Niridazole metabolism by rat embryos in vitro.

We report the results of studies on the reductive activation of the schistosomicidal agent, niridazole (NDZ). Intact rat embryos in vitro reduced this compound, generating a stable metabolite in the presence of 5% O2. By contrast, embryo and yolk sac homogenates or liver microsomes appeared to require anaerobiasis. Malformation incidence--specifically, axial asymmetry--showed a strong correlation with nitroreductase activity rates when the latter were modulated by oxygen tension. Data presented here suggest that when embryos are exposed to NDZ under conditions of low oxygen in vitro, redox cycling ensues with molecular oxygen serving to oxidize early reduction products. This process continues, regenerating the parent compound until oxygen is depleted locally. The basis of this localized depletion is unknown, but inability of the immature supply system to replete oxygen or demand by precociously aerobic tissues may be involved. Once local anaerobiasis is attained, further reduction could generate toxic metabolites capable of covalently binding cellular macromolecules. Localized hypoxia represents another potential mechanism of dysmorphogenesis.

Comparative trials of regimes for the treatment of urinary schistosomiasis in The Gambia.

Alternative regimes for the treatment of Schistosoma haematobium infection were compared in two trials. Praziquantel at a dose of 40 mg kg-1 appeared to cure 63% of a random sample of heavily infected subjects; significantly more than the 18% cured by three fortnightly doses of metrifonate at 10 mg kg-1. However, praziquantel led to a greater incidence of mild, transient side-effects. A single dose of metrifonate was found to be an inadequate treatment in the same group of subjects as it left 53% with an egg count of at least 100 ova/10 ml. A combination of 10 mg kg-1 of metrifonate and 25 mg kg-1 of niridazole had a similar effect to that of a single dose of metrifonate alone and it had more side-effects. Reduced doses of praziquantel had less effect on egg counts than the standard regime, but the difference was not significant in the case of 20 mg kg-1. Although a combination of metrifonate and praziquantel, each at 10 mg kg-1, had a greater effect than either constituent alone, the difference was not significant. Factors affecting the choice of drug for use in mass treatment of urinary schistosomiasis in The Gambia are discussed. The present findings suggest that the standard regime of praziquantel should be used or, if this is not possible, a three-dose metrifonate regime.

Influence of dosing interval and in-patient versus out-patient status on incidence of side-effects of niridazole.

The side-effects of niridazole used for urinary schistosomiasis were studied prospectively over a 3-month period in male patients receiving the standard dose of 25 mg day-1 kg-1 for 7 days. Side-effects were detected in 80% of in-patients but only in 33% of out-patients. The range of side-effects was greater in in-patients taking their daily doses in two portions than in those taking theirs in three. Cure rates and degree of schistosoma egg suppression were significantly lower in out-patients suggesting that compliance with treatment was poorer.

Niridazole-induced red/brown urine pigment is associated with increased urinary beta-glucuronidase excretion and a bladder site of formation.

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.

A comparative trial of praziquantel, metrifonate and niridazole against Schistosoma haematobium.

Praziquantel administered in a single oral dose of 30 mg kg-1 to subjects infected with Schistosoma haematobium produced minimal side effects and was more effective than established regimes of niridazole and metrifonate. Praziquantel should prove a major tool in schistosomiasis control programmes.

Oxamniquine versus niridazole for treatment of uncomplicated Schistosoma mansoni infection.

One hundred sixteen male patients with uncomplicated Schistosoma mansoni infection were randomized to treatment with oxamniquine (20 mg/kg a day for 3 days) or niridazole (15 mg/kg a day for 8 days) in an in-hospital study. Fifty-four patients were treated with oxamniquine; no serious drug side effects were noted. Twenty-six percent of children 16 years old and younger were cured, while 85% of adults were cured. Egg reduction was 89%. Sixty-two patients were treated with niridazole; four patients (one child and three adults) had serious side effects which necessitated discontinuing the drug. Seventy-one percent of children and 84% of adults were cured. Egg reduction was 84%. Minor clinical side effects occurred during therapy with both drugs (26% with oxamniquine, 48% with niridazole) but cleared after completion of therapy. Niridazole is the more effective drug for the child with uncomplicated Schistosomiasis mansoni, but oxamniquine is advised for the adult with this disease.

Preliminary report on long term cure of schistosomiasis using metrifonate (Bilarcil/Dipterex)--a new antischistosomal drug.

Twenty patients aged between 7 and 19 years with confirmed vesical schistosomiasis due to Schistosoma haematobium were treated with Metrifonate (Dipterex, Bilarcil) orally on a single dose of 7.5 mg/kg body weight repeated at fortnightly intervals until egg excretion ceased. This was achieved with a maximum of three doses. No symptoms of toxicity or significant side effects were observed. Four patients remained symptom free of the infection for up to three years after the initial treatment. These results suggest that Metrifonate (Bilarcil), a cheap, relatively non-toxic, orally administered and effective drug against Schistosoma haematobium, can be used successfully in the management of this crippling infection. They also suggest that, provided there is no re-exposure, the subjects can remain free of symptoms for more than three years.

Carcinogenic effects of niridazole on rodents infected with Schistosoma mansoni.

The carcinogenicity of 1-(5-nitro-2-thiazolyl)-2-imidazolidinone (niridazole), a widely used schistosomicide, was examined in Swiss mice and Syrian golden hamsters. Schistosoma mansoni infection was evaluated as a cofactor. High incidences of drug-related neoplasms of the forestomach, lungs, mammary glands, urinary tract, and ovaries were found in mice, and tumors of the forestomach and urinary tract were found in hamsters. Infection with schistosomes had no apparent influence on tumor incidence. The results indicated a need for reevaluation of the possible carcinogenicity of this drug in man and suggested that care should be taken during its clinical use.

Current chemotherapy of schistosomiasis japonica in the Philippines.

For the past several decades, the drug being used for the treatment of schistosomiasis in the Philippines has been Stibophen. It is administered intramuscularly at a dose of 1 ml per 10 kg body weight with a maximum of 5 ml every other day after 2 initial daily smaller sensitivity doses at a total dose of 45 to 70 ml fof adult patients. In recent years, a number of drugs for the treatment of schistosomiasis have been developed. These were evaluated clinically either in the hospital or in field trials in Leyte. Unfortunately, none of these were found to be suitable for mass treatment on account of toxicity to prolonged course of treatment. In view of the pressing need for a safe and effective schistosomicidal agent, the search for a better drug is imperative.

Drug trial of Schistosoma japonicum enfection in Indonesia.

A limited drug trial was carried out on 42 cases with schistosomiasis japonica from an endemic area of Central Sulawesi. The drugs used were niridazole and stibophen. The effects of treatment were reported and discussed. The results of this study offer promise for treating S. japonicum infection in Central Sulawesi on a larger scale.

Ambilhar in the treatment of Schistosoma japonicum infection and as an egg suppressant for mass treatment.

Ambilhar or niridazole at a dose of 25 mg per kg body weight for 7 days was found ineffective against Sl japonicum infection. Longer period of treatment for 10 to 14 days gave impressive stool negative conversion and egg reduction rates but with moderately severe reactions, the most alarming of which was hallucination. To minimize toxicity, the daily dose was reduced but given for a longer duration so that the total amount of the drug given per kilogram body weight was approximately the same as the 25 mg pre kg per day for 10 to 14 days. Of the two treatment schedules tried, the 15 mg per kg per day for 24 days was found relatively effective. Although the drug with this treatment regimen was well tolerated, a drop-out of 50.8% was observed. Ambilhar was therefore tried as an egg suppressant. With a 10-day treatment, all patients were again positive after 6 months. Egg reduction rates during the 6 months stool follow-up ranged from 69.8 to 93.5%. Further trials using this dose to be repeated every 3 to 6 months is contemplated.