The Antimalarial Activity of Tyrothricin Against Plasmodium Gallinaceum

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Abstract
Tyrothricin in various doses and by various routes has been tested against P. gallinaceum in 119 White Leghorn chickens (75-250 gm.) and its effect studied as compared with 44 untreated infections, with 26 infections treated with quinine by mouth, with 14 chickens given both tyrothricin and quinine and with 32 chickens treated with quinine intraven. Multiple doses of tyrothricin are not effective when given intraven. in dist. water, when given intraperit. in 9.5% alcohol or in dist. water, or when given in capsule by mouth, but are markedly effective curatively when given intraven. in 9.5% alcohol. The quinine equivalent of tyrothricin is approx. 4 for both sporozoite- and blood-induced infections when both drugs are given intraven. When tyrothricin is given intraven. as compared to quinine given per os, it is 20 or more times as effective. A comparable effective dose of tyrothricin (0.2 mg.), however, is nearer the lethal dose than is an effective intraven. dose of quinine (0.75 mg.) since chickens do not generally tolerate tyrothricin in intraven. doses larger than 0.3 mg. per 100 gm. chicken but easily withstand 2 mg. of quinine intraven. Tyrothricin produces predominantly parasiticidal effects and to a less extent inhibits growth and reproduction; quinine acts in the reverse order. The 2 drugs have an additive effect on the malarial infection and may act synergistically. Neither is prophylactic. Tyrothricin is effective curatively against sporozoite- or blood-induced infections if administered intraven. in 9.5% alcoholic soln. in approx. daily doses of 0.2-0.3 mg. per 100 gm. chicken from the time of infection through the crisis (about 12 to 15 doses). Smaller doses of 0.1 or 0.05 mg. are decreasingly effective. This treatment lengthens the incubation period of blood-induced (not of sporozoite-induced) infections, and lowers the peak of the acute infection and generally prevents fatal (but not slight) relapses in both sporozoite- and blood-induced infection. These last 2 effects are also noted if treatment is not begun until parasites appear in the blood (about 12-13 doses). A shorter course of treatment (2-6 daily doses) is effective in suppressing the acute rise of blood-induced (not tried in sporozoite-induced) infections if initiated when parasites first appear in the blood, but does not prevent fatal relapses. When initiated later during the acute rise of the infection, such a short course of treatment is progressively less effective until it becomes ineffective when the parasites exceed approx. 7,500 per 10,000 red blood cells. Tyrothricin on a wt. basis within a range of 0.1-0.5 mg. per ml. is more effective than quinine in inhibiting O2 consumption of parasitized red cells as measured in vitro by the Warburg Barcroft constant volume manometers. The course of P.gallinaceum in young chickens, as described by Brumpt and others, has been confirmed. The asexual cycle, as reported by Giovannola and others, is essentially 36 hrs. and is not markedly synchronous. The mean of merozoites per segmenter varies between 17 and 24 during the acute rise of the infection, but segmenters may form as few as 6 or as many as 36 merozoites (generally from 12 to 32). Exoerythrocytie forms, as first reported by James and Tate, have been found and are sometimes associated with fatal relapses in blood-induced infections after 3 weeks.