrosation reaction.

Schistosoma mansoni: chemotherapy of infections of different ages.

Mice were treated with potassium antimony tartrate, hycanthone, oxamniquine, niridazole, or praziquantel at different times after infection with Schistosoma mansoni. The rate of cure was assessed by perfusion of surviving worms approximately 4 weeks after treatment, and the percentage reduction in worm burden was estimated relative to the number of adult worms perfused from control mice, comparably infected but untreated. All six drugs were relatively inactive against S. mansoni between 3 and 4 weeks after infection when compared with treatment at 5 to 6 weeks. However, the drugs differed in the patterns of cure they achieved in the 2-week period after administration of cercariae and in the period around the onset of patency. Worms that had been subjected to amoscanate or hycanthone in the third week after infection showed evidence of this as adults in having a reduced fecundity. Factors such as worm or host physiology, or host immune status may have had roles in the outcome of chemotherapy at different stages of maturation of S. mansoni.

Antibacterial activity of niridazole against Salmonellae.

Fifty-six strains, representing eight species of salmonellae of diverse geographic origin and possessing a variety of antimicrobial resistance profiles, were tested for susceptibility to niridazole by the agar dilution method. Calculated MICs for 50 and 90% of strains were 4.8 and 16.0 mg/liter, respectively, with a susceptibility range of 0.25 to 32 mg/liter. No obvious species differences were noted. Niridazole was found to be rapidly and powerfully bactericidal. No significant difference was detected between MICs and MBCs. Except for a strain-dependent effect with a subset of multiply resistant salmonella isolates, no inoculum effect was demonstrated.

Antibacterial activity of GO 10213, a nitroimidazole derivative.

Compound GO 10213, a 5-nitroimidazole substituted at the 2 position, is more active against aerobic, microaerophilic, and anaerobic bacteria than metronidazole. The MICs for Salmonella typhimurium (2 to 128 micrograms/ml), Campylobacter spp. (0.06 to 16 micrograms/ml) and Bacteroides spp. (0.03 to 0.25 micrograms/ml) are definitely lower than those of metronidazole. Niridazole, a 5-nitrothiazole, is still more active.