1-(5-Nitro-2-thiazolyl)-2-imidazolidinon

Administration of niridazole to rats poisoned with copper caused a significant increase in both the urinary and biliary excretion of the metal. Although the urinary excretion of iron was increased by the drug, iron excretion was significantly decreased during the drug-induced excretion of copper after copper poisoning. Formation of a copper-niridazole chelate or chelates before excretion in the bile or urine may explain these findings. Polarity and molecular weights of the metal-drug chelates formed in vivo may be the directing forces not only in the selection of the metal for chelation, but also for its urinary or biliary excretion. The laboratory preparation of two copper-niridazole complexes lends support to these conclusions.

Oral acute toxicity of niridazole was increased 3-fold by the simultaneous administration of carbaril (carbaryl) and 2-fold by the administration of malathion in rats.

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

/SIGNS AND SYMPTOMS/ The antispermatogenic effect of niridazole was studied in 20 bilharzial male patients. Niridazole was found to induce defective spermatogenesis in the form of focal spermatocyte arrest and or germinal cell hypoplasia. The effect was transient, with active recovery occurring 3 months after therapy. Niridazole therapy must be postponed or changed for those subjects whose semen parameters prove to be subfertile.

/CASE REPORTS/ Niridazole caused red/brown urine pigment in a man during treatment for Schistosoma mansoni infection. The urine pigment has been observed during niridazole treatment of schistosomiasis, but has not been documented during treatment of other diseases. Urinary beta-glucuronidase (EC 3.2.1.31) concentration increased proportionately to the amount of red/brown pigment in the urine. Concurrently, sterile pyuria developed. The duration of the time urine was in the bladder was directly related to the concentration of beta-glucuronidase and to the intensity of the red/brown urine color, there being much more in infrequently than in frequently voided urine specimens. Pigment development appears to occur in the bladder. The associated and possibly contributing components appear to be niridazole or one of its metabolites, beta-glucuronidase from the kidneys or from urinary granulocytes, and possibly a schistosomal factor. Given time, this combination generated the red/brown pigment.

/CASE REPORTS/ A discussion of the various ECG changes frequently associated with the use of niridazole (Ambilhar; I), using a case report in a 35-yr-old male, is presented. The only laboratory abnormality was a type IV hyperlipoproteinemia pattern-increased cholesterol, triglycerides, and uric acid. ECG changes manifested were consistent with anterolateral ischemia. The type and location of these changes are consistent with reports from other investigators. Although the etiology of these changes is not clear, it appears that the primary T wave abnormalities are related to changes in myocardial cellular metabolism.

/CASE REPORTS/ A severe pulmonary sensitivity reaction occurred in an 18-year-old man treated for a Schistosoma mansoni infection with niridazole (Ambilhar). The reaction was reproducible when the drug was administered a second time.

Niridazole

Group 2B: Possibly carcinogenic to humans

Volume 13: (1977) Some Miscellaneous Pharmaceutical Substances

1987

1987

/LABORATORY ANIMALS: Acute Exposure/ The lethal potency of the antischistosomal agent niridazole was compared in C57BL/6J (B6) and DBA/2J (D2) mice and in their F1 hybrid, backcross and F2 progeny. A daily ip dosage range was chosen so that the lethal effect, ascribed to central nervous system toxicity, did not occur before 4 to 5 days. Death was always preceded by a generalized tonic-clonic seizure which terminated in respiratory arrest. In B6 mice the LD50 was 202 mg/kg/day while in D2 mice the LD50 was 146 mg/kg/day; the LD50 for niridazol in similarly treated F1 hybrid mice was found to be the arithmetic mean of the LD50 values for the parental strains (172 mg/kg/day). Determination of the level of niridazol in the plasma and brains of B6 and D2 mice treated subacutely with the same daily dose of niridazol failed to reveal any strain differences. Moreover, there was no evidence of in vivo accumulation of niridazole with subacute treatment which suggests that a niridazol metabolite is responsible for the observed toxicity. An association between susceptibility to the lethal effects of niridazol and the Ah locus is suggested by experiments in backcross and F2 mice. The incidence of death observed after subacute treatment with 162 mg/kg/day of niridazole matched that predicted on the basis of genotype, ie, it was lethal to 72% of nonresponsive and 38% of aromatic hydrocarbon responsive mice.[Blumer JL et al; J Pharmacol Exp Ther 212 (3): 509-13 (1980) ]

/LABORATORY ANIMALS: Acute Exposure/ After ip 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.[Catto BA et al; J Pharmacol Exp Ther 228 (3): 662-8 (1984)]

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Administration of 0.24, 0.16, 0.08, 0.04 or 0% niridazole in the diet of Syrian golden hamsters either infected with 30 Schistosoma mansoni cercariae by Yarinsky's method 56 days before or non-infected led to a significant increase in the incidence of tumors of the forestomach, mainly papillomas, at all doses (15-90% versus 0-3%) except the lowest; and a total of 13 transitional-cell papillomas of the bladder were observed among animals treated with the three highest dose levels. The minimum numbers of animals per group were 30 males and 29 females. Infection did not appear to influence tumor yield.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V13 126 (1977)]

Classification of carcinogenicity: 1) No data available in humans 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. NOTE: Overall evaluation based only on evidence of carcinogenicity in monograph (Volume 13; 1977). /From table/

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/