Neurotoxicity of the 8‐aminoquinolines. II. Reactions of various experimental animals to Plasmocid

Abstract

Plasmocidr6-methoxy-8-(3-diethylaminopropy1amino)quinolrine] was one of a large number of 8-aminoquinoline derivatives examined during the recent wartime search for more effective antimalarial drugs (Wiselogle, '46). As mas the general practice in this search, detailed studies of the reactions of various lower animals to the above compound were made preliminary t o a projected trial in liuman mal t~r i a .~ These investigations, which iiduded both acute and subacute experiments, revealed rather striking differences in the effects of Plasmocid on different experimental animals (Wiselogle, '46). In rhesus and cynomolgus monkeys, fatal intoxication produced a complex group of neurological symptoms including extreme hyperesthesia, nystagmus, loss of pupil1,ary reflexes. loss of equilibrium, and incoordination of lPart of the work described in this report was carried out under a contract recommended by the Committee on Medical Research beween the Office of Scientific Rmearch and Development and The Christ Hospital Institute of Medical Research.aThe compound was designated as SN 3115 in the records of the Survey of Antiinalarial Drugs (Wiselogle, '46). It was described originally by Fornrau, Tr6fouB1, Bovet and Benoit ('31) and has been designated since as F 7'10, Rliodoquine, Plasmocide, Plasmozid, and Plmmocid.S A s a result of the findings in experimental animals, the activity of Plasmocid against human nialaria was not studied during the OSRD program. 337

Relationships between chemical structures of 8-aminoquinolines and their capacities for radical cure of infections with Plasmodium cynomolgi in rhesus monkeys

“…Both have the diethylamino-n-propylamino side chain common to plasmocid, a 6-methoxy-8-substituted compound that once attracted interest as an antimalarial drug (25,65). Such interest vanished, however, when it was found that this compound, administered at approximately onefourth to one-eight of the minimum lethal dose to rhesus monkeys, evoked a syndrome attributable to destructive lesions in the spinal cord, brain stem, diencephalon, and corpus striatum (49) and that neurologic reactions, doubtless similar to these in origin, occurred in human subjects after administration of the compound either for treatment of malaria or as an abortifacient (50). Surprisingly, compounds 106 and 184 did not evoke symptoms of neuronal damage either at doses that were curative or at much larger doses up to and including those that were lethal.…”

Idiosyncratic quinoline central nervous system toxicity: Historical insights into the chronic neurological sequelae of mefloquine

“…A 1945 review of the foreign literature cited a diverse range of more serious neurological effects including severe ataxia, convergence disorder, smoothing of the nasolabial fold, and deviation of the tongue (Board for the Coordination of Malarial Studies, 1945) suggestive of focal brainstem dysfunction. A review of 76 human cases of neurological effects attributed to plasmocid toxicity found a range of lasting deficits, including in equilibrium, coordination, and eye muscle movement; some of these symptoms “persisted for months or years after termination of treatment” (Schmidt and Schmidt, 1949). …”

Tafenoquine and primaquine do not exhibit clinical neurologic signs associated with central nervous system lesions in the same manner as earlier 8-aminoquinolines

“…One of the first 8-aminoquinolines (8AQs) used in clinical practice, plasmocid, was found to cause severe neurologic adverse events at therapeutic doses [ 1 ]. Subsequently, a sub-set of these adverse events was also observed in rhesus monkeys and linked to drug-induced degeneration of specific neuro-anatomical structures [ 2 ].…”

“…For the purpose of this review, neurologic therapeutic indices (neurotoxic dose/antiparasitic dose) were calculated only for a single animal species: Rhesus monkeys. This is because: (i) the archetypal compound, plasmocid, although being neurotoxic in Rhesus, rats and dogs, displayed its most pronounced effects in Rhesus monkeys ([ 1 ], see Table 1 ); (ii) comparable data from other species was not available for pamaquine, pentaquine and PQ; and, (iii) there is no animal model other than the Plasmodium cynomolgi -infected Rhesus able to predict efficacy against P. vivax hypnozoites in humans [ 20 ].…”