Niridazole prodrugs: Synthesis, characterization and hydrolysis kinetics of some N-acyloxymethyl niridazoles

A series of 3-acyloxymethylniridazole have been prepared by acylation of 3-hydroxymethylniridazole. The structure of the prepared compounds was confirmed by IR, 1 H-NMR and elemental analysis. They were also evaluated with regard to water solubility, partition coefficient, hydrolysis kinetics and enzymatic cleavage. The water solubility of some of these prodrugs was markedly improved over that of niridazole. Meanwhile, their lipid solubility was comparable with that of the parent drug. In vitro chemical stability of all the synthesized prodrugs was studied at different pH-values, as well as in 80% human plasma for one of themas representative example to assess its cleavage enzymatically to the parent drug, in both cases a strict first- order hydrolysis kinetics was observed. The t 1/2 values varied with variation of the acyl-moiety. The obtained results show as significant improvement in physicochemical properties of the products relative to the parent drug

Combined drug therapy of intestinal bilharziasis with and without polyposis

In endemic areas treatment of intestimal schistosomiasis, especially when complicated with polyposis, is a major medical problem. In the past few years introduction of new drugs gave hope for treatment of such cases. These drugs were mainly niridazole and oxamniquine. Niridazole has to be given repeatedly at two months intervals over a period up to one year. Oxamniquine provides the advantage of short term therapy over 3 days but the cure rate was much lower than niridazole. The two drugs are different pharmacolozically and this encourages us to give both drugs in succession, then simultaneously without accentnation of the side or toxic effects than when either drug was given alone. In this study 493 patients of intestinal bilharziasis, 39 of them with bilharzial colonic polyposis were included, using different schedules of therapy. Niridazole in a dose 4 mg/ kg. B. W. daily for 20 days and oxamniquine 60 mg/kg. B.W. as a total dose divided over 3 days. The best results were obtained when both drugs were given simaltaneously. The cure rate in non polypotic bilharzial cases was 96.5% and in patients with plyposis 64.3%, while the cure rate using oxamniquine alone or using the two drugs in succession starting by either of them gave much less cure rate, [not more than 40%]. We can conchude that the best treatment of intestinal schistosomiasis with or without polyposis is the simultaneous administration of oxamniquine and niridazole in the above mentioned dosage schedule

Effects of ambilhar on the pregnant female rats and their neonates

The present work was undertaken to study the effect of ambilhar [antibilharzial drug] on the pregnant female rats and their necnates. Ten pregnant female rats were used in this work. They were divided into five experimental and five control animals. From the eighth till the fourteenth day of gestation, the experimental animals were given a daily oral dose of 6 mg Niridazole [ambilhar] dissolved in normal saline. All the rats were allowed to deliiver. The mothers and their neonates of both the experimental and the control groups were killed on the first day of delivery. The heart, liver, kidney and spleen were tajen for the histological and histochemical studied. Administration of ambilhar were followed by marked degenerative changes in the organs under investigation. Thansplacental passage was also proved in the present study as many histopathological changes were observed in the fetal organs. There were also a decrease in the activity of the alkaline phosphatase enzyme and the reaction of PAS. The significance of these findings was discussed

A schistosomiasis pilot control project in Lindu valley, Central Sulawesi, Indonesia.

This pilot control project was an intervention study, consisting of: 1) treating the positive cases with Niridazole; 2) spraying the foci with Niclosamide; 3) improving the water supply system and construction of public latrines. The intervention not only has lowered the human prevalence rate, but has also lowered the transmission of the disease in that area. Niridazole appeared relatively safe and effective, the cure rate after one year was 80%. Spraying the foci with Niclosamide 20-40 mg per litre did not appear very effective. Using this epidemiological data it was estimated that infected persons would become spontaneously negative after 4.75 years, if there was no reinfection.

Comparative toxicological study of some antibilharzial drugs

The data obtained in this work could be summarized as follows: 1. The LD 50 of tartar emetic was 49/kg, it produced a significant reduction of haemoglobin content and haematocrite value. It was the most toxic drug to the heart and lungs. Pharmacological studies showed that it produced direct depression on the isolated rabbits, heart, a perasympathomimetic effect manifested on isolated rabbits, intestine and blood pressure of anaesthetized dogs. 2. The LD 50 of astiban was 290 mg/kg. The results of subacute toxicity tests were similar to those obtained with tartar emetic but it was devoid of any toxic effect on heart. Pharmacological studies showed that it produced parasyupathomimetic effect on isolated rabbit's heart. 3. LD 50 of Hycanthone was 57 mg/ kg. No effect on the blood picture of rats was observed it was more toxic to the liver. It produced direct cardiac inhibition on the isolated rabbit's hearts, parasympathomimetic effect on the isolated rabbit's intestine and blood pressure of dog. 4. LD 50 of niridazole was 990 mg/ kg. The results of subacute toxicity tests were similar to those obtained with hycanthone. It is more toxic to brain it produced direct cardiac inhibition on the rabbit's heart and hypotension in dog

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.

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.

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.

Virulence of Entamoeba histolytica according to the strains in Korea III. Amebicial response of antiamoebic agents on several strains of Entamoeba histolytica in vitro

The amebicidal activity of traditional anitiamoebic drug (emetine, carbasone, diodoquin, chloroquine, atabrine, chloramphenicol and tertracycline) and newly appeared chemicals(niridazole, metronidazole and No. 8603 substance) were assayed by in vitro experiment using five strains of human originated E, histolytica. The variety of amebicidal activity of drugs by the strains were discussed. Ranges of amoebicidal activity of traditional antiamoebic drugs kept almost similar titers of previous reports at the concentration; 1:5,000 to 1:20,000 with emetine hydrochloride, 1:10.000 to 1:20,000 with carbarsone, 1:8,000 to 1:16,000 with diodoquin, 1:50,000 with chloroquine, 1:1,000 to 1: 4,000 with atabrine ,1:1,000 to 1:2,000 with chloramphencol and 1:5,000 to 1:8,000 with tetracycline. The newly appeared chemicals showed higher amebicidal titres at the concentration; 1:500,000 to 1:5,000,000 with niridazole, 1:50,000 to 1:100,000 with metronidazol and 1:100,000 to 1:500,000 with No.8603 substance. Emetine, chloramphenicol and No. 8603 substance showed amebicidal activities at lower concentration to intestine originated amebae (YS 14, YS 15 and NAMRU II strain) than to liver originated amebae (YS 24 and YS 25 strain ), while carbarsone, chloroquine and metronidazole showed the activity at higher concentrations. Diodoquin showed lower amebicidal titres to trophozoite borne amebae (NAMRU II, YS 24 and YS 25 strain) than to cyst borne amebae(YS 14 and YS 15 strain), but niridazole showed converse results. The concentration of atabrine for amebicidal activity was not constant according to strains of the amoeba, but tetracycline showed almost settled titers.