NationMaster - Encyclopedia: 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. The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ... Antimalarial drugs are designed to prevent or treat malaria. ... Prophylaxis refers to any medical or public health procedure whose purpose is to prevent, rather than treat or cure, disease. ... Malaria is a vector-borne infectious disease that is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. ... Hoffmann-La Roche, Ltd. ... This article is about the U.S. Army medical center/hospital (not the research institute). ... Quinine (IPA: ) is a natural white crystalline alkaloid having antipyretic (fever-reducing), antimalarial, analgesic (painkilling), and anti-inflammatory properties and a bitter taste. ...

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. Malaria is a vector-borne infectious disease that is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. ... Chloroquine is a 4-aminoquinoline drug long used in the treatment or prevention of malaria. ... Binomial name Plasmodium falciparum Welch, 1897 Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. ...

Mefloquine is the drug of choice to treat malaria (though not necessarily to prevent malaria) caused by chloroquine-resistant Plasmodium vivax.^[1] Binomial name Plasmodium vivax Grassi & Feletti 1890 The parasite Plasmodium vivax is the most frequent and widely distributed cause of benign, but recurring (tertian), malaria. ...

Advice to travelers

Mefloquine is one of the antimalarial drugs which the August 2005 issue of the CDC Travel Health Yellow Sheet advises travelers in areas with malaria risk — Africa, South America, the Indian subcontinent, Asia, and the South Pacific — to take. Other medicines with less risk of severe side-effects and which are equally effective for malaria prevention are Malarone and doxycycline. The Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, is recognized as the leading United States agency for protecting the public health and safety of people. ... Malarone: New Malaria Medication With Fewer Side-effects Malarone is a newly released medication for prevention and treatment of chloroquine-resistant forms of malaria, including cerebral malaria caused by Plasmodium falciparum. ... Doxycycline (INN) (IPA: ) is a member of the tetracycline antibiotics group and is commonly used to treat a variety of infections. ...

There are virulent strains of malaria that are resistant to one or more anti-malarial drugs; for example, there are mefloquine-resistant strains in Thailand, Cambodia and Myanmar. Travelers are advised to compare current recommendations before selecting an antimalarial drug as the occurrence of drug-resistant strains changes.

The CDC, the UK Guidelines for Malaria Prevention, and the WHO provide up-to-date recommendations for specific countries. Look up who in Wiktionary, the free dictionary. ...

The drug is taken once a week starting at least one week prior to entry into malaria endemic areas and continued for 4 weeks after leaving. Owing to the risk of neuropsychiatric disturbance, particularly disruption of sleep, UK advice is for people who have not previously used Mefloquine to start 3 weeks prior to departure; adverse effects usually manifest within one or two weeks, and so there would remain sufficient time to switch to an alternative drug.

Side-effects

Mefloquine may have severe and permanent adverse side-effects. It is known to cause severe depression, anxiety, paranoia, nightmares, insomnia, seizures, peripheral motor-sensory neuropathy,^[2] 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.[5] 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. Neuropathy is usually short for peripheral neuropathy, meaning a disease of the peripheral nervous system. ... A diagram showing the CNS: 1. ... Rather than surrender to US soldiers, the Mayor (BÃ¼rgermeister) of Leipzig Germany, committed suicide along with his wife and daughter on April 20, 1945. ... FDA logo The Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services and is responsible for regulating food, dietary supplements, drugs, biological medical products, blood products, medical devices, radiation-emitting devices, veterinary products, and cosmetics in the United States. ...

In the 1990s there were reports in the media^[3] 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 Somalia Affair was a Canadian military scandal in the mid-1990s. ... It has been suggested that Equilibrioception be merged into this article or section. ...

Neurological activity

In 2004, researchers found that mefloquine in adult mice blocks connexins called Cx36 and Cx50.^[4] 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. Connexins are four-pass transmembrane proteins, six of which assemble to form a channel, a connexon. ... This does not cite any references or sources. ... In psychology, memory is an organisms ability to store, retain, and subsequently recall information. ... Synchronization (or Sync) is a problem in timekeeping which requires the coordination of events to operate a system in unison. ...

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,Template:Fletcher et al 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. It is not known whether mefloquine goes through stereoisomeric switching in vivo. The term chiral (pronounced ) is used to describe an object which is non-superimposable on its mirror image. ... Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers (mirror images of each other). ... In chemistry, a racemate is a mixture of equal amounts of left- and right-handed stereoisomers of a chiral molecules. ... Hoffmann-La Roche, Ltd. ... Pharmacology (in Greek: pharmacon is drug, and logos is science) is the study of how chemical substances interfere with living systems. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... A diagram showing the CNS: 1. ... A psychoactive drug or psychotropic substance is a chemical that alters brain function, resulting in temporary changes in perception, mood, consciousness, or behaviour. ...

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

Mefloquine was invented at WRAIR in the 1970's. 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). This article is about the U.S. Army medical research institute (not the hospital). ...

"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:

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

External links

References

^ 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.
^ 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
^ Scott J. Cruikshank, Matthew Hopperstad, Meg Younger, Barry W. Connors, David C. Spray, Miduturu Srinivas, "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.
^ Mark Benjamin. Ripped from my headlines!. salon.com

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. A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... The Proceedings of the National Academy of Sciences of the United States of America, usually referred to as PNAS, is the official journal of the United States National Academy of Sciences. ... Salon. ...

Categories: Antimalarial agents | Quinolines Antiprotozoal agents (ATC code: ATC P01) is a class of pharmaceuticals used in treatment of protozoal infections. ... Antimalarial drugs are designed to prevent or treat malaria. ... A section of the Anatomical Therapeutic Chemical Classification System. ... The 8-aminoquinoline family of drugs contains three members, primaquine, tafenoquine and pamaquine and are used in the treatment of malaria. ... amidoquine ... Chloroquine is a 4-aminoquinoline drug long used in the treatment or prevention of malaria. ... Hydroxychloroquine is an antimalarial also used to reduce inflammation and treat arthritis and lupus. ... Pamaquine is an 8-aminoquinoline drug used for the treatment of malaria. ... Primaquine or Primaquine Phosphate. ... Biguanides (ATC A10 BA) form a class of oral hypoglycemic drugs used for diabetes mellitus treatment. ... Proguanil (proguanil hydrochloride) is a prophylactic antimalarial drug, which works by stopping the malaria parasite, Plasmodium falciparum, from reproducing once it is in the red blood cells. ... Quinine (IPA: ) is a natural white crystalline alkaloid having antipyretic (fever-reducing), antimalarial, analgesic (painkilling), and anti-inflammatory properties and a bitter taste. ... Pyrimethamine (DaraprimÂ®) is a medication used for protozoal infections. ... Artemisinin (IPA: ) is a drug used to treat multi-drug resistant strains of falciparum malaria. ... Artemisinin (IPA: ) is a drug used to treat multi-drug resistant strains of falciparum malaria. ... Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. ... Artemisinin is a drug used to treat multi-drug resistant strains of falciparum malaria. ... Arteether, also known as Rapither AB, Î±/Î² arteether, is a fast acting blood schizontocide specifically indicated for the treatment of chloroquine-resistant Plasmodium falciparum malaria and cerebral malaria cases. ... Halofantrine is a drug used to treat malaria. ...

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