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<!-- History, society and culture -->
<!-- History, society and culture -->
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]], a list of the most important medication needed in a basic [[health system]].<ref>{{cite web|title=WHO Model List of EssentialMedicines|url=http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1|work=World Health Organization|accessdate=22 April 2014|date=October 2013}}</ref>
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]], a list of the most important medication needed in a basic [[health system]].<ref>{{cite web|title=WHO Model List of EssentialMedicines|url=http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1|work=World Health Organization|accessdate=22 April 2014|date=October 2013}}</ref>

⚫
==FDA adds Black Box Warning==
⚫
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 (For a more complete list of potential side effects, see Additional Information for Patients)." <ref>{{cite web|url=http://www.fda.gov/drugs/drugsafety/ucm362227.htm]</ref>


==Medical uses==
==Medical uses==
Line 67: Line 64:
==Adverse effects==
==Adverse effects==
Mefloquine is contraindicated in those with a previous history of [[seizures]] or a recent history of [[psychiatric disorders]].<ref name=AHFS/> Severe side effects requiring hospitalization are rare.<ref name=Review10/> Rates of side effects appear similar to other medications used for malaria prevention.<ref name=Review99/>
Mefloquine is contraindicated in those with a previous history of [[seizures]] or a recent history of [[psychiatric disorders]].<ref name=AHFS/> Severe side effects requiring hospitalization are rare.<ref name=Review10/> Rates of side effects appear similar to other medications used for malaria prevention.<ref name=Review99/>

⚫
==FDA adds Black Box Warning==
⚫
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 (For a more complete list of potential side effects, see Additional Information for Patients)." <ref>{{cite web|url=http://www.fda.gov/drugs/drugsafety/ucm362227.htm]</ref>


===Neurologic and psychiatric===
===Neurologic and psychiatric===
Neuropsychiatric effects are reported with mefloquine use.<ref name=AHFS/> The FDA product guide states it can cause mental health problems, including anxiety, hallucinations, depression, unusual behavior, and suicidal ideations, among others.<ref name="FDA">http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088616.pdf</ref> 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%.<ref>{{cite journal|last=AlKadi|first=HO|title=Antimalarial drug toxicity: a review|journal=Chemotherapy|year=2007|volume=53|issue=6|pages=385–91|pmid=17934257|doi=10.1159/000109767}}</ref> When some measure of subjective severity is applied to the rating of adverse events, about 11-17% of travelers are incapacitated to some degree.<ref name=Review99/>
Neuropsychiatric effects are reported with mefloquine use.<ref name=AHFS/> The FDA product guide states it can cause mental health problems, including anxiety, hallucinations, depression, unusual behavior, and suicidal ideations, among others.<ref name="FDA">http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088616.pdf</ref> 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%.<ref>{{cite journal|last=AlKadi|first=HO|title=Antimalarial drug toxicity: a review|journal=Chemotherapy|year=2007|volume=53|issue=6|pages=385–91|pmid=17934257|doi=10.1159/000109767}}</ref> When some measure of subjective severity is applied to the rating of adverse events, about 11-17% of travelers are incapacitated to some degree.<ref name=Review99/>

In July 2013, the U.S. [[Food and Drug Administration]] issued a [[boxed warning]] regarding neurologic and psychiatric side effects.<ref name="fda_a">{{cite document | title = FDA Drug Safety Communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects. Subsection: "Safety Announcement." | date = July 29, 2013 | accessdate = Aug 9, 2013 | url = http://www.fda.gov/Drugs/DrugSafety/ucm362227.htm | publisher = Food and Drug Administration}}</ref>

Neurological side effects of mefloquine can include dizziness, loss of balance, ringing in the ears, convulsions, and insomnia.<ref name="fda.gov">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</ref> These effects can occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent.<ref name="fda_a" />


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.<ref name="fda.gov"/> These psychiatric problems may last for years after the patient stops taking the drug.<ref name=":0">Thomas, Katie. "F. D. A. Strengthens Warnings on Lariam, an Anti-Malarial Drug." ''The New York Times''. July 29, 2013.[http://www.nytimes.com/2013/07/30/business/fda-strengthens-warnings-on-lariam-anti-malaria-drug.html?_r=0]</ref> Mefloquine has been found to act as an agonist at 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> 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.<ref>{{Cite doi|10.1007/s00213-014-3446-0}}</ref>
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.<ref name="fda.gov"/> These psychiatric problems may last for years after the patient stops taking the drug.<ref name=":0">Thomas, Katie. "F. D. A. Strengthens Warnings on Lariam, an Anti-Malarial Drug." ''The New York Times''. July 29, 2013.[http://www.nytimes.com/2013/07/30/business/fda-strengthens-warnings-on-lariam-anti-malaria-drug.html?_r=0]</ref> Mefloquine has been found to act as an agonist at 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> 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.<ref>{{Cite doi|10.1007/s00213-014-3446-0}}</ref>

Revision as of 17:26, 28 May 2014

Mefloquine
Clinical data
Pregnancy
category
Routes of
administration		oral
ATC code
Pharmacokinetic data
MetabolismExtensively hepatic; main metabolite is inactive
Elimination half-life2 to 4 weeks
ExcretionPrimarily bile and feces; urine (9% as unchanged drug, 4% as primary metabolite)
Identifiers
  • [(R*,S*)-2,8-bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC17H16F6N2O
Molar mass378.312 g/mol g·mol−1
3D model (JSmol)
  • FC(F)(F)c2cccc1c(cc(nc12)C(F)(F)F)[C@H](O)[C@@H]3NCCCC3
  • 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 checkY
  • Key:XEEQGYMUWCZPDN-DOMZBBRYSA-N checkY
 ☒NcheckY (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.

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, a list of the most important medication needed in a basic health system.[2]

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.[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

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

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

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 (For a more complete list of potential side effects, see Additional Information for Patients)." [7]

Neurologic and psychiatric

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

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

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.[6]: 10 

Contraindications

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.

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.[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

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

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

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

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

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."[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 US Army Special Operations Command(USASOC) at Ft. Bragg, NC 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]

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.[27]

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 [28] and presynaptic actions.[29] The postsynaptic action to inhibit acetylcholinesterase changes transmission across synapses in the brain.[30]

References

  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 EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  3. ^ a b c d Schlagenhauf, P (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: unflagged free DOI (link)
  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 (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ a b c d e f "Lariam medication guide" (PDF). Hoffman La Roche. Retrieved 27 September 2013.
  7. ^ {{cite web|url=http://www.fda.gov/drugs/drugsafety/ucm362227.htm]
  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. ^ Cite error: The named reference fda.gov was invoked but never defined (see the help page).
  11. ^ Thomas, Katie. "F. D. A. Strengthens Warnings on Lariam, an Anti-Malarial Drug." The New York Times. July 29, 2013.[1]
  12. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1007/s00213-014-3446-0, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1007/s00213-014-3446-0 instead.
  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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  15. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1007/s00213-014-3446-0, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1007/s00213-014-3446-0 instead.
  16. ^ "Lariam product monogram" (PDF). Hoffman La Roche Limited. p. 3. Retrieved 24 April 2011.
  17. ^ "Lariam product monogram" (PDF). Hoffman La Roche Limited. p. 4. Retrieved 24 April 2011.
  18. ^ "Lariam product monogram" (PDF). Hoffman La Roche Limited. p. 6. Retrieved 24 April 2011.
  19. ^ "Lariam product monogram" (PDF). 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 I N US ARMY SPECIAL OPERATIONS COMMAND UNITS
  26. ^ http://transparentpolicy.org/2013/11/re-visiting-mefloquine-use-guantanamo-guest-post-dr-remington-nevin-2/
  27. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  28. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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