Mefloquine

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Mefloquine
Mefloquine2DCSD.svg
Mefloquine ball-and-stick.png
Systematic (IUPAC) name
[(R*,S*)-2,8-bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol
Clinical data
Trade names Lariam, Mephaquin or Mefliam
Pregnancy cat.
Legal status
Routes oral
Pharmacokinetic data
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)
Identifiers
CAS number 53230-10-7 YesY
ATC code P01BC02
PubChem CID 40692
DrugBank DB00358
ChemSpider 37171 YesY
UNII TML814419R YesY
KEGG D04895 YesY
ChEMBL CHEMBL416956 N
NIAID ChemDB 005218
Chemical data
Formula C17H16F6N2O 
Mol. mass 378.312 g/mol
 N (what is this?)  (verify)
Mefloquine (Lariam) 250mg tablets

Mefloquine (brand names: Lariam, Mephaquin or Mefliam) is an orally administered medication used in the prevention and treatment of malaria. Rare but serious neuropsychiatric problems have been associated with its use.[1]

Mefloquine was developed in the 1970s at the United States Department of Defense's Walter Reed Army Institute of Research as a synthetic analogue of quinine. The brand name drug, Lariam, is manufactured by the Swiss company Hoffmann–La Roche. In August 2009, Roche stopped marketing Lariam in the United States. Generic mefloquine from other manufacturers is still widely available. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[2]

Medical uses[edit]

Mefloquine is used to both prevent and treat certain forms of malaria.[1]

Malaria prevention[edit]

Mefloquine is useful for the prevention of malaria in all areas except for those where parasites may have resistance to multiple drugs.[3] It is typically taken for one to two weeks before entering an area with malaria.[1] Doxycycline and atovaquone/proguanil provide protection within one to two days and may be better tolerated.[4][5] If a person becomes ill with malaria despite prophylaxis with mefloquine, the use of halofantrine and quinine for treatment may be ineffective.[6]:4

Malaria treatment[edit]

Once a person has contracted malaria, mefloquine is recommended as a second-line treatment for chloroquine-sensitive or resistant Plasmodium falciparum malaria, and is deemed a reasonable alternative for uncomplicated chloroquine-resistant Plasmodium vivax malaria.[1][6]

It is not recommended for severe malaria infections, particularly infections from P. falciparum, which should be treated with intravenous antimalarials.[1][6] Mefloquine does not eliminate parasites in the liver phase of the disease, and people with P. vivax malaria should be treated with a second drug that is effective for the liver phase, such as primaquine.[6]:4

Adverse effects[edit]

Mefloquine is contraindicated in those with a previous history of seizures or a recent history of psychiatric disorders.[1] Severe side effects requiring hospitalization are rare.[3] Rates of side effects appear similar to other medications used for malaria prevention.[4]

FDA adds Black Box Warning[edit]

From the FDA Safety Announcement on 7-29-2013 - "The U.S. Food and Drug Administration (FDA) is advising the public about strengthened and updated warnings regarding neurologic and psychiatric side effects associated with the antimalarial drug mefloquine hydrochloride. A boxed warning, the most serious kind of warning about these potential problems, has been added to the drug label. FDA has revised the patient Medication Guide dispensed with each prescription and wallet card to include this information and the possibility that the neurologic side effects may persist or become permanent. The neurologic side effects can include dizziness, loss of balance, or ringing in the ears. The psychiatric side effects can include feeling anxious, mistrustful, depressed, or having hallucinations." [7]

Neurologic and psychiatric[edit]

Neuropsychiatric effects are reported with mefloquine use.[1] The FDA product guide states it can cause mental health problems, including anxiety, hallucinations, depression, unusual behavior, and suicidal ideations, among others.[8] Some have reported severe central nervous system events requiring hospitalization in about one in 10,000 people taking mefloquine for malaria prevention, with milder events (e.g., dizziness, headache, insomnia, and vivid dreams) in up to 25%.[9] When some measure of subjective severity is applied to the rating of adverse events, about 11-17% of travelers are incapacitated to some degree.[4]

Psychiatric side effects can include anxiety, feelings of mistrust towards others (paranoia), seeing or hearing things that are not there (hallucinations), depression, restlessness, confusion, and behavior that is unusual.[10] These psychiatric problems may last for years after the patient stops taking the drug.[11] Mefloquine has been found to act as an agonist at 5-HT2A and 5-HT2C receptors, which are the targets of psychedelic drugs such as LSD, and it has been suggested this may be partly responsible for the neuropsychiatric side effects.[12]

Pneumonitis[edit]

The FDA has reported an association with pneumonitis and eosinophilic pneumonia.[13]

Cardiac[edit]

Mefloquine may cause abnormalities with heart rhythms that are visible on electrocardiograms. Combining mefloquine with other drugs that cause similar effects, such as quinine or quinidine, can increase these effects. Combining mefloquine with halofantrine can cause significant increases in QTc intervals.[6]:10

Contraindications[edit]

Mefloquine is contraindicated in those with a previous history of seizures or a recent history of psychiatric disorders.[1] Women should not become pregnant and should use effective birth control while taking mefloquine.

Pregnancy and breastfeeding[edit]

A retrospective analysis of outcomes in more than 2,500 women found no evidence that mefloquine was associated with an increased risk of birth defects or miscarriages.[14] The drug may be used during breastfeeding, though it appears in breast milk in low concentrations.[3][6]:9 The World Health Organization gives approval for the use of mefloquine in the second and third trimesters of pregnancy and use in the first trimester does not mandate termination of pregnancy.[3]

Mechanism of action[edit]

The exact mechanism of action is uncertain. However, it is proposed to share a similar mechanism of action with chloroquine, which is inhibition of heme polymerase.

Mefloquine binds to a number of receptors in the brain, and has a relatively high affinity (Ki = 0.71–341 nM) to serotonin (5-HT)2A receptors. It is also a partial 5-HT2A agonist and a full 5-HT2C agonist, stimulating inositol phosphate accumulation, with similar potency and efficacy to the psychedelic drug dimethyltryptamine.[15]

Elimination[edit]

Mefloquine is metabolized primarily through the liver. Its elimination in anyone with impaired liver function may be prolonged, resulting in higher plasma levels and an increased risk of adverse reactions. The mean elimination plasma half-life of mefloquine is between two and four weeks. Total clearance is through the liver, and the primary means of excretion is through the bile and feces, as opposed to only 4% to 9% excreted through the urine. During long-term use, the plasma half-life remains unchanged.[16][17]

Liver function tests should be performed during long-term administration of mefloquine.[18] Alcohol use should be avoided during treatment with mefloquine.[19]

Chirality and structure activity relationships[edit]

Mefloquine is a chiral molecule with two asymmetric carbon centres, which means it has four different stereoisomers. 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. Essentially, it is two drugs in one. Plasma concentrations of the (–)-enantiomer are significantly higher than those for the (+)-enantiomer, and the pharmokinetics between the two enantiomers are significantly different. The (+)-enantiomer has a shorter half-life than the (–)-enantiomer.[4]

According to some research,[20] 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.

History[edit]

Mefloquine was invented at Walter Reed Army Institute of Research (WRAIR) in the 1970s shortly after the end of the Vietnam war. Mefloquine was number 142,490 of a total of 250,000 antimalarial compounds screened during the study.[21]

Mefloquine was the first Public-Private Venture (PPV) between the US Department of Defense and a pharmaceutical company. WRAIR transferred all its phase I and phase II clinical trial data to Hoffman LaRoche and Smith Kline. FDA approval as a treatment for malaria was swift. Most notably, phase III safety and tolerability trials were skipped.[21]

However, mefloquine was not approved by the FDA for prophylactic use until 1989. This approval was based primarily on compliance, while safety and tolerability were overlooked.[21] Because of the drug's very long half-life, the Centers for Disease Control originally recommended a mefloquine dosage of 250 mg every two weeks; however, this caused an unacceptably high malaria rate in the Peace Corps volunteers who participated in the approval study, so the drug regimen was switched to once a week.[4]

The first randomized, controlled trial on a mixed population was first performed in 2001. Roughly 67% of study participants reported greater than or equal to one adverse event, with 6% of the users reporting severe events requiring medical attention.[21]

With these data, the FDA and other international licensing authorities certainly would not have approved mefloquine for prophylactic use.[21]

No studies have been conducted on the effects of coadministration of mefloquine and other drugs. The ensuing fatal drug reactions might have been a result of this lack of knowledge of possible contraindications. Trials in the 1990s and early 2000s verified mefloquine's neurotoxicity and significant potential for neuropsychiatric side effects.[21]

Postmarketing data were discounted as anecdotal and "media hype" by US Army researchers and travel medicine practitioners.[21] Since the side effects mefloquine can cause have not been fully defined, and with no apparent incentive for the current manufacturers to further investigate mefloquine, the drug may be discarded.[21] As evidence, the US military dropped mefloquine as its primary antimalarial in 2009.[22][23]

Society and culture[edit]

United States military[edit]

On 2 February 2009, Lieutenant General Eric Schoomaker, Army Surgeon General, issued the following directive:

"In areas where doxycycline and mefloquine are equally efficacious in preventing malaria, doxycycline is the drug of choice. Mefloquine should only be used for personnel with contraindications to doxycycline and who 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 who have symptoms from a previous TBI. Malarone would be the treatment of choice for these soldiers who cannot take doxycycline or mefloquine."[23]

The following September, Hon. Ellen Embry, then Acting Assistant Secretary of Defense for Health, issued the same policy, making doxycycline the antimalarial of choice across all US armed services.[22]

The 2012 CDC travel yellow book was recently amended to include a section of "special considerations for US military deployments". It makes doxycycline the primary antimalarial prophylactic to be used for all military deployments. As a note of historical significance, Col Alan Magill and Col Robert Defriates coauthored this section.[24] Both were the primary promoters for the continued use of mefloquine by the US military in the late 1990s and early 2000s. Magill is the former commanding officer of the drug research unit at WRAIR that performed the studies to find a safer version of mefloquine.

On September 13, 2013, the Chief Surgeon for the United States Army Special Operations Command at Fort Bragg, North Carolina issued a directive banning the further use of mefloquine by US Army special forces.[25]

Mefloquine has also been used as a preventative measure for all detainees at Guantanamo Bay Detention Center. Many question its effectiveness and are concerned about the side effects associated with it, including the FDA.[26]

Canadian military[edit]

Three Canadian soldiers involved in the Somalia Affair were injected with mefloquine. It was suggested that mefloquine's side effects could have been partially responsible for the incident and a doctor with Health Canada resigned prior to the incident over her belief that it could produce "dangerous psychiatric reactions" in the soldiers.[27] It was noted that the drug carried a warning that people who had jobs requiring good judgement should not use it.[28]

Research[edit]

In June 2010, the first case report appeared of a progressive multifocal leukoencephalopathy being successfully treated with mefloquine. Mefloquine can also act against the JC virus. Administration of mefloquine seemed to eliminate the virus from the patient's body and prevented further neurological deterioration.[29]

WRAIR has published several papers outlining ongoing efforts at that institution to make mefloquine safer by producing a drug composed of only the (+)-enantiomer.

Mefloquine alters cholinergic synaptic transmission through both postsynaptic [30] and presynaptic actions.[31] The postsynaptic action to inhibit acetylcholinesterase changes transmission across synapses in the brain.[32]

References[edit]

  1. ^ a b c d e f g h "Lariam". The American Society of Health-System Pharmacists. Retrieved 3 April 2011. 
  2. ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  3. ^ a b c d Schlagenhauf, P; Adamcova, M; Regep, L; Schaerer, MT; Rhein, HG (2010-12-09). "The position of mefloquine as a 21st century malaria chemoprophylaxis". Malaria journal 9: 357. doi:10.1186/1475-2875-9-357. PMC 3224336. PMID 21143906. 
  4. ^ a b c d e Schlagenhauf, P. (1999). "Mefloquine for malaria chemoprophylaxis 1992-1998". Travel Med 6 (2): 122–123. doi:10.1111/j.1708-8305.1999.tb00843.x. PMID 10381965. 
  5. ^ Jacquerioz, FA; Croft, AM (2009-10-07). Jacquerioz, Frederique A, ed. "Drugs for preventing malaria in travellers". Cochrane database of systematic reviews (Online) (4): CD006491. doi:10.1002/14651858.CD006491.pub2. PMID 19821371. 
  6. ^ a b c d e f "Lariam medication guide". Hoffman La Roche. Retrieved 27 September 2013. 
  7. ^ http://www.fda.gov/drugs/drugsafety/ucm362227.htm.  Missing or empty |title= (help)
  8. ^ http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088616.pdf
  9. ^ AlKadi, HO (2007). "Antimalarial drug toxicity: a review". Chemotherapy 53 (6): 385–91. doi:10.1159/000109767. PMID 17934257. 
  10. ^ FDA Drug Safety Communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects. Subsection: "Additional Information for Patients." Issued July 29, 2013. Retrieved Aug 9, 2013. http://www.fda.gov/Drugs/DrugSafety/ucm362227.htm
  11. ^ Thomas, Katie. "F. D. A. Strengthens Warnings on Lariam, an Anti-Malarial Drug." The New York Times. July 29, 2013.[1]
  12. ^ Janowsky, A.; Eshleman, A. J.; Johnson, R. A.; Wolfrum, K. M.; Hinrichs, D. J.; Yang, J.; Zabriskie, T. M.; Smilkstein, M. J.; Riscoe, M. K. (2014). "Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro". Psychopharmacology 231 (14): 2771–83. doi:10.1007/s00213-014-3446-0. PMID 24488404.  edit
  13. ^ "Postmarketing Reviews - Volume 1, Number 4, Summer 2008". U.S. Food and Drug Administration. 2008. 
  14. ^ Schlagenhauf P, Blumentals WA, Suter P, et al. (2012). "Pregnancy and fetal outcomes after exposure to mefloquine in the pre- and periconception period and during pregnancy". Clin Infect Dis 54 (11): e124–31. doi:10.1093/cid/cis215. PMC 3348951. PMID 22495078. 
  15. ^ Janowsky, A.; Eshleman, A. J.; Johnson, R. A.; Wolfrum, K. M.; Hinrichs, D. J.; Yang, J.; Zabriskie, T. M.; Smilkstein, M. J.; Riscoe, M. K. (2014). "Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro". Psychopharmacology 231 (14): 2771–83. doi:10.1007/s00213-014-3446-0. PMID 24488404.  edit
  16. ^ "Lariam product monogram". Hoffman La Roche Limited. p. 3. Retrieved 24 April 2011. 
  17. ^ "Lariam product monogram". Hoffman La Roche Limited. p. 4. Retrieved 24 April 2011. 
  18. ^ "Lariam product monogram". Hoffman La Roche Limited. p. 6. Retrieved 24 April 2011. 
  19. ^ "Lariam product monogram". Hoffman La Roche Limited. p. 18. Retrieved 24 April 2011. 
  20. ^ Fletcher, A., and Shepherd, R. Use of (+)-mefloquine for the treatment of malaria. US 6664397 .
  21. ^ a b c d e f g h Croft, AM (2007). "A lesson learnt: the rise and fall of Lariam and Halfan". J R Soc Med. 4 (4): 170–4. doi:10.1258/jrsm.100.4.170. PMC 1847738. PMID 17404338. 
  22. ^ a b http://www.lariaminfo.org/pdfs/policy-memo-secy-defense%20malaria-prophylaxis.pdf
  23. ^ a b http://www.pdhealth.mil/downloads/DASG_Memorandum.pdf
  24. ^ http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-8-advising-travelers-with-specific-needs/special-considerations-for-us-military-deployments.htm
  25. ^ CEASING USE OF MEFLOQUINE IN US ARMY SPECIAL OPERATIONS COMMAND UNITS
  26. ^ http://transparentpolicy.org/2013/11/re-visiting-mefloquine-use-guantanamo-guest-post-dr-remington-nevin-2/
  27. ^ Ogle, James and Darnell Bass. "What Manner of Man", p. 144 and 163.
  28. ^ Worthington, Peter. Edmonton Sun, "Did we poison our Somalia soldiers?", January 3, 1998
  29. ^ Gofton TE, Al-Khotani1 A, O'Farrell B, Ang LC, McLachlan RS (June 2010). "Mefloquine in the treatment of progressive multifocal leukoencephalopathy". J Neurol Neurosurg Psychiatry 82 (4): 452–455. doi:10.1136/jnnp.2009.190652. PMID 20562463. 
  30. ^ McArdle JJ, Sellin LC, Coakley KM, Potian JG, Quinones-Lopez MC, Rosenfeld CA, Sutatos LG, Hognason K (June 2005). "Mefloquine inhibits cholinesterases at the mouse neuromuscular junction". Neuropharmacology 49 (8): 1132–1139. doi:10.1016/j.neuropharm.2005.06.011. PMID 16081111. 
  31. ^ McArdle JJ, Sellin LC, Coakley KM, Potian JG, Hognason K (September 2006). "Mefloquine selectively increases asynchronous acetylcholine release from motor nerve terminals". Neuropharmacology 50 (3): 345–353. doi:10.1016/j.neuropharm.2005.09.011. PMID 16288931. 
  32. ^ Zhou C, Xiao C, McArdle JJ, Ye JH (February 2006). "Mefloquine enhances nigral gamma-aminobutyric acid release via inhibition of cholinesterase". JPET 317 (3): 1155–1160. doi:10.1124/jpet.2005.106.101923. PMID 16501066. 

External links[edit]