ANTIMALARIALS OTHER THAN QUININE 
263 
standstill (Le Heiix and de Lind van 
Wijndgaarden 1928). In the heart-lung 
preparation, concentrations as small as 
1: 500,000 greatly decrease the ability of the 
heart to overcome increased peripheral re¬ 
sistance and a concentration of 1:50,000 
induces diastolic standstill. The minimal 
concentrations causing such an effect are, for 
plasmochin, 1: 2000; for atabrine, 1: 500; 
and for quinine, 1:300. Plasmochin, in 
small concentrations, causes vasoconstric¬ 
tion ; in large concentrations, vasodilatation 
in the frog’s leg, rabbit’s ear, coronary and 
pulmonary vessels. It lowers the blood 
pressure, primarily due to a direct effect 
on the heart. In a comparison of plas¬ 
mochin with atabrine and quinine in the 
electrocardiogram of man and dog, all three 
drugs were found to be negative chrono¬ 
tropic and negative dromotropic. All 
three cause in the isolated monkey-heart 
irregular beat and diastolic standstill (de 
Langen and Storm 1935). In contrast to 
quinine, which in submaximal doses in¬ 
creases the minute volume and does not 
affect the vasomotor center, both plas¬ 
mochin and atabrine in comparable doses 
decrease the minute volume and impair 
the function of the vasomotor center. 
The pharmacological effects of plasmochin 
on other organs or organ systems are not 
pronounced. It does not alter the diuresis 
(Le Heux and de Lind van Wijndgaarden 
1928) and, up to sublethal doses, does not in¬ 
fluence experimental fever, such an induced 
by the injection of Bacillus coli or puncture 
of the temperature regulating center in the 
midbrain (Girndt 1929). Even if injected 
into the brain or directly applied to the 
temperature center, it lowers the body tem¬ 
perature only for the duration of the 
severe toxic effects. 
Plasmochin is probably rapidly absorbed 
from, and not to any great extent destroyed 
in, the gastro-intestinal tract, since the 
toxic signs follow very rapidly its peroral 
administration. It appears in the urine 
within 20 minutes after administration, but 
the amount excreted is only small, e.g., of 
a total of 127.5 mg administered only 2 
mg were excreted during the first 2 days; 
probably it is quickly destroyed in the 
tissues. 
Atabrine 
Atabrine was synthesized in 1933 by 
Mietzeh and Mauss. It is an acridin dye 
of the formula 2-methoxy-6-chloro-9-a-di- 
ethylamino - S - pentylaminoacridin and is 
structurally not related to quinine. It is a 
powder of light yellowish color, with a M.P. 
of 245-255° C. In nputral solution it is 
readily water soluble, at room temperature 
up to 2.5 per cent; at 40° C up to 7 per cent. 
In ultraviolet light it shows a strong 
fluorescence which is easily detectable in 
aqueous solutions up to 1 part in a million. 
In its antimalarial action it resembles 
quinine far more than plasmochin, having 
the pronounced antischizontic effect of the 
former and lacking the gametocidal effect 
of the latter (Kikuth and Giovannola 
1933). Its activity in proteosoma infected 
canaries is about 4 times greater than that 
of quinine but 15 times less than that of 
plasmochin. Its chemotherapeutic index 
is 1: 30, the same as that of plasmochin. 
The toxicity of atabrine varies consider¬ 
ably with different species and with the 
mode of administration, ranging from 200 
mg per kg in cats and mice to 500 mg 
per kg in rabbits (Koyu 1937; Hecht 
1933). Particularly noteworthy is the great 
variation in toxicity with different meth¬ 
ods of administration. Thus the intra¬ 
venous lethal dose is 20 to 40 times smaller 
than the peroral, depending greatly upon 
the rate of injection (Dawson, Gingrich and 
Hollar 1935); e.g., intravenous injection of 
5 mg per kg to dogs over 30 to 60 seconds 
resulted in the death of 21 per cent of the 
animals while a similar injection of an even 
greater dose (7.5 mg per kg), but over a 
period of 60 to 90 seconds, caused only 4.8 
per cent deaths. Because of the marked 
increase in toxicity upon intravenous in¬ 
jection it has been suggested that for thera¬ 
peutic purposes this mode of administra¬ 
tion should be avoided except in emer¬ 
gencies. The cumulative effect of atabrine 
and its very slow and prolonged excretion 
are additional factors which suggest caution 
