EXPERIMENTAL CHEMOTHERAPY IN MALARIA 
By JOHN MAIER 
LABORATORIES OF THE INTERNATIONAL HEALTH DIVISION, ROCKEFELLER FOUNDATION, 
NEW YORK 
Present methods of malarial control are 
inapplicable in many regions of the world 
because of the high cost of antimosquito or 
antilarval measures. In these areas the use 
of antimalarial drugs probably constitutes 
the only practical control measure. Clark 
and his associates in Panama (1940) have 
shown that the intensive and widespread 
use of quinine and atabrine over a period 
of 9 years has not significantly altered the 
incidence of malaria; indeed, an epidemic 
occurred during the 9th year of the study. 
There is no question of the value of quinine 
or atabrine from the point of view of the 
individual with acute malaria. However, 
from the broader aspect of the control of 
malaria as a world problem, antimalarial 
drugs have been deficient. 
The failure of drug control of malaria 
is attributable principally to two well rec¬ 
ognized limitations: (1) The present anti¬ 
malarial drugs do not have any specific 
prophylactic action against the sporozoite. 
(2) They do not always sterilize the acute 
or chronic infection. This permits the oc¬ 
currence of clinical and parasitic relapses, 
and the accumulation of large reservoirs of 
carriers who are periodically infective for 
mosquitoes. 
It is possible that a drug superior in 
either respect to quinine, plasmochin or 
atabrine would be more efficient in malarial 
control. Further research in malarial 
chemotherapy is desirable, in the hope of 
discovering such a drug. Several consid¬ 
erations as to the best procedure are appar¬ 
ent. First, many thousand quinoline and 
acridine derivatives have'already been syn¬ 
thesized and tested in the research which 
led to the discovery of plasmochin and 
atabrine. These latter drugs, together with 
quinine, may be regarded as the best of 
their type. Further testing of related 
chemicals does not offer much hope of suc¬ 
cess. Accordingly, the best method of 
approach is the routine testing of unrelated 
chemicals until one is discovered which has 
an effect on either the sporozoite, tropho¬ 
zoite, or gametocyte. The only require¬ 
ment known for a potential antimalarial 
drug is that it must be able to penetrate 
the red cell as suggested by Hegner et al. 
(1928) and Shaw (1928). When some de¬ 
gree of activity has been found in a com¬ 
pound, all its derivatives can then be inves¬ 
tigated. Up to this point, however, the 
work must be more or less empirical. No 
completely rational selection of chemicals 
is possible because the mode of action is not 
known for any chemotherapeutic agent. 
Methods available for testing anti¬ 
malarial drugs are as follows: 
1. In vitro testing 
2. Experimental malaria 
a. Monkey malaria 
b. Canary malaria 
c. Chick malaria 
3. Human malaria 
a. Autochthonous infections 
b. Induced infections in paretics 
1. In Vitro Testing 
Because of the expense and difficulty of 
using large numbers of animals, a reliable 
m vitro test would greatly facilitate the 
testing of drugs. Fulton and Christophers 
(1938) found that quinine and atabrine 
produced inhibition of respiration of P. 
knowlesi as measured in a Warburg ma¬ 
nometer. This method was studied as a 
means of evaluating potential antimalarial 
drugs (Coggeshall and Maier 1941). One 
cc of blood from a heavily infected monkey 
is placed in a conical Warburg flask with 2 
cc of M/15 phosphate buffer, pH 7.35. An 
accurately weighed sample (10 to 20 mg) of 
the drug to be tested, dissolved or sus¬ 
pended in 0.5 cc of Ringer’s solution, is 
