Mefloquine - WikiHQ

Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure.

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. and is one of several anti-malarial medications recommended by the United States Centers for Disease Control and Prevention 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. If a person becomes ill with malaria despite prophylaxis with mefloquine, the use of halofantrine and quinine for treatment may be ineffective.

Malaria treatment

Mefloquine is used as a treatment for chloroquine-sensitive or resistant Plasmodium falciparum malaria, and is deemed a reasonable alternative for uncomplicated chloroquine-resistant Plasmodium vivax malaria.

It is not recommended for severe malaria infections, particularly infections from P. falciparum, which should be treated with intravenous antimalarials. 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. 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, Alcohol use should be avoided during treatment with mefloquine.

Neurologic and psychiatric

In 2013, the US Food and Drug Administration (FDA) added a boxed warning to the prescribing information 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, and tinnitus. Psychiatric effects include nightmares, visual hallucinations, auditory hallucinations, anxiety, depression, unusual behavior, and suicidal ideations.

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%. When some measure of subjective severity is applied to the rating of adverse events, about 11–17% of travelers are incapacitated to some degree.

Off-target activities

Mefloquine has known off-target activities. This includes affinity for the serotonin 5-HT2A receptor and to a lesser extent for the serotonin 5-HT2C receptor, but not for the serotonin 5-HT1A receptor. These properties of mefloquine, especially serotonin 5-HT2A receptor agonism, may be involved in the neurological and psychiatric adverse effects such as visual hallucinations that have been reported with its use particularly at high doses.

Pharmacokinetics

Mefloquine is metabolized primarily through the liver. 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 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.

Chemistry

thumb|right|class=skin-invert-image|250px|(R,S)-(+)-Mefloquine and (S,R)-(−)-mefloquine chemical formulae.

thumb|right|class=bg-transparent|250px|(R,S)-(+)-Mefloquine and (S,R)-(−)-mefloquine ball-and-stick models.

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. However, whereas tryptamine is an indolylethylamine, mefloquine is a quinolinylethylamine. who brought it to market with the name Lariam.

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. In July 2016, Roche took this brand off the market in Ireland.

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 named Barbara Raymond told the same committee that the evidence she had read failed to support the conclusion of indelible side effects.

In 2020 the UK Ministry of Defence (MoD) admitted to a breach of duty regarding the use of Mefloquine, 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

Hallucinogens You Probably Haven't Heard of: Mefloquine - Nervewing - Blogger