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At least 19 recordsLinked to original sources
PubMed1984

4-Keto niridazole: a major niridazole metabolite with central nervous system toxicity different than niridazole.

4-Keto niridazole, isolated by high-pressure liquid chromatography, was identified by high resolution electron impact mass spectral analysis as a major drug metabolite of niridazole in the serum or plasma of rats and mice treated orally or i.p. with niridazole. This metabolite has a pKa of 5.8 and is approximately 40% bound at physiologic pH to serum proteins of mice receiving therapeutic doses of niridazole. After i.p. injection of niridazole (160 mg/kg), peak serum levels of 4-keto niridazole (10.4 micrograms/ml) were reached within 6 hr in DBA/2J mice. The acute LD50 for 4-keto niridazole i.p. was 55 mg/kg in DBA/2J mice and 51 mg/kg in C57BL/6J mice; the comparable value for niridazole was 220 mg/kg in DBA/2J mice. Signs of acute 4-keto niridazole toxicity were different from those of niridazole toxicity and consisted of profound sedation and labored, irregular breathing terminating in respiratory arrest. Daily i.p. injection of 30 mg/kg of 4-keto niridazole for 5 days into DBA/2J mice resulted in no evidence of cumulative toxicity. The serum and brain concentrations of 4-keto niridazole after a 70-mg/kg i.p. LD90 dose of this compound were 93 micrograms/ml and 7.5 micrograms/g just before death. If an LD90 dose of niridazole (285 mg/kg) was injected into DBA/2J mice, the serum and brain concentrations of 4-keto niridazole just before death were 15 and 5%, respectively, of those found after an LD90 dose of 4-keto niridazole. Thus, 4-keto niridazole does not appear to account for the central nervous system toxicity of niridazole.

Animals↗
PubMed1979

Effect of niridazole and niridazole immunoregulatory factor (NIF) on cutaneous delayed hypersensitivity in mice.

It has been suggested that the suppression of cell-mediated immune phenomena following niridazole administration is most likely due to a niridazole metabolite rather than the parent drug. This hypothesis was tested using two inbred strains of mice that manifest different rates of microsomal niridazole oxidation and reduction. DBA/2J mice were found to metabolize niridazole at a rate approximately 3-fold greater than C57BL/6J mice under both aerobic and anaerobic conditions. Niridazole was found to be more potent with respect to suppression of cutaneous delayed hypersensitivity in the former than in the latter. An immunosuppressive component was isolated from the urine fraction obtained from niridazole-treated rats. This component was found to be chromatographically pure; have a simple UV absorbance spectrum containing no 360 nm absorbing material characteristic of niridazole; to show no strain difference with respect to potency or efficacy in the ear-swelling assay for cutaneous delayed hypersensitivity; and to be 10(7) times more potent than niridazole with respect to the suppression of cutaneous delayed hypersensitivity.

Animals↗
PubMed1978

Biochemical effects of niridazole. II. In vitro and in vivo effects of niridazole on the rate of gluconeogenesis and the rate of oxidation of pyruvate and some Krebs cycle intermediates in Schistosoma mansoni infected mice.

The effects of the antischistosomal drug, niridazole, on the rate of gluconeogenesis in kidney cortex slices and on the rate of oxidation of pyruvate and some Krebs cycle intermediates in liver homogenates of infected mice were described. The effect of schistosoma mansoni infection on the previously mentioned parameters was also described. The infection per se did not affect the rate of gluconeogenesis from pyruvate, succinate and alpha-ketoglutarate when used as gluconeogenic precursors. In case of the rates of oxidation of pyruvate, succinate alpha-ketoglutarate and citrate, the infection decreased them significantly. In vitro, niridazole did not increase the inhibition of the rate of oxidation of different substances studied caused by the infection per se. The rate of gluconeogenesis from alpha-ketoglutarate was also unaffected. In vivo, niridazole did not affect the oxidoreductases more than did the infection per se. In fact in many cases, the drug tended to normalize the inhibitory effect of the infection on some of the enzyme systems, particularly in the case of the citrate succinate and pyruvate. On administration of 100 mg/kg of niridazole for 5 days (i.e. low dosage only) the rate of gluconeogenesis from pyruvate and alpha-ketoglutarate was stimulated. Such effects seem to be related to the presence of metabolites rather than to the parent drug.

Animals↗
PubMed1978

Biochemical effects of niridazole. I. In vitro and in vivo effect of niridazole on the rate of gluconeogenesis and oxidation of pyruvate and some Krebs cycle intermediates in mice.

The effects of the antischistosomal drug, niridazole, on the rate of gluconeogenesis in kidney cortex slices and on the rate of oxidation of pyruvate and some Krebs cycle intermediates in liver homogenate of non infected mice were determined. In vitro, niridazole was found to inhibit the succinate and pyruvate oxidation at the high concentration tested (10(-3)M). The rate of gluconeogenesis from alpha-ketoglutarate was unaffected. In vivo, niridazole showed a stimulatory effect on the rate of gluconeogenesis from alpha-ketoglutarate and on the rate of oxidation of pyruvate at a dosage level of 100 mg/kg for 5 days. The observed changes were discussed and the differences observed between the in vivo and in vitro work were assumed to be due to exposure of the tissues to the unmetabolized drug in vitro and to the drug and its metabolites in vivo.

Animals↗
PubMed1983

Reductive metabolism of niridazole by adult Schistosoma mansoni. Correlation with covalent drug binding to parasite macromolecules.

Niridazole, an antischistosomal nitrothiazole derivative, is metabolized by adult Schistosoma mansoni to one or more reactive intermediates, as evidenced by extensive covalent binding of [14C]niridazole to parasite macromolecules. When worm pairs were incubated for 16 hr in culture medium containing 70 microM [14C]niridazole, 26-34% of the total parasite-associated radioactivity was irreversibly bound to trichloroacetic acid-precipitable material. Drug binding was both time- and [14C]niridazole concentration-dependent. Of the bound drug fraction, 85-90% was associated with parasite proteins, 3-5% with RNA and 4-7% with DNA. When schistosomes were recovered from infected mice, treated with periodic doses of [14C]niridazole, over 40% of the total parasite-associated radioactivity was bound to macromolecules. Niridazole caused up to a 40% decrease in the concentration of total nonprotein thiols in intact schistosomes incubated with the drug over an 8-hr period. Under strictly anaerobic conditions, cell-free schistosome preparations catalyzed a reduced pyridine nucleotide-dependent reduction of niridazole's essential nitro group, as evidenced by disappearance of absorption at 400 nm. Net nitroreduction did not occur under aerobic conditions, although the drug did stimulate oxidation of the pyridine nucleotide cofactor. Covalent binding of [14C]niridazole also took place in this cell-free system, with requirements identical with those needed for enzymatic nitroreduction. Covalent drug binding, but not nitroreduction, was inhibited up to 80-85% by 2 mM L-cysteine, N-acetyl-L-cysteine, or glutathione; S-carboxymethyl-L-cysteine, which has no free sulfhydryl group, was not inhibitory. [14C]4'-Methylniridazole, a nonschistosomicidal analogue of niridazole, was taken up by intact schistosomes in vitro, but was not metabolized and did not bind covalently to parasite macromolecules. Furthermore, 4'-methylniridazole did not affect the concentration of nonprotein thiols in intact parasites and did not serve as a substrate for schistosomal nitroreductase in vitro. These results indicate a positive correlation between proximal metabolic activation of niridazole within these facultative anaerobic organisms and its antiparasitic activity.

Animals↗
PubMed1980

Relative importance of bacterial and mammalian nitroreductases for niridazole mutagenesis.

Niridazole is a nitrothiazole anthelmintic agent used to treat schistosomiasis. Its antibacterial activity was found to require the presence of the nitro group; a synthetic desnitro analog was completely inactive. Niridazole was mutagenic for Salmonella tester strains TA1538, TA98, and TA100, suggesting that it was both a frame-shift- and a base substitution-type mutagen. It was effective under both aerobic and anaerobic conditions, while similar testing of the desnitro niridazole produced consistently negative results. Addition of rat liver S-9 fraction under either aerobic or anaerobic conditions did not enhance mutagenicity. However, since bacterial killing limited the dose of niridazole to 0.33 microgram/plate in standard tester strains (1/20 Km for the mammalian liver enzymes), further studies were performed using niridazole-resistant, histidine-dependent mutants derived from strains TA98 and TA100. These mutants were found to be nitroreductase deficient and to resist the mutagenic effects of niridazole, in the presence or absence of S-9, up to concentrations of 10 microgram/plate. In addition, even at niridazole concentrations of up to 100 microgram/plate, rat liver S-9 was ineffective in enhancing the mutagenicity of niridazole. These results suggest that the mutagenicity of niridazole is dependent on its aromatic nitro group and a specific bacterial nitroreductase.

Aerobiosis↗
PubMed1981

The formation of 1-thiocarbamoyl-2-imidazolidinone from niridazole in mouse intestine.

This study was designed to identify the site of formation of 1-thiocarbamoyl-2-imidazolidinone (TCI), a potent immunoactive metabolite of the antihelminthic drug, niridazole. When niridazole was administered intragastrically to C57Bl/6J mice, a 4-hr delay was observed before TCI was detected in the serum. By contrast, 4-hydroxyniridazole, a marker of hepatic niridazole metabolism, appeared in the serum within 30 min. Changing the route of niridazole administration from intragastric to intracaecal abolished the lag period in the rise of serum TCI concentrations relative to the 4-hydroxyniridazole marker. Pretreatment of mice with neomycin sulfate reduced the amount of TCI excreted in the urine by about 90% over a 24-hr period, but did not affect the amount of 4-hydroxyniridazole excreted. Injection of niridazole into isolated segments of mouse intestine resulted in TCI production, with the greatest conversion noted in the caecum. Subsequent incubation of niridazole with suspensions of mouse caecum contents in vitro also resulted in the formation of TCI, but not 4-hydroxyniridazole. Attempts to demonstrate TCI formation in vitro with various fractions of mouse liver were unsuccessful. These results indicate a dissociation of TCI formation from the major hepatic pathway of niridazole metabolism and support the view that TCI is formed from niridazole in the gastrointestinal tract as a result of the action of intestinal microflora.

Animals↗
PubMedDate not supplied

Formation of N-(5-nitro-2-thiazolyl)-N'-carboxymethylurea from 5-hydroxyniridazole. Role of aldehyde dehydrogenase in the oxidative metabolism of niridazole.

N-(5-nitro-2-thiazolyl)-N'-carboxymethylurea (NTCU) has been identified as a urinary metabolite of the antischistosomal drug niridazole [1-(5-nitro-2-thiazolyl)-2-imidazolidinone]. When DBA/2J mice were treated with [14C]niridazole, a metabolite comprising 12-14% of the total radioactivity in 24-hr urine samples was resolved by HPLC. The compound was subsequently isolated from pooled urine of niridazole-treated patients. It was identified as NTCU by mass spectrometry, and the deduced structure was confirmed by chemical synthesis. NTCU is unique among known niridazole metabolites, because it lacks an intact imidazolidinone ring. Its structure allows for a ketoenol tautomerism in which the enolate is stabilized by conjugation with the nitrothiazole ring, as evidenced by a pH-dependent 80-nm red shift in the absorption spectrum. We hypothesized that NTCU arises via oxidation of an acyclic aldehyde tautomer of 5-hydroxyniridazole, one of two proximate oxidative niridazole metabolites. Indirect evidence for the aldehyde tautomer included the fact that 5-hydroxyniridazole displayed the same pH-dependent spectral shift as NTCU with a single isobestic point at 388 nm. The proposed precursor-product relationship was confirmed when we found that NTCU formation from 5-hydroxyniridazole was catalyzed by NAD(+)-dependent aldehyde dehydrogenase (EC 1.2.1.3). The activity copurified with benzaldehyde dehydrogenase activity from mouse liver cytosol. Furthermore, benzaldehyde was a competitive inhibitor of 5-hydroxyniridazole dehydrogenase activity. These results demonstrate that 5hydroxyniridazole is not an end product of niridazole metabolism. Because biotransformation of niridazole to its 4- and 5-hydroxy derivatives has been implicated in the drug's carcinogenicity and central nervous system toxicity, NTCU formation appears to represent a detoxication pathway in mammals.

Aldehyde Dehydrogenase↗
PubMed1982

[Antibacterial effects of niridazole. II. Effects on aerobic and anaerobic bacteria].

Niridazole which is chemically related to metronidazole is endowed with much better antibacterial activity. First, several genera of aerobic bacteria, such as Salmonella and Escherichia, are susceptible to niridazole, whereas metronidazole is completely ineffective. There exist, however, some particular strains which are naturally resistant to niridazole. The in vitro activity of niridazole is still increased, if these facultative anaerobic bacteria are tested under anaerobic growth conditions. Second, niridazole has a higher in vitro activity against anaerobic bacteria, such as Bacteroides spp., Clostridium spp., Fusobacterium spp. and Peptococcus sp., than metronidazole. Extremely low MIC values of niridazole were found ranging from 0.0037 to 0.06 microgram/ml. Propionibacterium acnes, which are resistant to the action of metronidazole, are also relatively resistant to niridazole.

Aerobiosis↗
PubMedDate not supplied

Antibacterial effects of niridazole: its effect on microaerophilic campylobacter.

Niridazole, a nitrothiazole derivative, exhibited marked antimicrobial activity against a group of microaerophilic campylobacter. MICs ranged from 0.0037 to 2.0 mg/l, with an average of 0.25 mg/l. The activity of niridazole was compared to that of chemically related compounds (metronidazole, ornidazole, tinidazole). Although their activities ran parallel, niridazole was found to be markedly more potent. Thirteen other common antibiotics were also inferior to niridazole with respect to their inhibitory effect. The antibacterial activity of niridazole was bactericidal. Its in vivo activity was also tested in mice infected orally with campylobacter. The organisms, which caused a chronic colonization of the gut in untreated animals, disappeared rapidly from the faeces after treatment with niridazole, at least in the case of a highly susceptible campylobacter strain.

Animals↗
PubMed1984

Niridazole-mediated modulation of suppressor cells in Wistar rats.

The antischistosomal drug niridazole has been shown to inhibit inductive (Vadas and Bernard, 1981) as well as effector phases of delayed hypersensitivity (Sainis et al., 1983). Furthermore, it also abrogates help for delayed hypersensitivity in antigen-primed animals (Sainis et al., 1983). The effect of this drug on antigen-induced suppression was examined in the present studies. Profound suppression of delayed hypersensitivity to sheep erythrocytes was obtained in Wistar rats given 10(8) erythrocytes (i.v.) 6 days before the immunizing dose (2 x 10(9) erythrocytes, i.p.). When these rats were orally administered niridazole (50 mg/kg) 7 days before the tolerising dose of antigen, suppression of delayed hypersensitivity was not obtained. Splenic lymphocytes of rats given the tolerising dose 6 days earlier adoptively transferred the suppression to inbred recipients. Treatment of these afferent suppressor cells with sera from niridazole-treated unimmunized rats abrogated their function. Likewise, the efferent suppressor cells obtained from fully tolerised rats did not suppress the delayed hypersensitivity when co-transferred with immune lymphocytes, if they were pretreated with niridazole-active serum. The metabolite of niridazole present in this serum seems to impair the suppressor cells functionally. Niridazole may thus prove to be a versatile immunomodulator for effector, helper and suppressor T-cells.

Adjuvants, Immunologic↗
PubMed1977

Immunosuppressive properties of sera and urine dialysates from kidney-graft recipients treated with azathioprine, prednisolone, and niridazole.

Niridazole, an antischistosomal agent, was given to renal transplant recipients in addition to azathioprine and prednisolone, as there is experimental evidence that this combination of drugs is highly immunosuppressive. Sera obtained from kidney-graft recipients during the first two weeks after transplantation were examined for their ability to inhibit the one-way mixed lymphocyte reaction (MLR). Sera from seven patients receiving azathioprine, prednisolone, and niridazole (triple-drug treatment), five patients receiving azathioprine and prednisolone, and two other patients treated with niridazole alone for schistosomiasis produced MLR inhibition by comparison with pretreatment (control) sera.A mean of 78% inhibition was observed with sera taken after one day's treatment with the three-drug combination, whereas this level of in-vitro immunosuppression occurred only after eight days of treatment with azathioprine and prednisolone. Niridazole alone produced an effect similar to azathioprine and prednisolone. Concentrated dialysate of urine from a patient receiving triple-drug treatment not only inhibited the MLR but also significantly prolonged the survival of heterotopic heart allografts in rats, whereas dialysate from the same patient after niridazole had been stopped gave less MLR inhibition and failed to prolong heart allograft survival.Since niridazole thus increased the in-vitro and in-vivo immunosuppressive action of azathioprine and prednisolone, we suggest that this triple-drug combination might be useful for preventing early acute kidney graft rejection.

Azathioprine↗
PubMed1978

Effect of niridazole in cellular immunity in vivo and in vitro.

The influence of niridazole, an anti-helminthic drug, on cell-mediated immune responses was investigated. Allograft rejection in mice as well as the in vitro induction of cytotoxic T lymphocytes (CTL) against murine alloantigen were used as the test system. Repeated daily oral treatment of host mice with niridazole (100 mg/kg) prior to and during allotransplantation resulte in the postponement of graft rejection, inducing a transitory functional state of allograft tolerance. The time interval between the termination of niridazole administration and onset of graft rejection was estimated to be 5-7 days. In order to test the effect of niridazole or its derivatives on the in vitro induction of alloreactive CTL, the serum or urine of mice which were treated with niridazole were added to the cultures, instead of adding niridazole directly to the cultures. Such serum and urine were found to be inhibitory for in vitro induction of CTL. The serum and urine had no effect on the effector phase of CTL.

Administration, Oral↗
PubMed1984

1-thiocarbamoyl-2-imidazolidinone, a metabolite of niridazole in Schistosoma mansoni.

Niridazole, a nitro heterocyclic antischistosomal drug, is extensively metabolized to unknown metabolites by Schistosoma mansoni. We report that 1-thiocarbamoyl-2-imidazolidinone was isolated by high pressure liquid chromatography and identified by high resolution electron impact mass spectroscopy as a niridazole metabolite in schistosomes. After a 20-h in vitro incubation in 30 ml of medium containing 10 micrograms ml-1 [14C]niridazole (5.2 Ci mol-1), 100 S. mansoni worm pairs contained approximately 275 ng of 1-thiocarbamoyl-2-imidazolidinone. This amount represented 4% of the total metabolized fraction of niridazole in the parasite. Incubation of schistosomes with 1-thiocarbamoyl-2-[2 14C]imidazolidinone (2.7 Ci mol-1) indicated that this metabolite was not taken up. However, schistosomes released an average of 44 ng ml-1 or 1% of the total 1-thiocarbamoyl-2-imidazolidinone found in the worm back into 1 ml of medium during incubation. No host oxidative metabolites of niridazole were found in the parasites.

Animals↗
PubMed1975

Two stages in lymphocyte mediator production by differential susceptibility to blockade using niridazole.

Sera from guinea pigs given niridazole, an anti-schistosomal compound, have been shown to reversibly block the production of antigen-induced migration inhibitory factor by sensitized guinea pig lymph node cells. Since niridazole itself has no effect in vitro, the blockade of production of migration inhibitory factor is probably due to drug metabolites in the serum. We report here further studies on the mechanism of this drug-induced suppression of cellular hypersensitivity; the data show that niridazole active serum does not block the production of migration inhibitory factor once it has been initiated. Indeed, if niridazole active serum is added a little as 60 sec after the addition of antigen, the lymphocytes will produce migration inhibitory factor. These results suggest the presence of at least two stages in production of migration inhibitory factor after the addition of antigen to lymphocytes. The first, lasting less than 60 sec, is susceptible to blockade by niridazole active serum; the second is not. The elucidation of the mechanism of this blockade should lead to further understanding of the early events after antigen triggering of sensitized lymphocytes.

Animals↗
PubMed1987

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.

Animals↗
PubMed1989

[Synthesis of acylates of niridazole and its analogs as schistosomicides].

In order to decrease the toxicity and enhance the curative effect of niridazole against Schistosomiasis japonica, a series of acylates of niridazole has been prepared through acylation of niridazole, 2-substituted acetamido-5-nitrothiazoles and 1-(5-nitro-2-thiazolyl)-4-acylpiperazine were also prepared. The products has been tested against Schistosomiasis japonica in mice. Preliminary test results showed that the majority of aliphatic acylates of niridazole exhibited marked schistosomicidal effect against adult worms as well as larva (compounds 2, 4-8, 12, 13, 15, 18, 19), a few of aromatic and heterocyclic acylates (compounds 14, 22) and the analogs of niridazole (compounds 26, 39, 49) showed weak activity.

Acylation↗
PubMed1977

Identification and purification of immunosuppressive activity in the urine of rats and a human patient treated with niridazole.

Administration of the antischistosomal compound niridazole to mice, guinea pigs, and humans results in the suppression of several manifestations of cell-mediated immunity. Sera from animals treated with niridazole blocked the in vitro production of migration inhibitory factor (MIF) while niridazole itself was inactive, suggesting that these effects are caused by water soluble mediators. We now report that crude extracts prepared from the urine of rats and a patient receiving nirdazole, but not from pretreatment control urine, similarly suppress antigen-induced inhibition of migration of peritoneal exudate cells from sensitized guinea pigs. With immunosuppressive activity monitored by the direct MIF assay, combined solvent extraction and chromatographic techniques were used to fractionate immunosuppressive activity from the urine of niridazole-treated rats and the patient; the most active fractions, purified about 100-to 1000-fold as compared to methanol-water extracts of dried voided urine, inhibited MIF production at 0.1 to 0.01 ng/ml of assay mixture. These purified fractions also showed immunosuppressive activity by an in vivo assay wherein doses as low as 1 mug/kg injected intravenously (i.v.) into mice suppressed cell-mediated granuloma formation around Schistosoma manisoni eggs. Identically purified fractions prepared from urine of rats and the patient before they received niridazole showed no immunosuppressive activity either in the MIF or in the granuloma assay systems.

Acetone↗