Mefloquine 186497 225343486 2008-07-13T05:07:06Z SmackBot 433328 Date the maintenance tags or general fixes {{drugbox | | IUPAC_name = 2,8-bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol | image = Mefloquine structure.svg | CAS_number = 53230-10-7 | ATC_prefix = P01 | ATC_suffix = BC02 | PubChem = 4046 | DrugBank = APRD00300 | C=17 | H=16 | F=6 | N=2 | O=1 | molecular_weight = 378.312 g/mol | bioavailability = | metabolism = Extensively hepatic; main metabolite is inactive | elimination_half-life = 2 to 4 weeks | excretion = Primarily bile and feces; urine (9% as unchanged drug, 4% as primary metabolite | pregnancy_category = C <small>([[United States|U.S.]])</small> | legal_status = | routes_of_administration = [[Wiktionary:oral|oral]] }} '''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 Medical Center|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 [[Plasmodium falciparum|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]]''.<ref>{{cite journal | author=Maguire JD, Krisin, Marwoto H, Richie TL, Fryauff DJ, Baird JK | title=Mefloquine is highly efficacious against chloroquine-resistant ''Plasmodium vivax'' malaria and ''Plasmodium falciparum'' malaria in Papua, Indonesia | journal=Clin Infect Dis | year=2006 | volume=42 | issue=8 | pages=1067&ndash;72 | doi=10.1086/501357}}</ref> ==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]],<ref>{{cite journal | author=Jha S, Kumar R, Kumar R. | title=Mefloquine toxicity presenting with polyneuropathy&mdash;a report of two cases in India | journal=Trans R Soc Trop Med Hyg | year=2006 | volume=100 | issue=6 | pages=594&ndash;96 | doi=10.1016/j.trstmh.2005.08.006 }}</ref> vestibular (balance) damage and [[central nervous system]] problems. For a complete list of adverse physical and psychological effects &mdash; including suicidal ideation &mdash; 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.{{Fact|date=January 2008}} 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 publically acceptable as, for example, an allergic reaction to Penicillin. In the 1990s there were reports in the media<ref>[http://www.commando.org/somalia/mefloquine.html Somalia and Mefloquine]</ref> 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 system|vestibular]] damage following the use of mefloquine have been diagnosed by military physicians. The same damage has been diagnosed among business travelers and tourists{{Fact|date=July 2008}}. ===Neurological activity=== In 2004, researchers found that mefloquine in adult mice blocks [[connexin]]s called [[Cx36]] and [[Cx50]].<ref>Scott J. Cruikshank, Matthew Hopperstad, Meg Younger, Barry W. Connors, David C. Spray, Miduturu Srinivas, "[http://pubmedcentral.com/articlerender.fcgi?artid=514481 Potent block of Cx36 and Cx50 gap junction channels by mefloquine]," ''[[Proceedings of the National Academy of Sciences of the United States of America]]'', 101(33), 2004 August 17.</ref> 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, [[Visual perception|vision]] and [[memory]], likely due to a role in the [[synchronization]] of [[neural activity]]. ==Chirality and its implications== Mefloquine is a [[Chirality (chemistry)|chiral]] molecule with two [[asymmetric carbon]] centres, which means it has four different [[diastereomer]]s. 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,{{Fletcher et al}} the (+) enantiomer is more effective in treating malaria, and the (-) enantiomer specifically binds to [[adenosine receptor]]s 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. 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."[7] WRAIR defines the neurotoxicity of Mefloquine to be 25 µM from table 1 ref [7]. "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."[7] "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."[7] 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."[8] 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."[8] ==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". (see http://www.acq.osd.mil/osbp/sbir/solicitations/sttr06/army06.htm ) 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 "[[Law & Order: Special Victims Unit (season 6)#Goliath|Goliath]]" of the television series ''[[Law and Order: SVU]]''.<ref>Mark Benjamin. [http://dir.salon.com/story/ent/tv/review/2005/05/25/lo_svu/index_np.html Ripped from my headlines!]. [[salon.com]]</ref> ==External links== *[http://www.rocheusa.com/products/lariam/ Manufacturer's information page] *[http://www.lariaminfo.org/ Lariam Action USA, Clearinghouse for information on mefloquine news, research, toxicity] *[http://washingtontimes.com/upi-breaking/20040907-103916-2982r.htm 2004 UPI story about military suicides] *[http://feinstein.senate.gov/05releases/r-lariam-dodltr.pdf Senator Feinstein Urges Rumsfeld to Complete Lariam Study.] *[http://peacecorpsonline.org/messages/messages/2629/1008129.html Discussion of Lariam side-effects at PeaceCorpsOnline.org] ==References== {{reflist}} {{refbegin}} *6. Phillips-Howard, P. A., and F. O. ter Kuile. 1995. CNS adverse events associated with antimalarial agents: fact or fiction? Drug Saf. a370-383. *7. Dow, GS et al., Walter Reed Army Institute of Research (WRAIR), Antimicrobial Agents Chemotherapy, 48(7):2624-2632 (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, July 2004, p. 2624-2632, Vol. 48, No. 7. *8. G. Dow, R.Bauman, D. Caridha, M. Cabezas, F. Du, R. Gomez-Lobo, M. Park, K. Smith, and K. Cannard1, Divisions of Experimental Therapeutics,1 Military Casualty Research,2 Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland, 20910,3 FD Neurotechnologies, Inc., P.O. Box 785, Ellicott City, Maryland 210414. "Mefloquine Induces Dose-Related Neurological Effects in a Rat Model". Antimicrobial Agents and Chemotherapy, March 2006, p. 1045-1053, Vol. 50, No. 3. Fletcher, A., and Shepherd, R. Use of (+)mefloquine for the treatment of malaria. United States Patent 6664397. http://www.patentstorm.us/patents/6664397.html. Accessed May 2007. {{refend}} {{Antimalarials}} [[Category:Antimalarial agents]] [[Category:Quinolines]] [[Category:Piperidines]] [[Category:Organofluorides]] [[Category:World Health Organization essential medicines]] [[de:Mefloquin]] [[nl:Mefloquine]] [[ja:メフロキン]] [[pl:Meflochina]]