From Wikipedia, the free encyclopedia
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.
Systematic (IUPAC) name
Extensively hepatic; main metabolite is inactive
2 to 4 weeks
Primarily bile and feces; urine (9% as unchanged drug, 4% as primary metabolite
2.1 Neurological activity
3 Chirality and its implications
4 Recent peer-reviewed research findings from Walter Reed Army Institute of Research (WRAIR)
5 Proposed development of a commercially available safety test
6 Popular culture references
8 Further reading
9 External links
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.
Mefloquine may have severe and permanent adverse side effects. It is known to cause severe depression, anxiety, paranoia, aggression, nightmares, insomnia, seizures, birth defects, 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, EMGs and MRIs – come up negative.
3. Thousands of travelers 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 that 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.
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 centers, 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. 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 of only 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.”
In addition, WRAIR published the following in March 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. Evidence suggests that 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.
^ Maguire JD, Krisin, Marwoto H, Richie TL, Fryauff DJ, Baird JK (2006). “Mefloquine is highly efficacious against chloroquine-resistant Plasmodium vivax malaria and Plasmodium falciparum malaria in Papua, Indonesia”. Clin Infect Dis 42 (8): 1067–72. doi:10.1086/501357.
^ Jha S, Kumar R, Kumar R. (2006). “Mefloquine toxicity presenting with polyneuropathy—a report of two cases in India”. Trans R Soc Trop Med Hyg 100 (6): 594–96. doi:10.1016/j.trstmh.2005.08.006.
^ Somalia and Mefloquine
^ Cruikshank, Scott J.; et al. (2004). “Potent block of Cx36 and Cx50 gap junction channels by Mefloquine“. PNAS 101 (33): 12364–12369. doi:10.1073/pnas.0402044101.
^ Fletcher, A., and Shepherd, R. Use of (+)Mefloquine for the treatment of malaria. US patent 6664397.
^ a b c d Dow, Geoffrey S. (2004). “The Antimalarial Potential of 4-Quinolinecarbinolamines May Be Limited due to Neurotoxicity and Cross-Resistance in Mefloquine-Resistant Plasmodium falciparum Strains”. Antimicrobial Agents and Chemotherapy 48 (7): 2624–2632. doi:10.1128/AAC.48.7.2624-2632.2004.
^ a b Dow, G.; et al. (2006). “Mefloquine Induces Dose-Related Neurological Effects in a Rat Model”. Antimicrobial Agents and Chemotherapy 50 (3): 1045–1053. doi:10.1128/AAC.50.3.1045-1053.2006.
^ See http://www.acq.osd.mil/osbp/sbir/solicitations/sttr06/army06.htm
^ Benjamin, Mark (2005-05-25). “Ripped from my headlines!“. salon.com.
Phillips-Howard, P. A., and F. O. ter Kuile. 1995. CNS adverse events associated with antimalarial agents: fact or fiction? Drug Saf. a370-383.
Manufacturer’s information page
Lariam Action USA, Clearinghouse for information on Mefloquine news, research, toxicity
2004 UPI story about military suicides
Senator Feinstein Urges Rumsfeld to Complete Lariam Study.
Discussion of Lariam side-effects at PeaceCorpsOnline.org