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Quote Request FormConceived and designed the experiments: Compiled teduce individual studies: Analysed the clinical and parasitological response: Provided support to the statistical analysis: Supervised and analysed the in vivo studies: Did the molecular analysis:
Conceived and designed the experiments: Compiled the individual studies: Analysed the clinical and parasitological response: Provided support to the statistical analysis: Supervised and analysed the in vivo studies: Did the molecular analysis: Coordinated and analysed the in vitro studies: Coordinated the in vivo studies: Supervised and controlled the quality of all laboratory results: Supervised the research program: Artemisinin combination treatments ACT are recommended as first line treatment for falciparum malaria throughout the malaria affected world.
We reviewed the efficacy of a 3-day regimen of mefloquine and artesunate regimen MAS 3 , over a 13 year period of continuous deployment as first-line treatment in camps for displaced persons and in clinics for migrant population along the Thai-Myanmar border.
The proportion of patients with parasitaemia persisting on day-2 increased significantly from 4. MAS 3 efficacy has declined slightly but significantly Hazards ratio 1.
The in vitro susceptibility of P. Artesunate-mefloquine remains a highly efficacious antimalarial treatment in this area despite 13 years of widespread intense deployment, but there is evidence of a modest increase in resistance.
Of particular concern is the slowing of parasitological response to artesunate and the associated increase in gametocyte carriage. The Thai-Myanmar border harbors some of the world's most drug resistant malaria parasites. Plasmodium falciparum parasites in this region have developed significant resistance to commonly used antimalarials, except the artemisinin derivatives.
The treatment of uncomplicated P. In , MAS 2 was extended to all provinces along the borders with Myanmar and Cambodia, following evidence from these areas of inadequate clinical cure rates with mefloquine alone, or MSP  — .
Use of both drugs has been strictly controlled and neither mefloquine nor artesunate are available in the private sector on the Thai side of the border. In camps for displaced persons located along the Thai-Myanmar border, mefloquine and artesunate combination therapy has been evaluated since and deployed systematically since  , . MAS 3 , to ensure that artesunate covered two parasite asexual life-cycles, thereby reducing the parasite biomass exposed to mefloquine alone . This report presents a continuous description of the in vivo, in vitro and molecular correlates of MAS 3 efficacy in the thirteen years between January and December in camps for displaced people and clinics for migrant workers located along the northwestern border of Thailand.
The epidemiology of malaria in the area has been described in detail elsewhere . Briefly, malaria is seasonal, the transmission is low and unstable, P. All age groups are affected and nearly all the P.
Since , the Shoklo Malaria Research Unit SMRU has conducted 7 prospective randomized open-label controlled chemotherapeutic trials of new antimalarial drugs in which MAS 3 was one of the treatment arms  —  and two non-comparative trials of MAS 3 drug efficacy .
Three methodologies were use to evaluate MAS 3 efficacy: The in vivo efficacy of MAS 3 has been monitored annually  , . The prospective analysis of in vivo efficacy was restricted to studies after , when distinction of recrudescent from novel infections was made possible by the introduction of PCR parasite genotyping  , thereby ensuring accurate assessment of recrudescence rates.
Post-treatment follow-up was extended to 42—63 days to minimize underestimation of true failure rates  , . In vitro antimalarial drug susceptibility studies were carried out on fresh isolates of P. Studies in this location have demonstrated that amplification of pfmdr1 gene copy number is the major molecular determinant of mefloquine susceptibility and provides an important tool for monitoring drug resistance  , .
Specific study procedures have been described previously for each randomized controlled trial  —  ; most enrolment procedures were common to all studies. In brief patients, who presented to the SMRU clinics all located along km of the Thai-Myanmar border with a microscopically confirmed uncomplicated P. In the event of parasite reappearance during follow up patients were re-treated and followed-up again.
Children who were unable to swallow complete tablets received the same weight-adjusted dosage of crushed tablets mixed with water. Each drug administration was observed in all patients. This fixed dose combination has been shown to have comparable oral bioavailability and efficacy with the loose combination . Recurrent infection was defined as the presence of asexual forms of P. Recrudescent infections were differentiated from new infections using 3 loci genotyping as described previously .
In view of the importance of the parasite reduction ratio  , delayed parasite clearance was considered if patients were still parasitaemic 48 hours day-2 after the baseline malaria positive smear. Parasites isolates were obtained from patients with acute P. Only primary infections were assessed. Samples were kept at room temperature and transported within the next 4—6 hours to the main laboratory, where they were set up in continuous culture immediately.
The minimum parasitaemic threshold required for parasite growth in culture, as well as the necessity to take 5 ml of blood limited the evaluation of P. Drug susceptibility testing by hypoxanthine uptake has been described previously by Brockman . The solvent in the final concentrations had no significant effect on parasite growth when compared to culture media. All concentrations, including drug-free controls, were distributed in duplicate in well tissue culture plates.
The reproducibility of IC 50 measurements was assessed regularly using cloned K1 isolates of P. In order to investigate changes in resistance markers over time parasite genotypes were assessed each year since , with the exception of , and , using venous blood taken before treatment from a random selection of patients with primary P. Randomisation was stratified by age and sex to represent the population seeking care for malaria in the outpatient's clinics.
All reactions were performed in triplicate and were rejected if they did not conform to exponential kinetics. Differences in settings, sequence randomization, mefloquine treatment timing, and study procedures were included in the assessment of heterogeneity between studies using the Cochran Q test and the I2 test .
The cumulative risk of failure at day was calculated by survival using the Kaplan Meier method. Indeterminate genotyping results and new infections were censored at the date of the reappearance of the P. PCR results were deemed indeterminant if only one of the three gene locus was amplified, or if analysis of genetic frequency of alleles in the population revealed a recrudescent pair as statistically insignificant .
The risks of treatment failure PCR-adjusted over time were compared by the Mantel-Haenszel log rank test. In the multivariate analysis, temporal trends in efficacy were assessed by using a Cox regression model after controlling for known risk factors such as age, parasitaemia at baseline, and mixed parasite infection.
Prevalence rate on admission, overall carriage rate and among patients without gametocyte on admission were calculated yearly. Temporal trends for mefloquine and artesunate IC 50 were analyzed on the ln-transformed data.
Regression analysis on the ln-transformed values was performed to investigate association between the IC 50 and the pfmdr1 copy number using the isolates for which both the IC 50 and the copy number were available. The efficacy of the MAS 3 combination was evaluated in 3, patients with uncomplicated P. The admission characteristics of patients are presented in Table 2. The drug combination was generally well tolerated and few patients reported having serious adverse events  — .
Only one patient 0. None were related to malaria or to an adverse drug event. There were no significant differences in age, sex and presence of mixed infections on admission between patients lost to follow up and those who completed it. Mean haematocrit on admission was Mean fractional reductions in haematocrit from baseline at day-7 did not differ significantly by year overall mean reduction of 7.
Parasite clearance times were available for 3, patients After accounting for age, sex, presence of a mixed P.
Of the recurrent infections with P. The median time to recrudescence occurred at 21 days of follow-up range 7—42 days ; although time to recrudescence has increased by one week since , it has not changed significantly over the 13 year period, and neither has the time to re-infection Table 5. Parasitological efficacy non PCR-adjusted increased significantly over time as the risk of P.
Parasitological efficacy PCR-adjusted of the mefloquine-artesunate 3-day combination therapy was evaluated at Day of follow-up between and In total, 1, P. Mefloquine IC 50 s also rose between and , but fell again in —7 Figure 4b.
Between and , the geometric mean mefloquine IC 50 fell from Isolates from primary infections were used for genetic analysis between and Increase in isolates with 2 or more copy number is given in percentage of the total.
In the isolates with in vitro and molecular data, amplification of pfmdr1 was associated with a 2. The rise in IC 50 associated with increased pfmdr1 copy number was greater during the period — compared to thereafter for both artesunate Pre: In contrast there was no change in the risk of treatment failure associated with increased copy number over the study period.
The rapid development of mefloquine resistance in Tak province on the Thai-Myanmar border in the early s led to the introduction of the three day combination of artesunate and mefloquine MAS 3 as first line treatment for uncomplicated P.
In vitro susceptibility of P. However despite this unprecedented level of sustained efficacy over the 13 year period and a significant decline in the prevalence of falciparum malaria on the Thai side of the border, there are some worrying trends. Mefloquine susceptibility has fluctuated widely, and its association with the pfmdr1 copy number seems to have changed over the years.
These changes in antimalarial activity in vitro have not been associated with a sharp reduction in cure rates, as happened when mefloquine was used as monotherapy  , . The changes in artesunate susceptibility could be related to the increases in pfmdr1 copy number  although the patterns are dissimilar, and not well correlated with changes in mefloquine susceptibility.
Over the last 4 years, there has been no further increase in the proportion of isolates with increased pfmdr1 copy number, and yet there are indications that artemisinin efficacy has declined as evidenced by an increase in the parasite clearance time. The decrease in in vitro susceptibility to artesunate after could not be explained by mechanisms associated with mefloquine resistance predominantly pfmdr1 amplification.
The correlation between artesunate and mefloquine IC 50 s evident before was no longer evident afterwards. This suggests the emergence of a new factor affecting artesunate susceptibility, which could include either novel mutations within the pfmdr1 gene, increased gene expression or alternate genetic events. The changes in the early in vivo parasitological responses to MAS 3 are more concerning. Rapid parasite clearance is the pharmacodynamic hallmark of artemisinin and its derivatives.
This is associated with reduced gametocyte carriage compared with other antimalarial drugs.
The content of this present review are etiological factors, functional and by an enteral diet to stimulate bowel adaptation, reduce fluid loss and increase nutrient absorption. . Mg, Ca), mi ttelkettige .. "Zink 15mg/Tag (3,0±6,5 mg i.v.). Treffer Es liegt ein Cochrane Review vor, (Brosseau ) der konventionelle TENS (C- TENS) und Aku- Dosen Prednisolon (max 15 mg/Tag) ist wirksam, 3/10 no NSAR. MI. Beobachtungsstudien. 2/ NSAR, Placebo, COX2 Moher D, Wells GA, Tugwell P. The efficacy of folic acid and folinic acid in reducing. Aktuelle Cochrane-Reviews bzw. Cochrane-Reports Dosis von 4 × 10 mg/d ( beginnend mit 15 mg Tagesdosis und steigerbar auf 5 × 20 mg/d) bei .. Leite, M. I., E. Coutinho, et al. (). .. Reducing the hazards of treatment." N Engl J.