Neurotoxicity of the 8-Aminoquinolines

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

“…During early human testing of the 4-quinolinemethanols during the U.S. military’s World War II era drug discovery program (Alving et al, 1948) these drugs exhibited some evidence of the CNS toxicity observed from related synthetic quinoline compounds (Schmidt and Schmidt, 1951), including producing visual photosensitivity or photophobia (Pullman et al, 1948). One particularly efficacious 4-quinolinemethanol known as SN 10,275 induced headache and visual photosensitivity (Pullman et al, 1948) but also induced phototoxicity which may have masked recognition of underlying CNS effects.…”

“…Interestingly, in 1978, a leading authority involved in the development of mefloquine had noted that the drug “promises to be broadly useful” in the treatment and prophylaxis of malaria, but that “[if] this promise is not realized, it will doubtless not be for lack of antimalarial activity, but rather because of toxicological attributes not identified in the small-scale studies pursued to date” (Schmidt et al, 1978a). Two decades earlier, during testing of related 8-aminoquinoline antimalarials (Schmidt and Coatney, 1955), this same authority had presciently cautioned that since “…in doses well below the lethal level [these drugs] produced striking symptoms of [CNS] injury associated with severe lesions in the principal nuclei of the proprioceptive, visual-reflex, and vestibulo cerebellar pathways… their capacity to evoke reactions which might mask symptoms of low grade neuronal injury, plus the likelihood of their widespread use in malaria therapy, make a detailed search for CNS lesions highly desirable” (Schmidt and Schmidt, 1951). With awareness of the potential for lasting CNS toxicity finally emerging over 40 years after mefloquine’s initial development, it appears worthy of further investigation to determine precisely why such a “highly desirable” search was never performed, and why pre-licensure testing appears to have been limited only to “small-scale” studies.…”

Nature of the main contaminant in the drug primaquine diphosphate: SFC and SFC–MS methods of analysis

“…Primaquine and quinocide are highly toxic substances which can have a number of negative side effects upon treatment; methemoglobinemia [1][2][3][4][5] and neurotoxcity of the 8-aminoquinolines [6,7] cerebral oedema [8]. Neuropsychiatric manifestations after therapy with the quinoline derivative mefloquine for Plasmodium falciparum malaria and the carcinogenicity of primaquine have also been reported [9,10].…”

Nature of the main contaminant in the anti malaria drug primaquine diphosphate: a qualitative isomer analysis

“…Methemoglobinemia [14][15][16][17][18] and neurotoxicity of the 8-aminoquinolines are well known [19,20]. Polyamines may be involved in the development of a hepatic encephalopathy and cerebral oedema [21].…”