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Critical Reviews in Toxicology Mar 2021Mefloquine, a potent blood schizontocide, is effective against drug-resistant This property, along with its unique pharmacokinetic profile, makes mefloquine a widely... (Review)
Review
Mefloquine, a potent blood schizontocide, is effective against drug-resistant This property, along with its unique pharmacokinetic profile, makes mefloquine a widely prescribed antimalarial drug. However, several epidemiological studies have raised concerns on the safety of mefloquine as prophylaxis for malaria. Well-documented side-effects of mefloquine include abnormal dreams, insomnia, anxiety, and depressed mood, as well as nausea and dizziness (the last two most frequent effects). The mechanisms that underlie the neurological/psychiatric complications of mefloquine are poorly understood. The aim of this study was to review the literature on the neurotoxic mechanisms of action of mefloquine to better understand its potential toxicity in the central nervous system, highlighting the mechanisms that lead to its psychiatric disorders. Experimental studies on the neurotoxic effects of mefloquine discussed herein include brain transporters of mefloquine, alteration in neurotransmitters, disruption on calcium (Ca) homeostasis and neuroinflammation, generation of oxidative stress response in neurons (involving glutathione, increased F2-isoprostanes, accumulation of cytosolic lipid globules), and alteration of voltage-dependent channels, as well as gap junction intercellular communications. Although several hypotheses have been proposed for the mechanisms that mediate mefloquine-induced brain damage, they are not fully understood, necessitating additional studies in the future.
Topics: Antimalarials; Central Nervous System; Humans; Mefloquine; Nervous System
PubMed: 33905310
DOI: 10.1080/10408444.2021.1901258 -
BMJ (Clinical Research Ed.) Jan 1994
Topics: Humans; Malaria, Falciparum; Mefloquine
PubMed: 8124114
DOI: 10.1136/bmj.308.6924.286 -
BMJ Military Health Nov 2020
Topics: Antimalarials; Humans; Malaria; Mefloquine; Military Personnel; Pre-Exposure Prophylaxis
PubMed: 32086266
DOI: 10.1136/jramc-2019-001295 -
Molecules (Basel, Switzerland) Feb 2022Late-stage modification of drug molecules is a fast method to introduce diversity into the already biologically active scaffold. A notable number of analogs of... (Review)
Review
Late-stage modification of drug molecules is a fast method to introduce diversity into the already biologically active scaffold. A notable number of analogs of mefloquine, chloroquine, and hydroxychloroquine have been synthesized, starting from the readily available active pharmaceutical ingredient (API). In the current review, all the modifications sites and reactivity types are summarized and provide insight into the chemistry of these molecules. The approaches include the introduction of simple groups and functionalities. Coupling to other drugs, polymers, or carriers afforded hybrid compounds or conjugates with either easily hydrolyzable or more chemically inert bonds. The utility of some of the compounds was tested in antiprotozoal, antibacterial, and antiproliferative assays, as well as in enantiodifferentiation experiments.
Topics: Antimalarials; Chemistry Techniques, Synthetic; Humans; Hydroxychloroquine; Malaria; Mefloquine; Models, Molecular; Plasmodium; Quinolines
PubMed: 35164267
DOI: 10.3390/molecules27031003 -
Journal of Travel Medicine Jun 1999Mefloquine is an orally administered blood schizontocide for the chemoprophylaxis of malaria in nonimmune travelers. New pharmacokinetic data has shown that food... (Review)
Review
Mefloquine is an orally administered blood schizontocide for the chemoprophylaxis of malaria in nonimmune travelers. New pharmacokinetic data has shown that food increases the bioavailability of mefloquine. Steady-state pharmacokinetics of weekly prophylaxis in long term travelers have shown that toxic accumulation does not occur and that weekly dosing is associated with protective levels of the drug. The pharmacokinetics of mefloquine are highly stereospecific and all pharmacokinetic parameters, except tmax are significantly different for the (+) and (-) enantiomers. Mefloquine and its metabolite are not appreciably removed by hemodialysis. Steady-state levels of mefloquine can be attained in a reduced time frame of 4 days compared to 7-9 weeks using a loading dose strategy of 250 mg mefloquine daily for 3 days followed thereafter by weekly mefloquine dosage. This strategy, is however, associated with a higher incidence of an adverse event (AE). Cumulative evidence suggests a high protective efficacy of mefloquine (>91%) in nonimmune travelers to areas of chloroquine resistant Plasmodium falciparum (CRPF) except for clearly defined regions of multi-drug resistance. Reports from sub-Saharan Africa indicate a low but increasing level of resistance to this drug. Mefloquine resistance is associated with halofantrine and quinine resistance but not with chloroquine resistance. Penfluridol has been shown to reverse P. falciparum mefloquine resistance in vitro. There is some controversy regarding the tolerabilty of mefloquine for malaria chemoprophylaxis. A review of the studies conducted during 1992-1998 shows that in the reporting of any AE the incidence lies in the range (12-90%) and where there is a comparator, is equivalent to the incidence reported for almost all alternative regimens. When some measure of subjective severity is applied to the rating of AE, it appears that 11-17% of travelers are, to some extent, incapacitated by AE. Major studies and worldwide monitoring have shown that serious events are rare. A recent meta-analysis showed that rates of withdrawal and overall incidence of AE with mefloquine were not significantly higher than those observed with comparator regimens except that mefloquine was more likely to cause insomnia and fatigue. Withdrawals in mefloquine arms were higher than in placebo arms. No performance deficit or functional impairment was observed in five clinical toxicity studies of mefloquine prophylaxis, including a study of driving performance. There is limited data regarding use of mefloquine in pregnancy. Early animal studies have documented teratogenic and embryotoxic effects associated with the use of high dose mefloquine. Two studies have shown a relatively high incidence of spontaneous abortions in mefloquine users. Cumulative evidence, however, is reassuring and has led the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to sanction the use of mefloquine in pregnant women during the second and third trimesters. In conclusion, mefloquine prophylaxis is recommended for travelers to high risk areas of chloroquine resistant Plasmodium falciparum. The risk of malarial infection and the proven efficacy of mefloquine to prevent malaria should be weighed against the risk of drug associated adverse events.
Topics: Antimalarials; Drug Resistance; Female; Humans; Malaria, Falciparum; Mefloquine; Pregnancy; Pregnancy Complications, Parasitic; Travel
PubMed: 10381965
DOI: 10.1111/j.1708-8305.1999.tb00843.x -
Travel Medicine and Infectious Disease Jan 2009A literature review revealed that mefloquine neurotoxicity has been demonstrated at both the preclinical and clinical levels, with nausea, dizziness, sleep disturbances,... (Review)
Review
A literature review revealed that mefloquine neurotoxicity has been demonstrated at both the preclinical and clinical levels, with nausea, dizziness, sleep disturbances, anxiety and psychosis, amongst other adverse neuropsychiatric events, reported in users. Females and individuals of low body mass index (BMI) are at apparent greater risk. Mechanisms of possible neurotoxicity may include binding to neuroreceptors and cholinesterases, inhibition of sarcoendoplasmic reticulum ATPase (SERCA) and interference with cellular Ca(2+) homeostasis, accumulation in the CNS, and reductions in CNS efflux in individuals possessing certain MDR1 polymorphisms. It may be prudent to avoid mefloquine in females and low BMI individuals, and in combination with other potentially neurotoxic agents such as the artemisinin antimalarials.
Topics: Animals; Antimalarials; Artemisinins; Body Mass Index; Central Nervous System; Female; Male; Mefloquine; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sex Factors
PubMed: 19174293
DOI: 10.1016/j.tmaid.2008.12.004 -
The American Journal of Emergency... Nov 2016
Topics: Adult; Antimalarials; Emergency Service, Hospital; Humans; Malaria; Male; Mefloquine; Rhabdomyolysis
PubMed: 27103081
DOI: 10.1016/j.ajem.2016.03.059 -
Drugs Mar 1993Mefloquine is an orally administered blood schizontocide. Initial dose-finding and comparative studies performed between 1977 and 1989 demonstrated efficacy of... (Review)
Review
Mefloquine is an orally administered blood schizontocide. Initial dose-finding and comparative studies performed between 1977 and 1989 demonstrated efficacy of mefloquine as prophylaxis in nonimmune individuals and in the suppression and treatment of malaria in adults and children caused by multidrug-resistant Plasmodium falciparum. It was also effective against P. vivax infection, while data concerning the treatment of P. ovale and P. malariae infections were limited. In an attempt to delay the emergence of resistance to this promising antimalarial agent, mefloquine was combined with sulfadoxine and pyrimethamine. Although initial clinical trials indicated that this regimen was effective in preventing and treating falciparum malaria, recent treatment failures, the potential for severe dermatological reactions and lack of therapeutic advantage over mefloquine alone has prompted the World Health Organization to recommended that the combination be no longer used for treatment or prophylaxis of malaria. Mefloquine is generally well tolerated in both adults and children, with nausea, vomiting, diarrhoea, headache, dizziness, rash, pruritus and abdominal pain being the most common adverse effects, although it is difficult to distinguish between disease- and treatment-related events. The incidence of these adverse effects is similar to or lower than those observed with other antimalarial agents. Cardiovascular changes, such as bradycardia, occasionally occur. The most notable adverse effects associated with mefloquine are neuropsychiatric disturbances; precipitation of such events should be closely monitored and requires termination of prophylaxis or therapy. The eventual emergence of resistance to mefloquine, as with many other antimalarial agents, was inevitable. Mefloquine resistance is established in certain areas of Thailand and may be becoming a growing problem in other regions of the world. In order to preserve the efficacy of mefloquine in non-resistant areas, this useful agent should be used with care and only prescribed for prophylaxis in travellers and treatment in areas of multidrug-resistant plasmodia. Future options to combat mefloquine resistance may include the combination of mefloquine with other antimalarial agents such as qinghaosu derivatives. Thus, with cautious use and possible combination with other agents, mefloquine is likely to remain an important treatment option for falciparum malaria, a widespread parasitic disease for which an increasing number of drugs have proved inadequate.
Topics: Animals; Humans; Malaria, Falciparum; Mefloquine
PubMed: 7682911
DOI: 10.2165/00003495-199345030-00009 -
Clinical Pharmacokinetics Oct 1990Mefloquine, a quinoline-methanol antimalarial, is effective single dose therapy for all species of malaria infecting humans, including multi-drug-resistant Plasmodium... (Review)
Review
Mefloquine, a quinoline-methanol antimalarial, is effective single dose therapy for all species of malaria infecting humans, including multi-drug-resistant Plasmodium falciparum. It is used both in prophylaxis and treatment. Mefloquine is available either as the hydrochloride salt alone, or in a combined preparation with sulfadoxine and pyrimethamine. There is no parenteral formulation. Several assay methodologies have been developed, but high performance liquid chromatography has been the most used in recent pharmacokinetic studies. These have shown in healthy volunteers that mefloquine is absorbed with a half-life of 1 to 4 hours and a time to peak concentration of 7 to 24 hours (median 16.7 hours). Mean peak blood concentrations have ranged between 50 and 110 (median 83) ng/ml/mg/kg. Estimates of total apparent volume of distribution (Vd/f) have ranged from 13.3 to 40.9 (median 19.2) L/kg, systemic clearance (CL/f) from 0.022 to 0.073 L/h/kg (median 0.026 L/h/kg), and terminal elimination half-life from 13.8 to 40.9 days (median 20 days). Systemic clearance appears to be increased in late pregnancy. In uncomplicated falciparum malaria, peak blood concentrations are 2 to 3 times higher than those in healthy subjects ranging from 112 to 209 (median 144) ng/ml/mg/kg because of contraction in the total apparent volume of distribution. Systemic clearance is usually reduced but elimination rates are increased (possibly because of reduced enterohepatic recycling). Mefloquine absorption appears to be reduced in severe falciparum malaria; plasma protein binding exceeds 98% in both healthy subjects and patients. No important drug interactions have been identified as yet, but the potential for serious interactions with quinine has not been adequately investigated. More studies are needed on the disposition of mefloquine in children.
Topics: Animals; Antimalarials; Drug Combinations; Drug Interactions; Humans; Malaria; Mefloquine; Plasmodium falciparum; Pyrimethamine; Sulfadoxine
PubMed: 2208897
DOI: 10.2165/00003088-199019040-00002 -
Malaria Journal Feb 2014Control of malaria in pregnant women is still a major challenge as it constitutes an important cause of maternal and neonatal mortality. Mefloquine (MQ) has been used... (Review)
Review
BACKGROUND
Control of malaria in pregnant women is still a major challenge as it constitutes an important cause of maternal and neonatal mortality. Mefloquine (MQ) has been used for malaria chemoprophylaxis in non-immune travellers for several decades and it constitutes a potential candidate for intermittent preventive treatment in pregnant women (IPTp).
METHODS
The safety of MQ, including its safety in pregnancy, is controversial and a continuing subject of debate. Published studies which evaluated the use of MQ for malaria prevention or treatment in pregnant women and which reported data on drug tolerability and/or pregnancy outcomes have been reviewed systematically.
RESULTS
Eighteen articles fitted the inclusion criteria, only one study was double-blind and placebo controlled. No differences were found in the risk of adverse pregnancy outcomes in women exposed to MQ compared to those exposed to other anti-malarials or to the general population. MQ combined with artesunate seems to be better tolerated than standard quinine therapy for treatment of non-severe falciparum malaria, but a MQ loading dose (10 mg/kg) is associated with more dizziness compared with placebo. When used for IPTp, MQ (15 mg/kg) may have more side effects than sulphadoxine- pyrimethamine.
CONCLUSIONS
In the published literature there are no indications that MQ use during pregnancy carries an increased risk for the foetus. Ideally, the use of MQ to prevent malaria should be based on a risk-benefit analysis of adverse effects against the risk of acquiring the infection. For this purpose double-blinded randomized controlled trials in African pregnant women are much needed.
Topics: Antimalarials; Chemoprevention; Female; Humans; Malaria; Mefloquine; Pregnancy; Pregnancy Complications, Infectious
PubMed: 24581338
DOI: 10.1186/1475-2875-13-75