Mefloquine

Chemistry

Photograph: Coey Yeung

Mefloquine, an antimalarial drug also known as Lariam.

In WWII, Western nations were cut off from their usual quinine supply. Thus, to meet the rising demand of antimalarial drugs, synthetic antimalarial drugs arose: mepacrine and chloroquine.

Mepacrine has side effects of turning skin and urine yellow in addition to causing toxic psychosis.

Chloroquine was used as well, but malaria parasites (Plasmodium falciparum) built resistance to both

drugs. New drugs had to be developed.

quinine >

< mepacrine

In both antimalarial drugs, comparisons can be made between mefloquine and quinine.

Enantiomers and most antimalarial drugs have a 4-quinoline nucleus, and an amino alcohol side chain:

Production:

The isomer above is (+)-(11R, 12S)-isomer. Mefloquine has two chiral centres, resulting in four different enantiomers in two racemic forms.

The drug is currently manufactured and sold as a racemate of the (R,S)- and (S,R)-enantiomers. The (+)-enantiomer has a shorter half-life than the (–)-enantiomer.

Mechanism of antimalarial activity:

Mefloquine has antimalarial properties as it inhibits merozoite invasion of plasmodium parasites into red blood cells. Merozoites are complex entities specialized for the capture and entry of red blood cells. They have specific (to red blood cells) surface antigens and invasion ligands which help them bind to red blood cells. After invasion, merozoites multiply within them. Plasmodium merozoites have two key proteins RON2 and AMA1 which is critical for invasion by triggering junction formation between the merozoite and the red blood cell. After the junction is formed, the parasitophorous vacuole is induced into the red blood cell.

Mefloquine is a protein synthesis inhibitor, that intracts with the 80S ribosome (of the plasmodium

parasite). (+)-mefloquine binds to the ribosome GTPase-associated centre and inhibits its ability to

synthesize proteins involved with parasite membrane lipid trafficking and nutrient uptake. This

inhibition mechanism was proved by mutating parasites to have less mefloquine-binding sites. The

mutated parasites had increased resistance to mefloquine.

Besides, mefloquine may bind to haem and form a complex that is toxic to parasites.

< mefloquine’s activity is comparable to chloroquine, forming complexes with haem groups.

History and Chinese equivalent:

In 1965, when American troops arrived in Vietnam, there were serious problems with chloroquine resistance in the area. Between 1965 and 1971, there were more than 80,000 cases of malaria and resulting in the deaths of 53 US soldiers. However, pharmaceutical companies were unwilling to develop a new antimalarial drug due to the insufficient financial return. Thus, the US army started a research program in 1963, testing 400 compounds with structures similar to common antimalarial drugs. The best compound discovered was WR-142490: mefloquine. This was then synthesized in 1969. Initially, this proved to be very successful as it had a 100% success rate against chloroquine-resistant plasmodium parasites. Similarly, the North Vietnamese Army had issues with chloroquine-resistant malaria. They appealed to the Chinese for help. Maybe because of the Chinese Premier Zhou En Lai’s experience with malaria 40 years prior, the Chinese leadership set up a military project 523 (on 23/5/1967) to find the lifesaving antimalarial drug. The Chinese consulted a 2000-year-old (Jin dynasty, 東晉) pharmacopoeia: Ge Hong’s (葛洪) “The Handbook of Prescriptions for Emergency Treatments” (肘後備急方). From the Handbook, qinghaosu (⻘蒿素), or essence of wormwood, was identified as a remedy for fevers (fever being one of malaria’s symptoms). The ancient texts advised: 「⻘蒿一握,以水二升漬,絞取汁,盡服之」, which roughly translates to “a handful of wormwood/qinghao, soaked in two litres of water; wring and extract juice, then drink.”) The Chinese scientists had limited success when it came to following the text’s instructions, but when they extracted wormwood with cold ether, antimalarial activity was observed. The antimalarial artemisinin was later isolated from the extract in 1972 and its structure determined three years later.

< the antimalarial activity of artemisinin stems from the novel endoperoxide bridge

Modern plasmodium parasites have now become resistant to artemisinin. ACT (Artemisinin Combination Therapy) which involves the combination of mefloquine with artemisinin, was

used. It is effective as parasites are unlikely to be resistant to multiple drugs.

Controversy and modern uses:

Once mefloquine was developed, the FDA quickly approved of its use. Phase III safety and tolerability trials were skipped. This was done due to the urgent demand for an antimalarial drug; however, issues quickly arose. In 1994, two years after mefloquine was widely prescribed, severe psychiatric side effects (e.g. anxiety, depression, hallucinations, acute psychosis, and seizures) were observed during treatment and use. The incidence of these side effects is 1 in 13,000 with prophylactic use and 1 in 250 with therapeutic use. It was only until 2001 that the first randomized, controlled trial on mefloquine prophylaxis was carried out. 67% of participants reported at least one adverse effect,

with 5% reporting severe medical emergencies requiring medical attention. In 2009, the US government soon forbade the marketing of mefloquine, and its use was later banned in 2013 for US

Special Forces.

However, mefloquine is still prescribed to British armed forces now (with 4 prescriptions of

mefloquine between 1/10/2020 and 31/3/2021). It is backed by Public Health England as the drug of

choice for military personnel in malarial areas. The Ministry of Defence has stockpiled more than

11,500 packs of mefloquine and “continues to prescribe mefloquine as part of the range of recommended malaria prevention treatments which help protect personnel from this life-

threatening disease.”

The manufacturer of the drug, Roche, claimed that, "A recent regular safety assessment conducted by EU health authorities reinforced previous guidance that the benefits of Lariam (mefloquine) outweigh the potential risk of the treatment." This prescription of mefloquine is still ongoing despite proven cases:

An Oxford astrophysicist Steven Rawlings died in January 2012, having suffered a heart attack; he had been pinned to the floor by his oldest friend, Devinderjit Sivia, who was acting in self-defence.

Moments before his death, Rawlings allegedly threatened to kill Silva before attacking him. It later

emerged that Rawlings had experienced mental health problems since taking mefloquine on holiday

in Kenya 15 years earlier. In 2015, a senior British army officer said:

"Longer-term, the effects (of mefloquine) manifested into clinical depression - something that is

entirely new for me and which has a broad and devastating effect, especially on my family... I believe

firmly that the mefloquine I was given by the Army as an anti-malarial has induced lasting

psychotropic effects, as I have never been affected by anything like this before.

Conclusion:

Mefloquine gives us an insight into the real pharmaceutical world. Indeed, the development of new

drugs have allowed quick recovery, and even near eradication of certain diseases, but it comes at a

cost. To drive efficacy of the same life-saving developments is to have profit at the centre of it all.

From this, it is impossible to consider all the possible long-term effects or interaction with every

drug. One can only succour for the resulting martyrs of this unavoidably incomplete system.