264 
MALARIA 
in its administration. Atabrine has been 
found in the urine of patients as late as 9 
weeks after the termination of the course of 
treatments (Roehl 1926), and it has there¬ 
fore been suggested that treatment should 
not be repeated within an interval of less 
than 8 weeks and that the total amount 
given in any one period of treatment should 
not exceed 2 gm (0.3 gm per day). 
Cumulative effects have been observed in 
animals (Martin, Cominole and Clark 1939; 
Dawson et al. 1935). Thus, with a single 
peroral administration the lethal dose of 
atabrine in dogs was 300 mg per kg, but 
a dose of 100 mg per kg was fatal when 
administered daily over 15 to 27 days, and 
even a dose as small as 10 mg per kg re¬ 
sulted in a loss of weight in all dogs. 
The signs of atabrine poisoning are 
anorexia, salivation, vomiting, epigastric 
pain of colicky type, occasional headache 
and yellowing of the skin (the latter due 
to the staining properties of the drug and 
not to liver damage (Kingsbury 1934)). 
Occasionally psychic disturbances have been 
reported after administration of relatively 
small therapeutic doses (6 to 15 tablets) 
starting within 1 % to 9 days after initiation 
of the treatment and lasting up to several 
days. However, while in these cases the 
mental disturbances were sufficiently severe 
to necessitate hospitalization in a mental 
asylum, the frequency as well as the danger 
of this complication is rather small (Craig 
1939). The cause of this side-effect, which 
is not found with other antimalarials, is 
not yet definitely established; it may be due 
to a direct effect of the drug on the brain 
or to an increased liberation of parasitic 
toxins during the first few days of treat¬ 
ment. 
The pathological findings in atabrine 
poisoning consist of a marked hyperemia 
and toxic central injury to the liver and a 
fatty degeneration of the renal tubules. 
In liver and kidney function tests on 
dogs it was found (Clark, Cominole and 
Martin 1939) that the degree of liver im¬ 
pairment depends upon the dose and the 
length of administration. The kidney func¬ 
tion, tested by urea clearance, non-protein 
nitrogen in blood and phenolsulphonphtha- 
lein, showed no evidence of damage in 11 
out of 12 dogs after daily administration 
of 17 to 66 per cent of the minimum lethal 
dose for a period up to 40 days. 
In experiments with the Warburg 
method on isolated brain and testicular 
tissue atabrine did not depress the oxygen 
consumption, indicating that it is not a 
general protoplasma poison. Unlike plas- 
mochin it does not cause methemoglobin 
formation or hemolysis in vitro or in vivo 
(Hecht 1933). 
Atabrine is rapidly absorbed from the 
gastrointestinal tract and within a few 
minutes after administration is found 
evenly distributed over the body tissues 
(Hecht 1936). After 2| hours a greater 
concentration is found in the liver, gall 
bladder and intestines, and it accumulates 
subsequently in the duodenum and upper 
ileum, while only little is found in the lower 
portion of the small intestine and in the 
feces. After 5 days it is still detectable in 
the gall bladder and upper portion of the 
gastrointestinal tract and it requires 7 to 8 
days before the last traces disappear from 
all organs. The accumulation of atabrine 
in the liver offers an explanation for the 
great difference between the peroral and 
intravenous toxicity (Blaze and Simeons 
1935). Atabrine is probably selectively 
adsorbed by the erythrocytes and parasites, 
since it has been shown (Fischl and Singer 
1934) that even washing with alcohol fails 
to extract it completely from blood. 
Atabrine is only occasionally found in 
the cerebrospinal fluid and appears in the 
brain only after injection of lethal doses. 
It is excreted in part in chemically un¬ 
changed form; the amounts present in the 
urine and feces are about of the same order 
of magnitude. After discontinuation of 
the administration, the excretion drops to 
a low level which is maintained for several 
days (Tropp and Weiss 1933). 
The distribution of atabrine in various 
body fluids and tissues has been studied in 
cats, dogs and rabbits with an extremely 
sensitive method, capable of detecting 0.5 
micrograms in 1 gram organ (Hecht 1936). 
