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Phenothiazine—A Remarkably Efficient Anthelmintic
dosed with 80 times an effective anthelmintic dose without any signs of intoxi-
cation being produced. Horses appear to be only slightly less tolerant,
Lapage, as reported in this symposium, having given as much as 500 grammes
without producing marked symptoms, and a repeat dose of the same amount
without causing a fatal intoxication; further data given by him, however,
strongly suggest that 1,000 grammes produced a fatal result, although lesions
found on post-mortem examination suggested that other pathological conditions
may have been involved in the cause of death. Cattle, on the other hand,
appear to be more sensitive to the toxic action of phenothiazine, 85 grammes
having produced a fatal intoxication in a 105 lb. calf. The observations that
we have been able to make concerning the use of the drug in cattle are few, but
even in these animals the difference between the anthelmintic and the toxic
dose appears to be considerably greater than it is with most, if not all other
efficient anthelmintics.
Our observations have, however, revealed evidence of individual idiosyn-
crasy, or possibly of some special susceptibility associated with diet, so that we
cannot yet write with certainty on the general safety of the larger doses. Our
experience with goats provides an example of this point in that doses of 20
grammes and 30 grammes produced decided symptoms of intoxication at one
time (shortly after the arrival of the animals at the Laboratory) and at a later
date amounts as great as 400 grammes failed to produce any signs of even the
slightest indisposition.
Some evidence of this occasional intoxication has also been seen in horses,
slight constitutional disturbance having been shown on a few occasions, in the
form of dullness and inappetence lasting for about 24 hours after the adminis-
tration of the dose.
Observations made to determine the toxic dose in rabbits showed that a
single dose of 6 grammes causes more or less marked constitutional disturbance
and that 10 grammes is fatal, representing a toxic dose of 4 grammes per kilo.
The effect of repeated daily doses proved to be more marked ; one rabbit
died after only four consecutive daily doses of 2 grammes, another after seven
daily doses of 5 grammes, a third after 17 daily doses of 1 gramme and a fourth
was still surviving and showed little sign of intoxication after 28 daily doses
of 0.5 grammes. The toxic repeated daily dose is therefore seen to lie some-
where between 0.05 and 0.1 gramme per kilo.
The principal lesion seen on post-mortem examination was that of acute
gastritis, the condition being less acute, and progressing to ulceration confined
to the pyloric end of the stomach, in the lower doses. In one or two instances,
the small intestine was slightly inflamed, the liver sometimes showed signs of
fatty, degeneration and the kidneys were sometimes pale in colour and
enlarged.*
Further evidence of the greater toxicity of the repeated small doses over
one large one was also obtained in experiment No. 8 in which daily doses of
only 10 grammes killed one sheep and caused a relatively severe constitutional
* We have not yet had the opportunity of examining this and other material micro-
scopically. Eddy et al. (1937), however, failed to find any injury to tissue after 295
consecutive daily doses to rats although the rats became stunted if the dose was suffi-
ciently high.