Mefloquine
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| Systematic (IUPAC) name |
| [(R*,S*)-2,8-bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol |
| Clinical data |
| Pregnancy cat. |
B (US) |
| 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 Y |
| ATC code |
P01BC02 |
| PubChem |
CID 40692 |
| DrugBank |
DB00358 |
| ChemSpider |
37171 Y |
| UNII |
TML814419R Y |
| KEGG |
D04895 Y |
| ChEMBL |
CHEMBL416956 N |
| NIAID ChemDB |
005218 |
| Chemical data |
| Formula |
C17H16F6N2O |
| Mol. mass |
378.312 g/mol |
SMILES
- FC(F)(F)c2cccc1c(cc(nc12)C(F)(F)F)[C@H](O)[C@@H]3NCCCC3
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InChI
-
InChI=1S/C17H16F6N2O/c18-16(19,20)11-5-3-4-9-10(15(26)12-6-1-2-7-24-12)8-13(17(21,22)23)25-14(9)11/h3-5,8,12,15,24,26H,1-2,6-7H2/t12-,15+/m1/s1 Y
Key:XEEQGYMUWCZPDN-DOMZBBRYSA-N Y
|
N (what is this?) (verify)
|
Mefloquine (Lariam) 250mg tablets
Mefloquine hydrochloride (Lariam, Mephaquin or Mefliam) is an orally administered medication used in the prevention and treatment of malaria. 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. Rare but serious neuropsychiatric problems have been associated with its use.
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Contents
- 1 Medical uses
- 1.1 Malaria prevention
- 1.2 Malaria treatment
- 1.3 In pregnancy and breastfeeding
- 2 Adverse effects
- 2.1 Neuropsychiatric
- 2.2 Pneumonitis
- 2.3 Cardiac
- 3 Mechanism of action
- 4 Elimination
- 5 Chirality
- 6 History
- 7 Society and culture
- 7.1 United States military
- 8 Research
- 9 References
- 10 External links
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Medical uses
Mefloquine is used to both prevent and treat certain forms of malaria.[1]
Malaria prevention
Mefloquine is useful for the prevention of malaria in all areas except for those where parasites may have resistance to multiple drugs.[2] 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.[3][4] If a person becomes ill with malaria despite prophylaxis with mefloquine, the use of halofantrine and quinine for treatment may be ineffective.[5]
Malaria treatment
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][5]
It is not recommended for severe malaria infections, particularly infections from P. falciparum, which should be treated with intravenous antimalarials.[1][5] 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]
In pregnancy and breastfeeding
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.[7]
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.[2] Women should not become pregnant and should use effective birth control while taking mefloquine.[8] It may be used during breastfeeding, though the drug appears in breast milk in low concentrations.[2][9]
Adverse effects
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.[2] Rates of side effects appear similar to other medications used for malaria prevention.[3]
Neuropsychiatric
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%.[10] When some measure of subjective severity is applied to the rating of adverse events, about 11-17% of travelers are incapacitated to some degree.[3]
Pneumonitis
The FDA has reported an association with pneumonitis and eosinophilic pneumonia.[11]
Cardiac
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.[12]
Mechanism of action
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.
Elimination
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.[13][14]
Liver function tests should be performed during long-term administration of mefloquine.[15] Alcohol use should be avoided during treatment with mefloquine.[16]
Chirality
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.[3]
According to some research,[17] 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.
History
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.[18]
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.[18]
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.[18] 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.[3]
The first randomized, controlled trial on a mixed population was first performed in 2001. Roughly 67% reported greater than or equal to one adverse event, with 6% of the users reporting severe events requiring medical attention.[18]
With these data, the FDA and other international licensing authorities certainly would not have approved mefloquine for prophylactic use.[18]
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.[18]
Postmarketing data were easily discounted as anecdotal and "media hype" by the US Army researchers and travel medicine practitioners.[18] 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.[18] As evidence, the US military dropped mefloquine as its primary antimalarial in 2009.[19][20]
Society and culture
United States military
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."[20]
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 the US armed services.[19]
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.[21] 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. Defraites chaired the investigation into the 2002 murder/suicides at Ft. Bragg. There, four soldiers were accused of murdering their wives; two of these soldiers committed suicide. Their actions, as well as other military suicides, have been linked to Lariam use.[22][23]
Research
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.[24]
WRAIR has published several papers outlining ongoing efforts at that institution to make mefloquine safer by producing a drug composed of only the (+)-enantiomer.
References
- ^ a b c d e f "Lariam". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
- ^ 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.
- ^ 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.
- ^ Jacquerioz, FA; Croft, AM (2009-10-07). "Drugs for preventing malaria in travellers". In Jacquerioz, Frederique A. Cochrane database of systematic reviews (Online) (4): CD006491. doi:10.1002/14651858.CD006491.pub2. PMID 19821371.
- ^ a b c "Lariam medication guide". Hoffman La Roche. p. 4. Retrieved 14 April 2011.
- ^ "Lariam medication guide". p. 4.
- ^ 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.
- ^ a b http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088616.pdf
- ^ "Lariam medication guide". Hoffman La Roche. p. 9. Retrieved 14 April 2011.
- ^ AlKadi, HO (2007). "Antimalarial drug toxicity: a review". Chemotherapy 53 (6): 385–91. doi:10.1159/000109767. PMID 17934257.
- ^ "Postmarketing Reviews - Volume 1, Number 4, Summer 2008". U.S. Food and Drug Administration. 2008.
- ^ "Lariam medication guide". p. 10.
- ^ "Lariam product monogram". Hoffman La Roche Limited. p. 3. Retrieved 24 April 2011.
- ^ "Lariam product monogram". Hoffman La Roche Limited. p. 4. Retrieved 24 April 2011.
- ^ "Lariam product monogram". Hoffman La Roche Limited. p. 6. Retrieved 24 April 2011.
- ^ "Lariam product monogram". Hoffman La Roche Limited. p. 18. Retrieved 24 April 2011.
- ^ Fletcher, A., and Shepherd, R. Use of (+)-mefloquine for the treatment of malaria. US 6664397 .
- ^ 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.
- ^ a b http://www.lariaminfo.org/pdfs/policy-memo-secy-defense%20malaria-prophylaxis.pdf
- ^ a b http://www.pdhealth.mil/downloads/DASG_Memorandum.pdf
- ^ http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-8-advising-travelers-with-specific-needs/special-considerations-for-us-military-deployments.htm
- ^ "The Dark Side Of Lariam". CBS News.
- ^ http://www.military.com/NewsContent/0,13319,FL_lariam_022604,00.html
- ^ 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.
External links
- Manufacturer's information
- Mefloquine (Lariam) Action, Clearinghouse for information on mefloquine news, research, toxicity
- Controversies and Misconceptions in Malaria Chemoprophylaxis for Travelers
- The position of mefloquine as a 21st century malaria chemoprophylaxis
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Antiparasitics – antiprotozoal agents – Chromalveolate antiparasitics (P01)
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|
Alveo-
late |
Apicom-
plexa |
Conoidasida/
(Coccidiostats) |
| Cryptosporidiosis |
|
|
| Isosporiasis |
- trimethoprim/sulfamethoxazole#
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|
| Toxoplasmosis |
- pyrimethamine
- sulfadiazine
|
|
|
| Aconoidasida |
| Malaria |
Individual
agents |
Hemozoin
inhibitors |
| aminoquinolines |
- (4-): amodiaquine#
- chloroquine#
- (8-): primaquine#
- pamaquine
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|
| 4-methanolquinolines |
- mefloquine#
- quinine#
- quinidine
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| Other |
|
|
|
| Antifolates |
DHFR inhibitors
(antifols) |
- proguanil#
- chlorproguanil
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|
| Sulfonamides |
- sulfadoxine
- sulfamethoxypyrazine
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|
| Coformulation |
- sulfadoxine/pyrimethamine (SP)#
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|
|
Sesquiterpene
lactones |
- artemether#
- artesunate#
- dihydroartemisinin
- artemotil
- artemisinin
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|
| Other |
- atovaquone (with proguanil as as Malarone)
- tetracycline
- doxycycline#
- clindamycin
- pyronaridine
- piperaquine
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|
|
Combi-
nations |
| Fixed-dose (coformulated) ACTs |
- artemether/lumefantrine#
- artesunate/amodiaquine (ASAQ)
- artesunate/mefloquine (ASMQ)
- dihydroartemisinin/piperaquine
- artesunate/pyronaridine
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Other combinations
(not co-formulated) |
- artesunate/SP
- artesunate/mefloquine
- quinine/tetracycline
- quinine/doxycycline
- quinine/clindamycin
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| Babesiosis |
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Cilio-
phora |
- Balantidiasis: Tetracycline
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Hetero-
kont |
- Blastocystosis: Metronidazole
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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