Mefloquine, sold under the brand name Lariam among others, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to prevent or treat

malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...

. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It can be used to treat mild or moderate malaria but is not recommended for severe malaria. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Common side effects include vomiting, diarrhea, headaches, sleep disorders, and a rash. Serious side effects include potentially long-term mental health problems such as depression,

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

s, and

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

and neurological side effects such as poor balance, seizures, and ringing in the ears. It is therefore not recommended in people with a history of mental health problems or

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

. It appears to be safe during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

and

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

. Mefloquine was developed by the United States Army in the 1970s and came into use in the mid-1980s. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.

Medical uses

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

Malaria prevention

Mefloquine is useful for the prevention of malaria in all areas except for those where parasites may have resistance to multiple medications, and is one of several anti-malarial medications recommended by the United States

Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the National public health institutes, national public health agency of the United States. It is a Federal agencies of the United States, United States federal agency under the United S ...

for this purpose. It is also recommended by the Infectious 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. It is typically taken for one to two weeks before entering an area with malaria.

Doxycycline Doxycycline is a Broad-spectrum antibiotic, broad-spectrum antibiotic of the Tetracycline antibiotics, tetracycline class used in the treatment of infections caused by bacteria and certain parasites. It is used to treat pneumonia, bacterial p ...

and atovaquone/proguanil provide protection within one to two days and may be better tolerated. If a person becomes ill with malaria despite prophylaxis with mefloquine, the use of halofantrine and

quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to ''Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg ...

for treatment may be ineffective.

Malaria treatment

Mefloquine is used as a treatment for chloroquine-sensitive or resistant ''

Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans and is the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mos ...

'' malaria, and is deemed a reasonable alternative for uncomplicated chloroquine-resistant '' Plasmodium vivax'' malaria. It is one of several drugs recommended by the United States' Centers for Disease Control and Prevention. It is not recommended for severe malaria infections, particularly infections from ''P. falciparum'', which should be treated with intravenous antimalarials. 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.

Resistance to mefloquine

Resistance to mefloquine is common around the west border in

Cambodia Cambodia, officially the Kingdom of Cambodia, is a country in Southeast Asia on the Mainland Southeast Asia, Indochinese Peninsula. It is bordered by Thailand to the northwest, Laos to the north, and Vietnam to the east, and has a coastline ...

and other parts of Southeast Asia. The mechanism of resistance is by increase in '' Pfmdr1'' copy number.

Contraindications

Mefloquine is contraindicated in those with a previous history of seizures or a recent history of psychiatric disorders.

Pregnancy and breastfeeding

Available data suggests that mefloquine is safe and effective for use by pregnant women during all trimesters of pregnancy, and it is widely used for this indication. In pregnant women, mefloquine appears to pose minimal risk to the fetus, and is not associated with increased risk of birth defects or miscarriages. 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, though it appears in breast milk in low concentrations. The

World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...

(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.

Adverse effects

Common side effects include vomiting, diarrhoea, headaches, and a rash. Severe side effects requiring hospitalization are rare, but include mental health problems such as depression,

and neurological side effects such as poor balance, seizures, and ringing in the ears. Mefloquine is therefore not recommended in people with a history of psychiatric disorders or

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

Neurologic and psychiatric

In 2013, the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) added a boxed warning to the prescription label of mefloquine regarding the potential for neuropsychiatric side effects that may persist even after discontinuing administration of the medication. In 2013 the FDA stated "Neurologic side 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." Neurologic effects include dizziness, loss of balance,

seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

, and

tinnitus Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...

. Psychiatric effects include nightmares, visual hallucinations, auditory hallucinations,

, depression, unusual behavior, and suicidal ideations. Central nervous system events requiring hospitalization occur in about one in 100 (see below) people taking mefloquine for malaria prevention, with milder events (e.g., dizziness, headache,

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

, and vivid dreams) in up to 25%. When some measure of subjective severity is applied to the rating of adverse events, about 11–17% of travelers are incapacitated to some degree.

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 Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...

, can increase these effects. Combining mefloquine with halofantrine can cause significant increases in QTc intervals.

Pharmacology

Pharmacodynamics

The

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

of mefloquine is unclear and several competing hypotheses exist.

Off-target activities

Mefloquine has known off-target activities. This includes affinity for the serotonin 5-HT_2A receptor and to a lesser extent for the serotonin 5-HT_2C receptor, but not for the serotonin 5-HT_1A receptor. Mefloquine acts as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of both the serotonin 5-HT_2A and 5-HT_2C receptors, similarly to serotonergic psychedelics like LSD, DOM, and DMT. It also binds to the serotonin transporter and acts as a serotonin reuptake inhibitor, acts as a serotonin 5-HT₃ receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

D₃ receptor, among other actions. These properties of mefloquine, especially serotonin 5-HT_2A receptor agonism, may be involved in the neurological and psychiatric

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...

s such as visual hallucinations that have been reported with its use particularly at high doses. Mefloquine is a drug that is thought to have potential antiepilectic effects due to its ability to non-specifically block connexin hemi-channels and pannexons.

Pharmacokinetics

Mefloquine is metabolized primarily through the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

. Its elimination in persons with impaired liver function may be prolonged, resulting in higher plasma levels and an increased risk of adverse reactions. The mean plasma elimination half-life of mefloquine is between 2 and 4weeks. Total clearance is through the liver, and the primary means of

excretion Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, Kidney (vertebrates), kidneys, and skin. This is in contrast with secretion, where the substa ...

is through the

bile Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...

and

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

, as opposed to only 4% to 9% excreted through the

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

. During long-term use, the plasma half-life remains unchanged.

Chemistry

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 Hoffmann-La Roche, 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 pharmacokinetics between the two enantiomers are significantly different. The (+)-enantiomer has a shorter half-life than the (–)-enantiomer. Specifically it is used as mefloquine hydrochloride. The

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

of mefloquine is similar to that of tryptamine and its

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

s. However, whereas tryptamine is an indolylethylamine, mefloquine is a quinolinylethylamine. Mefloquine's structure is also particularly similar to that of 10,11-secoergoline (α,''N''-tetramethylenetryptamine).

History

Mefloquine was formulated 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. 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. The drug was first approved in Switzerland in 1984 by Hoffmann-LaRoche, who brought it to market with the name ''Lariam''. 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. 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 The Peace Corps is an Independent agency of the U.S. government, independent agency and program of the United States government that trains and deploys volunteers to communities in partner countries around the world. It was established in Marc ...

volunteers who participated in the approval study, so the drug regimen was switched to once a week. By 1991, Hoffman was marketing the drug on a worldwide basis. By the 1992 UNITAF, Canadian soldiers were being prescribed the drug ''en masse''. By 1994, medical professionals were noting "severe psychiatric side effects observed during prophylaxis and treatment with mefloquine", and recommending that "the absence of contraindications and minor side effects during an initial course of mefloquine should be confirmed before another course is prescribed." Other doctors at the University 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 The first randomized, controlled trial on a mixed population was performed in 2001. Prophylaxis with mefloquine was compared to prophylaxis with atovaquone-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. In August 2009, Roche stopped marketing Lariam in the United States. Retired soldier

Johnny Mercer John Herndon Mercer (November 18, 1909 – June 25, 1976) was an American lyricist, songwriter, and singer, as well as a record label executive who co-founded Capitol Records with music industry businessmen Buddy DeSylva and Wallichs Music Cit ...

, who was later appointed Minister for Veterans Affairs by Boris Johnson, told in 2015 that he had received "a letter about once or twice a week" about ill-effects from the drug. In July 2016, Roche took this brand off the market in Ireland.

Military

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. Between 2001 and 2012, 16,000 Canadian soldiers sent to Afghanistan were given the drug as a preventative measure. In 2013, the US Army banned mefloquine from use by its special forces such as the Green Berets. 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. In early December 2016, the German defence ministry removed mefloquine from the list of medications it would provide to its soldiers. In autumn 2016, Canadian Surgeon General Brigadier General Hugh Colin MacKay told a parliamentary committee that faulty science supported the assertion that the drug has indelible noxious side effects. An expert from

Health Canada Health Canada (HC; )Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the Structure of the Canadian federal government#Departments, with subsidiary units, department of the Gove ...

named Barbara Raymond told the same committee that the evidence she had read failed to support the conclusion of indelible side effects. Canadian soldiers who took mefloquine when deployed overseas have claimed they have been left with ongoing mental health problems. In 2020 the UK Ministry of Defence (MoD) admitted to a breach of duty regarding the use of Mefloquine. by acknowledging numerous instances of failure to assess the risks and warn of potential side effects of the drug.

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

References

External links

* {{Authority control 5-HT2A agonists 5-HT2C agonists 5-HT3 antagonists American inventions Antimalarial agents Chirality Drug safety Drugs developed by Hoffmann-La Roche Medical controversies Piperidines Quinolines Racemic mixtures Hallucinogens Serotonin reuptake inhibitors Trifluoromethyl compounds World Health Organization essential medicines Wikipedia medicine articles ready to translate