Mefloquine, sold under the brand nameLariam among others, is amedication used to prevent or treatmalaria.[4] When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure.[4] It can be used to treat mild or moderate malaria but is not recommended for severe malaria.[4] It is takenby mouth.[4]
Common side effects include vomiting, diarrhea, headaches, sleep disorders, and a rash.[4] Serious side effects include potentially long-term mental health problems such asdepression,hallucinations, andanxiety and neurological side effects such aspoor balance,seizures, andringing in the ears.[4] It is therefore not recommended in people with a history of mental health problems orepilepsy.[4] It appears to be safe duringpregnancy andbreastfeeding.[1]
Mefloquine is useful for the prevention of malaria in all areas except for those where parasites may haveresistance to multiple medications,[11] and is one of several anti-malarial medications recommended by the United StatesCenters for Disease Control and Prevention for this purpose. It is also recommended by theInfectious Disease Society of America for malaria prophylaxis as a first or second-line agent, depending on resistance patterns in the malaria found in the geographic region visited.[12][13] It is typically taken for one to two weeks before entering an area with malaria.[10]Doxycycline andatovaquone/proguanil provide protection within one to two days and may be better tolerated.[14][15] If a person becomes ill with malaria despite prophylaxis with mefloquine, the use ofhalofantrine andquinine for treatment may be ineffective.[16]: 4
Mefloquine is used as a treatment forchloroquine-sensitive or resistantPlasmodium falciparum malaria, and is deemed a reasonable alternative for uncomplicated chloroquine-resistantPlasmodium vivax malaria.[10][16] It is one of several drugs recommended by the United States' Centers for Disease Control and Prevention.[17]It is not recommended for severe malaria infections, particularly infections fromP. falciparum, which should be treated with intravenousantimalarials.[10][16] Mefloquine does not eliminate parasites in the liver phase of the disease, and people withP. vivax malaria should be treated with a second drug that is effective for the liver phase, such asprimaquine.[16]: 4
Resistance to mefloquine is common around the west border inCambodia and other parts of Southeast Asia.[18] The mechanism of resistance is by increase inPfmdr1 copy number.[19]
Available data suggests that mefloquine is safe and effective for use by pregnant women during all trimesters of pregnancy,[20] and it is widely used for this indication.[21] In pregnant women, mefloquine appears to pose minimal risk to the fetus,[21][22] and is not associated with increased risk of birth defects or miscarriages.[23] Compared to other malaria chemoprophylaxis regimens, however, mefloqinone may produce more side effects in non-pregnant travelers.
Mefloquine is also safe and effective for use during breastfeeding,[20] though it appears in breast milk in low concentrations.[11][16]: 9 TheWorld Health Organization (WHO) 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.[11]
Liver function tests should be performed during long-term administration of mefloquine.[24] Alcohol use should be avoided during treatment with mefloquine.[25]
Central nervous system events requiring hospitalization occur 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%.[29] When some measure of subjective severity is applied to the rating of adverse events, about 11–17% of travelers are incapacitated to some degree.[14]
Mefloquine may cause abnormalities with heart rhythms that are visible onelectrocardiograms. Combining mefloquine with other drugs that cause similar effects, such as quinine orquinidine, can increase these effects. Combining mefloquine with halofantrine can cause significant increases inQTc intervals.[16]: 10
Mefloquine is achiral molecule with twoasymmetric carbon centres, which means it has four differentstereoisomers. The drug is currently manufactured and sold as aracemate of the (R,S)- and (S,R)-enantiomers byHoffmann-La Roche, a Swisspharmaceutical company. Essentially, it is two drugs in one. Plasma concentrations of the (–)-enantiomer are significantly higher than those for the (+)-enantiomer, and the pharmacokinetics between the two enantiomers are significantly different. The (+)-enantiomer has a shorter half-life than the (–)-enantiomer.[14] Specifically it is used as mefloquine hydrochloride.
Thechemical structure of mefloquine is similar to that oftryptamine and itsderivatives.[39] However, whereas tryptamine is an indolylethylamine, mefloquine is a quinolinylethylamine.[39] Mefloquine's structure is also particularly similar to that of10,11-secoergoline (α,N-tetramethylenetryptamine).[39]
Mefloquine was formulated atWalter 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.[5]
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 andSmith Kline. FDA approval as a treatment for malaria was swift. Most notably, phase III safety and tolerability trials were skipped.[5]
The drug was first approved in Switzerland in 1984 by Hoffmann-LaRoche,[40] who brought it to market with the nameLariam.[41]
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.[5] Because of the drug's very long half-life, theCenters for Disease Control originally recommended a mefloquine dosage of 250 mg every two weeks; however, this caused an unacceptably high malaria rate in thePeace Corps volunteers who participated in the approval study, so the drug regimen was switched to once a week.[14]
By 1991, Hoffman was marketing the drug on a worldwide basis.[41]
By the 1992UNITAF, Canadian soldiers were being prescribed the drugen masse.[42]
By 1994, medical professionals were noting "severe psychiatric side effects observed during prophylaxis and treatment with mefloquine", and recommending that "the absence ofcontraindications and minor side effects during an initial course of mefloquine should be confirmed before another course is prescribed."[43] Other doctors at theUniversity Hospital of Zurich noted in a case of "a 47-year-old, previously healthy Japanese tourist" who had severe neuropsychiatric side-effects from the drug that[44]
The neuropsychiatric side effects of the antimalarial drug mefloquine are well documented. They include anxiety, depression, hallucinations, acute psychosis, and seizures. The incidence of these side effects is 1 in 13,000 with prophylactic use and 1 in 250 with therapeutic use.
The first randomized, controlled trial on a mixed population was performed in 2001. Prophylaxis with mefloquine was compared to prophylaxis withatovaquone-proguanil. Roughly 67% of participants in the mefloquine arm reported greater than or equal to one adverse event, versus 71% in the atovaquone-proguanil arm. In the mefloquine arm, 5% of the users reported severe events requiring medical attention, versus 1.2% in the atovaquone-proguanil arm.[5][45]
In August 2009, Roche stopped marketing Lariam in the United States.[46]
Retired soldierJohnny Mercer, who was later appointed Minister for Veterans Affairs byBoris Johnson, told in 2015 that he had received "a letter about once or twice a week" about ill-effects from the drug.[47] In July 2016, Roche took this brand off the market in Ireland.[46]
In 2006, the Australian military deemed mefloquine "a third-line drug" alternative, and over the five years from 2011 only 25 soldiers had been prescribed the drug, and only in cases of their intolerance for other alternatives.[46] Between 2001 and 2012, 16,000 Canadian soldiers sent to Afghanistan were given the drug as a preventative measure.[46] In 2013, the US Army banned mefloquine from use by its special forces such as theGreen Berets.[46] In autumn 2016, the UK military followed suit with their Australian peers after a parliamentary inquiry into the matter revealed that it can cause permanent side effects and brain damage.[46]
In early December 2016, the German defence ministry removed mefloquine from the list of medications it would provide to its soldiers.[46]
In autumn 2016, CanadianSurgeon General Brigadier GeneralHugh Colin MacKay told a parliamentary committee that faulty science supported the assertion that the drug has indelible noxious side effects. An expert fromHealth Canada namedBarbara Raymond told the same committee that the evidence she had read failed to support the conclusion of indelible side effects.[46] Canadian soldiers who took mefloquine when deployed overseas have claimed they have been left with ongoing mental health problems.[48]
In 2020 the UK Ministry of Defence (MoD) admitted to a breach of duty regarding the use of Mefloquine.[49] by acknowledging numerous instances of failure to assess the risks and warn of potential side effects of the drug.
In June 2010, the first case report appeared of aprogressive multifocal leukoencephalopathy being successfully treated with mefloquine. Mefloquine can also act against theJC virus. Administration of mefloquine seemed to eliminate the virus from the patient's body and prevented further neurological deterioration.[50]
^World Health Organization (2019).World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^World Health Organization (2021).World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization.hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^abcde"Lariam".The American Society of Health-System Pharmacists.Archived from the original on 7 January 2012. Retrieved3 April 2011.
^abcdeHolden JM, Slivicki R, Dahl R, Dong X, Dwyer M, Holley W, et al. (2015)."Behavioral effects of mefloquine in tail suspension and light/dark tests".SpringerPlus.4 702.doi:10.1186/s40064-015-1483-8.PMC4648841.PMID26609504.The mechanisms by which mefloquine could potentially create adverse effects on mood and emotional functioning are numerous. Mefloquine has also been shown to affect gap junction activity by blocking the connexin36 protein (Nevin 2012c; Voss et al. 2009; Juszczak and Swiergiel 2009; Alisky et al. 2006), to alter dopaminergic and cholinergic activity, and calcium homeostasis (Juszczak and Swiergiel 2009; Alisky et al. 2006; Nevin 2011; Allison et al. 2011), to stimulate 5-HT2A and 5-HT2C receptors with similar potency and efficacy as the hallucinogen dimethyltryptamine (Janowsky et al. 2014), to alter activity in basolateral amygdala, important to the mediation of fear and anxiety states (Chung and Moore 2009), to impair fear-based learning through blocking of hippocampal gap junctions (Bissiere et al. 2011), to potentially alter sleep-waking related activity in reticular activating sites (Beck et al. 2008; Garcia-Rill et al. 2007), and to antagonize adenosine receptors (Alisky et al. 2006; Shepherd 1988).
^Styka AN, Savitz DA (2020). "Mefloquine". In Savitz DA, Styka AN (eds.).Assessment of Long-Term Health Effects of Antimalarial Drugs When Used for Prophylaxis. pp. 91–176.Bibcode:2020nap..book25688N.doi:10.17226/25688.ISBN978-0-309-67210-8.PMID32369311.Binding assays suggest that mefloquine has the capacity to bind to neurotransmitter receptors. Mefloquine is a partial 5-HT2A agonist with an EC50 value of 1.9 µM (Janowsky et al., 2014), and it is also a 5-HT3A and 5-HT3AB antagonist with respective IC50 values of 0.66 and 2.7 µM (Thompson and Lummis, 2008). Though the studies were not performed in neuronal cells, the results suggest that there is a potential for in vivo action on serotonin signaling under some conditions, which are associated with but not causally linked to psychiatric conditions, including depression, suicidality, and low mood.
^Angus JA, Betrie AH, Wright CE (2015). "annexin-1 channels do not regulate α1-adrenoceptor-mediated vasoconstriction in resistance arteries".Eur J Pharmacol.750:43–51.doi:10.1016/j.ejphar.2015.01.024.PMID25637780.
^Adams S (6 September 2017)."Cure or curse?". Canvet Publications Ltd. Legion Magazine.
^Hennequin C, Bourée P, Bazin N, Bisaro F, Feline A (October 1994). "Severe psychiatric side effects observed during prophylaxis and treatment with mefloquine".Archives of Internal Medicine.154 (20):2360–2362.doi:10.1001/archinte.1994.00420200116012.PMID7944858.
^McArdle JJ, Sellin LC, Coakley KM, Potian JG, Quinones-Lopez MC, Rosenfeld CA, et al. (December 2005). "Mefloquine inhibits cholinesterases at the mouse neuromuscular junction".Neuropharmacology.49 (8):1132–1139.doi:10.1016/j.neuropharm.2005.06.011.PMID16081111.S2CID28938736.
^McArdle JJ, Sellin LC, Coakley KM, Potian JG, Hognason K (March 2006). "Mefloquine selectively increases asynchronous acetylcholine release from motor nerve terminals".Neuropharmacology.50 (3):345–353.doi:10.1016/j.neuropharm.2005.09.011.PMID16288931.S2CID13245990.
^Zhou C, Xiao C, McArdle JJ, Ye JH (June 2006). "Mefloquine enhances nigral gamma-aminobutyric acid release via inhibition of cholinesterase".The Journal of Pharmacology and Experimental Therapeutics.317 (3):1155–1160.doi:10.1124/JPET.106.101923.PMID16501066.S2CID22205111.
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