| BackgroundMalaria is still a global epidemic disease,with 219 million cases all over the world in 2017.At present,malaria is considered to be one of the most important diseases that endanger the health of African people.Children are the main victims of malaria.Malaria is one of the important causes of child deaths in African countries.Children who survived from malaria are also prone to brain damage or paralysis,which will bring heavy financial burdens to the family.If women in malaria-endemic areas become pregnant,malaria will increase the incidence of underweight,anemia,and even death of the newborn children,in addition to increase the health problems of pregnant women themselves.The direct costs of malaria include personal and public expenditures for prevention and treatment.In some countries where malaria is highly prevalent,malaria treatment costs can account for 40%of public health expenditures,while malaria cases accounts for 30-50%of inpatients and up to 60%of outpatient visits.Malaria can lead to increased poverty,affecting education and labor,reducing attendance in schools and workplaces,and adversely affecting socio-economic development.88%of global malaria deaths occur in African countries,with Asian countries accounting for approximately 11%and the Americas accounting for less than 1%.The Comoros is an archipelago of the Indian Ocean in the northern part of the Mozambique Strait between the eastern coast of Africa and northern Madagascar.It consists of three volcanic islands,Grande Comore,Moheli Island and Anjouan Island.The population of the country is approximately 652,202,and the area is 2236km2.Grande Comore is the largest island in the Comoros Union(1024 square kilometers)and has the highest mountain(the top of the Caltara volcano is 2361 meters).With the support of Guangzhou University of Chinese Medicine and Guangdong New Southern Artemisia Technology Co.,Ltd.,a series of anti-malaria measures were carried out on Moheli Island and Anjouan Island respectively.The malaria epidemic was effectively controlled,the prevalence of malaria in Moheli Island and Anjouan Island has fallen by more than 98%,and the mortality rate of malaria in children under five years old has fallen from 3.75 to 0.75 from 2010 to 2005.At present,Grande Comore is the main area of anti-malaria work in Comoros.In order to achieve the goal of eliminating malaria in Comoros,it is particularly important to develop a local anti-malaria policy in Grande Comore.Due to the frequent population movement between Grande Comore and the two neighboring islands or countries,at the same time,the local population migration registration system is not well established,which will bring adverse effects on malaria control,Drug-resistant Plasmodium from India,Southeast Asia or East Africa is also likely to be imported,which will increase the difficulty of malaria prevention and control in Grande Comore.Chinese medicine’s understanding of malaria is "the malaria is in the camp,it belongs to Shaoyang half-and-a-half",and the pathogenesis of malaria is caused by the invasion of the human body by warm evil,which belongs to the category of warm disease.Chinese medicine believes that malaria occurs mostly in summer and autumn.When the human body is attacked by malaria,the body fights evilly,causing infectious diseases characterized by chills,heat,headache,sweating,and rest.According to the development of the patient’ s constitution and condition.According to the analysis of the blood syndrome differentiation theory of the Weiqi camp,Ye Tianshi of the Qing Dynasty-doctors believes that the pathological changes of the blood of the Weiqi camp will lead to the pathological changes of the warm disease,which will cause the "sickness invades qi after wei,sickness invades blood after camp".When treating malaria,the theory of blood circulation of Weiqiying can help to distinguish the type of syndrome of the disease and analyze the severity,urgency and depth of the disease.The Chinese medicine book records that Artemisia annua L.is bitter,cold,easy to go into the ganjing,can treat the main heat in the joints and bones,and can treat damp fever.Chinese medicine book has recorded that "Fresh juice makes of a handful of artemisia annua and water can be used to treat malaria",so based on the Chinese medicinal properties,Artemisia annua can be used as an anti-malaria drug.Modern medical scientists and pharmacy scientists have also confirmed that artemisinin,a component proposed from Artemisia annua,has antimalarial effects.Drug-induced QT prolongation increases the risk of torsade de pointes,a form of polymorphic ventricular arrhythmia that can cause a range of clinical symptoms,such as dizziness or loss of consciousness,even can lead to death.Cardiac safety assessment has become one of the hot spots of antimalarial safety research because of the widespread use of antimalarial drugs in countries and regions where malaria is endemic.Although the World Health Organization has published a document about the cardiotoxicity of commonly used antimalarial drugs,the effect of the artemisinin-piperaquine compound used in this study on cardiac function has not been reported in detail.The data of the cardiac safety evaluation of the compound in clinical doses is still relatively lacking.MDA refers to the treatment of all people in a certain geographical area,regardless of whether they are sick or not,under the specific circumstances.MDA is used for malaria control and elimination for a long history,and the antimalarial effect of MDA depends on medication coverage and drug effectiveness.The main reason for the impact of drug coverage is the public’s lack of understanding of the MDA and concerns about adverse drug reactions.Most of the asymptomatic malaria parasites cannot be examined by microscopy or rapid diagnostic tests,but can continue to spread malaria parasites.In areas where malaria spreads seasonally,mosquitoes are infected by asymptomatic infected people,and malaria is transmitted by mosquito bites.The infection status of each person is not detected in MDA,and all individuals are treated to help block the transmission of malaria parasites in asymptomatic infected people.The side effects of the people taking the medicine are mainly caused by the selected drugs.Common side effects include abdominal pain,headache,vomiting,dizziness,sneezing,muscle aches,fever,nausea and discomfort.Most of the side effects caused by the drug can be alleviated after treatment.Therefore MDA is a safe malaria control method.ObjectiveBased on the successful experience of Moheli Island and Anjouan Island,this study aims to treat malaria based on Chinese medicine after considering the local economic level,medical and health level,population distribution,cultural level and religious beliefs of Grande Comore and then evaluates the effectiveness and safety.As the measure of Mass Drug Administration(MDA)uses drugs for a wide range of people,including malaria patients and healthy people,drug safety assessment is a top priority.Therefore,evaluating the cardiac safety of the compound by retrospectively analyzing the electrocardiogram data of the clinical trial of artemisinin-piperaquine compound before the MDA.The relationship between artemisinin-based combination therapy and artemisinin resistance is not fully understood.This study evaluated the artemisinin resistance by monitoring the changes in gene polymorphisms of local malaria parasites after MDA.Methods1.Organize a analysis of 93 malaria patients collected in Cambodia from 2003 to 2005 who were diagnosed with malaria.The malaria case was treated with artemisinin-piperaquine compound after diagnosis by clinical symptom diagnosis and laboratory test.Electrocardiogram was performed before taking the medicine,4 hours after taking the first dose of medicine,and 4 hours after taking the second dose of medicine.The PR interval,QRS duration,RR interval,and QT interval were performed by a professional electrocardiographer.The QT interval was corrected by the Friderici and Bazett formulas.The electrocardiogram parameters of the patients in the three specific periods were compared,and the effect of the artemisinin-piperaquine compound on the electrocardiogram was evaluated and the cardiac safety of the compound was analyzed.2.Collect baseline data of Grande Comore,including:the results of the latest census,the structure of the local health management organization,the establishment of medical institutions,the number of personnel at all levels,the situation of primary health organizations,the organization of malaria control organizations,and the status of anti-malaria personnel.Collect data on malaria-positive cases in medical institutions.Investigate the distribution and coverage of mosquito nets,the implementation of malaria prevention measures for special populations,the use of artemisinin compounds,and the residual spraying of insecticides.Investigate local malaria diagnosis methods and diagnostic accuracy.After completing the baseline data collection,two rounds of universal drug use were conducted on Grande Comore.Artemisinin-piperaquine compound was taken in some areas at random,and artemisinin-piperaquine combined with low-dose primaquine was administered in other areas.Compare the rates of malaria-positive cases,children’s parasitemia rates,and children’s gametocytes positive rate in Grande Comore after MDA.Evaluate the impact of MDA on the local malaria epidemic,analyze the occurrence of adverse reactions in the people who have taken drugs,and evaluate the safety of artemisinin-piperaquine combined with or without low-dose primaquine.3.Blood samples from patients with falciparum malaria were col lected from March 2006 to October 2007(before MDA)and from March 2016 to August 2017(after MDA)using EDTA anticoagulation tubes.DNA was isolated from blood samples using the Takara DNA kit,amplified by polymerase chain reaction,and subjected to nucleotide sequencing using a DNA sequencer.Detect the occurrence of polymorphisms of K13 gene D464H,S477Y,N490H,V520A,N554H and A578S in Plasmodium strains,and to compare the differences between the above-mentioned sites before and after MDA,and to evaluate the relationship between the drug and artemisinin resistance.Results1.4 hours after the first dose,QTcF was prolonged in 38 cases(41.76%),and QTcF was shortened in 54 cases(59.34%),of which 8 cases(8.79%)were moderately prolonged,no severe prolongation cases.QTcB prolonged in 24 cases(26.37%),QTcB was shortened in 67 cases(72.63%),4 cases(4.40%)were moderately prolonged,and 1 case(1.10%)was severely prolonged.4 hours after the second dose,QTcF was prolonged in 37 cases(40.66%),QTcF was shortened in 55 cases(60.44%),of which 12 cases(13.19%)were moderately prolonged,1 case(1.10%)was severely prolonged.QTcB was prolonged in 21 the case(23.08%),QTcB was shortened in 71 cases(78.02%),3 cases(3.30%)were moderately prolonged,and 3 cases(3.30%)were severely prolonged.There was no significant difference in QTcF between the two doses after administration(P=0.08).QTcB was shortened at 4h-1st ose and 4h-2nd dose(P=0.00).This study did not document abnormal electrocardiographic findings of torsade de pointes or other arrhythmias.2.In the first round,the drug-taking rate in the AP area was 82.43%,and the rate of AP+PMQ area was 82.40%.In the second round,the drug-taking rate in the AP area was 80.07%,and the rate of AP+PMQ area was 80.50%.There was no significant difference between the first round and the second round of drug coverage in the two regions(P=0.853,P=0.640,respectively).There was no significant difference in the incidence of adverse reactions between the first and second rounds of the MDA(P=0.720,P=0.341,respectively).The rate of malaria-positive cases in all areas of Grande Comore after the MDA has shown a significant downward trend since 2014.The prevalence rate in most areas has started to increase slightly in 2016,and the increase in 2017 is more obvious.There was no significant difference in the children’s parasitemia rate between different medication regimens(P=0.809),and the difference between the months after MDA was statistically significant(P=0.000).There was no significant difference in children’ s gametocytes positive rate between different medication regimens(P=0.159),and there was a statistically significant difference between months after MDA(P=0.000).3.There was no significant difference in the ratio of D464H,S477Y,N490H,V520A,N554H and A578S mutations before and after MDA(P>0.05).Conelusions1.AP compound does not have significant cardiotoxicity when used within a safe dose range and can be safely applied to malaria treatment.AP combination is still necessary for cardiotoxicity assessment in people at risk of QT prolongation or arrhythmia.2.Artemisinin-piperaquine compound with or without primaquine can effectively control malaria,and rapidly reduce the rate of malaria-positive cases,children’s parasitemia rate,and gametocytes positive rate in a short period of time.At the same time,the local malaria prevention and epidemic level can be maintained at a low level,and the adverse reactions are mild.Therefore,this MDA program can be used as the main malaria prevention and control method in a region if the drug coverage can be guaranteed to higher levels.3.MDA did not cause K13 gene mutation that is related to artemisinin resistance of Plasmodium falciparum.The local malaria parasite was still sensitive to ACT treatment in Grande Comore.The detection of subsequent malaria parasite resistance index was of great significance for local antimalarial prevention and treatment work. |
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