EXPERIMENTAL CHEMOTHERAPHY IN MALARIA 
271 
just as only virulent strains of hemolytic 
streptococci are susceptible to sulfanila¬ 
mide. 
P. cynomolgi produces a milder infection 
in the rhesus monkey, never fatal in our 
experience, and characterized by a chronic 
course of long duration, with a few para¬ 
sites (2 to 10 per 10,000 red cells) almost 
constantly in the circulating blood over a 
period of months. P. inui produces the 
same type of infection but of shorter dura¬ 
tion. P. cynomolgi can be transmitted by 
A. quadrimaculatus, which makes it possi¬ 
ble to test drugs for effect on the sporo¬ 
zoites of this parasite. These parasites are 
much less susceptible to sulfanilamide and 
its derivatives than is P. knowlesi. By giv¬ 
ing 0.5 gm intraperitoneally and 1.0 gm by 
mouth on 2 successive days, it is usually 
possible to free the blood temporarily of 
circulating parasites, which, however, re¬ 
appear in about 2 weeks, so that there is 
no sterilization comparable to that achieved 
with P. knowlesi. With P. cynomolgi and 
P. inui infections sterilization is the only 
reliable criterion on which to evaluate a 
drug inasmuch as the course of the infec¬ 
tion is so variable. For this reason, they 
are less satisfactory for chemotherapeutic 
testing than P. knowlesi infections where 
protection from death can be regarded as 
demonstrating the effect of a drug. 
b. Canary malaria. Canaries are more 
satisfactory for the routine testing of large 
numbers of new drugs of unknown toxicity. 
The Hartman strain of P. cathemerium 
produces a standardized type of infection 
to which normal canaries are uniformly 
susceptible. The acute infection results in 
parasite counts of varying height and may 
progress to death or to a crisis after which 
parasites disappear from the blood.stream 
within 1 or 2 days. Because the behavior 
of a given acute infection cannot be pre¬ 
dicted or controlled, we do not use its re¬ 
sponse to treatment in the evaluation of the 
effectiveness of a drug. Increase in the 
incubation period of the infection, with 
retarded appearance of the parasites in the 
blood stream, is a better index, uncompli¬ 
cated by factors of immunity, as suggested 
by Roehl (1926). Birds are inoculated in 
the pectoral muscle with 0.02 cc of blood 
from a heavily infected canary (parasite 
count 1000 per 10,000 red cells or more). 
Parasites first appear in the circulating 
blood in 3 to 5 days. Solutions or suspen¬ 
sions of drugs to be tested are fed by stom¬ 
ach tube (No. 9 soft rubber catheter at¬ 
tached to a tuberculin syringe) for 6 days, 
beginning on the day of inoculation. 
Delay in the time of appearance of the 
parasites is taken as a measure of effective¬ 
ness against the parasite. Quinine dihydro¬ 
chloride (2 mg per day per bird) when 
given in this manner will delay the incu¬ 
bation period to 15 days or more. Birds 
treated with atabrine (1 mg per day per 
bird) or plasmochin (2 mg per day per 
bird) usually fail to show circulating para¬ 
sites for periods up to a month, which is 
as far as experiments have been carried. 
Such birds in several cases were success¬ 
fully reinoculated, proving that they had 
been protected against the infection com¬ 
pletely. 
It is also readily possible to obtain sporo¬ 
zoites of P. cathemerium from Culex 
pipiens in order to test drugs for prophy¬ 
lactic action. 
Sodium sulfathiazole given in very large 
doses (62.5 mg per day per bird) failed 
to prolong the incubation period over that 
of the controls. In addition, the parasite 
count rose to levels as high as those found 
in the controls. P. cathemerium seems to 
resemble human plasmodia closely in its 
behavior toward drugs and should be a 
more reliable guide in chemotherapeutic 
testing than P. knowlesi seems to be. This 
is another reason why canary testing is 
superior to monkey testing. 
c. Chick malaria. P. lophurae is the 
only parasite available which is infectious 
for chicks. It has not been extensively 
used in chemotherapeutic tests because of 
the variability and short duration of the 
infection and the necessity for intracar¬ 
diac or intravenous inoculation. Wolf son 
(1940) has stated that ducks are very sus- 
