34

     Subcutaneous Quinine infusions being debarred, Quinine by the mouth.
with or soon after meals suggests itself as particularly suited for the treatment
of malaria in which sporulation is irregular, and also for prophylaxis. Quinine
by the mouth while fasting would be serviceable two or three hours before a
paroxysm where sporulation recurred regularly.

     In the curve representing absorption when Quinine is given with meals
(absorption in such a case according to Mariani^l3 is at its height between the
sixth and twelfth hours) it will be noticed that absorption from the fifth to the
thirteenth hour, i.e., for eight hours, is higher than it ever reaches when an or-
dinary Quinine hypodermic injection containing the same dose of Quinine is
given. It follows therefore that Quinine given with (or soon after) meals three
times a day every eight hours, will keep the amount of Quinine in the body at
a higher level than one could ever hope to do by giving similar doses of
Quinine hypodermically in the usual concentrated solutions.

Local and Post=mortem Changes found in the Guinea=pigs
used for the Minimum-Lethal Dose Experiments.

     A few minutes after injection into the subcutaneous connective tissue,
the skin overlying the injection become discoloured and yellow, and soon an
area of skin corresponding to the size of the injection had undergone necrosis
—killed directly by the action of the Quinine. The epidermis and hairs over
this area could be peeled off by rubbing it with the blunt edge of a knife. If
the animal survived, a red raw ulcer resulted; no pus was seen, possibly owing
to the tissues at the base and edge being saturated with Quinine which checks
diapedesis of leucocytes. In one case, where the injection had been large,
necrosis had extended on the deeper surface through all the abdominal muscles
right down to the peritoneum. The layer of muscle underneath the injection
was invariably necrosed and looked like washed gray leather. Not infre-
quently the yellow necrosed mass became surrounded by an inflamed indurated
area prior to the eschar being cast off. Even Quinine solutions so dilute as
1 in 150 had a severe necrotic action on all tissues with which they came in
contact: the superficial muscular layer of the abdominal wall was invariably
necrosed, as was also the skin, the result being generally, if the animal sur-
vived, a huge ulcer occupying the greater part of the surface of the abdominal
wall. This extensive ulceration and necrosis preclude Quinine infusions from
clinical use.

     If any blood vessels happened to be included in the eschar, they appeared
like black threads and could easily be picked out in the pale necrosed tissues:
the blood they contained was invariably clotted. In several instances, includ-