Investigating the safety of antimalaria drugs

  • Ashley Croft

Student thesis: Doctoral Thesis

Abstract

This portfolio of research comprises twelve original papers published during 1995–
2019. The unifying theme of the papers is the safety of antimalaria drugs – and
specifically, of quinoline drugs to prevent malaria.
I was the first or sole author in ten of the published papers, and the second author in the remaining two. In total, I collaborated with fourteen other researchers.
Historically, drug manufacturers and policymakers have downplayed the adverse effects of antimalaria drugs. This research adds to the body of emerging scientific evidence that the adverse effects of chloroquine and (especially) of mefloquine can be severe and long-lasting. Because malaria prevention drugs are now available that are as effective as mefloquine, but without the accompanying risk of potentially severe and long-lasting neuropsychiatric adverse effects, it is my view that this drug should not be used routinely as first-line malaria prophylaxis. I and my co-investigators first advanced this position in July 2005 in the New England Journal of Medicine. It is a position that, as far as I am aware, all militaries now adopt.
Since March 2002 I and my co-researchers have proposed what we consider to be a plausible mechanism that explains much of the phenomenology of the observed adverse effects of quinoline antimalaria drugs, and of other disease states. We propose that many of these harms represent a chemically-induced liver dysfunction. Toxic concentration of stored vitamin A compounds (‘retinoids’) spill from the liver into the circulation, causing an endogenous chronic form of hypervitaminosis A. At the same time, the liver-thyroid axis is disrupted, causing symptomatic thyroid disturbance.
Our hypothesis on the causation of quinoline drug adverse effects has not yet been formally tested. If it were tested and shown to be correct, our understanding of this class of drugs would be enhanced. They could be prescribed more safely.
Date of Award2022
Original languageEnglish
Awarding Institution
  • University of Portsmouth
SupervisorKaren Elizabeth Pilkington (Supervisor), Isobel Helen Ryder (Supervisor) & Graham Mills (Supervisor)

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