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1 : 1 mixture (racemate)
Systematic (IUPAC) name
(R*,S*)-2,8-bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol
Identifiers
CAS number 53230-10-7
ATC code P01BC02
PubChem 4046
DrugBank APRD00300
Chemical data
Formula C 17H16F6N2O 
Mol. mass 378.312 g/mol
Pharmacokinetic data
Bioavailability  ?
Metabolism Extensively hepatic; main metabolite is inactive
Half life 2 to 4 weeks
Excretion Primarily bile and feces; urine (9% as unchanged drug, 4% as primary metabolite
Therapeutic considerations
Pregnancy cat. C (U.S.)
Legal status
Routes oral
 Yes check.svgY(what is this?)  (verify)
Lariam 250mg tablets

Mefloquine is an orally administered antimalarial drug used prophylactically against and as a treatment for malaria. It also goes by the trade name Lariam (manufactured by F. Hoffmann–La Roche) or Mefaquin and by the 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.

Contents

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.

According to the Center for Disease Control and Prevention (CDC) guidelines to prevent malaria, Mefloquine is no longer the drug of choice to treat malaria (and it is not necessarily the best drug to prevent malaria) caused by chloroquine-resistant Plasmodium vivax.[1]

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.[1]

Side-effects

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,[2] vestibular (balance) damage and central nervous system are taken to local hospitals usually with acute psychiatric symptoms. Since few doctors know what a Lariam/mefloquine toxicity reaction looks like, they attribute 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 travelers do take mefloquine every year. However, the adverse reaction data is spurious and under-reported because side effects occur usually in a location distant from the doctor who originally prescribed the drug.

4. Because data are unreliable and under-reported, reports of mefloquine reactions are readily discounted as "anecdotal," since mefloquine toxicity is not as well known as, for example, an allergic reaction to penicillin.

In the 1990s, reports appeared in the media[3] saying that the drug may have played a role in the Somalia Affair, which involved the torture and murder of a Somali citizen in the custody of Canadian peacekeeping troops. Three murder-suicides involving Special Forces soldiers at Fort Bragg, N.C., in the summer of 2002 also aroused controversy related to the drug. 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.[4] Cx36 is found in the brain and Cx50 is located in the lens of the eye. 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 stereoisormers. The drug is currently manufactured and sold as a racemate of the (R,S)- and (S,R)-enantiomers by Hoffman-LaRoche, a Swiss pharmaceutical company. According to some research,[5] 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 WRAIR

Mefloquine was invented at Walter Reed Army Institute of Research (WRAIR) in the 1970s. WRAIR has published several papers outlining efforts at that institution to make mefloquine safer by producing a drug 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 mefloquine for chemoprophylaxis. However, milder CNS events (e.g., dizziness, headache, insomnia, and vivid dreams) are more frequently observed, occurring in up to 25% of patients."[6]

WRAIR defines the neurotoxicity of mefloquine to be 25 µM from table 1 ref.[6]

"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."[6]

"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."[6]

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."[7]

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."[7]

Recent U.S. Army Surgeon General Guidance:
Switch from mefloquine to doxycycline.

On 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."[8]

This directive goes on to mandate that the wallet card provided with the Lariam Medication Guide must be given to each person prescribed Lariam or generic forms of mefloquine.

FDA posts mefloquine-induced pneumonitis warning

FDA 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 of 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 prophylactic doses of mefloquine. No prior medical history was reported for this patient. Seventy-seven percent of the patients (10/13) fully recovered when mefloquine was discontinued. Thirty-eight percent of the patients (5/13) improved with systemic carticosteroid therapy. One patient was rechallenged with mefloquine and developed severe pneumonitis. In a number of cases, the recognition of the relationship between pneumonitis and the use of mefloquine was delayed."

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".[9] This document calls for the development of a commercially-available "safety test" for Mefloquine users.

References

  1. ^ 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.  
  2. ^ 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.  
  3. ^ Somalia and Mefloquine
  4. ^ 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.  
  5. ^ Fletcher, A., and Shepherd, R. Use of (+)-mefloquine for the treatment of malaria. US patent 6664397.
  6. ^ a b c d Dow, Geoffrey S.; Koenig, ML; Wolf, L; Gerena, L; Lopez-Sanchez, M; Hudson, TH; Bhattacharjee, AK (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. PMID 15215119.  
  7. ^ 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. PMID 16495267.  
  8. ^ http://www.pdhealth.mil/downloads/DASG_Memorandum.pdf
  9. ^ See http://www.acq.osd.mil/osbp/sbir/solicitations/sttr06/army06.htm

Further reading

  • Phillips-Howard, P. A., and F. O. ter Kuile. 1995. CNS adverse events associated with antimalarial agents: fact or fiction? Drug Saf. a370-383.

External links








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