Disease relevance of mefloquine

• Blood concentrations of mefloquine were lower during the second week of the alternate-week regimen than during the first week, suggesting that blood levels are too low during the second week to suppress parasitemia [1].
• Mefloquine-resistant falciparum malaria on the Thai-Burmese border [2].
• The mean (95% Cl) serum mefloquine concentration at the time of first recrudescence was 638 (546-730) ng/ml, a value previously associated with successful treatment [2].
• Mefloquine-induced Stevens-Johnson syndrome [3].
• Fatal toxic epidermal necrolysis associated with mefloquine antimalarial prophylaxis [4].

Psychiatry related information on mefloquine

• Acute depressive symptoms after mefloquine treatment [5].
• Increased spontaneous motor activity was observed only during the rats' normal sleeping phase, suggesting a correlate to mefloquine-induced sleep disorders [6].
• A 4-week course of cognitive-behavioral therapy was used to effectively treat this substance-induced anxiety disorder, which had been caused by treatment with mefloquine [7].
• In a comparison between patients currently using mefloquine with all past users of antimalarials combined, the risk estimate was elevated for current users of mefloquine for both psychosis (odds ratio [OR] 8.0, 95% CI 1.0-62.7; p < 0.05) and panic attacks (OR 2.7, 95% CI 1.1-6.5; p < 0.05) [8].
• Bipolar disorder after mefloquine treatment [9].

High impact information on mefloquine

• However, conclusive evidence of a direct causal association between pfmdr1 and resistance to these antimalarials has remained elusive, and a single genetic cross has suggested that Pgh1 is not involved in resistance to chloroquine and mefloquine [10].
• Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologue 1 (Pgh1) protein of Plasmodium falciparum, have been linked to chloroquine resistance; Pgh1 has also been implicated in resistance to mefloquine and halofantrine [10].
• INTERPRETATION: In this area of low malaria transmission, early diagnosis and treatment with combined artesunate and mefloquine has reduced the incidence of P. falciparum malaria and halted the progression of mefloquine resistance [11].
• Acute fatty liver after malaria prophylaxis with mefloquine [12].
• Patients with early treatment failure were retreated with 25 mg/kg mefloquine, but 27% had a further recrudescence of infection within 28 days [2].

Chemical compound and disease context of mefloquine

• The spread of chloroquine-resistant Plasmodium falciparum malaria has led to increased use of mefloquine prophylaxis by US Peace Corps volunteers in sub-Saharan Africa. We compared long-term mefloquine with other drug regimens for effectiveness and tolerance [13].
• Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria [14].
• Trials of mefloquine in vivax and of mefloquine plus 'fansidar' in falciparum malaria [15].
• Qinghaosu, mefloquine, and pyrimethamine-sulfadoxine in falciparum malaria [16].
• Subjects were randomized to simultaneously receive mefloquine, chloroquine or proguanil, or oral polio or yellow fever vaccine [17].

Biological context of mefloquine

• The pfmdr1 gene has been associated with a drug-resistant phenotype in Plasmodium falciparum, and overexpression of pfmdr1 has been associated with mefloquine- and halofantrine-resistant parasites, but little is known about the functional role of pfmdr1 in this process [18].
• The mefloquine-selected parasite lines also showed an inverse relationship between the level of chloroquine resistance and increased pfmdr1 gene copy number [19].
• Macrorestriction maps of chromosome 5, where pfmdr1 is encoded, showed that this chromosome has increased in size in response to mefloquine selection, indicating the presence of a gene(s) in this area of the genome that confers a selective advantage in the presence of mefloquine [19].
• 3D7 parasites were subsequently treated with experimentally derived IC50 concentrations of mefloquine, quinine and pyrimethamine. pfmdr1 transcript levels specifically increased 2.5-fold at 6 h in mefloquine-treated parasites and threefold in parasites treated with quinine for 30 min [20].
• In the current issue of Molecular Microbiology, Sidhu and colleagues use powerful reverse genetics to demonstrate the importance of commonly occurring alleles of pfmdr1 in conferring resistance to the second-line drugs quinine and sensitivity to the new alternatives mefloquine and artemisinin [21].

Anatomical context of mefloquine

• Mefloquine also blocked channels formed by the lens gap junction protein, Cx50 (IC(50) approximately 1.1 microM) [22].
• Mefloquine, at 25 microM, blocked gap junctional coupling between interneurons in neocortical slices, with minimal nonspecific actions [22].
• The more lipophilic quinolinemethanol drugs mefloquine and quinine do not appear to be concentrated so extensively in the food vacuole and may act on alternative targets in the parasite [23].
• Equal numbers of parasitized erythrocytes were treated with various concentrations of pyrimethamine or mefloquine [24].
• The strongest effect was observed with mefloquine, which abolished almost completely the neutrophil burst at concentrations of greater than 10 micrograms/ml whatever the stimulus used [25].

Associations of mefloquine with other chemical compounds

• Two randomised double-blind trials were conducted to examine the activity and tolerability of mefloquine alone and in combination with sulfadoxine/pyrimethamine (MSP) [15].
• Combination of mefloquine with sulfadoxine-pyrimethamine compared with two sulfadoxine-pyrimethamine combinations in malaria chemoprophylaxis [26].
• While most cases occurred because of noncompliance with personal protective measures or chemoprophylaxis, both mefloquine and doxycycline chemoprophylactic failures occurred [27].
• Effects of amodiaquine, chloroquine, and mefloquine on human polymorphonuclear neutrophil function in vitro [25].
• In vitro interactions of artemisinin with atovaquone, quinine, and mefloquine against Plasmodium falciparum [28].

Gene context of mefloquine

• Block of KvLQT1/minK by mefloquine may involve an interaction with the closed state of the channel [29].
• Interactions of the antimalarial drug mefloquine with the human cardiac potassium channels KvLQT1/minK and HERG [29].
• Thus, mefloquine is expected to be a useful tool to study the functional roles of Cx36 and Cx50 [22].
• Potent block of Cx36 and Cx50 gap junction channels by mefloquine [22].
• In this study, serum levels of transforming growth factor-beta (TGF-beta) were determined with an enzyme-linked immunosorbent assay in 37 patients with acute Plasmodium falciparum malaria prior to, during, and after therapy and in 17 healthy controls in Bangkok, Thailand. Patients were treated with artesunate and mefloquine [30].

Analytical, diagnostic and therapeutic context of mefloquine

• Failure of mefloquine chemoprophylaxis for malaria in Somalia [31].
• Mefloquine concentrations were no lower in those with recrudescent infections than in age-matched successfully treated patients, suggesting that pharmacokinetic factors were not responsible for the high treatment-failure rate [2].
• Where an effective alternative drug is available, mefloquine should not be used after treatment of severe malaria [32].
• Recrudescent infections were associated with increased gametocyte carrier rates (relative risk 2.2 [1.6-3.0]; p<0.0001), but retreatment with artemisinin derivatives reduced subsequent gametocyte carriage 18.5 fold [3.5-98] compared with mefloquine retreatment and 6.8 fold (3.1-15.1) compared with quinine retreatment (p<0.001) [33].
• The present status of malaria chemotherapy: mefloquine, a novel antimalarial [34].

References