270 
MALARIA 
TABLE II 
The Chemotherapeutic Activity op 0.01 M 
Sodium Sulfathiazole Against 
Various Plasmodia 
0 2 uptake 
(mmyhr/10 e 
Coeffi¬ 
Plasmo¬ 
dium 
parasites) 
cient 
of 
inhibi¬ 
Thera¬ 
Con¬ 
Flask 
peutic 
trol 
with 
tion 
effect 
flask 
drug 
l-llfl 
I 
II 
mm 3 
mm 3 
P. cathe¬ 
merium ... 
9.5 
6.1 
36 
0 
21.4 
13.7 
36 
P. cyno¬ 
molgi . 
5.9 
2.9 
51 
+ 
2.2 
1.1 
50 
P. inui . 
6.4 
2.7 
58 
+ 
P. lophurae 
12.2 
9.5 
22 
0 
0 No effect. 
+ Temporary diminution in circulating parasites. 
the same dosage and the same manner to 
monkeys with P. cynomolgi or P. inui infec¬ 
tions, it produces only a temporary diminu¬ 
tion in number of circulating parasites, 
without sterilization. 
Sodium sulfathiazole also produces inhi¬ 
bition of respiration of P. cathemerium (36 
per cent) and P. lophurae (22 per cent). 
It has no demonstrable effect on the infec¬ 
tions produced by these parasites in ca¬ 
naries and chickens, respectively. 
It can be stated, therefore, that inhibi¬ 
tion of in vitro respiration cannot be used 
as a sole guide to the chemotherapeutic 
efficiency of a drug, but should be used only 
in conjunction with other information. 
The in vitro method is valuable for com¬ 
paring the effectiveness of closely related 
compounds in a series. However, its use¬ 
fulness is limited to relatively soluble 
chemicals of simple structure, active in 
their original form, and not converted from 
an inactive to an active form in the body. 
Since the mode of action of sulfanilamide 
and its derivatives is not known, there is 
no explanation of the lack of correlation 
between the marked in vitro effect on the 
respiration of P. inui and P. cynomolgi and 
the slight in ■vivo effect. Similarly, there 
is no explanation for the complete lack of 
effect of sodium sulfathiazole upon P. 
cathemerium and P. lophurae infections, 
although the drug inhibits the respiration 
of both parasites in vitro. It can only be 
said that some factor other than a direct 
effect of drug on parasite as evidenced by 
inhibition of respiration, is responsible for 
the sterilization of P. knowlesi infections. 
2. Experimental M at, ar t a 
It is apparent from these facts that in 
vivo testing is necessary to exclude inactive 
drugs and to give some indication of the 
activity of effective drugs to be tested 
further. Of the common laboratory ani¬ 
mals, rhesus monkeys, canaries, and chicks 
are available for testing purposes. 
a. Monkey malaria. Three plasmodia 
which are infectious for monkeys are avail¬ 
able. Of these, P. knowlesi is the best for 
drug testing because of the highly stand¬ 
ardized type of infection which it produces. 
It causes death in 5 to 6 days from the time 
of appearance of circulating parasites in 
over 99 per cent of normal animals. Hence, 
any animal which lives after being given a 
drug can be said to have been protected by 
that drug, within a very small margin of 
error. Sulfanilamide was shown by Cog- 
geshall (1938b) to sterilize P. knowlesi 
infections in rhesus monkeys. Since then 
sulfathiazole, sulfapyridine, prontosil, neo- 
prontosil, and sulfadiazine have been 
shown to be equally effective. The only 
sulfanilamide derivative which has not 
produced complete sterilization of this in¬ 
fection has been quinine sulfanilamide 
bisulfate. Its failure is probably due to 
the fact that only 28 per cent of the mole¬ 
cule is sulfanilamide, and doses large 
enough to include the necessary amount of 
sulfanilamide are fatal. 
There is no indication that any of these 
drugs have any significant effect on human 
malaria. There is apparently some charac¬ 
teristic peculiar to P. knowlesi which ren¬ 
ders it susceptible to sulfanilamide and 
allied compounds. Perhaps the fact that it 
is one of the most virulent of the malarias 
makes it more readily affected by a drug, 
