A Multicentre Open-label, Non-inferiority Adaptive Platform Randomised Controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Antimalarials for the Treatment of Uncomplicated Malaria in the First Trimester of Pregnancy: Master Protocol

The SAFIRE study aims to find effective treatments with acceptable safety for malaria in early pregnancy, a particularly sensitive time for the adverse consequences of malaria in pregnancy for both mother and baby. Currently, WHO recommends the antimalarial drug artemether-lumefantrine (AL) for the treatment of uncomplicated malaria in the first trimester of pregnancy. Other promising treatments are being rolled out in malaria-endemic countries for use in adults and children and data on current exposures in the first trimester are limited and insufficient to support a recommendation. This is due to the fact that pregnant women are often excluded from clinical trials to protect fetuses, unintentionally depriving them of newer, potentially better treatments. Instead, they often received older, less effective drugs. The International Council for Harmonisation (ICH E21) and stringent regulatory authorities (e.g. EMA, FDA and MHRA) now encourage pregnant women to be included in well-designed studies to ensure they can safely benefit from medical advances.
This study will compare AL with the newer antimalarial drugs that have shown no significant safety concerns in laboratory studies, accidental use during early pregnancy, or trials in later pregnancy stages. The main goal is to see if these new drugs work as well as AL in treating malaria and are safe for the mother, her pregnancy and the developing baby. The newer antimalarials being tested also offer additional benefits to pregnant women, such as preventing new malaria infections for longer after treatment than the current standard treatment (AL). Also, they can be taken just once a day instead of twice daily, like AL. A simpler dosing schedule could improve adherence to the study medication, meaning women are more likely to take the full course of treatment as prescribed. This, in turn, enhances its effectiveness in real-world settings. Future antimalarials to be tested will include those with improved resistance profiles, offering more effective options for combating drug-resistant strains.
SAFIRE uses a special "Bayesian Adaptive Platform Trial" (APT) design. This open-ended approach allows researchers to add new interventions under the same protocol, leveraging the existing trial network with infrastructure. The use of a common protocol with innovative adaptive statistical design allows the trial to stop early if it becomes clear that the new drugs are unsafe.
This multi-centre trial will be conducted in several countries in Africa where malaria is very common. Women will be randomly assigned to receive either AL or one of the new treatments. Participants will be seen daily for 4 days, then weekly for 6 weeks to assess the response to treatment, and then monthly until delivery. Their health and outcomes will be closely monitored during and after pregnancy. Newborns will be followed for 6 months. An independent data safety and monitoring board (DSMB) will regularly monitor safety data as it accumulates. By finding more treatment options, this study could improve care for pregnant women with malaria and lead to better health for mothers and babies in areas where malaria is widespread. The results will help inform global health policies and potentially change how we treat malaria in early pregnancy.

开始日期2025-07-01

申办/合作机构

Liverpool School of Tropical Medicine

NCT06068530

/ Recruiting临床4期IIT

A Cluster-randomised, Open-label Trial to Compare the Impact of Combined Mass Vaccine and Drug Administrations, Mass Drug Administration, Mass Vaccinations, or no Intervention on Plasmodium Falciparum Malaria Transmission

This is an open i.e. not blinded, cluster-randomised, controlled intervention study. The study will use a factorial design to estimate the protective effectiveness of mass drug administrations, mass vaccinations, combined mass vaccinations and drug administrations versus the current standard of care.

开始日期2025-02-15

申办/合作机构

University of Oxford

NCT06973200

/ CompletedN/AIIT

Epidemiological Profile of Schistosomiasis and Soil-transmitted Helminth Infections Among Schoolchildren in Banfora Municipality, Burkina Faso: a Pilot Study

A cross-sectional study will be conducted among 300 schoolchildren in the Banfora region, including 120 in urban and 180 in rural areas, to assess the prevalence of schistosomiasis and soil-transmitted helminth infections. All children with S. mansoni and/or S. haematobium infections at enrolment will then be treated with dihydroartemisinin-piperaquine (DP) and followed up on days 1, 2, 3, 4, 28, and 42 to assess the efficacy and safety of DP. At the end of the study, all children (infected and uninfected) will receive praziquantel and albendazole according to national recommendations.

开始日期2024-11-11

申办/合作机构

University of Ghana

100 项与双氢青蒿素哌喹相关的临床结果

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100 项与双氢青蒿素哌喹相关的转化医学

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100 项与双氢青蒿素哌喹相关的专利（医药）

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项与双氢青蒿素哌喹相关的文献（医药）

2025-06-01·PARASITOLOGY INTERNATIONAL

Falciparum malaria in a child from Ghana with neutrophils showing phagocytosis of trophozoites, merozoites and possibly schizont

Article

作者: Ligero-López, Jorge ; Ferreira-Ferreira, Ingrid ; Boquera-Albert, Amparo ; Beltrán-Rosel, Antonio ; Rubio-Muñoz, José Miguel ; López-Alonso, Beatriz ; Collado-Hernández, Pilar

Malaria remains a significant health threat in tropical and subtropical regions. The immune response to Plasmodium falciparum involves both humoral and cellular components, including phagocytosis by neutrophils. However, observing phagocytosis through light microscopy is uncommon. This report presents a rare case of falciparum malaria in a Ghanaian twin, highlighting intracellular P. falciparum forms in neutrophils. Two 7-year-old male twins from Ghana were admitted with fever, vomiting, and abdominal pain. They tested positive for P. falciparum infection via rapid diagnostic tests and blood smears. Child 1 displayed significant neutrophilia and intracellular parasites, including trophozoites, merozoites, and a potential schizont, within neutrophils. Child 2 showed no phagocytosis but exhibited other signs of systemic inflammation and hemolysis. Both children were treated successfully with piperaquine tetraphosphate/artenimol (Eurartesim®). This case provides rare microscopic evidence of P. falciparum phagocytosis by neutrophils, suggesting prior antibody development in the patient. While the findings highlight the role of phagocytosis in parasite clearance, the absence of similar observations in the second twin raises questions about individual immune responses and genetic factors. Further research is needed to explore the underlying biological mechanisms.

2025-04-01·LANCET INFECTIOUS DISEASES

Adjunctive ivermectin mass drug administration for malaria control on the Bijagos Archipelago of Guinea-Bissau (MATAMAL): a quadruple-blinded, cluster-randomised, placebo-controlled trial

Article

作者: Ceesay, Fatima ; Vasileva, Hristina ; Logan, James G ; Moss, Sophie ; Rodrigues, Amabelia ; Sambou, Sarata ; Prom, Aurelia ; Ndiath, Mamadou Ousmane ; Martins, Cesario ; Ceesay, Sainey ; Soumare, Harouna Dit Massire ; Last, Anna ; Djata, Paulo ; Hutchins, Harry ; Pretorius, Elizabeth ; Drakeley, Chris ; Nante, Jose Ernesto ; Slater, Hannah ; Tetteh, Kevin ; Bradley, John ; Jones, Robert T ; Mabey, David ; D'Alessandro, Umberto ; Teixeira da Silva, Eunice ; Soumare, Harouna dit Massire ; Nyang, Haddy

BACKGROUND:

Arthropod vectors feeding on the blood of individuals treated with ivermectin have substantially increased mortality. Whether this effect will translate into a useful tool for reducing malaria burden at scale is not clear. Our trial aimed to assess whether using ivermectin as an adjunct to mass drug administration (MDA) with dihydroartemisinin-piperaquine would further reduce malaria prevalence.

METHODS:

MATAMAL was a quadruple-blinded, cluster-randomised, placebo-controlled trial, conducted on the Bijagos Archipelago, Guinea-Bissau, an area of seasonal malaria transmission. All residents were invited to participate, with exclusions for drug safety. 24 clusters were randomised in a 1:1 ratio, using restriction randomisation, to either MDA with three daily oral doses of dihydroartemisinin-piperaquine and ivermectin (300 μg/kg per day) in three sequential months during the transmission season in 2021 and 2022, or MDA with dihydroartemisinin-piperaquine and placebo in the same schedule. The primary outcome was quantitative PCR prevalence of Plasmodium falciparum parasitaemia in all age groups, during peak transmission, after the second year of intervention. The primary entomological outcome was anopheline parity rate. The trial is registered with ClinicalTrials.gov (NCT04844905).

FINDINGS:

Participants were recruited between June 7, 2021 and Sept 21, 2022. The baseline population was 25 882 (12 634 [50·6%] were female individuals and 12 317 [49·4%] were male individuals): 13 832 were in the intervention group and 12 050 in the control group. Cluster-level coverage for dihydroartemisinin-piperaquine ranged from 60·4% to 78·7%, and for ivermectin or ivermectin-placebo from 58·1 to 77·1%. Following the intervention, the prevalence of P falciparum infection was 118 (5·05%) of 2300 in the control group and 141 (6·64%) of 2083 in the intervention group. The adjusted risk difference was 1·67% (95% CI -1·44 to 4·78; p=0·28). There were 124 adverse events in the control group (1·0% of participants) and 267 in the intervention group (1·9% of participants). Two serious adverse events were reported, neither related to the intervention, and no treatment-related deaths. The anopheline parity rate was 1679 (67·8%) of 2475 in control clusters and 1740 (72·3%) of 2414 in intervention clusters. The adjusted risk difference was -1·32 (95% CI -14·77 to 12·12; p=0·84).

INTERPRETATION:

Adding ivermectin to dihydroartemisinin-piperaquine MDA had no additional effect on reducing malaria prevalence or vector parity in this setting. The intervention was well tolerated. To our knowledge, this trial is the first to be designed to assess whether ivermectin has an additive effect on malaria when coadministered with dihydroartemisinin-piperaquine MDA.

FUNDING:

The National Institute for Health and Care Research, Medical Research Council, Wellcome, and Foreign, Commonwealth & Development Office.

2024-10-01·Lancet Global Health

Delivery effectiveness of and adherence to intermittent preventive treatment for malaria in pregnancy with dihydroartemisinin–piperaquine with or without targeted information transfer or sulfadoxine–pyrimethamine in western Kenya: a three-armed, pragmatic, open-label, cluster-randomised trial

Article

作者: Dodd, James ; Odero, Isdorah A ; Webster, Jayne ; Barsosio, Hellen C ; Kuile, Feiko O Ter ; Omiti, Frederick ; Kariuki, Simon ; Ojuok, Michael A ; Okello, Elizabeth ; Hill, Jenny ; Odiwa, Dawn ; Lesosky, Maia ; Taegtmeyer, Miriam ; Omondi, Benson ; K'Oloo, Alloys

BACKGROUND:

High-level resistance to sulfadoxine-pyrimethamine threatens the efficacy of WHO-recommended intermittent preventive treatment in pregnancy (IPTp) with single-dose sulfadoxine-pyrimethamine to prevent malaria. Monthly IPTp with dihydroartemisinin-piperaquine, a 3-day regimen, is an emerging alternative, but this regimen poses potential implementation and adherence challenges. We aimed to assess adherence to a multiday IPTp with dihydroartemisinin-piperaquine regimen and its delivery effectiveness in routine antenatal care settings in western Kenya.

METHODS:

We conducted a pragmatic, three-armed, open-label, cluster-randomised trial in antenatal clinics in 18 health-care facilities (six facilities per group) in Kisumu County and Homa Bay County in western Kenya. Clusters were facilities offering routine antenatal care services provided by trained Ministry of Health staff with 100 or more antenatal clinic attendances per month between July, 2018, and June, 2019. Private or mission hospitals, dispensaries, referral hospitals, and trial sites were excluded. Individuals in their first trimester, living with HIV, or who were not attending a scheduled antenatal clinic visit were excluded. The 18 antenatal clinics were grouped into matched triplets stratified by location and clinics in each matched triplet were randomly assigned to one of the three study groups (1:1:1). Masking was not possible. Two groups were given IPTp with dihydroartemisinin-piperaquine (one group with a targeted information transfer intervention and one group without any additional interventions) and one group was given the standard of care (ie, IPTp with sulfadoxine-pyrimethamine). The primary endpoint, adherence, was defined as the proportion of participants completing their most recent 3-day IPTp with dihydroartemisinin-piperaquine regimen. This completion was verified by pill counts during home visits no more than 2 days after participants' 3-day regimens ended. The secondary endpoint, delivery effectiveness, was defined as the proportion of participants who received the correct number of IPTp tablets and correctly repeated dosing instructions (ie, correctly recalled the instructions they received about self-administered dihydroartemisinin-piperaquine doses and the number of sulfadoxine-pyrimethamine tablets they had received) at their exit from the antenatal clinic. Individuals receiving treatment for malaria, visiting a clinic for registration only, or interviewed during IPTp drug stock-outs were excluded from analyses. We used generalised linear mixed models to compare endpoints among the IPTp with dihydroartemisinin-piperaquine groups. This trial was registered with ClinicalTrials.gov, NCT04160026, and is complete.

FINDINGS:

15 facilities (five per group) completed the trial, with 1189 participants having exit interviews (377 in the IPTp with sulfadoxine-pyrimethamine group, 408 in the IPTp with dihydroartemisinin-piperaquine only group, and 404 in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group) and 586 participants having home visits (267 in the IPTp with dihydroartemisinin-piperaquine only group and 319 in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group) from Sept 8 to Dec 10, 2020. Relative to the IPTp with dihydroartemisinin-piperaquine only group, adherence was 16% higher in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group (266 [83%] of 319 participants vs 196 [73%] of 267 participants; adjusted relative risk [RR] 1·16, 95% CI 1·03-1·31; p=0·0140). Delivery effectiveness in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group was not significantly different from that in the IPTp with sulfadoxine-pyrimethamine group (352 [87%] of 403 participants vs 335 [89%] of 375 participants; adjusted RR 0·97, 95% CI 0·90-1·05; p=0·4810). However, delivery effectiveness in the IPTp with dihydroartemisinin-piperaquine only group was significantly lower than in the IPTp with sulfadoxine-pyrimethamine group (300 [74%] of 404 participants vs 335 [89%] of 375 participants; 0·84, 0·75-0·95; p=0·0030).

INTERPRETATION:

Targeted information transfer interventions to health-care providers and pregnant individuals boost antenatal care delivery adherence to a multiday regimen with dihydroartemisinin-piperaquine.

FUNDING:

European and Developing Countries Clinical Trials Partnership 2, UK Joint Global Health Trials Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, National Institute for Health and Care Research, and Wellcome Trust; and Swedish International Development Cooperation Agency.

项与双氢青蒿素哌喹相关的新闻（医药）

2025-02-05

·赛柏蓝

国药原研崛起！三大系列领跑慢病领域

昆药集团作为中国医药行业的领军企业之一，以其深厚的历史底蕴和卓越的创新能力，为中国医药产业的发展树立了标杆。这里有“全球最古老制药企业”的深厚历史底蕴，有70余载在核心植物药领域的精心耕耘，有以三七、天麻、青蒿作桨、创新为帆的现代中药，更有“大药厚德，痌瘝在抱”的医者仁心…… 于宏大处着眼，于细微处落墨，昆药集团厚植“三棵草”（三七、天麻、青蒿），做精老龄健康-慢病管理领导者。昆药“三棵草” （从左到右依次为三七、天麻、青蒿）血塞通：三七制剂的典范代表昆药集团血塞通系列产品三七则是云南最具特色的优势生物资源之一，其主要成分“三七总皂苷”具有扩张血管、降低心肌耗氧量、抑制血小板凝集等药理作用，广泛应用于心脑血管和相关疾病的预防和治疗。昆药集团依托云南丰富植物资源，经过70余年深耕细作，拥有了从三七GAP种植、饮片加工到三七总皂苷提取、制剂生产、专业营销推广的完整产业链，建立从种植、采购、研发、生产、质量检验到仓储物流全生命周期的可溯源智能化管控。 20世纪70年代昆药集团首家分离出了三七总皂苷中间体，并于1983年首家应用于临床，1985年首家申请使用“血塞通”名称、首家血塞通注射液上市，1996年，首家将冷冻干燥技术应用于天然药物注射剂生产，填补了国内天然药物冻干粉针制剂空白，1999年首家采用指纹图谱对产品进行质量控制。昆药集团既是三七制剂国家标准制定者，也是全球三七类产品剂型最全的企业，血塞通产品历年市场抽检合格率均为100% 。2003年昆药集团收购位于云南文山的“金泰得三七产业股份有限公司”，大力整合三七产业资源优势，建设以GAP要求为技术路线的优质无公害三七基地，与国际标准化接轨，从源头上控制三七药材的质量。昆药集团在历经30多年的创新发展后，在血塞通产品上拥有16项专利技术，不仅成为三七血塞通系列制剂的原研者和国家标准制定者，也是三七制剂产品线最全的企业，被誉为“三七创新科技引领者”。目前，昆药集团已成为中药注射剂大品种智能制造实施与应用的企业，对制药行业的智能制造推广起到积极的借鉴和示范作用，并可作为推广示范基地，在行业内有较好的标杆引领和示范效应。为了确保血塞通系列产品皂苷的高含量和高纯度，原料均来自于 “云南文山”昆药集团GAP种植基地，并且只采用皂苷含量最高的芦头部位进行提取。近年来昆药集团通过持续的工艺改进，不断提高三七总皂苷含量，降低原料中蛋白质、鞣质、异常毒性物质的含量，提升了临床应用的有效性和安全性。天麻素：中国原创化药的代表之作昆药集团天麻素系列产品天麻素是昆药集团的另一大创新成果，不仅被誉为“中药西制”的经典之作，更将中国当时化药研发水平推向了一个新的高度。纵观天麻素制剂40余年临床应用，昆药集团走出了一条中国原创化药的光辉之路，以原研的品质造福了更多的临床患者。头晕和眩晕是常见的临床综合征，也是老年人群就医的前3个主要原因，其发病率高、病程长、易复发，给患者和社会带来了严重的负担。数千年前，天麻就以卓越的药用价值，为无数患者带来了健康与希望。明代著名医学家李时珍在《本草纲目》中详细描述了天麻的神奇功效：“天麻主肝气不足，头晕目眩，为定风神药。”时光流转至20世纪70年代末，昆药集团（昆明制药厂）与中国科学院昆明植物研究所的周俊院士合作，凭借其卓越的科研智慧和不懈的努力，首次从天麻中分离提取出活性物质——天麻素，并成功实现了化学合成。1984年，中国首创天麻素注射液——天眩清正式上市。昆药集团天麻素注射液的研发工作并未止步于上市。昆药集团在后续的40余年中，不断致力于提升产品质量和技术水平。1990年代，昆药集团起草了第一份天麻素国家质量标准，为天麻素制剂的生产提供了科学依据。此后，昆药集团多次承担天麻素注射液国家标准的修订工作，进一步完善了质量控制体系。昆药集团作为天麻素注射液质量标准的修订者，始终将质量把控置于核心地位，其企业内控标准不仅严格遵循国家法定标准，更在此基础上进一步提升，确保产品质量优于国标。药品的纯度和杂质控制率是影响其临床疗效的重要因素，通过严格的质量控制措施，可以确保药品在临床应用中的安全性和有效性，从而为患者提供更可靠的治疗选择。2020年2月，甘肃省药品检验研究院发布天麻素注射液质量评价结果，天眩清质量控制最严，杂质限度控制最窄，品质最优。天眩清品质在同类产品中表现卓越，其原料由昆药集团自产，从源头上保证了产品的高质量。此外，天眩清的有效期长达36个月，显著优于普通天麻素注射液的24个月有效期。这不仅说明其稳定性高，也反映了昆药集团作为天麻素系列产品原研企业在生产工艺和储存条件上的优势，以更好的品质造福临床患者。青蒿：全球疟疾防治的希望之光昆药集团青蒿系列产品青蒿素是中医药献给世界的一份礼物，而昆药集团作为全球第一家青蒿素生产企业、全球最大的抗疟原料药供应商、全球抗疟产品种类最齐全的企业。多年来，昆药集团在青蒿素的研发、生产和推广方面做出了巨大贡献。 20世纪60年代，疟疾在全球肆虐，传统抗疟药物氯喹逐渐失效，人类面临巨大的健康危机。为应对这一挑战，中国启动了代号“523”的抗疟药物研发项目，昆药集团的前身——昆明制药厂，作为全国唯一一家企业参与了这一项目，与60多个科研院所的专家们共同踏上了研制抗疟新药的艰辛之路。目前，昆药集团拥有七个蒿甲醚系列产品品种，并参与起草了5个蒿甲醚系列药品质量标准。这些标准被收载于国际药典，确保了青蒿素产品的高质量和安全性。昆药集团生产的复方蒿甲醚系列药剂已成为全球主要的抗疟药物，蒿甲醚制剂已出口到全球40余个国家和地区，连续13年保持了中国单一药物制剂出口第一的业绩，拯救了全球尤其是发展中国家数千万患者的生命。 2025年1月，昆药集团双氢青蒿素哌喹片(科泰复)成功获得全球基金（TheGlobal Fund to Fight AIDS， Tuberculosis and Malaria）的首次订单。这是昆药在全球公共卫生领域迈出的重要一步，是昆药始终秉持人类命运共同体理念，积极响应“一带一路”倡议。积极践行利他精神的生动例证。未来，昆药集团将以创新为驱动，以质量为保障，为全球抗击疟疾事业持续贡献中国智慧与中国力量，与世界各国携手共进，守护人类的健康福祉。结语昆药集团以血塞通、天麻素和青蒿素制剂三大系列产品为代表，展现了其在医药领域的深厚底蕴和创新精神。从中药现代化到国际化拓展，昆药集团始终坚持以科技创新为核心，不断推动传统中药与现代科技的深度融合。这些成就不仅为患者带来了福音，也为中国医药产业的发展注入了强大动力，成为“国药之光”的杰出代表；诚秉华光风雨兼程，朝夕润泽始得玉成，昆药集团也始终致力于成为老龄健康-慢病管理领导者。昆药集团“三七产业链标杆” “三七创新科技引领者”“天然植物药产业的摇篮” 声明：此篇文章受众仅为医药、医疗等健康产业专业伙伴，仅供医学药学专业人士使用，不针对普通消费大众。

并购

2024-11-29

·CPHI制药在线

抗疟疾药物研发进展

关注并星标CPHI制药在线在全球健康的版图中，疟疾一直是一块难以攻克的“顽疾”。据世界卫生组织（WHO）统计，2021年全球约有2.47亿疟疾病例，61.9万人因此失去生命，其中95%的病例和96%的死亡发生在撒哈拉以南非洲地区。疟疾不仅严重威胁人类健康，还对经济发展造成巨大阻碍，每年导致该地区约120亿美元的经济损失。今天，就让我们深入了解疟疾的现状、抗疟药物的研发进展，以及未来面临的挑战与希望。 1、现有抗疟疗法及耐药困境（1）常用药物与疗法当前，治疗非重症恶性疟原虫疟疾，主要依靠以青蒿素为基础的联合疗法（ACTs）。其中，蒿甲醚 - 苯芴醇（artemether lumefantrine，AL）在非洲市场占据了75%的份额，青蒿琥酯 - 阿莫地喹（artesunate amodiaquine）则作为二线选择，拥有24%的市场占有率。这些药物在一定程度上有效控制了疟疾的发展，但它们也面临着日益严峻的耐药问题。除了ACTs，还有双氢青蒿素 - 哌喹（dihydroartemisinin piperaquine，DHA - PPQ）、阿托伐醌 - 氯胍（atovaquone proguanil，Malarone）等药物组合，但使用相对较少。对于重症疟疾，静脉注射青蒿琥酯（artesunate）是首选治疗方法，金鸡纳霜（quinine）也可作为替代选择。而针对间日疟原虫疟疾的根治，氯喹（Chloroquine）与伯氨喹（primaquine）或他非诺喹（tafenoquine）的联合使用是常见方案；孕期间歇性预防治疗则采用磺胺多辛 - 乙胺嘧啶（sulfadoxine-pyrimethamine，SP）；在非洲的季节性疟疾高发地区，对于6个月至5岁（部分国家至10岁）的儿童，每月使用SP和阿莫地喹进行季节性疟疾化学预防（SMC）（图1）。（2）药物耐药性问题疟原虫耐药问题由来已久，20世纪初有对奎宁耐药的报告，50年代起氯喹和SP耐药性在疟疾流行区扩散，致死亡人数上升。21世纪ACTs虽为一线疗法，但耐药问题仍存。东南亚大部分地区DHA - PPQ因耐药失效，非洲大陆AL虽仍有效，但卢旺达已现青蒿素部分耐药，乌干达恶性疟原虫临床分离株对咯萘啶（pyronaridine）和DHA敏感性降低，这些耐药现象严重威胁全球疟疾防控成效。图1.在疟原虫生命周期下的疟疾治疗来源：出自参考文献【1】 2、抗疟药物研发进展（1）传统与现代的研发策略在抗疟药物研发的漫长历程中，传统策略主要包括从天然产物中分离和修饰活性成分，以及筛选化合物库、设计已知靶点抑制剂等。然而，这种基于天然产物的研发方式面临着诸多挑战，如供应不稳定、成分多变、生物测定引导分馏后复杂混合物相关的实际挑战。此外，对现有天然产物进行改进以克服耐药性的难度较大，这使得研发人员不得不寻求新的方法。随着科学技术的发展，现代抗疟药物研发主要采用表型筛选和基于靶点和虚拟药效团的方法。表型筛选：通过对全细胞寄生虫培养进行大规模化学库筛选，可发现具有新颖作用模式的化合物，许多在研药物由此发现，但靶点未知会给后续优化带来困难。基于靶点和虚拟药效团方法：基于靶点的方法可开发新的生化测定，合理设计化合物，但可能成本高且存在耐药风险；虚拟筛选虽初期成本低，但需大量后续工作确认化合物与靶点的结合及对寄生虫的功能抑制，目前尚未产生具有强细胞活性的新化合物。（2）新靶点及治疗药物为了开发更有效的抗疟药物，科学家们已经发现了一些具有潜力的靶点，如细胞色素B（CytB）、二氢蝶酸合成酶（DHPS）、二氢叶酸还原酶 - 胸苷酸合成酶（DHFR - TS）和血红素等，这些都是已有的临床验证靶点（图2）。此外，还有一些较新的靶点，如ATP酶4（ATP4）、延伸因子2（eEF2）、脯氨酰tRNA合成酶（PRS）和磷脂酰肌醇4 - 激酶（PI4K）等。图2.具有临床验证的抗疟靶点来源：出自参考文献【1】在抗疟药物的研发进程中，众多药物处于不同的研究阶段（图3），给我们带来了新的希望。患者探索阶段： ZY - 19489是一种快速杀伤无性血液阶段寄生虫且耐药倾向低的化合物，在志愿者感染研究中，其安全性、药代动力学和抗疟活性表现优异，支持其进一步开发。 ferroquine是一种含二茂铁基环的4 - 氨基喹啉类药物，具有快速杀伤和长半衰期的特点，与ZY - 19489组合使用，有望实现儿童疟疾的单剂量治疗，为应对ACTs耐药性提供了潜在解决方案。 cabamiquine对寄生虫无性肝、血和性阶段均有活性，但其耐药性发展较快，因此与咯萘啶联用，以增强疗效并延缓耐药性的产生。 ganaplacide对无性肝、血和性阶段的恶性疟原虫均有强效作用，与优化配方的苯芴醇联用，在临床研究中取得了积极结果，有望成为自2000年以来首个非ACT治疗药物。 cipargamin可使寄生虫僵化并快速清除，对传播阻断也有效，但由于存在耐药风险，目前正在探索注射用新配方，以确保其长期有效性。临床I期阶段： atoguanil是阿托伐醌 - 氯胍的新配方，旨在提高药物的疗效和安全性。 MMV688533是通过基于同源性的筛选策略发现的TCP - 1候选药物，其作用机制虽尚未完全明确，但耐药风险低，在实验室条件下难以产生耐药性，目前正在进行临床I期研究。 INE963是诺华发现的快速杀伤化合物，对无性血液阶段寄生虫具有高效作用，且耐药倾向低，近期已进入临床I期试验，后续还将在治疗组合的II期试验中进行评估。临床前阶段：共有11种候选小分子和1种抗体正在深入研究。其中， MMV183是一种抑制AcAS的抗代谢物，具有显著的传播阻断和无性血液阶段活性； GSK701是酰基辅酶A合成酶ACS10和ACS11的新型抑制剂，具有TCP - 1活性特征； WM382和BRD5018分别是 plasmepsins IX和X以及FRS的抑制剂，具有多阶段活性，对寄生虫的多个生命周期阶段均有作用； SC83288是一种新型注射候选药物，用于治疗重症疟疾，但其作用机制尚不清楚； GSK484和IWY357是通过表型筛选发现的快速杀伤化合物，具有低耐药倾向，虽然其结构和作用机制尚未公布，但在抗疟药物研发中具有潜在价值； MMV371是阿托伐醌前药，ELQ - 331是ELQ - 300的口服前药，两者均通过抑制寄生虫CytB发挥作用； S011 - 1793是下一代4 - 氨基喹啉，能够克服氯喹和PPQ耐药性； MMV1793609是PfATP4抑制剂，具有低剂量高效的特点，是2022年发现的备选药物。图3.抗疟药物研发进展和研发管线来源：出自参考文献【1】 3、抗疟之路的未来挑战与展望疟疾防控工作面临着诸多复杂的挑战，疟原虫耐药机制研究复杂，实验室研究多基于单基因变化，但实际临床分离株往往涉及多个突变，且寄生虫遗传背景对耐药性产生的影响机制尚不明确，不同地区疟原虫的遗传差异也导致耐药性表现和传播方式各异。此外，药物递送与药代动力学也存在难题，例如长效注射剂面临疗效持续时间、体积和安全性等挑战，不同人群对药物代谢和反应的差异也增加了研发复杂性...... 尽管挑战重重，但过去15年在疟疾防控方面取得了一定成果，新靶点不断被发现，候选药物进入研发管线，新治疗方法如首个疟疾疫苗获批问世。这些成绩的取得离不开全球各方的紧密合作，未来仍需进一步加强合作，整合资源、加大研发投入、鼓励创新，通过共享数据、技术和经验来加速抗疟药物研发进程，实现疟疾的有效控制和消除。疟疾防控是全球性持久战，每一次突破都使我们向战胜疟疾的目标更近一步，我们应共同关注和支持抗疟工作，期待人类能早日摆脱疟疾威胁。参考文献 [1]Siqueira-Neto, Jair L et al. “Antimalarial drug discovery: progress and approaches.” Nature reviews. Drug discovery vol. 22,10 (2023): 807-826. doi:10.1038/s41573-023-00772-9 [2]Carter, Richard, and Kamini N Mendis. “Evolutionary and historical aspects of the burden of malaria.” Clinical microbiology reviews vol. 15,4 (2002): 564-94. doi:10.1128/CMR.15.4.564-594.2002 [3]Rasmussen, Charlotte et al. “Current and emerging strategies to combat antimalarial resistance.” Expert review of anti-infective therapy vol. 20,3 (2022): 353-372. doi:10.1080/14787210.2021.1962291 END 【智药研习社近期直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

临床研究孤儿药

2024-01-13

·Science Daily

African women living with HIV have an effective option to prevent malaria during pregnancy

In women living with HIV, preventive treatment with DHA-PPQ is a safe and effective strategy to prevent malaria during pregnancy, according to the final results of the MAMAH clinical trial. In women living with HIV, preventive treatment with DHA-PPQ is a safe and effective strategy to prevent malaria during pregnancy, according to the final results of MAMAH, a clinical trial funded by the European & Developing Countries Clinical Trials Partnership (EDCTP) and coordinated by the Barcelona Institute for Global Health (ISGlobal), an institution supported by "la Caixa" Foundation. The study, published in the Lancet Infectious Diseases, could help protect the health of the estimated one million pregnant women who suffer from a double infection with malaria and HIV every year. Pregnant women are particularly vulnerable to malaria infection. Hence the recommendation to offer preventive treatment (IPTp) based on sulphadoxine and pyrimethamine (SP) to pregnant women living in malaria-endemic areas. The problem is that these drugs are incompatible with co-trimoxazole (CTX), an antibiotic given to people with HIV to prevent bacterial infections. "This means that the population most vulnerable to malaria infection and its consequences, namely pregnant women living with HIV, are also the least protected," explains ISGlobal researcher Raquel González, technical coordinator of the MAMAH project, led by Clara Menéndez, director of ISGlobal's Maternal, Child and Reproductive Health Initiative. The aim of the project was to evaluate the safety and efficacy of two other drugs: dihydroartemisinin and piperaquine (DHA-PPQ) to prevent malaria during pregnancy in women living with HIV. The research team conducted the trial in Gabon and Mozambique with more than 600 pregnant women taking CTX in addition to antiretroviral treatment for HIV. One group of pregnant women received DHA-PPQ and the other group received a placebo. Lower risk of malaria infection and disease Although there was no significant difference in malaria infection at the time of delivery, women in the DHA-PPQ group had a significantly lower risk of developing clinical malaria throughout pregnancy (almost eight times lower than the placebo group) and also a lower risk (almost half) of becoming infected. DHA-PPQ was effective in women taking different antiretroviral treatments. No serious side effects were observed, and DHA-PPQ had no effect on mother-to-child transmission of HIV. "We show that preventive treatment with DHA-PPQ is effective even in low malaria transmission settings," says Gonzalez. "Adding this strategy to malaria control tools could significantly improve the health of thousands of mothers and their babies, especially in sub-Saharan Africa, a region where an estimated one million women living with HIV are infected with malaria during pregnancy every year," she adds. "We congratulate the MAMAH team on these important results in the field of malaria research, and, in particular, in providing better health to pregnant women living with HIV in malaria-endemic areas," says Montserrat Blázquez-Domingo, EDCTP Senior Project Officer. "This study underlines the value of collaborative research that EDCTP supports and our focus on priority infectious disease affecting sub-Saharan Africa in populations often excluded from clinical trials -- such as pregnant women." The MAMAH study is part of the EDCTP2 Programme supported by the European Union (grant number RIA2016MC-1613-MAMAH).

临床结果临床研究

100 项与双氢青蒿素哌喹相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
-	双氢青蒿素哌喹	P01BF05	-

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适应症	国家/地区	公司	日期
恶性疟	中国	贝克诺顿（浙江）制药有限公司	2004-12-07

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适应症	最高研发状态	国家/地区	公司	日期
间日疟原虫感染	临床3期	巴西	-	2018-07-05

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04487145 (DPART, CTgov)	临床4期	药物相互作用 \| HIV感染	194	Dihydroartemisinin-piperaquine (HIV-infected Children on EFV-based ART (E3))	淵窪醖窪齋願製醖餘積(鹽顧淵簾夢鹹齋艱製衊) = 艱齋築餘襯醖遞憲築淵廠鑰襯醖淵醖鏇遞蓋繭 (製齋齋製醖糧簾鏇窪繭, 簾壓選獵製齋醖夢醖蓋 ~ 獵積醖範醖襯顧齋製範) 更多	-	2025-03-14
				Dihydroartemisinin-piperaquine (HIV-infected Children on DTG-based ART (D3))	淵窪醖窪齋願製醖餘積(鹽顧淵簾夢鹹齋艱製衊) = 齋淵壓鹹鑰醖壓窪簾膚廠鑰襯醖淵醖鏇遞蓋繭 (製齋齋製醖糧簾鏇窪繭, 蓋鏇鏇廠餘製鹽願獵鑰 ~ 構築積選繭構夢觸窪夢) 更多
NCT03178643 (EPiTOMISE, CTgov)	临床4期	恶性疟 \| 镰状细胞血症	246	Proguanil Oral Tablet (Proguanil Oral Tablet)	餘網鏇憲憲鏇艱鬱齋襯 = 鬱製顧膚襯餘艱壓獵襯鹽餘鏇壓艱繭憲壓築廠 (網構窪醖窪壓鏇獵窪淵, 夢膚夢鹹壓鏇鏇鑰膚鑰 ~ 鬱鑰糧餘觸獵願餘築膚) 更多	-	2024-03-27
				Sulfadoxine/pyrimethamine+Amodiaquin (Sulfadoxine/Pyrimethanine-Amodiaquine)	餘網鏇憲憲鏇艱鬱齋襯 = 選範艱鬱餘鬱鏇選艱餘鹽餘鏇壓艱繭憲壓築廠 (網構窪醖窪壓鏇獵窪淵, 窪獵醖淵憲繭壓憲鬱衊 ~ 鏇製築夢衊鹹積淵簾廠) 更多
NCT00852371 (CTgov)	临床3期	疟疾	780	Dihydroartemisinin-Piperaquine (Dihydroartemisinin-piperaquine)	積壓範鏇衊構糧網顧蓋 = 鹽鹽鏇範淵網蓋糧鏇窪構糧蓋夢願醖網願衊襯 (顧製構獵蓋遞遞窪餘憲, 廠齋鏇獵膚憲遞窪醖窪 ~ 醖窪網壓鑰廠憲醖廠壓) 更多	-	2024-03-21
				sulfadoxine-pyrimethamine+amodiaquine (Combination of Amodiaquine +Sulfadoxine-pyrimethamine)	積壓範鏇衊構糧網顧蓋 = 鑰醖憲窪艱衊齋簾觸鬱構糧蓋夢願醖網願衊襯 (顧製構獵蓋遞遞窪餘憲, 壓顧鏇艱簾齋膚積積衊 ~ 觸獵醖壓選醖鏇構憲窪) 更多
NCT04158713 (Pubmed \| Lancet) 人工标引	临床3期	疟疾 HIV	895	Co-trimoxazole p dihydroartemisinin-piperaquineine	餘製齋鏇鬱餘餘醖積窪(鬱醖壓衊築齋壓範齋繭) = 醖艱淵衊網網齋壓壓廠鏇繭鹹鏇廠積糧夢鏇鬱 (鹽構觸廠鬱廠顧遞範願 ) 更多	积极	2024-01-01
				Co-trimoxazole plus placebo	餘製齋鏇鬱餘餘醖積窪(鬱醖壓衊築齋壓範齋繭) = 選遞蓋顧蓋構壓顧蓋鹹鏇繭鹹鏇廠積糧夢鏇鬱 (鹽構觸廠鬱廠顧遞範願 ) 更多
NCT02793622 (Pubmed \| Clin Infect Dis)	临床3期	-	782	Dihydroartemisinin-piperaquine (DHA-PQ)	壓網糧製鑰繭範築繭憲(選範鑰獵顧顧餘鹹醖壓) = Nine women given DHA-PQ had grade 3-4 cardiac adverse events 鏇鏇遞糧醖製簾範鹽鑰 (範積鬱淵艱繭遞鏇構網 )	-	2021-12-02
NCT02163447 (Pubmed \| Nat Commun)	临床3期	疟疾	300	DP every 4 weeks	網顧窪獵願齋鏇夢夢餘(鹽窪簾願衊願鏇積構膚) = 壓繭蓋膚範窪鬱壓鹽願網淵蓋構膚積願艱鏇願 (願蓋艱遞獵鹽餘齋鏇糧 ) 更多	-	2021-11-18
NCT01054248 (Pubmed \| BMC Med)	临床3期	妊娠期感染性疾病	511	Dihydroartemisinin-piperaquine (DP)	顧獵製鑰衊壓壓憲夢鑰(願鬱構窪淵壓構糧遞餘) = 遞製夢製構窪鹽鹹鑰鏇簾夢遞簾選鹹構餘淵簾 (廠齋鑰簾鏇壓選觸鹽齋, 81.6 ~ 97.9) 更多	-	2021-06-10
				Artesunate-mefloquine (ASMQ)	顧獵製鑰衊壓壓憲夢鑰(願鬱構窪淵壓構糧遞餘) = 網襯願餘願鑰遞鹹遞鏇簾夢遞簾選鹹構餘淵簾 (廠齋鑰簾鏇壓選觸鹽齋, 66.1 ~ 88.1)
NCT02315690 (Pubmed \| BMJ Glob Health)	临床3期	疟疾	4,000	Reactive focal mass drug administration (rfMDA) using dihydroartemisinin-piperaquine	網製醖構鬱鬱窪範遞襯(襯艱餘夢衊願鏇顧鏇膚) = 網膚齋鏇膚鹽襯壓憲壓餘窪膚鹹醖壓獵衊糧衊 (窪顧艱遞憲積築範齋顧, 1.00 ~ 1.67)	-	2021-06-01
				Reactive case detection (RACD) involving RDTs and artemether-lumefantrine	網製醖構鬱鬱窪範遞襯(襯艱餘夢衊願鏇顧鏇膚) = 廠築網鑰憲憲憲餘艱獵餘窪膚鹹醖壓獵衊糧衊 (窪顧艱遞憲積築範齋顧, 0.71 ~ 1.34)
NCT02793622 (PROMOTE-BC3, CTgov)	临床3期	疟疾	782	Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy (Monthly Sulfadoxine-Pyrimethamine (SP) During Pregnancy)	壓淵願鏇夢糧淵衊鬱網 = 簾窪憲膚壓獵觸選遞膚醖鬱壓選憲鬱鑰鏇鹹蓋 (艱蓋鑰鹽蓋鑰網蓋衊齋, 積淵鹽觸齋鏇襯夢選夢 ~ 鏇選鹽醖範網鹹範艱鹽) 更多	-	2021-04-14
				Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy (Monthly Dihydroartemisinin-Piperaquine (DP) During Pregnancy)	壓淵願鏇夢糧淵衊鬱網 = 淵窪餘繭蓋衊築糧簾夢醖鬱壓選憲鬱鑰鏇鹹蓋 (艱蓋鑰鹽蓋鑰網蓋衊齋, 襯鑰鹹簾廠衊鑰蓋襯築 ~ 顧繭齋鏇繭餘網顧鹹簾) 更多
NCT02793622 (Pubmed \| BMC Med)	临床3期	妊娠期感染性疾病	782	Dihydroartemisinin-piperaquine	積艱淵獵膚醖廠醖簾選(衊壓築衊憲選糧蓋夢餘) = 積衊廠選鏇衊顧壓窪鑰積衊淵範餘鬱夢壓醖顧 (鹽蓋壓鹹觸蓋艱遞簾蓋 )	-	2020-08-10
				Sulfadoxine-pyrimethamine	積艱淵獵膚醖廠醖簾選(衊壓築衊憲選糧蓋夢餘) = 衊鏇顧遞願築壓衊鏇選積衊淵範餘鬱夢壓醖顧 (鹽蓋壓鹹觸蓋艱遞簾蓋 )