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British Journal of Clinical Pharmacology Jul 19901. A dose finding pharmacokinetic study was performed in 20 Karen women in the third trimester of pregnancy receiving antimalarial prophylaxis with mefloquine. Ten... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
1. A dose finding pharmacokinetic study was performed in 20 Karen women in the third trimester of pregnancy receiving antimalarial prophylaxis with mefloquine. Ten received 250 mg mefloquine base weekly and ten received identical tablets of 125 mg base/week. 2. Both dose regimens were well tolerated. Malaria was prevented effectively, there were no serious adverse effects, all pregnancies proceeded normally, and there were no abnormalities in the babies followed up to 2 years. 3. The median time from dose administration to peak whole blood mefloquine concentration was 6 (range 3-24) h. Mean (+/- s.d.) peak and trough concentrations in the seventh week were 722 +/- 279 and 488 +/- 155 ng ml-1 with the 250 mg/week dose, and 390 +/- 81 and 185 +/- 53 ng ml-1 with the 125 mg/week dose regimens respectively. These blood concentration values are lower than those reported previously in non-pregnant adults. 4. One and two compartmental models were fitted to the whole blood concentration-time data. Mean (+/- s.d.) clearance (CL/F) was 0.78 +/- 0.27 ml min-1 kg-1, and the apparent terminal elimination half-life (t1/2) was 11.6 +/- 7.9 days. 5. Further studies to determine the oral bioavailability of mefloquine are needed, but these results suggest that clearance may be increased in late pregnancy. These preliminary results of good efficacy without significant toxicity are encouraging, and a more extensive evaluation of mefloquine antimalarial prophylaxis in pregnancy is now warranted.
Topics: Birth Weight; Female; Humans; Malaria; Mefloquine; Pregnancy; Pregnancy Complications, Infectious; Thailand
PubMed: 2390434
DOI: 10.1111/j.1365-2125.1990.tb03746.x -
Travel Medicine and Infectious Disease 2016
Topics: Antimalarials; Chemoprevention; Humans; Malaria; Mefloquine
PubMed: 27471174
DOI: 10.1016/j.tmaid.2016.07.007 -
Parasitology Research Mar 2012The aim of the present study is to further understand and analyze the interaction of mefloquine with praziquantel against adult Schistosoma japonicum in vitro. Mice...
The aim of the present study is to further understand and analyze the interaction of mefloquine with praziquantel against adult Schistosoma japonicum in vitro. Mice infected with S. japonicum cercariae for 35-37 days were sacrificed, and adult schistosomes were collected by perfusion. Schistosomes were placed to each of 12 wells of a Falcon plate and maintained in RPMI 1640 supplemented by 10% calf serum. For determination of 50% and 95% lethal concentration (LC50 and LC95) of the two drugs in vitro, schistosomes were exposed to mefloquine at concentrations of 1, 2, 3, 4, 5, 6, 7, and 10 μg/mL or praziquantel at concentrations of 0.001, 0.01, 0.05, 0.1, 0.2, 0.5, 1, 10, and 30 μg/mL. The plate was incubated at 37°C in 95% air + 5% CO₂ for 72 h. According to the half-life of oral mefloquine and praziquantel in mice, mefloquine combined with praziquantel simultaneously, mefloquine administered within 1 h after praziquantel and praziquantel administered within 17 h after mefloquine were used to evaluate the effect of mefloquine in combination with praziquantel against S. japonicum in vitro. The results showed that the LC50 and LC95 of mefloquine calculated by the Bliss method were 6.17 μg/mL (95% confidence limits, 5.84-6.517 μg/mL) and 8.703 μg/mL (95% confidence limits, 7.632-9.797 μg/mL), respectively. As to praziquantel, no worm death was seen when schistosomes were exposed to praziquantel at concentrations of 0.005-0.2 μg/mL for 72 h. While in the worms exposed to praziquantel 1, 10, and 30 μg/mL, strong spasmodic contractions of the worm body and vesiculation along the worm surface were observed, but 48-75% of the schistosomes survived the exposure in 72-h incubation. Meanwhile, the number of dead worms that emerged in each group was not proportion to the increasing concentrations. Therefore, it is not appropriate to calculate the LC50 and LC95 of praziquantel. For evaluation of the interaction with the two drugs, praziquantel 0.1 or 0.2 μg/mL, which may induce moderate or strong spasmodic contractions of the worm body and vesiculation along the worm surface, was combined with mefloquine 5, 6, or 7 μg/mL. It was found that when mefloquine combined with praziquantel simultaneously or administered 1 h after addition of praziquantel, the spasmodic contraction of the male worm body was antagonized by mefloquine in various degrees according to the concentrations of mefloquine used. Meanwhile, praziquantel-induced weakened motor activity could be reversed by mefloquine. In female worms, morphological alterations and stimulated motor activity induced by mefloquine still developed. Interestingly, using these two regimens to combine mefloquine with praziquantel resulted in no impact or a decrease in worm mortality. On the other hand, praziquantel 0.2 μg/mL administered within 17 h after mefloquine 5 or 6 μg/mL promoted the damage to the tegument of the worms, which led to enhance the worm mortality compared with that of worms exposed to mefloquine alone. The results indicate that in vitro higher concentrations of praziquantel administered within 17 h after mefloquine may increase the effect against adult schistosomes, while praziquantel combined with mefloquine simultaneously or administered 1 h before addition of mefloquine exhibits no impact or decrease in the effect against schistosomes.
Topics: Animals; Anthelmintics; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; Male; Mefloquine; Mice; Parasitic Sensitivity Tests; Praziquantel; Schistosoma japonicum
PubMed: 21853223
DOI: 10.1007/s00436-011-2621-z -
Malaria Journal Dec 2013The objectives of the study were to elucidate the gender-specific distribution of mefloquine in cellular and fluid blood compartments when given at therapeutic dosage,...
BACKGROUND
The objectives of the study were to elucidate the gender-specific distribution of mefloquine in cellular and fluid blood compartments when given at therapeutic dosage, to assess its correlation with the occurrence of treatment-related adverse events, and to explore the necessity of adjusting treatment guidelines for females.
METHODS
The distribution of mefloquine following the administration of standard therapeutic doses (1,250 mg mefloquine in split dose) to 22 healthy Caucasian volunteers was assessed in whole blood, serum, plasma, red blood cells (RBCs), white blood cells, and platelets using high performance liquid chromatography.
RESULTS
Plasma mefloquine concentrations after 14 hours were considerably higher in female subjects than in males (2,778 vs 1,017 ng/ml at H14), concordant with a significantly higher frequency, duration, and severity of adverse reactions. However, mean drug concentrations of RBC appeared slightly higher in male volunteers (857 vs 719 ng/ml). At H48, a similar situation prevailed, and at H168 the mefloquine concentrations in plasma continued to be higher in females compared to males (1,353 vs 666 ng/ml), while the concentrations of RBC were similar in females (389 vs 375 ng/ml). Since the observations relate to healthy individuals, they do not take into account selective uptake of mefloquine by Plasmodium-infected erythrocytes as in the case of therapeutic drug use.
CONCLUSION
Although plasma mefloquine concentrations in female healthy volunteers are considerably higher and the concentrations of the RBCs are initially lower compared to males, they do not seem to justify an adjustment of treatment guidelines for mefloquine in female Caucasian individuals.
Topics: Adult; Antimalarials; Blood Cells; Female; Healthy Volunteers; Humans; Male; Mefloquine; Middle Aged; Plasma; Pregnancy; Sex Factors; White People; Young Adult
PubMed: 24321055
DOI: 10.1186/1475-2875-12-443 -
Expert Opinion on Drug Safety Jul 2016Antimalarial drugs are the primary weapon to treat parasite infection, save lives, and curtail further transmission. Accumulating data have indicated that at least some... (Review)
Review
INTRODUCTION
Antimalarial drugs are the primary weapon to treat parasite infection, save lives, and curtail further transmission. Accumulating data have indicated that at least some antimalarial drugs may contribute to severe neurological and/or psychiatric side effects which further complicates their use and limits the pool of available medications.
AREAS COVERED
In this review article, we summarize published scientific studies in search of evidence of the neuropsychiatric effects that may be attributed to the commonly used antimalarial drugs administered alone or in combination. Each individual drug was used as a search term in addition to keywords such as neuropsychiatric, adverse events, and neurotoxicity.
EXPERT OPINION
Accumulating data based on published reports over several decades have suggested that among the major commonly used antimalarial drugs, only mefloquine exhibited clear indications of serious neurological and/or psychiatric side effects. A more systematic approach to assess the neuropsychiatric adverse effects of new or repurposed antimalarial drugs on their safety, tolerability and efficacy phases of clinical studies and in post-marketing surveillance, is needed to ensure that these life-saving tools remain available and can be prescribed with appropriate caution and medical judgment.
Topics: Antimalarials; Humans; Malaria; Mefloquine; Mental Disorders; Neurotoxicity Syndromes
PubMed: 27077782
DOI: 10.1080/14740338.2016.1175428 -
Revista Da Sociedade Brasileira de... 1999Three cases of cutaneous leishmaniasis were treated orally with a mefloquine dose of 4.2 mg/kg/day for six days in the Teaching Hospital of the Faculdade de Medicina do...
Three cases of cutaneous leishmaniasis were treated orally with a mefloquine dose of 4.2 mg/kg/day for six days in the Teaching Hospital of the Faculdade de Medicina do Triângulo Mineiro, Uberaba, MG, Brazil. Three weeks later a new series was repeated. No patient was cured.
Topics: Antimalarials; Humans; Leishmaniasis, Cutaneous; Mefloquine
PubMed: 10881095
DOI: 10.1590/s0037-86821999000500018 -
Antimicrobial Agents and Chemotherapy Dec 2000Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are...
Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response =28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.
Topics: Antimalarials; Dose-Response Relationship, Drug; Drug Resistance; Humans; Malaria; Mefloquine; Models, Chemical; Predictive Value of Tests; Recurrence; Time Factors
PubMed: 11083649
DOI: 10.1128/AAC.44.12.3414-3424.2000 -
Zhongguo Ji Sheng Chong Xue Yu Ji Sheng... Apr 2012In recent years, antimalarial drug mefloquine, an amino alcohol compound, has been found to exhibit potential effect against schistosomes. The feature of... (Review)
Review
In recent years, antimalarial drug mefloquine, an amino alcohol compound, has been found to exhibit potential effect against schistosomes. The feature of antischistosomal properties of mefloquine is that the drug possesses similar killing effect against various development stages of juvenile and adult schistosomes. This paper summarizes the recent three years' progress in experimental studies of mefloquine against schistosomes and other helminthes.
Topics: Animals; Anthelmintics; Helminths; Mefloquine; Schistosoma
PubMed: 22908816
DOI: No ID Found -
Neuroscience Letters May 2012Mefloquine is an effective treatment drug for malaria. However, it can cause several adverse side effects, and the precise mechanism associated with the adverse...
Mefloquine is an effective treatment drug for malaria. However, it can cause several adverse side effects, and the precise mechanism associated with the adverse neurological effects of Mefloquine is not clearly understood. In this study, we investigated the effect of Mefloquine on autophagy in neuroblastoma cells. Mefloquine treatment highly induced the formation of autophagosomes and the conversion of LC3I into LC3II. Moreover, Mefloquine-induced autophagy was efficiently suppressed by an autophagy inhibitor and by down regulation of ATG6. The autophagy was also completely blocked in ATG5 deficient mouse embryonic fibroblast cells. Moreover, suppression of autophagy significantly intensified Mefloquine-mediated cytotoxicity in SH-SY5Y cells. Our findings suggest that suppression of autophagy may exacerbate Mefloquine toxicity in neuroblastoma cells.
Topics: Animals; Autophagy; Cell Death; Cell Line, Tumor; Cells, Cultured; Fibroblasts; Humans; Mefloquine; Mice; Neurons
PubMed: 22465322
DOI: 10.1016/j.neulet.2012.03.040 -
Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers.Journal of Clinical Pharmacy and... Jun 2005Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine.
OBJECTIVE
To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers.
METHODS
In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection.
RESULTS
Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC0-t, t(1/2), and Cmax when compared with mefloquine alone by 79% (P < 0.001), 39% (P < 0.05) and 64% (P < 0.001) respectively. The AUC0-t , and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0.05) and 31% (P < 0.05), respectively when compared with mefloquine alone.
CONCLUSIONS
Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drug-drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy.
Topics: Adolescent; Adult; Antifungal Agents; Antimalarials; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Half-Life; Humans; Ketoconazole; Male; Mefloquine
PubMed: 15896247
DOI: 10.1111/j.1365-2710.2005.00651.x