258 
MALARIA 
when they occur. The arguments for and 
against these respective plans lie outside 
the scope of this paper. 
With respect to the mode of action of 
quinine on the malarial plasmodium, it 
cannot be said that any real explanation 
exists. The earlier workers believed that 
the drug exerted a simple direct antiplas- 
modial action, and current texts on phar¬ 
macology to some extent still reflect this 
view. But the matter is not so simple. In 
the first place it has long been known that 
incubation of malarial blood with rela¬ 
tively high concentrations of quinine does 
not destroy the infectiveness of this blood 
in the production of therapeutic malaria 
(Kirschbaum 1923). The concentrations 
reached in the blood after either oral or 
intravenous administration are in the first 
place not high, and secondly they are not 
maintained (Chopra, Roy and Das Gupta 
1934) for more than a very brief period. 
It is difficult, therefore, to think that the 
action of the quinine in the blood stream 
or on the blood cells is a direct one on the 
parasite. The suggestion has been made 
that the drug retards the reproduction rate 
of the parasites. Acton and Chopra 
(1927), for example, hold that “it probably 
hinders reproduction by the formation of a 
smaller number of merozoites.” Krishnan 
(1933) added that quinine might increase 
the length of time necessary to complete 
an asexual cycle. There have been a num¬ 
ber of experimental studies on bird malaria 
which indicate that for these forms at least 
such disturbances of reproduction occur, 
both by retardation of the cycle and reduc¬ 
tion of the number of merozoites formed at 
schizogony (Manwell 1934; Boyd and Allen 
1934; Lourie 1934; Boyd and Dunn 1939). 
Observations such as these do seem to offer 
an explanation of the puzzling observation 
that a drug like quinine, so effective in 
reducing the number of parasites, fails to 
destroy all of them. They are also con¬ 
sistent with the observation that quinine is 
ineffective in reducing the number of 
gametocytes. Boyd and Dunn (1939) em¬ 
phasize the fact that these actions on repro¬ 
duction in experimental malaria in birds 
are observed when quinine is given during 
the growth period of the trophozoites. In 
human beings, James (1933) found that 
pretreatment of the patient with quinine 
did not prevent or retard the development 
of naturally induced malaria. 
The observations just listed do not offer 
a complete explanation of the action of 
quinine. At various times it has been held 
that some of the breakdown products of 
quinine might be responsible for the anti- 
malarial action, since quinine itself is not 
very toxic for the malarial organism. An¬ 
other way of getting around this difficulty 
has been to suggest that quinine favored the 
production or activation of some natural 
antibodies (Yorke and Macfie 1924b). Other 
observers have assigned to the reticulo¬ 
endothelial system a role in the activity 
of quinine and other antimalarial drugs. 
This view is based on the finding that pre- 
treatment with trypan blue, which blocks 
the reticulo-endothelial system, reduces 
the effectiveness of antimalarial drugs in 
the treatment of experimental infections 
(Kritschewski and Demidowa 1934). 
While quinine is the alkaloid present in 
cinchona bark in greatest amount, other 
alkaloids are present to an extent justify¬ 
ing investigation of their effectiveness 
against malaria. Investigations of the effec¬ 
tiveness of these alkaloids have been com¬ 
plicated by the difficulty of obtaining com¬ 
pletely pure specimens of the individual 
alkaloids. The complete separation of these 
alkaloids is apparently not feasible except 
as a research project, and the ordinary 
medicinal preparations are far from pure. 
In Table II are given the probable impuri¬ 
ties, according to Dawson. 
The first and still the most extensive com¬ 
parative study is that of the Madras Cin¬ 
chona Commission (1867-68). This work 
was done before the discovery of the ma¬ 
larial parasite, and the criterion of cure 
was “cessation of febrile paroxysms.” 
Although the alkaloids used certainly were 
not pure, the results obtained serve as con¬ 
vincing evidence that there is no great dif¬ 
ference in clinical effectiveness of the four 
major alkaloids. In Table III is given a 
