By Dr Remington Nevin,

This month’s approval by the U.S. Food and Drug Administration (FDA) of tafenoquine, both for radical cure of P. vivax and for the prevention of malaria, would appear at first glance to mark the end of the U.S. military’s decades-long search for an effective causal prophylactic drug. Since the beginning, in the early 1940s, of the U.S. government’s ambitious World War II-era antimalarial drug development program, scientists have searched for a drug that would act not merely as a blood-stage suppressant, but that would essentially sterilize both the blood and liver of any malaria infection.

Towards the end of WWII, researchers thought they had found such a causal prophylactic drug in one of the approximately 15,000 compounds they had tested. So hopeful were these researchers of the military prospects for this newly-synthesized drug, an 8-aminoquinoline, they named it “pentaquine”, apparently in homage to the U.S. military’s newly built “pentagon”. Unfortunately, only years after its synthesis, development of pentaquine was abandoned, after both clinical testing and neurohistopathological testing in rhesus monkey revealed it had unacceptable central nervous system (CNS) neurotoxicity.

Chloroquine, a 4-aminoquinoline, and the penultimate drug to emerge from this WWII-era development program had only suppressive schizonticidal activity and was considered a far less-desirable product. The U.S. military also already had such a drug in quinacrine (Atabrine), essentially a ring-substituted version of chloroquine, and which had been widely in use from the earliest days of the South Pacific campaign.

When chloroquine was first tested clinically by German scientists years earlier, it was deemed too toxic for human use and was abandoned. What prompted chloroquine’s further development in the U.S. WWII-era program was, in part, that quinacrine itself had unacceptable neuropsychiatric adverse effects. Quinacrine psychosis often preceded by a prodrome of nightmares, insomnia, anxiety, and mood changes was a common feature in the South Pacific campaign and in other combat theatres where quinacrine was used. Symptoms of this psychosis would often mimic symptoms of combat stress neurosis — a condition we would today call post-traumatic stress disorder (PTSD). Only years later would the CNS neurotoxicity of the 4-aminoquinolines be recognized, and chloroquine itself recognized as having similar neuropsychiatric adverse effects.

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Malariologists have lamented that it has taken the better part of seven decades for a new 8-aminoquinoline to come to market. One reason may be that all drugs of the 8-aminoquinoline class are likely to be neurotoxic. As described by a leading researcher of the U.S. WWII-era program, all of the nearly 140 8-aminoquinolines then tested were found to produce “rather remarkable and highly specific lesions in the central nervous system”. The signs and symptoms observed clinically with use of these drugs reflect the localization of the CNS neurotoxic injury observed when tested in rhesus monkey and at autopsy following fatal human use.

Even primaquine, the only 8-aminoquinoline to emerge from the remnants of the U.S. WWII-era program, is itself neurotoxic. Although often claimed by malariologists to be safe, primaquine has never undergone randomized blinded testing of its neuropsychiatric safety. In much postmarketing pharmacovigilance, any neuropsychiatric adverse effects from primaquine may have been misattributed to malaria, or to chloroquine, which was a ubiquitous co-exposure during U.S. military use in the 1950s through the 1970s. More recently, any such adverse effects may have been misattributed to mefloquine, a 4-quinolinemethanol well-known to share the liability to neuropsychiatric effects of quinacrine and chloroquine, and which is itself known to exhibit CNS neurotoxicity. Interestingly, researchers at the U.S. military’s Walter Reed Army Institute of Research have found that tafenoquine is even more neurotoxic in vitro than mefloquine.

The lesson from the U.S. military’s accumulated experience with these drugs is that CNS neurotoxicity is not just a property of the 4-aminoquinolines, or the 8-aminoquinolines, or the 4-quinoline methanols, but of many antimalarial drugs of the quinoline class. Although individual risk factors for clinically significant neuropsychiatric effects from this CNS neurotoxicity are unknown, more serious effects are often preceded by prodromal psychiatric symptoms, including insomnia and abnormal dreams.

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This lesson appears to be reflected in FDA’s new warnings for tafenoquine, which caution users to seek medical care if insomnia, nightmares, anxiety, or changes in mood are severe or last 3 days or longer. These echo FDA’s warnings for mefloquine, which a “black box” now cautions should be discontinued at the onset of psychiatric symptoms. European drug regulators now even specifically warn that insomnia and abnormal dreams and nightmares are psychiatric symptoms that require mefloquine’s immediate discontinuation.

Such warnings are likely to prove a fatal blow to the prospects of tafenoquine. As our group has recommended, these preclude the safe use of the drug in many settings. Critically, these include military deployments, where, as with quinacrine in WWII and mefloquine in more recent wars, prodromal symptoms risk being misattributed to the effects of combat or other stressors, risking the development of more serious adverse effects.

History teaches that the antimalarial quinolines are inherently neurotoxic drugs. Tafenoquine may prove to be simply the next such quinoline originally deemed reasonably safe, only to be abandoned as evidence emerges of its CNS neurotoxicity. The question for malariologists is whether the lessons of history will speed recognition of these effects, or whether this recognition will be tragically delayed, as with mefloquine, for the better part of four decades.

The Author

Dr Remington Nevin is executive director of The Quinism Foundation, a Vermont-based nonprofit organization that promotes and supports education and research on medical disorders caused by quinoline poisoning.

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