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Stable Artesunate Resistance in A Humanized Mouse Model of Plasmodium falciparum 恶性疟原虫人源化小鼠模型青蒿琥酯稳定耐药性的研究
Pub Date : 2021-10-12 DOI: 10.5772/intechopen.100381
S. Saini, Rajinder Kumar, R. Tyagi
Plasmodium falciparum, the most devastating human malaria parasite, confers higher morbidity and mortality. Although efforts have been made to develop an effective malaria vaccine, stage- and species-specific short-lived immunity crippled these efforts. Hence, antimalarial drug treatment becomes a mainstay for the treatment of malaria infection in the wake of the unavailability of an effective vaccine. Further, there has been a wide array of antimalarial drugs effective against various developmental stages of P. falciparum due to their different structures, modes of action, and pharmacodynamics as well as pharmacokinetics. The development of resistance against almost all frontline drugs by P. falciparum indicates the need for combination therapy (artemisinin-based combination therapy; ACT) to treat patients with P. falciparum. A higher pool of parasitemia under discontinuous in vivo artemisinin drug pressure in a developed humanized mouse allows the selection of artesunate resistant (ART-R) P. falciparum. Intravenously administered artesunate, using either single flash doses or a 2-day regimen, to the P. falciparum-infected human blood chimeric NOD/SCID.IL-2Rγ−/− immunocompromised (NSG) mice, with progressive dose increments upon parasite recovery, was the strategy deployed to select resistant parasites. Parasite susceptibility to artemisinins and other antimalarial compounds was characterized in vitro and in vivo. P. falciparum has shown to evolve extreme artemisinin resistance as well as co-resistance to antimalarial drugs. Overall, the present information shall be very useful in devising newer therapeutic strategies to treat human malaria infection.
恶性疟原虫是最具破坏性的人类疟疾寄生虫,具有较高的发病率和死亡率。尽管为研制有效的疟疾疫苗作出了努力,但针对阶段和物种的短期免疫削弱了这些努力。因此,在没有有效疫苗的情况下,抗疟疾药物治疗成为治疗疟疾感染的主要手段。此外,由于其不同的结构、作用方式、药效学和药代动力学,已经有多种抗疟药物对恶性疟原虫的不同发育阶段有效。恶性疟原虫对几乎所有一线药物的耐药性的发展表明需要联合治疗(以青蒿素为基础的联合治疗;以治疗恶性疟原虫患者。在发达的人源化小鼠体内不连续的青蒿素药物压力下,较高的寄生虫血症池允许选择青蒿琥酯耐药(ART-R)恶性疟原虫。静脉注射青蒿琥酯,使用单次快速剂量或2天方案,对恶性疟原虫感染的人血液嵌合NOD/SCID。IL-2Rγ−/−免疫功能受损(NSG)小鼠,在寄生虫恢复后逐渐增加剂量,是选择耐药寄生虫的策略。在体外和体内研究了寄生虫对青蒿素和其他抗疟药物的敏感性。恶性疟原虫已显示出对青蒿素的极端耐药性以及对抗疟疾药物的共同耐药性。总的来说,目前的信息对于制定治疗人类疟疾感染的新治疗策略将非常有用。
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引用次数: 0
Molecular Approaches for Malaria Therapy 疟疾治疗的分子方法
Pub Date : 2021-07-28 DOI: 10.5772/intechopen.98396
Mitali Mishra, V. Mishra, Varsha Kashaw, S. Kashaw
Malaria is a potentially fatal blood disease spread by mosquitos. Malaria is preventable, but it is more prevalent in developing countries where prevention is difficult and prophylaxis is often inaccessible. Malaria remains one of the world’s most serious public health problems, according to the World Health Organisation (WHO). The development of resistance is a current problem that poses a danger to the environment. Resistance is a current problem that could jeopardise the use of well-established and cost-effective antimalarials. The World Health Organisation recommends an artemisinin-based drug combination (ACT) to avoid or postpone the development of resistance. This book’s chapter discusses current medicines as well as potential and rational possibilities for finding new drugs to treat malady. There were also WHO recommendations for both complicated and non-complicated malaria. Other preventive measures such as ITN and IPT are listed in the manuscript in addition to routine care. While a brief overview of the vaccine tested so far has been included, there is currently no vaccine available to treat malaria.
疟疾是一种由蚊子传播的潜在致命血液疾病。疟疾是可以预防的,但它在发展中国家更为普遍,那里预防困难,而且往往无法获得预防。据世界卫生组织(WHO)称,疟疾仍然是世界上最严重的公共卫生问题之一。耐药性的发展是当前的一个问题,对环境构成了威胁。耐药性是当前的一个问题,可能危及使用行之有效且具有成本效益的抗疟药。世界卫生组织建议使用一种以青蒿素为基础的药物组合(ACT)来避免或延缓耐药性的发展。这本书的章节讨论了现有的药物以及潜在的和合理的可能性,以寻找新的药物来治疗疾病。世卫组织还对复杂和非复杂疟疾提出了建议。除常规护理外,手稿中还列出了其他预防措施,如ITN和IPT。虽然已对迄今所测试的疫苗作了简要概述,但目前尚无可用于治疗疟疾的疫苗。
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引用次数: 1
P. falciparum and Its Molecular Markers of Resistance to Antimalarial Drugs 恶性疟原虫及其抗疟药物耐药分子标记
Pub Date : 2021-07-08 DOI: 10.5772/INTECHOPEN.98372
Peter Hodoameda
The use of molecular markers of resistance to monitor the emergence, and the spread of parasite resistance to antimalarial drugs is a very effective way of monitoring antimalarial drug resistance. The identification and validation of molecular markers have boosted our confidence in using these tools to monitor resistance. For example, P. falciparum chloroquine resistance transporter (PfCRT), P. falciparum multidrug resistance protein 1 (PfMDR1), P. falciparum multidrug kelch 13 (pfk13), have been identified as molecular markers of resistance to chloroquine, lumefantrine, and artemisinin respectively. The mechanism of resistance to antimalarial drugs is mostly by; (1) undergoing mutations in the parasite genome, leading to expelling the drug from the digestive vacuole, or (2) loss of binding affinity between the drug and its target. Increased copy number in the pfmdr1 gene also leads to resistance to antimalarial drugs. The major cause of the widespread chloroquine and sulfadoxine-pyrimethamine resistance globally is the spread of parasites resistant to these drugs from Southeast Asia to Africa, the Pacific, and South America. Only a few mutations in the parasite genome lead to resistance to chloroquine and sulfadoxine-pyrimethamine arising from indigenous parasites in Africa, Pacific, and South America.
利用耐药分子标记监测寄生虫对抗疟药物耐药性的出现和传播是一种非常有效的监测抗疟药物耐药性的方法。分子标记的鉴定和验证增强了我们使用这些工具监测耐药性的信心。例如,恶性疟原虫氯喹耐药转运蛋白(PfCRT)、恶性疟原虫多药耐药蛋白1 (PfMDR1)、恶性疟原虫多药kelch 13 (pfk13)已分别被鉴定为对氯喹、氨苯曲明和青蒿素耐药的分子标记。抗疟药耐药的机制主要是由;(1)寄生虫基因组发生突变,导致药物从消化液泡中排出,或(2)药物与靶标之间失去结合亲和力。pfmdr1基因拷贝数的增加也会导致对抗疟疾药物产生耐药性。全球普遍存在氯喹和磺胺多辛-乙胺嘧啶耐药性的主要原因是对这些药物具有耐药性的寄生虫从东南亚传播到非洲、太平洋和南美洲。在非洲、太平洋和南美洲,只有少数寄生虫基因组突变导致对氯喹和磺胺多辛-乙胺嘧啶产生耐药性。
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引用次数: 1
Drug Design for Malaria with Artificial Intelligence (AI) 基于人工智能(AI)的疟疾药物设计
Pub Date : 2021-07-07 DOI: 10.5772/INTECHOPEN.98695
B. Ghosh, Soham Choudhuri
Malaria is a deadly disease caused by the plasmodium parasites. Approximately 210 million people get affected by malaria every year resulting in half a million deaths. Among several species of the parasite, Plasmodium falciparum is the primary cause of severe infection and death. Several drugs are available for malaria treatment in the market but plasmodium parasites have successfully developed resistance against many drugs over the years. This poses a serious threat to efficacy of the treatments and continuing discovery of new drug is necessary to tackle the situation, especially due to failure in designing an effective vaccine. People are now trying to design new drugs for malaria using AI technologies which can substantially reduce the time and cost required in classical drug discovery programs. In this chapter, we provide a comprehensive overview of a road map for several AI based computational techniques which can be implemented in a malaria drugs discovery program. Classical computers has limiting computing power. So, researchers are also trying to harness quantum machine learning to speed up the drug discovery processes.
疟疾是一种由疟原虫引起的致命疾病。每年约有2.1亿人感染疟疾,造成50万人死亡。在几种寄生虫中,恶性疟原虫是导致严重感染和死亡的主要原因。市场上有几种治疗疟疾的药物,但疟原虫多年来已经成功地对许多药物产生了耐药性。这对治疗的效力构成严重威胁,必须继续发现新的药物来解决这一问题,特别是由于未能设计出有效的疫苗。人们现在正试图利用人工智能技术设计新的疟疾药物,这可以大大减少传统药物发现项目所需的时间和成本。在本章中,我们全面概述了几种基于人工智能的计算技术的路线图,这些技术可以在疟疾药物发现计划中实现。传统计算机的计算能力有限。因此,研究人员也在试图利用量子机器学习来加速药物发现过程。
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引用次数: 2
Malaria: Introductory Concepts, Resistance Issues and Current Medicines 疟疾:介绍概念、耐药性问题和当前药物
Pub Date : 2021-07-04 DOI: 10.5772/INTECHOPEN.98725
Dejen Nureye
Malaria continues to be the main community health problem in numerous nations. Six species of Plasmodium are documented as the cause of human malaria infection. Among others, Plasmodium falciparum and Plasmodium vivax parasites produce an immense challenge in the public health. Anopheles funestus and Anopheles gambiae are the major transimmiter of the disease (malaria) from one person to another. The disease parasite has a complicated cycle of life that occurs in human and mosquitoes. In general, malaria diagnosis is divided into parasitological and clinical diagnosis. Internationally, the death rate of malaria becomes reduced although few records from Ethiopia describe the presence of raised prevalence of malaria in certain areas. Apart from reduction in incidence and prevalence, transmission of malaria is continued throughout the globe. Hence, its control needs a combined approach comprising treatment with effective antimalarial agents. A lot of novel compounds are under pre-clinical and clinical studies that are triggered by the occurrence of resistance among commonly used antimalarial drugs. In addition to the already known new compounds and targets for drug discovery, scientists from all corner of the world are in search of novel targets and chemical entities.
疟疾仍然是许多国家主要的社区卫生问题。六种疟原虫被记录为人类疟疾感染的原因。其中,恶性疟原虫和间日疟原虫对公共卫生构成巨大挑战。funestus按蚊和冈比亚按蚊是这种疾病(疟疾)在人与人之间的主要传播者。这种疾病寄生虫在人类和蚊子中有一个复杂的生命周期。一般来说,疟疾诊断分为寄生虫学诊断和临床诊断。在国际上,疟疾的死亡率有所下降,尽管埃塞俄比亚很少有记录说明某些地区的疟疾流行率有所上升。除了发病率和流行率下降之外,疟疾在全球的传播仍在继续。因此,控制疟疾需要一种综合方法,包括使用有效的抗疟药进行治疗。许多新化合物正在临床前和临床研究中,这些化合物是由常用抗疟药的耐药性引起的。除了已知的新化合物和新靶点之外,世界各地的科学家都在寻找新的靶点和化学实体。
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引用次数: 2
Plasmodium Species and Drug Resistance 疟原虫种类与耐药性
Pub Date : 2021-06-23 DOI: 10.5772/intechopen.98344
Sintayehu Tsegaye Tseha
Malaria is a leading public health problem in tropical and subtropical countries of the world. In 2019, there were an estimated 229 million malaria cases and 409, 000 deaths due malaria in the world. The objective of this chapter is to discuss about the different Plasmodium parasites that cause human malaria. In addition, the chapter discusses about antimalarial drugs resistance. Human malaria is caused by five Plasmodium species, namely P. falciparum, P. malariae, P. vivax, P. ovale and P. knowlesi. In addition to these parasites, malaria in humans may also arise from zoonotic malaria parasites, which includes P. inui and P. cynomolgi. The plasmodium life cycle involves vertebrate host and a mosquito vector. The malaria parasites differ in their epidemiology, virulence and drug resistance pattern. P. falciparum is the deadliest malaria parasite that causes human malaria. P. falciparum accounted for nearly all malarial deaths in 2018. One of the major challenges to control malaria is the emergence and spread of antimalarial drug-resistant Plasmodium parasites. The P. vivax and P. falciparum have already developed resistance against convectional antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine, and atovaquone. Chloroquine-resistance is connected with mutations in pfcr. Resistance to Sulfadoxine and pyrimethamine is associated with multiple mutations in pfdhps and pfdhfr genes. In response to the evolution of drug resistance Plasmodium parasites, artemisinin-based combination therapies (ACTs) have been used for the treatment of uncomplicated falciparum malaria since the beginning of 21th century. However, artemisinin resistant P. falciparum strains have been recently observed in different parts of the world, which indicates the possibility of the spread of artemisinin resistance to all over the world. Therefore, novel antimalarial drugs have to be searched so as to replace the ACTs if Plasmodium parasites develop resistance to ACTs in the future.
疟疾是世界热带和亚热带国家的主要公共卫生问题。2019年,全世界估计有2.29亿疟疾病例,40.9万人死于疟疾。本章的目的是讨论引起人类疟疾的不同疟原虫。此外,本章还讨论了抗疟药耐药性问题。人类疟疾是由五种疟原虫引起的,即恶性疟原虫、疟疾疟原虫、间日疟原虫、卵形疟原虫和诺氏疟原虫。除这些寄生虫外,人患疟疾也可能由人畜共患疟疾寄生虫引起,其中包括犬疟原虫和食蟹疟原虫。疟原虫的生命周期包括脊椎动物宿主和蚊子载体。疟疾寄生虫的流行病学、毒力和耐药模式各不相同。恶性疟原虫是导致人类疟疾的最致命的疟疾寄生虫。2018年,恶性疟原虫几乎占了所有疟疾死亡人数。控制疟疾的主要挑战之一是抗疟药疟原虫的出现和传播。间日疟原虫和恶性疟原虫已经对氯喹、磺胺多辛-乙胺嘧啶和阿托伐醌等常规抗疟药物产生了耐药性。氯喹耐药性与pfcr突变有关。对磺胺多辛和乙胺嘧啶的抗性与pfdhps和pfdhfr基因的多重突变有关。为应对疟原虫耐药性的演变,自21世纪初以来,以青蒿素为基础的联合疗法已被用于治疗无并发症的恶性疟疾。然而,最近在世界不同地区发现了耐青蒿素恶性疟原虫菌株,这表明青蒿素耐药性有可能在世界各地蔓延。因此,如果将来疟原虫对ACTs产生耐药性,必须寻找新的抗疟药物来替代ACTs。
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引用次数: 7
Regulation of T-reg/Th-17 Balance: One Step Closer Towards Immunotherapy Against Malaria Infection T-reg/Th-17平衡调节:向疟疾感染免疫治疗迈进了一步
Pub Date : 2021-06-21 DOI: 10.5772/intechopen.97045
S. Mukherjee, Soubhik Ghosh, A. Bhattacharyya
According to World Malaria Report 2020, the rate of decline in malaria case incidence and deaths caused by malaria has ceased in latter half of the past decade. Though Artemisinin Combination Therapy (ACT) is still the major therapeutic approach globally to treat malaria patients, increased resistance of Plasmodium sp. to artemisinin can be looked upon as a major factor responsible for the rate of decline. In the present world, immunotherapeutic approaches are in the limelight to treat several infections, autoimmune disorders, cancers but application of such therapeutic measures in case of malaria are yet not available. Among different immune cells, T-regulatory cells (T-reg) and Th-17 cells and the balance between them, helps in determining the outcome of the immune response in host during both lethal and non-lethal malaria. TGFβ and IL-6 are two major cytokines that play important role in fine tuning the Treg/Th-17 balance by modulating dendritic cell responses, specially by regulating the ratio between myeloid DC and plasmacytoid DC (mDC/pDC). Studies in rodent malaria models have revealed that neutralization of IL-6 by using anti IL-6 monoclonal antibodies in-vivo has been found effective in declining the parasitemia, malaria induced deaths and also in reverting back the altered T-reg/Th-17 balance to normal levels. Apart from these, autophagy is one of the major factors which also contributes to regulate the T-reg/Th-17 balance. In malaria infected mice, autophagy induction has been found to normalise the dysregulated T-reg/Th-17 ratio and promote anti-inflammatory Th-2 pathway by supressing pro-inflammatory Th-1 pathway. So, Treg/Th-17 balance and its associated regulators can be important immunotherapeutic targets for malaria prevention in near future.
根据《2020年世界疟疾报告》,在过去十年的后半期,疟疾病例发病率和疟疾造成的死亡的下降速度已经停止。尽管青蒿素联合疗法(ACT)仍是全球治疗疟疾患者的主要治疗方法,但疟原虫对青蒿素的耐药性增强可被视为导致发病率下降的一个主要因素。在当今世界,免疫治疗方法是治疗几种感染、自身免疫性疾病和癌症的焦点,但这种治疗措施在疟疾病例中的应用尚不存在。在不同的免疫细胞中,t调节细胞(T-reg)和Th-17细胞及其之间的平衡有助于确定致死性和非致死性疟疾期间宿主免疫反应的结果。TGFβ和IL-6是两种主要的细胞因子,通过调节树突状细胞反应,特别是通过调节髓细胞DC和浆细胞DC (mDC/pDC)的比例,在微调Treg/Th-17平衡中发挥重要作用。在啮齿动物疟疾模型中进行的研究表明,体内使用抗IL-6单克隆抗体中和IL-6可有效降低寄生虫病和疟疾引起的死亡,并使改变的T-reg/Th-17平衡恢复到正常水平。除此之外,自噬也是调节T-reg/Th-17平衡的主要因素之一。在疟疾感染小鼠中,自噬诱导已被发现使失调的T-reg/Th-17比率正常化,并通过抑制促炎Th-1途径促进抗炎Th-2途径。因此,Treg/Th-17平衡及其相关调节因子可能成为近期疟疾预防的重要免疫治疗靶点。
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引用次数: 1
Recent Advances in Antimalarial Drug Discovery: Challenges and Opportunities 抗疟药物发现的最新进展:挑战与机遇
Pub Date : 2021-06-21 DOI: 10.5772/intechopen.97401
Imrat, A. Verma, P. R. Mina
Malaria is a global health problem that needs attention from drug discovery scientists to investigate novel compounds with high drug efficacy, safety and low cost to encounter the malaria parasites that are resistant to existing drug molecules. Antimalarial drug development follows several approaches, ranging from modifications of existing agents to the design of novel agents that act against novel targets. Most of market and clinical drugs act on blood schizonticide are in current therapy for malaria reduction. This chapter will intend to highlight the currently available drugs including various novel agents. In addition, emphasis has been given on the prospective pharmacophores that are likely to emerge as effective clinical candidates in the treatment of malaria. Besides all aspects, some alternative approaches will also be highlight.
疟疾是一个全球性的健康问题,需要药物发现科学家的关注,研究具有高药效、安全性和低成本的新型化合物,以对抗对现有药物分子具有耐药性的疟疾寄生虫。抗疟药物的开发遵循几种方法,从修改现有药物到设计针对新靶点的新药物。目前市面上和临床上的大部分药物都是用于治疗疟疾的。本章将重点介绍目前可用的药物,包括各种新型药物。此外,还强调了可能成为治疗疟疾的有效临床候选药物的潜在药效团。除了所有方面,一些替代方法也将是重点。
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引用次数: 4
Adaptive Drug Resistance in Malaria Parasite: A Threat to Malaria Elimination Agenda? 疟原虫的适应性耐药性:对消除疟疾议程的威胁?
Pub Date : 2021-06-04 DOI: 10.5772/INTECHOPEN.98323
M. Okpeku
Malaria is a global disease of importance, especially in the sub-Saharan African region, where malaria accounts for great losses economically and to life. Fight to eliminate this disease has resulted in reduced disease burden in many places where the diseases is endemic. Elimination strategies in most places is focus on the use of treated nets and drug application. Exposure of malaria parasites to anti-malaria drugs have led to the evolution of drug resistance in both parasites and host. Development of drug resistance vary but, studies on adaptive drug resistance has implications and consequences. Our knowledge of this consequences are limited but important for the pursuit of an uninterrupted malaria elimination agenda. This chapter draws our attention to this risks and recommends interventions.
疟疾是一种重要的全球疾病,特别是在撒哈拉以南非洲区域,疟疾造成了巨大的经济和生命损失。为消除这一疾病而进行的斗争减少了许多疾病流行地区的疾病负担。大多数地方的消除战略侧重于使用处理过的蚊帐和使用药物。疟疾寄生虫暴露于抗疟疾药物导致寄生虫和宿主的耐药性进化。耐药的发展各不相同,但适应性耐药的研究具有重要的意义和意义。我们对这一后果的了解有限,但对实现不间断的消除疟疾议程很重要。本章提请我们注意这些风险,并建议采取干预措施。
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引用次数: 0
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Plasmodium Species and Drug Resistance [Working Title]
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