Mefloquine is the drug of choice to treat malaria (though not necessarily to prevent malaria) caused by chloroquine-resistant Plasmodium vivax.
Attempting to obtain a diagnosis of Mefloquine toxicity is frustrated by the following reasons:
1. It may cause bad dreams
2. In most cases, results from the primary tools used by neurologists, CAT scans, EMG's and MRI's, come up negative.
3. Thousands of travellers do take Mefloquine every year, however the adverse reaction data is spurious and under-reported because side effects occur usually in a location away from the doctor who originally prescribed the drug.
4. Because the data is spurious and under reported, reports of Mefloquine reactions are readily discounted as "anecdotal" since Mefloquine toxicity is not as well known and publicly acceptable as, for example, an allergic reaction to Penicillin.
In the 1990s there were reports in the media that the drug may have played a role in the Somalia Affair, which involved the torture and murder of a Somali citizen whilst in the custody of Canadian peacekeeping troops. There has been similar controversy since three murder-suicides involving Special Forces soldiers at Fort Bragg, N.C., in the summer of 2002. To date more than 19 cases of vestibular damage following the use of mefloquine have been diagnosed by military physicians. The same damage has been diagnosed among business travelers and tourists.
The (+) enantiomer has a shorter half life than the (-) enantiomer.
Mefloquine was invented at WRAIR in the 1970s. WRAIR has published several papers outlining their efforts to make Mefloquine safer by producing a version of Mefloquine that is composed only of the (+) enantiomer (photo isomer).
"Adverse central nervous system (CNS) events have been associated with mefloquine use. Severe CNS events requiring hospitalization (e.g., seizures and hallucinations) occur in 1:10,000 patients taking mefloquinefor chemoprophylaxis. However, milder CNS events (e.g., dizziness, headache, insomnia, and vivid dreams) are more frequently observed, occurring in up to 25% of patients."
WRAIR defines the neurotoxicity of Mefloquine to be 25 µM from table 1 ref.
"we recently showed that mefloquine severely disrupts calcium homeostasis in rat neurons in vitro at concentrations in excess of 20 µM, an effect closely related to the acute neurotoxicity of the drug in terms of dose effect and kinetics."
"However, the drug crosses the blood-brain barrier and accumulates as much as 30-fold in the central nervous system and mefloquine brain concentrations as high as 50 µM have been reported in human postmortem cases. Mefloquine brain concentrations as high as 90 µM have been reported in rats given a therapy-equivalent dose rate, with concentrations in subcompartments in the brain exceeding 100 µM. Since it has long been known that a prolonged disruption of neuronal calcium homeostasis may lead to neuronal cell death and injury, it is reasonable to suppose that such events may contribute to the clinical neuropathy of the drug."
Additionally, WRAIR published the following in Mar 2006 regarding treatment level brain stem damage in rats:
1. "At the time this study was conceived, no formal FDA guidelines for neurotoxicity testing existed. In contrast, first-tier neurological screens, such as those recommended by the U.S. Environmental Protection Agency (EPA), are often employed to detect a broad range of possible neurological effects that may be induced by uncharacterized test compounds."
The FDA "approval" process in 1970 did not require safety testing for neurotoxicity since no protocol existed at the time. Apparently it still does not exist since the Walter Reed researchers had to use a test protocol from the EPA to write this paper.
2. "It is also important to point out that the mefloquine-induced brain stem injury revealed by silver staining is permanent in nature."
WRAIR recently released a funding document STTR A06-T034 "Neurotoxicity Associated with Mefloquine, an Anti-Malarial Drug". This document calls for the development of a commercially available "safety test" for Mefloquine users.