Insights into the pyrimidine biosynthetic pathway of human malaria parasite Plasmodium falciparum as chemotherapeutic target

Malaria is a major cause of morbidity and mortality in humans. Artemisinins remain as the first-line treatment for Plasmodium falciparum(P. falciparum) malaria although drug resistance has already emerged and spread in Southeast Asia. Thus, to fight this disease, there is an urgent need to develop new antimalarial drugs for malaria chemotherapy. Unlike human host cells, P. falciparum cannot salvage preformed pyrimidine bases or nucleosides from the extracellular environment and relies solely on nucleotides synthesized through the de novo biosynthetic pathway. This review presents significant progress on understanding the de novo pyrimidine pathway and the functional enzymes in the human parasite P. falciparum. Current knowledge in genomics and metabolomics are described, particularly focusing on the parasite purine and pyrimidine nucleotide metabolism. These include gene annotation, characterization and molecular mechanism of the enzymes that are different from the human host pathway. Recent elucidation of the three-dimensional crystal structures and the catalytic reactions of three enzymes: dihydroorotate dehydrogenase, orotate phosphoribosyltransferase, and orotidine 5'-monophosphate decarboxylase, as well as their inhibitors are reviewed in the context of their therapeutic potential against malaria.

Malaria parasite carbonic anhydrase:inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential

Plasmodium falciparum(P.falciparum) is responsible for the majority of life-threatening cases of human malaria,causing 1.5-2.7 million annual deaths.The global emergence of drug-resistant malaria parasites necessitates identification and characterisation of novel drug targets and their potential inhibitors.We identified the carbonic anhydrase(CA) genes in P.falciparum.The pfGA gene encodes an α-carbonic anhydrase,a Zn^(2+)-metalloenzme,possessing catalytic properties distinct from that of the human host CA enzyme.The amino acid sequence of the pfCA enzyme is different from the analogous protozoan and human enzymes.A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds were found to be very good inhibitors for the malarial enzyme at moderate-low micromolar and submicromolar inhibitions.The structure of the groups substituting the aromatic-ureido-or aromatic-azomethine fragment of the molecule and the length of the parent sulfonamide were critical parameters for the inhibitory properties of the sulfonamides.One derivative,that is,4-(3,4-dichlorophenylureido)thioureidobcnzcnesulfonamide(compound 10) was the most effective in vitro Plasmodium falciparum CA inhibitor,and was also the most effective antimalarial compound on the in vitro P.falciparum growth inhibition.The compound 10 was also effective in vivo antimalarial agent in mice infected with Plasmodium berghei,an animal model of drug testing for human malaria infection. It is therefore concluded that the sulphonamide inhibitors targeting the parasite CA may have potential for the development of novel therapies against human malaria.

Antimalarial qinghaosu/artemisinin: The therapy worthy of a Nobel Prize

Malaria is a major cause of human morbidity and mortality in the tropical endemic countries worldwide. This is largely due to the emergence and spread of resistance to most antimalarial drugs currently available. Based on the World Health Organization recommendation, artemisinin-based combination therapies are now used as first-line treatment for Plasmodium falciparum malaria. Artemisinin or qinghaosu(Chinese name) and its derivatives are highly potent, rapidly acting antimalarial drugs. Artemisinin was discovered in 1971 by a Chinese medical scientist Youyou Tu, who was awarded the Nobel Prize in 2015 on her discovering the antimalarial properties of qinghaosu from the traditional Chinese qinghao plant. Nevertheless, artemisinin resistance in falciparum malaria patients has first emerged on the Thai-Cambodian border in 2009, which is now prevalent across mainland Southeast Asia from Vietnam to Myanmar. Here, we reviewed malaria disease severity, history of artemisinin discovery, chemical structure, mechanism of drug action, artemisinin-based combination therapies, emergence and spread of drug resistance, including the recent findings on mechanism of resistance in the falciparum malaria parasite. This poses a serious threat to global malaria control and prompts renewed efforts for the urgent development of new antimalarial drugs.

From control to eradication of malaria:the end of being stuck in second gear?

More than 2 billion people are at risk of malaria,which primarily affects poor populations in tropical and subtropical areas,including Southern Asia.As malaria incidence has been reduced strongly in some parts of endemic regions by combinations of interventions,including artemisinin-based therapies and insecticide-treated bed nets,a new goal has been established recently by charity foundations which support research on malaria:the worldwide eradication of the pathology.Doing away with control approaches which have been applied for the last 50 years and more focus on elimination objectives will deeply change priorities in the area of malaria treatment,chemoprevention,vector control,vaccine research and health system assessment.In this review,actual knowledge on pathogenesis and pharmacology is discussed,and new drugs, vaccines and insecticides are described.

Artemisinin resistance or tolerance in human malaria patients

Malaria is a major cause of morbidity and mortality in the developing world.This situation is mainly due to emergence of resistance to most antimalarial drugs currently available. Artemisinin-based combination treatments are now first-line drugs for Plasmodium falciparum (P.falciparum) malaria.Artemisinin(qinghaosu) and its derivatives are the most rapid acting and efficacious antimalarial drugs.This review highlights most recent investigations into the emergence of artemisinin resistance in falciparum malaria patients on the Thai-Cambodian border,a historical epicenter for multidrug resistance spread spanning over 50 years.The study presents the first evidence that highlights the parasites reduced susceptibility to artemisinin treatment by prolonged parasite-clearance times,raising considerable concern on resistance development.Although the exact mechanism of action remains unresolved,development of resistance was proposed based from both in vitro experiments and human patients.Lines of evidence suggested that the parasites in the patients are in dormant forms,presumably tolerate to the drug pressure.The World Health Organization has launched for prevention and/or containment of the artemisinin-resistant malaria parasites.Taken together,the emergence of artemisinin resistance to the most potent antidote for falciparum malaria,poses a serious threat to global malaria control and prompts renewed efforts for urgent development of new antimalarial weapons.

Modelling the impact of antimalarial quality on the transmission of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum

Background:The use of poor quality antimalarial medicines,including the use of nonrecommended medicines for treatment such as sulfadoxine-pyrimethamine(SP)monotherapy,undermines malaria control and elimination efforts.Furthermore,the use of subtherapeutic doses of the active ingredient(s)can theoretically promote the emergence and transmission of drug resistant parasites.Methods:We developed a deterministic compartmental model to quantify the impact of antimalarial medicine quality on the transmission of SP resistance,and validated it using sensitivity analysis and a comparison with data from Kenya collected in 2006.We modelled human and mosquito population dynamics,incorporating two Plasmodium falciparum subtypes(SP-sensitive and SP-resistant)and both poor quality and good quality(artemether-lumefantrine)antimalarial use.Findings:The model predicted that an increase in human malaria cases,and among these,an increase in the proportion of SP-resistant infections,resulted from an increase in poor quality SP antimalarial use,whether it was full-or half-dose SP monotherapy.Interpretation:Our findings suggest that an increase in poor quality antimalarial use predicts an increase in the transmission of resistance.This highlights the need for stricter control and regulation on the availability and use of poor quality antimalarial medicines,in order to offer safe and effective treatments,and work towards the eradication of malaria.

Hidden reservoir of resistant parasites:the missing link in the elimination of falciparum malaria

Background:To successfully eliminate malaria,an integrated system that includes a number of approaches and interventions-aimed at overcoming the threat of antimalarial drug resistance-is required.Significant progress has been made in reducing malaria incidence through large-scale use of artemisinin-based combination therapies and insecticide-treated nets.To consolidate these gains,attention should be paid to the missing links in the elimination of malaria.One of these gaps is the residual reservoir of submicroscopic resistant parasites,which remains after case management or other control measures have been carried out.Therefore,the present opinion piece highlights the importance of exploring the role that submicroscopic resistant parasites could play in hindering malaria elimination by allowing the persistence of transmission,particularly in areas of low transmission or in the pre-elimination and/or elimination phase.Discussion:If malaria elimination interventions are to be effective,the relative role of the hidden reservoir of resistant parasites needs to be assessed,particularly in regions that are low-transmission settings and/or in pre-elimination and/or elimination phases.Various ongoing studies are focusing on the role of submicroscopic malaria infections in malaria transmission but overlook the possible build-up of resistance to antimalarial drugs among submicroscopic parasite populations.This is an important factor as it may eventually limit the effectiveness of malaria elimination strategies.Conclusions:An evidence-based estimation of the“true”reservoir of resistant parasites can help target the existing and emerging foci of resistant parasites before they spread.Emergence and spread of artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia underline the need to contain drug resistance.

Modeling and targeting an essential metabolic pathway of Plasmodium falciparum in apicoplast using Petri nets

Petri net(PN) is one of the promising computational and mathematical formalisms used to represent and study the behavior of complex metabolic networks. The various available analysis techniques of PN could be used to validate and analyze the network in different scenarios. Plasmodium falciparum is one of the threatening parasites which causes malaria, a deadly disease affecting a large number of today’s world population. The development of antimalarial drug resistance is an emerging global threat, highlighting the need to discover novel antimalarial targets. The fatty acid biosynthesis of malarial parasite is one of the essential metabolic pathways required for its growth and is present in apicoplast, a non-photosynthetic plastid. The malarial parasite obtains fatty acids by using type two fatty acid synthase(FAS II) enzyme,which is different from type one enzyme used by human host, making it an ideal drug target.This article proposes and studies the PN model of the parasite’s FAS II pathway to analyze the mechanism of potential drug targets in this pathway. The proposed PN model can serve as a base for further findings in the field of antimalarial drug targets to decrease the malaria mortality rate.

Malaria epidemiology in Kobeni department,southeastern Mauritania from 2015 to 2017

Background:Plasmodium falciparum malaria is endemic in the southern sahelian zone of Mauritania where intense internal and trans-border human and livestock movement occurs.The risk of importation and spread of drugresistant parasites need to be regularly assessed in this region.The objective of the study was to assess the recent malaria situation near the Mauritania-Mali border.Methods:Between February 2015 and December 2017,patients with fever or history of fever during the previous 48 h,presenting at the health centre of Kobeni city,were screened for malaria using a rapid diagnostic test(RDT)and microscopic examination of blood smears.The diagnosis was later confirmed by PCR.Cohen’s kappa statistics was used to estimate the degree of agreement between diagnostic methods.Fisher’s exact test was used to compare proportions.The odds ratio was calculated to measure the association between the use of bed nets and malaria infection.Results:A total of 2326 febrile patients(mean age,20.2 years)were screened for malaria.The presence of malaria parasites was detected by RDT and microscopy in 53.0%and 49.3%of febrile patients,respectively,and was confirmed by PCR in 59.7%(45 missing data).Of 1361 PCR-positive samples,1205(88.5%)were P.falciparum,47(3.5%)P.vivax,and 99(7.3%)P.falciparum-P.vivax mixed infection.Malaria transmission occurred mostly during and shortly after the rainy season.The annual rainfall was relatively low in 2016(267 mm)and 2017(274 mm),compared to 2015(448 mm),and coincided with a decline in malaria prevalence in 2016–2017.Although 71.8%of febrile patients reported to possess at least one bed net in the household in our questionnaire,its reported use was not protective against malaria infection(odds ratio:1.1,95%CI:0.91–1.32).Conclusions:Our study confirmed that P.falciparum is the dominant species in the sahelian zone and that malaria transmission is seasonal and associated with rainfall in this zone.The application of the current national policy based on rapid and reliable malaria diagnosis,case management with artemisinin-based combination therapy,intermittent preventive treatment for pregnant women,distribution and use of long-lasting insecticide impregnated bed nets,and the planned introduction of seasonal malaria chemoprevention for all children under 6 years old is expected to sustainably reduce malaria transmission in this zone.

Investigation of Plasmodium falciparum Resistance Biomarkers among Primary School Children in Western Kenya

Background: A marked decrease in malaria-related deaths worldwide has been attributed to the administration of effective antimalarials against Plasmodium falciparum. However, the continuous spread of P. falciparum resistance to anti-malarial drugs is raising a serious problem in controlling Malaria to the vulnerable children’s immune system. In recent studies, Plasmodium falciparum Kelch 13 propeller gene (Pfk13) has been reported to develop resistance to artemisinin in South Asia. In this study, we checked Plasmodium falciparum chloroquine resistance transporter gene (Pfcrt) involved in chloroquine (CQ) resistance. Method: In this study, archived 280 samples were collected from Alupe primary school children in Busia, Western Kenya from May, 2016 to November, 2016. Genomic DNA was extracted using the MightyPrep reagent. The samples were investigated for P. falciparum positivity out of which 67 of them tested positive giving a prevalence rate of 24%. The sixty-seven were subjected to PCR amplification for the molecular marker resistance to Pfcrt. After PCR amplification, the amplicons were purified and sequenced using Sanger Sequencing. The sequence data were analyzed using BioEdit software to identify point mutations. Results: 14 samples sequences were analyzed on Bioedit software giving the following amino acid changes F76C, Y66H, L70A, Y58C, T59V, V65I, P67L, T81L, Y60S, Y66S, P67T and I71F). New mutations have been reported at position 76 leading to an amino acid change, one of Pfcrt gold standard biomarkers. However, amino acid changes Y66H, L70A, Y58C, T59V, V65I, P67L, T81L, Y60S, Y66S, P67T and I71F are newly reported giving an increase in Pfcrt prevalence of concern from zero to 5.0%. A phylogenetic evolutionary relationship was constructed as shown below. Generally, the results showed a continuous resistance of P.falciparum to Pfcrt which calls for robust continuous monitoring and surveillance. Conclusion: Due to the increase of the resistant Pfcrt gene prevalence, continuous development of new mutants against chloroquine indicates that there is need to repurpose anti-malarial drugs for future partner drugs.

青蒿琥酯片治疗恶性疟的剂量再探索

为探索青蒿琥酯治疗恶性疟的最佳剂量和疗程，本研究在中国海南岛抗性恶性疟流行地区，采用青蒿琥酯片５ｄ疗程总量６００ｍｇ和７ｄ疗程总量８００ｍｇ治疗无并发症恶性疟疾，进行开放性随机比较。每组治疗５０例，全部病例住院２８ｄ观察原虫复燃情况。结果：两组病例临床症状均被迅速控制。５ｄ疗程组和７ｄ疗程组退热时间分别为（２４．０±１３．６）ｈ和（２０．０±１０．１）ｈ，原虫转阴时间分别为（６１．７±２１．１）ｈ和（５５．８±１５．８）ｈ，两组无显著性差异。２８ｄ内原虫复燃率７ｄ组为４．２％（２／４８），５ｄ组为１９．１％（９／４７），治愈率分别为９５．８％和８０．９％。两组比较有非常显著性差异（χ２＝５．２１，Ｐ＜０．０１），表明７ｄ疗程可使复燃率明显下降。两组皆未见临床不良反应。提示青蒿琥酯７ｄ疗程总量８００ｍｇ是一个高治愈率的给药方案，可作为标准疗程剂量。

青蒿琥酯治疗脑型疟的临床疗效

在多重抗药性恶性疟流行区的越南南方采用青蒿琥酯３６０～４２０ｍｇ／５ｄ静脉注射治疗１６８例脑型疟，配合积极的对症处理和支持疗法，治愈１５２例（９０．５％）、死亡１６例（９．５％）；平均原虫转阴时间为（５８．５±２９．０）ｈ，平均退热时间为（５４．３±３８．３）ｈ，平均昏迷清醒时间为（３７．５±３３．８）ｈ。全部病人在治疗过程中均未发现与药物有关的毒副反应。结果表明：在多重抗药性恶性疟流行区治疗重症疟疾患者，青蒿琥酯是一个理想的速效。

双氢青蒿素和奎宁对恶性疟原虫早期配子体作用的随机比较

【目的】研究双氢青蒿素对恶性疟原虫早期配子体的抑杀作用。【方法】仅骨髓带恶性疟原虫早期配子体而骨髓与外周血液均无成熟配子体的患者 11例 ,随机分为A、B 2组。A组 6例口服双氢青蒿素片 7d总量 4 80mg ;B组 5例口服硫酸奎宁片 7d总量 10 50 0mg ,定时取骨髓和外周血液涂片 ,观察两组配子体密度的变化。【结果】A组骨髓早期配子体药后 10d全部转阴 ;而B组全部阳性 ,至药后 14d仍有 2 / 5例阳性。外周血液配子体转阴时间 ,A组为 ( 4 .8± 0 .9)d ;B组为 ( 2 2 .0± 5.8)d。【结论】双氢青蒿素能杀灭恶性疟原虫早期配子体 。

青蒿琥酯对恶性疟原虫早期配子体的作用

为了研究青蒿琥酯对恶性疟原虫早期配子体（ＰＦＧｅ）的作用，选择经骨髓涂片查到ＰＦＧｅ，但未有成熟配子体（ＰＦＧｍ）的脑型疟患者３４例，对其治疗前后ＰＦＧｅ的改变进行了专门观察。方法是采用青蒿琥酯静脉给药，５ｄ疗程总量３６０～４２０ｍｇ。治疗后，于当天（Ｄ０）和第７天（Ｄ７）或加第１０天（Ｄ１０）作骨髓涂片，观察ＰＦＧｅ的变化，每天取外周血片计算ＰＦＧｅ和ＰＦＧｍ数，连续２８ｄ或直至ＰＦＧ消失。结果３４例治疗后，Ｄ７骨髓ＰＦＧｅ消失２７例，Ｄ１０消失７例。２９例外周血查到ＰＦＧｅ者，全部于治疗后２～８ｄ消失，平均（４．５±１．９）ｄ。３３例骨髓和外周血均一直未查到ＰＦＧｍ，仅１例于首剂给药后１０ｈ，外周血查到少量ＰＦＧｍ，持续至Ｄ１１消失。结果表明，青蒿琥酯对Ⅰ～Ⅳ期ＰＦＧｅ都有杀灭作用。只有极少数接近成熟的配子体未被控制而出现于外周血液。

双氢青蒿素对恶性疟原虫有性生殖期的影响

１８ 例带配子体的恶性疟患者随机分为２ 组： 双氢青蒿素组１０ 例， 口服５ ｄ 疗程总量３６０ ｍｇ ； 奎宁组８ 例， 口服７ ｄ 疗程总量１０ ５００ ｍｇ 。全部患者每天涂血片计算配子体密度， 于给药当天（Ｄ０） ， 药后４ 、７ 、１０ 、１４ 、２１ 和２８ ｄ （Ｄ４ 、Ｄ７ 、Ｄ１０ 、Ｄ１４ 、Ｄ２１ 、和Ｄ２８） 取血作大劣按蚊感染试验。患者血中配子体转阴时间， 双氢青蒿素组为２１ ．８ ±５ ．２ ｄ ； 奎宁组为３１ ．５ ±８ ．７ ｄ 。按蚊感染试验结果： 双氢青蒿素组有４ 例在Ｄ０Ｄ４ 、Ｄ７ 、Ｄ１０ 、Ｄ１４ 均未能感染按蚊； 其余６ 例于Ｄ０ 、Ｄ４ 、Ｄ７ 、Ｄ１０ 、Ｄ１４ 、Ｄ２１ 按蚊感染阳性例数为６／６ 、６／６ 、６／６ 、２／６ 、０／６ 和０／６ 。奎宁组Ｄ０ 、Ｄ４ 、Ｄ７ 、Ｄ１０ 、Ｄ１４ 、Ｄ２１ 和Ｄ２８ 按蚊感染阳性例数为４／８ 、８／８ 、８／８ 、８／８ 、８／８ 、２／８ 和０／８ 。这表明双氢青蒿素５ ｄ 总量３６０ ｍｇ 对恶性疟原虫有性生殖期发育有明显抑制作用， 对生理上未成熟的配子体， 可中断其发育。

复方萘酚喹及其组分单药治疗恶性疟的临床研究

目的 对比观察复方萘酚喹(Co-NQ)与组分单药萘酚喹(NQ)和青蒿素(QHS)对恶性疟的疗效和安全性。方法 用Co-NQ(总量含NQ400mg及QHS1000mg)、NQ(总量1000mg)和QHS(总量2500mg)分别治疗恶性疟患者100例、100例和30例。所有患者住院7d,随访28d,观察疗效和安全性。结果 Co-NQ、NQ和QHS3组的平均退热时间分别为(17.5±12.3)h,(32.7±17.7)h和(18.1±9.7)h;平均原虫转阴时间分别为(30.0±8.8)h,(45.5±10.0)h和(29.1±6.0)h;28d治愈率分别为97.0％,100.0％和66.7％。Co-NQ组临床未见不良反应。结论 Co-NQ具有QHS的速效和NQ的持效作用,是一个高效、速效、持效的新复方。

甲氟喹治疗恶性疟与青蒿琥酯的随机比较

目的：评价甲氟喹治疗恶性疟的疗效与安全性。方法：采用甲氟喹７５０ｍｇ一次顿服与青蒿琥酯片５ｄ疗程总量６００ｍｇ各治疗无合并症恶性疟３０例，进行随机比较。结果：两组病例均能迅速控制临床症状，平均退热时间两组相似，分别为甲氟喹组（２４．２±１４．７）ｈ和青蒿琥酯组（１８．３±９．０）ｈ（ｔ＝１．８４３，Ｐ＞０．０５）。平均原虫转阴时间甲氟喹组（５７．２±２０．０）ｈ慢于青蒿琥酯组（４３．０±１７．１）ｈ（ｔ＝２．９０７，Ｐ＜０．０１）。追踪观察２８ｄ，甲氟喹组治愈率为７６．７％，原虫复燃率为２３．３％；青蒿琥酯组治愈率为７３．３％，复燃率为２６．７％，两组无显著性差异（χ２＝０．０８９，Ｐ＞０．０５）。两组除极少数患者可见轻微的恶心或呕吐，可能与病情本身有关外，未见其他明显毒副作用。结论：甲氟喹７５０ｍｇ一次顿服与青蒿琥酯５ｄ疗程总量６００ｍｇ治疗恶性疟的治愈率及症状控制疗效相似，甲氟喹组原虫清除时间慢于青蒿琥酯组。

复方双氢青蒿素2天疗程治疗恶性疟50例

为寻找高效、速效、低毒的治疗恶性疟复方 ,采用复方双氢青蒿素 (由双氢青蒿素、磷酸哌喹和甲氧苄啶组成 ) 2天疗程成人总量 8片方案治疗无并发症恶性疟 50例。结果 :平均退热时间为 (17.2± 9.9)h ,平均原虫转阴时间为 (52 .0± 2 0 .2 )h。 4 6例追踪观察 2 8d ,无 1例复燃。 34例患者治疗前检查血液学、丙氨酸氨基转移酶 (ALT)、天门冬酸氨基转移酶 (AST)和总胆红素 ,发现小部分患者有异常改变 ;治疗后7d复查 。

两种双氢青蒿素复方治疗海南岛无并发症恶性疟的临床对照研究

[目的]比较双氢青蒿素的两个复方Artekin与Artekin(T)治疗无并发症恶性疟的有效性和安全性。[方法]将80例无并发症恶性疟病人随机分成两组,每组40例,采用2d共4次给药(2片/次),成人总量8片的给药方案,观察治愈率、平均原虫转阴时间、退热时间和不良反应。[结果]Artekin组的平均原虫转阴时间为(60.8±19.8)h,Artekin(T)组为(61.8±20.5)h;平均退热时间Artekin组为(17.3±9.1)h,Altekin(T)为(22.8±14.7)h;随访28 d,两组各有1例复燃,Artekin组和Artekin(T)组治愈率均为97.5％。患者对两复方均有较好的耐受性,恶心、腹痛等症状均轻微而且是自限性的。[结论]初步显示双氢青蒿素两个复方均有高效、速效和低毒等优点,对治疗有多重抗药性恶性疟流行区海南岛的无并发症恶性疟有良好疗效。

复方萘酚喹对伯氏疟原虫ANKA株红内期超微结构的影响

为观察复方萘酚喹及其各单药 (磷酸萘酚哇、双氢青蒿素、甲氧苄啶 )对伯氏疟原虫ANKA株红内期超微结构的影响 ,将感染伯氏疟原虫ANKA株的小鼠分别以复方萘酚喹 2 6 0mg·kg- 1·d- 1× 1d (内含磷酸萘酚喹 149mg、双氢青蒿素 37mg、甲氧苄啶 74mg) ,磷酸萘酚喹 149mg·kg- 1·d- 1× 1d ,双氢青蒿素 180mg·kg- 1·d- 1× 1d和甲氧苄啶 1152mg·kg- 1·d- 1× 1d灌胃给药。给药后 1、 2、 4、 8、 12和 2 4h ,采血作标本 ,经包埋 ,切片 ,染色后 ,用电镜镜检。结果 :复方萘酚喹于给药 2h后多数晚期滋养体出现质膜肿胀、破裂 ,有的呈空腔状 ;食物泡膜肿胀 ;线粒体膜肿胀、分层、剥离 ;色素颗粒变形。给药 4h后进一步加剧。 8h后小部分晚期滋养体结构已经融化崩解 ,内容物结构模糊。 12h后绝大多数晚期滋养体结构已完全破坏或消失。结论 :复方萘酚喹对伯氏疟原虫红内期超微结构的影响较其组分中各单药起效更快、力度更强和作用相对彻底。