SOME PHARMACOLOGICAL AND TOXICOLOGICAL PROPERTIES OF SULFANILAMIDE AND BENZYLSULFANILAMIDE

¹ Merck Institute of Therapeutic Research, Rahway, New Jersey

1. In oral toxicity experiments the l.d. 50 of sulfanilamide (suspended in gum acacia) was 4.8 grams per kilogram in mice, 6.2 grams per kilogram in rats and 3 grams per kilogram in rabbits. Oral administration of benzylsulfanilamide did not produce death at any dose level.

2. The cumulative toxicity of sulfanilamide and benzylsulfanilamide was determined in mice and rats by feeding single daily doses for 10 consecutive days. Under these conditions the toxicity of benzylsulfanilamide remained practically unchanged, while that of sulfanilamide was increased, the l.d. 50 being 3.5 grams per kilogram for mice and 4.2 grams per kilogram for rats.

3. The chronic toxicity was studied by daily feeding with stomach tube of sulfanilamide and benzylsulfanilamide to rats for 120 days, to rabbits for 32 days and to dogs for 50 days. Benzylsulfanilamide remained nontoxic, while the toxicity of sulfanilamide became more pronounced. Animals were sacrificed after 10, 20, 30, 50 and 120 days of feeding and examined anatomically and histologically. The organs of the benzylsulfanilamide animals were found to be normal, while the sulfanilamide animals showed a pronounced enlargement of the spleen and occasional degenerative changes in the liver and kidney.

4. Nervous symptoms such as ataxia, clonic convulsions and paralysis, which are regularly produced by large doses of sulfanilamide, were not found with benzylsulfanilamide.

5. No significant changes in the circulatory and respiratory system are produced by either drug. After administration of lethal doses of sulfanilamide death occurs from respiratory failure.

6. While doses of sulfanilamide up to 2 grams per kilogram produced no significant changes on the water diuresis of rats, larger doses (3 and 4 grams per kilogram) markedly decreased the urinary output. No significant changes were observed with benzylsulfanilamide.

7. Administration of large amounts of fluid together with or following the administration of sulfanilamide increases its toxicity. This is probably due to an increased rate of absorption and a decreased urinary output, since within one hour the blood concentration of sulfanilamide in the animals receiving water is considerably greater than in the control animals.

8. The liberation of sulfanilamide in the blood of mice, rats, rabbits and dogs fed benzylsulfanilamide was determined. The concentration found may be sufficient to account for the therapeutics properties reported for benzylsulfanilamide.

9. If the therapeutic effect of benzylsulfanilamide is solely due to the liberation of sulfanilamide, its clinical usefulness would appear to be limited to infections which will respond favorably to the moderate concentration of sulfanilamide in the blood.

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