恶性疟原虫对青蒿素的抗性与延缓抗性的建议
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摘要
抗疟药可以起到治疗病人、保护人群、消灭传染源和阻断传播的作用,是疟疾防治的重要武器。疟原虫为生存繁殖与抗疟药开展殊死斗争,主要表现是产生抗性。本文就疟原虫对当前治疗恶性疟的一线青蒿素类药物抗性研究现状加以评述,提出延缓抗性建议。研究发现恶性疟原虫对青蒿素的敏感性已经下降,柬埔寨、泰柬、泰缅、缅甸、越南等地发现ACTs治愈率下降,治疗失败病例增加;目前的研究结果,还缺乏证实恶性疟原虫对青蒿素产生了抗性的充分的证据;治疗失败不等于抗性(可能包含抗性病例),多数病例都是通过青蒿素延长疗程增加剂量而获得治愈。青蒿素治疗指数高,提高1~2倍剂量也是安全的,建议增加剂量,疗程延长至4~5 d,以提高治愈率,延缓抗性。重点地区重点人群开展疗效评价和抗性监测;全程足量规范使用青蒿素类药物;线索追踪,清点拔源;防止输入性青蒿素抗性恶性疟扩散等对策可以有效延缓和遏制恶性疟原虫对青蒿素的抗性。建议继续推广应用,并不断完善。
Anti-malarial drugs are an important weapon for treating patients,protecting people,eradicating infectious resources and interrupting transmission in malaria control.The resistance is a kind of malaria parasite way for survival and reproduction.This paper reviews the resistance situation of the first line drugs for falciparum malaria treatment,and then presents suggestions on how to delay resistance development.The results of researches found the decreased artemisinin sensitivity in Plasmodium falciparum and cure rates,increased number of treatment failure cases in Cambodia,Myanmar,Vietnam and Thailand-Cambodian-Myanmar border.However,these research results can still not be used to confirm fully resistant P.falciparum to artemisinin.The treatment failure does not mean or equal to the resistance.Most treatment failure cases(maybe including resistant cases)have been cured by increasing the dosages and longer treatment courses.Artemisinin has a high safety,and double dosing is still safe.It is suggested that World Health Organization and Chinese related authorities can recommend increasing the dosage and using 4-5 d treatment courses,which may increase the cure rates and delay the resistance development.However,this needs to carry out therapeutic efficacy study and resistance surveillance,and fully appropriate use of artemisinin.The strategies of investigation and clearing up of malaria foci in time,prevention from imported artemisinin resistant falciparum malaria and its spread can effectively slow down the artemisinin resistance development in P.falciparum.It is suggested continuously scaling up and improving the strategy.
Anti-malarial drugs are an important weapon for treating patients,protecting people,eradicating infectious resources and interrupting transmission in malaria control.The resistance is a kind of malaria parasite way for survival and reproduction.This paper reviews the resistance situation of the first line drugs for falciparum malaria treatment,and then presents suggestions on how to delay resistance development.The results of researches found the decreased artemisinin sensitivity in Plasmodium falciparum and cure rates,increased number of treatment failure cases in Cambodia,Myanmar,Vietnam and Thailand-Cambodian-Myanmar border.However,these research results can still not be used to confirm fully resistant P.falciparum to artemisinin.The treatment failure does not mean or equal to the resistance.Most treatment failure cases(maybe including resistant cases)have been cured by increasing the dosages and longer treatment courses.Artemisinin has a high safety,and double dosing is still safe.It is suggested that World Health Organization and Chinese related authorities can recommend increasing the dosage and using 4-5 d treatment courses,which may increase the cure rates and delay the resistance development.However,this needs to carry out therapeutic efficacy study and resistance surveillance,and fully appropriate use of artemisinin.The strategies of investigation and clearing up of malaria foci in time,prevention from imported artemisinin resistant falciparum malaria and its spread can effectively slow down the artemisinin resistance development in P.falciparum.It is suggested continuously scaling up and improving the strategy.
引文
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[16]HUANG F,TAKALAHARRISON S,JACOB C G,et al.A single mutation in K13 predominates in Southern China and is associated with delayed clearance of Plasmodium falciparum following artemisinin treatment[J].Journal of Infectious Diseases,2015,212(10):1629-1635.
[17]HUANG F,TANG L,YANG H,et al,Molecular epidemiology of drug resistance markers of Plasmodium falciparumin Yunnan Province,China[J].Malaria Journal,2012,11(1):243.
[18]高白荷,杨恒林,黄开国.云南省恶性疟原虫抗青蒿琥酯株的体外培养选育[J].中国病原生物学杂志,2000,13(3):215-217.
[19]杨恒林,高白荷,黄开国.青蒿琥酯敏感与抗性株恶性疟原虫对本芴醇、蒿甲醚、双氢青蒿素的体外敏感性[J].中国病原生物学杂志,2000,13(1):14-16.
[20]杨恒林,高白荷,黄开国.恶性疟原虫青蒿琥酯敏感株与抗性株对氯喹及氨酚喹敏感性的比较[J].中国寄生虫学与寄生虫病杂志,1999,17(6):353-355
[21]杨恒林,高白荷,杨品芳,等.青蒿琥酯与萘酚喹联用延缓恶性疟原虫抗性实验研究[J].中国血吸虫病防治所杂志,2003,15(6):426-428.
[22]汤林华.中国消除疟疾的目标、策略与路径[J].中国热带医学,2016,16(4):301-304.
[23]杨恒林,肖宁,杨亚明,等.云南边境消除疟疾的挑战与对策[J].中国热带医学,2017,17(4):321-324,330.
[2]刘旭.青蒿琥酯的研究与开发[M].桂林:漓江出版社,2010.
[3]YANG H L,YANG Y M,YANG P F,et al.Monitoring Plasmodium falciparum chloroquine resistance in Yunnan Province,China[J].Acta Trop,2008,108(1):44-49.
[4]YANG H,LIU D,YANG Y,et al.changes in susceptibility of plasmodium falciparum to artesunate in vitro in yunnan province,china[J].Trans R Soc Trop Med Hyg,2003,97(2):226-228.
[5]WHO.The global plan for artemisinin resistance containment[R].Geneva:World Health Organization,2011.
[6]KUMAR A,CHERY L,BISWAS C,et al.Malaria in South Asia:prevalence and control[J].Acta Tropica,2012,121(3):246-255.
[7]SáJ M,CHONG J L,WELLEMS T E.Malaria drug resistance:new observations and developments[J].Essays in Biochemistry,2011,51(1):137-160.
[8]WHO.Artemisinin and artemisinin-based combination therapy resistance[R].World Health Organization,2016.
[9]WITKOWSKI B,AMARATUNGA C,KHIM N,et al.Novel phenotypic assays detect artemisinin-resistant Plasmodium falciparum malariain Cambodia:in-vitro and ex-vivo drug response studies[J].Lancet Infect Dis,2013,13(12):1043-1049.
[10]NOEDL H,SE Y,SCHAECHER K,et al.Evidence of artemisininresistant malaria in western Cambodia[J].N Engl J Med,2008,359(24):2619-2620.
[11]AMARATUNGA C,MAO S,SRENG S.Slow parasite clearance rates in response to artemether in patients with severe malaria[J].Lancet Infect Dis,2013,13(2):113-114.
[12]HIEN T T,THUY-NHIEN N T,PHU N H.In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province,Vietnam[J].Malar J,2012,11(1):1-11.
[13]PHYO A P,NKHOMA S,STEPNIEWSKA K,et al.Emergence of artemisinin-resistant malaria on the western border of Thailand:a longitudinal study[J].Lancet,2012,379(9830):1960-1966.
[14]LIU H,YANG H L,TANG L H,et al.In vivo monitoring of dihydroartemisinin-piperaquine sensitivity in Plasmodium falciparum along the China-Myanmar border of Yunnan Province,China from 2007 to 2013[J].Malaria Journal,2015,14(1):47-52.
[15]ARIEY F,WITKOWSKI B,AMARATUNGA C,et al.A molecular marker of artemisinin-resistant Plasmodium falciparum malaria[J].Natture,2014,505(7481):50-55
[16]HUANG F,TAKALAHARRISON S,JACOB C G,et al.A single mutation in K13 predominates in Southern China and is associated with delayed clearance of Plasmodium falciparum following artemisinin treatment[J].Journal of Infectious Diseases,2015,212(10):1629-1635.
[17]HUANG F,TANG L,YANG H,et al,Molecular epidemiology of drug resistance markers of Plasmodium falciparumin Yunnan Province,China[J].Malaria Journal,2012,11(1):243.
[18]高白荷,杨恒林,黄开国.云南省恶性疟原虫抗青蒿琥酯株的体外培养选育[J].中国病原生物学杂志,2000,13(3):215-217.
[19]杨恒林,高白荷,黄开国.青蒿琥酯敏感与抗性株恶性疟原虫对本芴醇、蒿甲醚、双氢青蒿素的体外敏感性[J].中国病原生物学杂志,2000,13(1):14-16.
[20]杨恒林,高白荷,黄开国.恶性疟原虫青蒿琥酯敏感株与抗性株对氯喹及氨酚喹敏感性的比较[J].中国寄生虫学与寄生虫病杂志,1999,17(6):353-355
[21]杨恒林,高白荷,杨品芳,等.青蒿琥酯与萘酚喹联用延缓恶性疟原虫抗性实验研究[J].中国血吸虫病防治所杂志,2003,15(6):426-428.
[22]汤林华.中国消除疟疾的目标、策略与路径[J].中国热带医学,2016,16(4):301-304.
[23]杨恒林,肖宁,杨亚明,等.云南边境消除疟疾的挑战与对策[J].中国热带医学,2017,17(4):321-324,330.