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MefloquineSystematic (IUPAC) name2,8-bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanolIdentifiersCAS number53230-10-7ATC codeP01BC02PubChem4046DrugBankAPRD00300Chemical dataFormulaC17H16F6N2O Mol. mass378.312 g/molPharmacokinetic dataBioavailability ?MetabolismExtensively hepatic; main metabolite is inactiveHalf life2 to 4 weeksExcretionPrimarily bile and feces; urine (9% as unchanged drug, 4% as primary metaboliteTherapeutic considerationsPregnancy cat.C (U.S.)Legal statusRoutesoralMefloquine 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.// UsesMefloquine 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-effectsMefloquine 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. Initial side effects such as bad dreams, urinary disorders, etc. usually ocurr well away from the doctor who originally prescibed the drug. Patients are taken to local hospitals usually whith acute psychiatric symptoms. Since few doctors know what a Lariam toxicity reaction looks like, they attirbute the symptoms to other known conditions.2. In most cases, results from the primary tools used by neurologists - CAT scans, EMGs and MRIs - 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 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. Neurological activityIn 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 implicationsMefloquine 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. 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: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. 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." Recent Army Surgeon General Guidance -switch from Mefloquine to DoxycyclineOn 2 February 2009, Lieutenant General Eric Schoomaker, Army Surgeon General, issued the following directive:"In areas where doxycycline and mefloquine are equally effacious in preventing malaria, doxycycline is the drug of choice. Mefloquine should only be used for personnel with contraindications to doxycycline and do not have any contraindications to the use of mefloquine...Mefloquine should not be given to Soldiers with recent history of Traumatic Brain Injury (TBI) or have symptomatic TBI. Malarone would be the treatment of choice for these Soldiers who cannot take doxycycline or mefloquine."This directive goes on to mandate that the wallet card provided with the Larima Medication Guide must be given to each person prescribed Lariam or generic forms of Mefloquine. FDA posts Mefloquine induced pneumonitis warningFDA Drug Safety Newsletter Volume 1, Number 4 summer 2008 issued the following warning about Mefloquine:"A postmarket safety review of mefloquine, an antimalarial agent, identified cases of pneumonitis or eosinophilic pneumonia associated with the use fo this drug. This review was prompted by the manufacturer's request to revise the Adverse Reactions - Postmarketing section of the label to include pneumonitis of possible allergic etiology. The product label has been updated to reflect this new safety information..........The 13 cases of pneumonitis reported to AERS involved patients ranging in age from 4-68 years(median age of 53 years). Sixty-nine percent of the patients (9/13) were female. Five patients received mefloquine for treatment of malaria. Six patients were given mefloquine as prophylaxis for malaria. In two cases, information on the underlying condition for which mefloquine therapy was begun was unknown. The median time-to-onset from first administration of mefloquine to respiratory symptoms was 2 days(range 1-84 days). All patients in this case series were hospitalized with various respiratory diagnoses, including pneumonitis, diffuse interstitial pneumopathy, and dyspnea/lung infiltration. Radiographic imaging indicated bilateral lung infiltrates in seven patients. In two cases, fluid from bronchoalveolar lavage (BAL) showed elevated eosinophils and neutrophils. In one patient, lung biopsy revealed an autoimmune interstitial alveolitis. A four-year-old female died after developing pneumonitis. This patient developed symptoms (pulmonary fibrosis and interstitial pneumonitis) after several

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Lariam

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 ...

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Mefloquine - Wikipedia, the free encyclopedia

Get Legal Assistance: No-Cost Consultation Lariam Legal Claims and Lawsuits Lariam Side Effects Lariam History: Story of Problems FDA Warnings and Label Changes

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ЛАРИАМ . lariam Регистрационный номер № 011044 (20.04.99) Мефлохин Противомалярийное средство

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LARIAM

Learn about the prescription medication Lariam (Mefloquine), drug uses, dosage, side effects, drug interactions, warnings, and patient labeling.

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Prescribing Information; LARIAM Medication Guide; These documents are available to you in Adobe Acrobat's .PDF format. If you do not have the Acrobat Reader ...

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