Mefloquine

Mefloquine is an orally administered antimalarial drug used as a prophylaxis against and treatment for malaria. It also goes by the trade name Lariam (manufactured by Roche Pharmaceuticals) and chemical name mefloquine hydrochloride (formulated with HCl). Mefloquine was developed in the 1970s at the Walter Reed Army Institute of Research in the U.S. as a synthetic analogue of quinine.

Uses

Mefloquine is used to prevent malaria (malaria prophylaxis) and also in the treatment of chloroquine-resistant falciparum malaria. As mefloquine resistance spreads, mefloquine has started to lose its efficacy.

Mefloquine is the drug of choice to treat malaria (though not necessarily to prevent malaria) caused by chloroquine-resistant Plasmodium vivax.

Mefloquine has shown efficacy in an in vitro assay against Progressive Multifocal Encephalopathy (PML). Biogen Idec has recently announced that a trial of Mefloquine in HIV related PML is beginning.

Side-effects

Mefloquine may have severe and permanent adverse side-effects. It is known to cause severe depression, anxiety, paranoia, aggression, nightmares, insomnia, seizures, peripheral motor-sensory neuropathy, vestibular (balance) damage and central nervous system problems. For a complete list of adverse physical and psychological effects — including suicidal ideation — see the most recent product information. Central nervous system events occur in up to 25% of people taking Lariam, such as dizziness, headache, insomnia, and vivid dreams. In 2002 the word "suicide" was added to the official product label, though proof of causation has not been established. Since 2003, the Food and Drug Administration (FDA) in the USA has required that patients be screened before mefloquine is prescribed. The latest Consumer Medication Guide to Lariam has more complete information.

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.

Neurological activity

In 2004, researchers found that mefloquine in adult mice blocks connexins called Cx36 and Cx50. Cx36 is found in the brain and Cx50 is located in the eye lens. Connexins in the brain are believed to play a role in movement, vision and memory, likely due to a role in the synchronization of neural activity.

Chirality and its implications

Mefloquine is a chiral molecule with two asymmetric carbon centres, which means it has four different diastereomers. The drug is currently manufactured and sold as a racemate of the (+/-) R*,S* enantiomers by Hoffman-LaRoche, a Swiss pharmaceutical company. According to some research, the (+) enantiomer is more effective in treating malaria, and the (-) enantiomer specifically binds to adenosine receptors in the central nervous system, which may explain some of its psychotropic effects. Some believe that it is irresponsible for a pharmaceutical company to sell mefloquine as a racemic mixture, especially considering the thalidomide tragedy. It is not known whether mefloquine goes through stereoisomeric switching in vivo.

The (+) enantiomer has a shorter half life than the (-) enantiomer.

Recent peer reviewed research findings from Walter Reed Army Institute of Research (WRAIR)

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:

It states:

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."

Proposed development of a commercially available safety test

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.

Popular culture references

The fictional drug "Quinium", which has significant similarities to mefloquine, was featured in the episode "Goliath" of the television series Law and Order: SVU.