-
Lancet (London, England) May 1991Mefloquine is the treatment of choice for uncomplicated multiresistant falciparum malaria, and in combination with sulphadoxine and pyrimethamine (MSP) at a single dose... (Clinical Trial)
Clinical Trial Comparative Study
Mefloquine is the treatment of choice for uncomplicated multiresistant falciparum malaria, and in combination with sulphadoxine and pyrimethamine (MSP) at a single dose of 15/30/1.5 mg/kg, respectively, has been used in Thailand for the past 6 years. In 1985-86, MSP cured over 98% of 5192 patients with falciparum malaria on the Thai-Burmese border. 4 years later we studied the efficacy of MSP in 395 patients at the same location. The cure rate at 28 days was 70.8% (95% Cl 67-77.2%). The proportion of early treatment failures (in whom parasitaemia did not clear) had risen from 0.27 to 3.7% (p less than 0.0001). Failure rates were 50% in children under 6 years old, 29% in the 6-15 age group, and 19% in adults (p less than 0.001). Patients with early treatment failure were retreated with 25 mg/kg mefloquine, but 27% had a further recrudescence of infection within 28 days. 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. 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. Plasmodium falciparum has developed resistance to mefloquine rapidly, despite the addition of sulphadoxine and pyrimethamine and strict control of drug administration. The MSP combination should now be abandoned.
Topics: Adolescent; Adult; Animals; Child; Child, Preschool; Drug Combinations; Drug Evaluation; Drug Resistance; Female; Follow-Up Studies; Humans; Incidence; Malaria; Male; Mefloquine; Myanmar; Plasmodium falciparum; Prospective Studies; Pyrimethamine; Recurrence; Refugees; Sulfadoxine; Thailand; Vomiting
PubMed: 1674024
DOI: 10.1016/0140-6736(91)92798-7 -
Cell Communication & Adhesion Dec 2009The authors' laboratory has reported potent block of Pannexin1 (Panx1) currents by the antimalarial quinine derivative mefloquine. However, other laboratories have found...
The authors' laboratory has reported potent block of Pannexin1 (Panx1) currents by the antimalarial quinine derivative mefloquine. However, other laboratories have found little or no mefloquine sensitivity of Panx1 currents or processes attributable to these channels. In order to resolve this issue, the authors have performed extensive dose-response studies on Panx1-transfected neuroblastoma (Neuro2A) and rat insulinoma (Rin) cells, comparing mefloquine obtained from three suppliers and also comparing the sensitivity to diastereomers. Results indicate a 20-fold difference in sensitivity to the (-)-threo-(11R/2R) diastereomer compared to the erythro enatiomers and much lower potency of (+/-)-erythro-(R*/S*)-mefloquine obtained from one of the commercial sources. This markedly lower efficacy presumably accounts for the disparity in results from different laboratories who have applied it in Panx1 studies.
Topics: Animals; Antimalarials; Cell Line, Tumor; Connexins; Dose-Response Relationship, Drug; Ion Channel Gating; Mefloquine; Mice; Molecular Structure; Nerve Tissue Proteins; Patch-Clamp Techniques; Rats; Recombinant Fusion Proteins; Stereoisomerism
PubMed: 20218915
DOI: 10.3109/15419061003642618 -
International Journal of Antimicrobial... Aug 2016Repurposing of drugs to treat tuberculosis (TB) has been considered an alternative to overcome the global TB epidemic, especially to combat drug-resistant forms of the...
Repurposing of drugs to treat tuberculosis (TB) has been considered an alternative to overcome the global TB epidemic, especially to combat drug-resistant forms of the disease. Mefloquine has been reported as a potent drug to kill drug-resistant strains of Mycobacterium tuberculosis. In addition, mefloquine-derived molecules have been synthesised and their effectiveness against mycobacteria has been assessed. In this work, we demonstrate for the first time the activities of mefloquine and its oxazolidine derivative compound 1E in a murine model of TB infection following administration of both drugs by the oral route. The effects of associations between mefloquine or 1E with the clinically used antituberculosis drugs isoniazid, rifampicin, ethambutol, moxifloxacin and streptomycin were also investigated. Importantly, combination of mefloquine with isoniazid and of 1E with streptomycin showed a two-fold decrease in their minimum inhibitory concentrations (MICs). Moreover, no tested combinations demonstrated antagonist interactions. Here we describe novel evidence on the activity of mefloquine and 1E against a series of quinolone-resistant M. tuberculosis strains. These data show MICs against quinolone-resistant strains (0.5-8 µg/mL) similar to or lower than those previously reported for multidrug-resistant strains. Taking these results together, we can suggest the use of mefloquine or 1E in combination with clinically available drugs, especially in the case of resistant forms of TB.
Topics: Animals; Antitubercular Agents; Bacterial Load; Disease Models, Animal; Drug Interactions; Drug Repositioning; Male; Mefloquine; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazoles; Tuberculosis, Multidrug-Resistant
PubMed: 27364701
DOI: 10.1016/j.ijantimicag.2016.04.029 -
Forensic Science International Sep 1994Mefloquine is currently the drug-of-choice for malaria prophylaxis among military personnel. Four active duty military personnel receiving 250 mg mefloquine per week...
Mefloquine is currently the drug-of-choice for malaria prophylaxis among military personnel. Four active duty military personnel receiving 250 mg mefloquine per week were killed in the line of duty under combat conditions. Samples of blood, bile, liver, kidney, muscle, brain, spleen and lung were submitted to the Division of Forensic Toxicology, Office of the Armed Forces Medical Examiner, for routine toxicologic analysis. Qualitative screening revealed only the presence of ethanol (< 25 mg/dl, probably attributable to postmortem formation) and mefloquine. Quantitation of mefloquine was performed using an HP 5880 gas chromatograph equipped with a nitrogen/phosphorus detector. The column was an HP-5 cross-linked 5% phenyl methyl silicone fused silica capillary column (15 m x 0.25 mm i.d. x 0.25 microns film thickness). The temperature program began at 110 degrees C, was held for 1 min and ramped at 20 degrees C/min to 200 degrees C, held for 1 min and then ramped at 10 degrees C/min to 280 degrees C and held for 10 min. Mefloquine elutes with a relative retention time similar to that of the tricyclic antidepressants. No postmortem data concerning mefloquine concentrations or tissue distribution was available. Quantitated blood concentrations in the presented cases were greater than the expected therapeutic values indicating the possibility of postmortem redistribution of this drug. No mefloquine overdoses were identified in the literature making comparison to the postmortem therapeutic concentrations impossible at this time.
Topics: Adult; Autopsy; Humans; Male; Mefloquine; Military Personnel; Tissue Distribution
PubMed: 7959478
DOI: 10.1016/0379-0738(94)90376-x -
PloS One 2023Declining in susceptibility of Plasmodium falciparum to mefloquine is reported in South-East Asia. A revisiting on mefloquine pharmacokinetics-pharmacodynamics (PK/PD)...
BACKGROUND
Declining in susceptibility of Plasmodium falciparum to mefloquine is reported in South-East Asia. A revisiting on mefloquine pharmacokinetics-pharmacodynamics (PK/PD) could assist in finding new appropriate dosage regimens in combination with artesunate as a three-day course treatment.
OBJECTIVE
This study aimed to investigate promising alternative artesunate-mefloquine combination regimens that are effective for the treatment of patients with mefloquine-sensitive and resistant P. falciparum malaria.
METHODS
Data collected during 2008-2009 from 124 patients with uncomplicated P. falciparum malaria were included in the analysis, 90 and 34 patients with sensitive and recrudescence response, respectively. All patients were treated with a three-day combination of artesunate-mefloquine. Population PK-PD models were developed. The developed models were validated with clinically observed data. Simulations of clinical efficacy of alternative mefloquine regimens were performed based on mefloquine sensitivity, patients' adherence and parasite biomass.
RESULTS
The developed PK/PD models well described with clinically observed data. For mefloquine-resistant P. falciparum, a three-day standard regimen of artesunate-mefloquine is suitable (>50% efficacy) only when the level of parasite sensitivity was < 1.5-fold of the cut-off level (IC50 < 36 nM). For mefloquine-sensitive parasite with IC50 < 23.19 nM (0.96-fold), all regimens provided satisfactory efficacy. In the isolates with IC50 of 24 nM, regimen-I is recommended. Curative treatment criteria for mefloquine and artesunate were C336h (>408 ng.mL-1) or Cmax/IC50 (>130.1 g.m/M), and Cmax/IC50 (>381.2 g.m/M), respectively.
CONCLUSIONS
Clinical use of a three-day standard artesunate-mefloquine is suitable only when the IC50 of P. falciparum isolates is lower than 36 nM. Otherwise, other ACT regimens should be replaced. For mefloquine-sensitive parasite, a dose reduction is recommended with the IC50 is lower than 23.19 nM.
Topics: Humans; Antimalarials; Mefloquine; Artesunate; Artemisinins; Malaria, Falciparum; Plasmodium falciparum; Drug Therapy, Combination; Sesquiterpenes
PubMed: 36821622
DOI: 10.1371/journal.pone.0282099 -
International Journal For Parasitology.... Aug 2020The current chemotherapeutical treatment against alveolar echinococcosis relies exclusively on benzimidazoles, which are not parasiticidal and can induce severe...
The current chemotherapeutical treatment against alveolar echinococcosis relies exclusively on benzimidazoles, which are not parasiticidal and can induce severe toxicity. There are no alternative treatment options. To identify novel drugs with activity against Echinococcus multilocularis metacestodes, researchers have studied potentially interesting drug targets (e.g. the parasite's energy metabolism), and/or adopted drug repurposing approaches by undertaking whole organism screenings. We here focus on drug screening approaches, which utilize an in vitro screening cascade that includes assessment of the drug-induced physical damage of metacestodes, the impact on metacestode viability and the viability of isolated parasite stem cells, structure-activity relationship (SAR) analysis of compound derivatives, and the mode of action. Finally, once in vitro data are indicative for a therapeutic window, the efficacy of selected compounds is assessed in experimentally infected mice. Using this screening cascade, we found that the anti-malarial mefloquine was active against E. multilocularis metacestodes in vitro and in vivo. To shed more light into the mode of action of mefloquine, SAR analysis on mefloquine analogues was performed. E. multilocularis ferritin was identified as a mefloquine-binding protein, but its precise role as a drug target remains to be elucidated. In mice that were infected either intraperitoneally with metacestodes or orally with eggs, oral treatment with mefloquine led to a significant reduction of parasite growth compared to the standard treatment with albendazole. However, mefloquine was not acting parasiticidally. Assessment of mefloquine plasma concentrations in treated mice showed that levels were reached which are close to serum concentrations that are achieved in humans during long-term malaria prophylaxis. Mefloquine might be applied in human AE patients as a salvage treatment. Future studies should focus on other repurposed anti-infective compounds (MMV665807, niclosamide, atovaquone), which showed stronger in vitro activity against E. multilocularis than mefloquine.
Topics: Albendazole; Animals; Anticestodal Agents; Antimalarials; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Repositioning; Echinococcosis; Echinococcus multilocularis; Ferritins; Humans; Mefloquine; Mice
PubMed: 32636148
DOI: 10.1016/j.ijpddr.2020.06.002 -
The Medical Letter on Drugs and... Feb 1990
Topics: Adult; Animals; Child; Drug Interactions; Drug Resistance; Humans; Malaria; Mefloquine; Plasmodium falciparum; Plasmodium vivax
PubMed: 2405246
DOI: No ID Found -
The European Respiratory Journal Nov 2001This report presents a case of acute lung injury developing within hours after administration of mefloquine for a low-level Plasmodium falciparum malaria, which was...
This report presents a case of acute lung injury developing within hours after administration of mefloquine for a low-level Plasmodium falciparum malaria, which was persistent despite halofantrine therapy. Extensive microbiological investigation remained negative and video-assisted thoracoscopic lung biopsy demonstrated diffuse alveolar damage. The evolution was favourable without treatment. This is the second report of acute lung injury and diffuse alveolar damage caused by mefloquine. Glucose-6-phosphate dehydrogenase deficiency was present in the former case and was thought to contribute to the lung injury. However, glucose-phosphate dehydrogenase was normal in the present case, suggesting that it is not a predisposing condition to the lung injury.
Topics: Antimalarials; Humans; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Pulmonary Alveoli; Respiratory Distress Syndrome; Tomography, X-Ray Computed
PubMed: 11757641
DOI: 10.1183/09031936.01.00208001 -
Drug and Therapeutics Bulletin Jun 1991
Topics: Humans; Malaria; Mefloquine
PubMed: 1935587
DOI: No ID Found -
Annals of Internal Medicine Jun 1997Mefloquine and doxycycline are the two drugs recommended for prophylaxis of malaria for visitors to areas where Plasmodium falciparum is resistant to chloroquine. (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Mefloquine and doxycycline are the two drugs recommended for prophylaxis of malaria for visitors to areas where Plasmodium falciparum is resistant to chloroquine.
OBJECTIVE
To compare the efficacy and tolerability of mefloquine with those of doxycycline as prophylaxis for malaria.
DESIGN
Randomized, double-blind, placebo-controlled field trial of chemoprophylaxis of malaria.
SETTING
Northeastern Irian Jaya, Indonesia.
PARTICIPANTS
204 Indonesian soldiers.
INTERVENTION
After radical curative treatment, participants were randomly assigned to receive 100 mg of doxycycline per day and mefloquine placebo; 250 mg of mefloquine per week (preceded by a loading dose of 250 mg/d for 3 days) and doxycycline placebo; or placebos for both drugs. Prophylaxis lasted approximately 13 weeks.
MEASUREMENTS
The primary end point for efficacy was the first occurrence of malaria, as documented by a positive malaria smear. Malaria smears were obtained weekly and when patients had symptoms suggesting malaria. Reported symptoms were recorded daily, and an exit study questionnaire was conducted.
RESULTS
In the placebo group, 53 of 69 soldiers developed malaria (9.1 person-years), resulting in an attack rate of 5.8 cases per person-year (95% CI, 4.3 to 7.7 cases per person-year). Plasmodium falciparum accounted for 57% of cases, and P. vivax accounted for 43% of cases. No malaria occurred in the 68 soldiers (16.9 person-years) in the mefloquine group; thus, the protective efficacy of mefloquine was 100% (CI, 96% to 100%). In the doxycycline group, P. falciparum malaria occurred in 1 of 67 soldiers (16.0 person-years), yielding a protective efficacy of 99% (CI, 94% to 100%). Both drugs were very well tolerated.
CONCLUSIONS
Mefloquine and doxycycline were both highly efficacious and well tolerated as prophylaxis of malaria in Indonesian soldiers.
Topics: Adult; Antimalarials; Double-Blind Method; Doxycycline; Drug Packaging; Follow-Up Studies; Humans; Indonesia; Malaria; Male; Mefloquine; Patient Compliance; Placebos
PubMed: 9182474
DOI: 10.7326/0003-4819-126-12-199706150-00006