| ObjectivesArtemisinin-based combination therapies have benefited billions of people at risk of malaria.Millions of doses of artemisinin-based combination therapies are donated by World Health Organization,Global Fund,charities and borderless organizations every year.However,the anti-malarial coverage and treatment effect are insignificant in the circumstances of billions of annual malaria cases around the world.Especially,in malaria epidemics in Sub-Saharan Africa,on account of comprehensive factors of economy,geography,transportation,and payment ability of public,most malaria patients cannot get access to prompt and effective treatments of artemisinin-based combination therapies,which have brought direct or indirect economic losses up to bill ions of US dollars yearly and severely hindered the social economic development in Africa.Furthermore,dozens of years have witnessed traditional malaria prevention and control strategies at huge cost with less short-term effect.Even malaria cases in some regions tend to ascend year by year,seriously threating public health.Therefore,in the context of the pressing need of malaria control globally,it is urgent to seek for suitable prevention and control strategies for malaria prevalence,to fast control malaria in a short period by reducing malaria cases and death cases,and improve malaria prevention and control system to monitor the effect,and reach the goal of blocking regional transmission so as to eliminate malaria.The strategy of mass prevention and mass treatment by mass drug administration through artemisinin-based combination therapies is effective to prevention and control in regional malaria prevalence.The result on Anjouan Island in Comoros with an over-two-year implementation period has sufficiently approved the project on feasibility,high efficiency,accessibility and low cost.This study aims at in-depth exploration on commonalities on mass drug administration through artemisinin-based combination therapies.It attaches importance to the research on efficacy,safety,and resistance of artemisinin-based combination therapies,as well as the evaluation on rationality and ethicality of mass drug administration in view of malaria epidemiology and health economics,to probe out malaria prevention and control strategies suitable to wide malaria epidemics and bring benefits to them based on the anti-malaria experiences and artemisinin-based combination therapies from China.Practicing the prevention and treatment on severe infectious diseases through Chinese medicine theory,is to bring regional anti-malarial project into force by mass prevention and treatment,and mass drug administration,varying with time,sites and individual concerned,under the principal of holism and syndrome differentiation of Chinese medicine.Based on Chinese successful experience on malaria prevention and treatment,and to combine the basic theory of Chinese medicine with the practice on malaria prevention and control,the method of initiative drug intervention aims at eliminating asexual and gametophytic plasmodia,instead of individual treatment,which has effectively curbed regional malaria and promptly leveled its high transmission settings to low ones,with no local malaria death cases observed,and has developed fast anti-malarial technical solution on inlands and provided a new model for fast anti-malarial strategies that can be applied throughout Africa.The method attaches great importance to scaling up the mass prevention and control for regional malaria by artemisinin-based combination therapies by verifying the fact that mass drug administration in a short period is not easy to result in the resistance to artemisinin.It includes combination of local malaria prevention and treatment system,and capacity building to establish a long-acting system for titer evaluation;monitoring evaluation on adverse drug reaction by collecting all kinds of data of adverse reactions to combine with that in clinical tests and analyzing the uncommon and unseen ones to establish animal model for drug toxicity research;system evaluation on the efficacy on artemisinin-based combination therapies to plasmodium falciparum in Comoros;monitoring evaluation on drug resistance and species structure mutation under the drug pressure to eliminate plasmodium falciparum in population;suitable animal model of mouse malaria with dampness-heat concerning the factors of climate,constitution and pathogenic microorganism and so on,by simulating natural infection,combined with the external environment of high temperature and high wet as it was in African malaria epidemic,under the guidance of Chinese medicine;research on the resistance of plasmodium to artemisinin-piperaquine tablets in dampness-heat by cultivating the plants of artemisinin and piperaquine based on the model.MethodsTwo types of mass drug administration through artemisinin-based combination therapies were carried out in seven districts in Anjouan Island of Comoros:1)Consecutive three rounds of artemisinin and piperaquine tablets(artemisinin 62.5mg/tablet,piperaquine 375mg/tablet)were conducted in five districts every thirty days.A total of four tablets were as a course of treatment for adults.The dose for children decreases progressively by age group.2)Consecutive three rounds of artemisinin and piperaquine tablets(artemisinin 62.5mg/tablet,piperaquine 375mg/tablet)combined with primaquine tablets(9mg/tablet)were conducted in the other two districts every thirty days.A total of four artemisinin and piperaquine tablets and one primaquine tablet were as a course of treatment for adults.The dose for children decreases progressively by age group.Malaria prevention and treatment system,and capacity building were improved to monitor children parasite carriage rate,malaria confirmed cases and death cases in medical institutions and adverse drug reaction,which was compared before and two years after two types of mass drug administration.As the drug resistance closely related to plasmodium heredity,it' s of great importance to monitor the heritable changes of plasmodium species to eliminate regional malaria.Molecular biology markers were selected to test the drug resistance of plasmodium falciparum and the heritable polymorphism of species structure.Based on the genetic polymorphism of plasmodium in different areas and the distribution of species gene,to rapidly determine gene and imported malaria and transmission trend can provide the basic of efficiently monitoring regional malaria epidemic in time and consolidating the effect.The resistance group in dampness-heat and the normal group of artemisinin and piperaquine were cultivated to respectively extract DNA.Gene fragments were amplified by nested PCR with genotype-specific primers.Mutation frequency of related locus of drug resistance was analyzed by Mege software;the gene of drug resistance was confirmed by linkage disequilibrium analysis and transgenic method;the effect of drug resistance of artemisinin and piperaquine in two different conditions was compared.Suitable animal model of mouse malaria with dampness-heat was established,concerning the factors of climate,constitution and pathogenic microorganism and so on,by simulating natural infection,under the guidance of Chinese medicine;the plants of artemisinin and piperaquine were cultivated based on the model.The study selects artemisinin-piperaquine tablets,artemisinin,piperaquine,piperaquine phosphate,and primaquine phosphate to observe the effect to reproductive system and reproductive endocrine system in female rats.Healthy and unpregnant female rats were selected and administered test samples for 14 days.The estrous cycle and the level of estradiol in serum,follicle-stimulating hormone,luteinizing hormone,prostaglandin,and adrenocorticotrophic hormone were tested before administered samples.After administration,the estrous cycle was tested to observe the effect of samples to it.After the 14-day administration,the above hormones levels were tested to observe the effect of samples to them.The reproductive organs and relevant endocrine system,including thalamus,hypophysis,adrenal gland,ovary,uterus,were observed and made into pathological sections by HE staining method for histopathological examination tests.ResulisIn regional mass drug administration by artemisinin-based combination therapies,the drug coverage rate in every district was 83.2%-95.5%,and rose as drug-taking time increased.After 18 months of mass drug administration,in five districts on full doses of artemisinin and piperaquine tablets,children parasite carriage rate decreased from 14.9%to 0.5%(P<0.05),the monthly malaria confirmed cases in medical institutions dropped from 905 to 2(P<0.05),the annual malaria death cases descended from 5 to 0(P<0.05),which has reduced by 96.6%,99.8%and 100%respectively compared with that before mass drug administration;Meanwhile,in the other two districts on full doses of artemisinin and piperaquine tablets combined with primaquine tablets,children parasite carriage rate decreased from 12.3%to 0.6%(P<0.01),the monthly malaria confirmed cases in medical institutions dropped from 301 to 2(P<0.01),the annual malaria death cases descended from 3 to 0(P<0.01)),which has reduced by 95.1%,99.3%and 100%respectively compared with that before mass drug administration.Furthermore,the drugs on two types of measures were well-tolerated,with no severe adverse events.In Anjouan Island,Comoros,there was no significant difference between treatment dose of artemisinin and piperaquine tablets,and that of artemisinin and piperaquine tablets combined with primaquine tablets in the descend range of children parasite carriage rate,malaria confirmed cases and death cases in medical institutions,and the adverse reaction(P>0.05).The measure has effectively curbed regional malaria epidemic,and promptly leveled its high transmission settings to low ones,with no local malaria death cases observed,which has developed fast anti-malarial technical solution on inlands.By nested PCR and DNA sequencing,207 samples of plasmodium falciparum in Comoros were tested without observation of resistance plants of K13 of plasmodium falciparum that were prevalent in South-east Asia;High fat-high sucrose diet were fed to form wet inside,while high temperature and high wet condition were formed to wet outside.K173 of plasmodium were injected into mouse abdomen to stimulate the invasion of exogenous pathogenic factors.Multiple factors inside and outside were super-posi tioned to modeling.Based on the successful buildup of mouse malaria model in dampness-heat,normal group and dampness-heat group of resistance of artemisinin and piperaquine were cultivated from the 1st to 15th generations.ED50 and ED90 in each group in every five generations were measured for comparative analysis.The study selects artemisinin-piperaquine tablets,artemisinin,piperaquine,piperaquine phosphate,and primaquine phosphate to observe the effect to reproductive system and reproductive endocrine system in female rats.Healthy and unpregnant female rats were selected and administered test samples for 14 days.The estrous cycle and the level of estradiol in serum,follicle-stimulating hormone,luteinizing hormone,prostaglandin,and adrenocorticotrophic hormone were tested before administered samples.After administration,the estrous cycle was tested to observe the effect of samples to it.After the 14-day administration,the above hormones levels were tested to observe the effect of samples to them.The reproductive organs and relevant endocrine system,including thalamus,hypophysis,adrenal gland,ovary,uterus,were observed and made into pathological sections by HE staining method for histopathological examination tests.After administration of all the samples to rats,there were no abnormalities detected in automatic activities,sensory functions,and muscle functions,and no toxicity in central nervous system,such as tic and stand,and no abnormalities in physical signs,such as weight and food ration.The main ingredients of artemisinin-piperaquine tablets are artemisinin and piperaquine.Because there was no evidence to indicate artemisinin had a toxic effect on the estrus cycle,it was determined that the effect of artemisinin-piperaquine tablets to the estrus cycle resulted from piperaquine.ConclusionsWith the principal of holism and syndrome differentiation of Chinese medicine,the method to improve local malaria prevention and treatment system,and capacity building,bring regional anti-malarial project into force by mass prevention and treatment,and mass drug administration,varying with time,sites and individual concerned,can effectively curb malaria prevalence in short-term,and bring adverse reaction pre-warning system into perfection,which has demonstrated mass drug administration is safety-controllable in regional malaria prevention and treatment.On condition of coverage rate reaches 80%,both treatment dose of artemisinin and piperaquine tablets,and that of artemisinin and piperaquine tablets combined with primaquine tablets in mass drug administration,can basically control the regional malaria transmission and prevalence in a short period.On condition of coverage rate reaches 80%,and the cure rate of treatment dose of artemisinin and piperaquine tablets for uncomplicated plasmodium falciparum patients reaches 90%,the measure to combine with primaquine tablets in mass drug administration,cannot significantly enhance the efficacy of fast control malaria transmission and prevalence.Due to long-term systematic surveillance,there was no evidence for resistance occurrences to artemisinin-based combination therapies and gene mutation of K13 to plasmodium falciparum in mass drug administration;suitable animal model of mouse malaria in dampness-heat was established by stimulating thermal-humidity environment of high temperature and wet as it was in Africa in a natural infection way taking many factors like climate,constitution and pathogenic microorganism into consideration;normal group and dampness-heat group of resistance to artemisinin and piperaquine were cultivated from the 1st to 15th generations to seek for the mutation sites to determine the resistance gene.The generation mechanism of resistance to artemisinin and piperaquine as well as the differences was preliminarily researched in a molecular level.Molecular resistance makers were fast studied and applied to monitor resistance to artemisinin to guide the process of reasonable application of artemisinin and mitigation of resistance occurrence.The study results can provide scientific basis for new measures and ideas on the application for fast malaria control in other high malaria epidemic regions. |
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