JOURNALOF NEUROPATHOLOGY & EXPERIMENTAL NEUROLOGIC

VOLUME 10 JULY 1051 N U M B E R 3

N E U I I O TO X I C I T Y O F T H E 8-AMINOQUINOLINES
I I I . THE EFFECTS OF PENTAQVINE, ISOM:NT:WINNE, PRIMAQVINE, AND
PAILkl/CINE ON TUE CENTILLL NERVOUS SYSTEM OF THE
RHESUS MONKEet
IDA G. SCHMIDT, Pu.D.
Aso
L. 11. SCILM1DT, Pu.D.
[Cincinnati, Ohio)

The systematic search f o r curative antimalarial drugs, carried o u t during

World War I I (1) and in the period thereafter, has led to the development of
three 8-aminoquinoline derivatives which, as judged b y studies on a limited
number of human volunteers (2, 3), appear t o be significantly superior to the
older compound, pamaquine (Plasmochin). These new derivatives are penta-
quine, isopentaquine, and primaquine,' the chemical structures o f which are
set forth in Figure 1.
The basic experiments (4), which assisted in establishing the position of the
above 8-aminoquinolines in the treatment of relapsing malaria in man, included
studies of the reactions of the rhesus monkey to these drugs with special refer-
ence to effects on the central nervous system. Interest in the latter effects rested
on the observation t h a t the closely related compound, Plasmocid, when a d -
ministered t o rhesus monkeys, evoked a complex group of neurological symp-
toms, associated with severe and widespread degenerative lesions in various cell
groups of the spinal cool, brain stem, and cerebellum (1, 5-7). Whereas intoxica-
tion w i t h even multilethal doses of pentaquine, isopentaquine, or primaquine
did n o t evoke similar symptoms, the close structural relations o f these com-
pounds to Plasmocid (fig. 1), their high inherent toxicity and capacity to evoke
reactions which might mask symptoms of low grade neuronal injury, plus the
likelihood of their widespread use in malaria therapy made a detailed search for
central nervous system lesions highly desirable.
The present report deals with the results of systematic histological studies of
the brains and spinal cords of rhesus monkeys with varying degrees of intoxica-
tion w i t h pentaquine, isopentaquine, o r primaquine. Studies on the older 8 -
aminoquinoline, pamaquine (fig. I ) , arc presented for comparison.
• From the Department of Anatomy, College of Medicine, University of Cincinnati,
and The Christ Hospital Institute of Medical Research, Cincinnati, Ohio.
The work described in this report was initiated under a contract, recommended by
the Committee on Medical Research, between the Office of Scientific Research and De-
velopment and The Christ Hospital Institute of Medical Research and carried to com-
pletion with the partial support of a gmnt-in•aid from the Division of Research Grants
and Fellowships, National Institutes of Health, United States Public Health Service.
1These compounds were first prepared during the war years, under auspices of the
Survey of Antimalarial Drugs, which designated the compounds as follows: pentaquine,
SN 13,276; isopentaquine, SN 13,274; primaquine, SN 13,272; and pamaquine, SN 971.
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