Experimental Chemotherapy of Trypanosomiasis

III. Effect of Achromycin against Trypanosoma Equiperdum and Trypanosoma Cruzi

R. I. Hewitt Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York

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W. S. Wallace Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York

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A. R. Gumble Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York

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E. R. Gill Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York

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J. H. Williams Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York

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Summary

The effects of Achromycin, a new antibiotic isolated from Streptomyces albo-niger, against Trypanosoma equiperdum in mice and rabbits, and T. cruzi in vitro and in mice are described. When administered intraperitoneally to mice in multiple doses, beginning within 2 to 6 hours after inoculation with trypanosomes, the total dosage required to cure T. equiperdum infections is about 70 to 140 mg. per kg. (10 to 20 mg. per kg. for 7 doses). It is effective orally at slightly higher doses. When treatment is withheld until near the crisis of infections, correspondingly higher doses are required to produce curative effects. Single parenteral doses of 100 mg. per kg. or greater are required to produce cures, although there is a positive correlation in this respect between the number of trypanosomes used for inoculum and the dosage of Achromycin administered. In rabbits, infected with T. equiperdum, 20 mg. per kg., once daily, intravenously for from 7 to 14 days (total dosage, 140 to 280 mg. per kg.) has caused the disappearance of well developed lesions with no relapse for 3 to 5 months thereafter. Intramuscular treatment is effective at 40 mg. per kg. for four or more doses. Trypanostatic effects against T. cruzi in vitro are produced by Achromycin in dilution of 1–40,000 or less, and variable effects are produced in vivo against this parasite in mice when treatment with 20 mg. per kg. or more twice daily, for 12 to 24 doses is administered, starting treatment within 24 hours after inoculation. Some mice have been “cured” at these doses and others have not. Achromycin is apparently not effective against the tissue stages of T. cruzi. The LD50 values of Achromycin in mice are 360 mg. per kg. (intravenous), 520 mg. per kg. (intraperitoneal) and 678 mg. per kg. (oral), and there is evidence of kidney damage after the repeated administration of 25 to 100 mg. per kg. parenterally to rats for from 1 to 4 weeks.

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