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Vaccines for Human Leishmaniasis: Where Do We Stand and What Is Still Missing? 人类利什曼病疫苗:我们做了什么,还有什么缺失?
Pub Date : 2018-10-10 DOI: 10.5772/INTECHOPEN.75000
P. Cecílio, Fabiano Oliveira, Anabela Cordeiro da Silva
Responsible for up to 30,000 deaths annually, leishmaniasis is a complex spectrum of diseases endemic in 97 countries around the globe. Disease control relies heavily on the early diagnosis and treatment of the active cases (relevant for anthroponotic disease), although it is widely accepted that a prophylactic vaccine for human leishmaniasis is the way to achieve the successful elimination of human disease (taking in consideration the vast list of non-human reservoirs that enable the perpetuation of parasites all around the globe). The notion that infection leads to strong and long-lasting immunity against leishmaniasis supports vaccination as an achievable goal. However, and in spite of the different candidates tested along the years, till date, we still do not have an approved vaccine for humans. In this chapter, we will explore the last advances made in the field of vaccines against Leishmania without forgetting the historical perspective, essential to the understanding of the road already undergone. We will then discuss the correlates of disease and protection, still neither consensual nor definitive, as well as the issue of pre-clinical to clinical translation. The complete understanding of these issues will be essential for the approval of a successful vaccine for human leishmaniasis.
利什曼病每年造成多达3万人死亡,是全球97个国家流行的一系列复杂疾病。疾病控制在很大程度上依赖于活动性病例(与人源性疾病有关)的早期诊断和治疗,尽管人们普遍认为,人类利什曼病的预防性疫苗是成功消除人类疾病的途径(考虑到使寄生虫在全球各地长期存在的大量非人类宿主)。感染可导致对利什曼病产生强大而持久的免疫力,这一概念支持疫苗接种是一个可实现的目标。然而,尽管多年来测试了不同的候选疫苗,但到目前为止,我们仍然没有批准用于人类的疫苗。在本章中,我们将探讨利什曼原虫疫苗领域取得的最新进展,同时不忘记历史观点,这对理解已经经历的道路至关重要。然后我们将讨论疾病和保护的相关性,仍然不是共识或明确的,以及临床前到临床转化的问题。对这些问题的全面了解对于成功批准人类利什曼病疫苗至关重要。
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引用次数: 17
3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGR) Enzyme of the Sterol Biosynthetic Pathway: A Potential Target against Visceral Leishmaniasis 甾醇生物合成途径的3-羟基-3-甲基戊二酰辅酶A还原酶(HMGR):对抗内脏利什曼病的潜在靶点
Pub Date : 2018-10-10 DOI: 10.5772/INTECHOPEN.75480
Sushma Singh, N. Babu
Sterol biosynthetic pathway is explored for its therapeutic potential for Visceral Leish­ maniasis. In Leishmania , this pathway produces ergosterol which is absent in host and there­ fore is a promising strategy to combat proliferation of both extracellular and intracellular forms of the parasite with minimal host toxicity. The present chapter focuses on 3­hydroxy­ 3­methylglutaryl­CoA reductase (HMGR) enzyme which is the rate­limiting enzyme of the ergosterol biosynthesis. HMGR gene of L. donovani was biochemically and biophysically characterized for the first time. HMGR over expressing transgenic parasites were generated to evaluate its role in parasite growth and infection ability. A series of statins like atorvas ­ tatin, simvastatin and mevastatin were evaluated for its therapeutic efficacy and mode of action elucidated. Atorvastatin and mevastatin were found to be killing both the promas ­ tigote and amastigote forms of the parasite without exhibiting host cytotoxicity. Besides, non-statin class of molecules like resveratrol and glycyrrhizic acid were also analyzed for antileishmanial potential. Two antidepressants, ketanserin and mianserin were found to kill both L. donovani promastigotes and intracellular amastigotes with no apparent toxicity to the host cells. Since targeting of the sterol biosynthetic pathway enzymes may be useful therapeutically, the present work may have implications in treatment of Leishmaniasis. The present review encompasses functional characterization of L. donovani HMGR enzyme and the evaluation of the effect of various HMGR inhibitors as potential candidates for treat ­ ment of Leishmaniasis. Inhibitors which showed inhibition of both the extracellular and intra­ cellular forms of the parasites at low micromolar range with no cytotoxicity to host cells are promising antileishmanial candidates. They can be further explored in an experimental ani­ mal model of VL to evaluate its anti-VL efficacy.
探讨甾醇生物合成途径对内脏利什-狂躁症的治疗潜力。在利什曼原虫中,这种途径产生麦角甾醇,而这种麦角甾醇在宿主中是不存在的,因此是一种很有希望的策略,可以以最小的宿主毒性对抗寄生虫的细胞外和细胞内形式的增殖。3 -羟基- 3 -甲基戊二酰辅酶a还原酶(HMGR)是麦角甾醇生物合成的限速酶。首次对多诺瓦菌HMGR基因进行了生物化学和生物物理表征。制备过表达HMGR的转基因寄生虫,评价其对寄生虫生长和侵染能力的影响。评价了阿托伐他汀、辛伐他汀、美伐他汀等一系列他汀类药物的疗效,并阐明了其作用方式。研究发现,阿托伐他汀和美伐他汀可同时杀死原鞭毛体和无鞭毛体形式的寄生虫,而不表现出宿主细胞毒性。此外,还分析了非他汀类分子如白藜芦醇和甘草酸的抗利什曼潜能。两种抗抑郁药酮色林和米安色林均可杀灭多诺瓦氏L. promastigotes和细胞内无尾线虫,且对宿主细胞无明显毒性。由于靶向甾醇生物合成途径酶可能是有用的治疗,目前的工作可能对利什曼病的治疗有意义。本文综述了多诺瓦氏L. HMGR酶的功能表征和各种HMGR抑制剂作为治疗利什曼病的潜在候选药物的效果评价。在低微摩尔范围内对寄生虫的细胞外和细胞内形式均有抑制作用且对宿主细胞无细胞毒性的抑制剂是有希望的抗利什曼原虫候选药物。它们可以在VL的实验动物模型中进一步探索,以评估其抗VL的功效。
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引用次数: 3
Nanomedicines for Cutaneous Leishmaniasis 皮肤利什曼病的纳米药物
Pub Date : 2018-10-10 DOI: 10.5772/INTECHOPEN.75750
Ariane J. Sousa-Batista, B. Rossi-Bergmann
Leishmaniasis is a vector-borne disease caused by Leishmania parasites, which cause a range of clinical manifestations in man. These are didactically classified into cutane - ous leishmaniasis (CL), the most common form of the disease, and visceral leishmaniasis (VL), the life-threatening form. There are so far no vaccines approved for humans. Conventional drugs pose limitations ranging from low efficacy and high cost to systemic toxicity. Low efficacy derives in part from difficult drug access to the parasites, which rides themselves inside macrophage phagosomes. This prompts to high dosage, with consequent increased toxicity. Difficult intracellular drug access can be overcome with nanomedicines such as biocompatible lipid and polymeric nanoparticles that can be phagocytosed by the infected macrophages. Besides cell membranes, appropriate drug nanostructuring may allow tissue barrier penetration and drug administration through higher compliance routes such as skin and intestine, in contrast to the usual intravenous and intramuscular routes. In general, CL and VL are both treated with toxic systemic injections, disregard of disease severity. This chapter will review and discuss studies with nanomedicines that have reached the market such as liposomal amphotericin B for intravenous administration, and innovative preclinical studies aiming at developing effective cutaneous and oral drugs with focus on CL .
利什曼病是一种由利什曼原虫寄生虫引起的媒介传播疾病,在人类中引起一系列临床表现。这些疾病在教学上分为皮肤利什曼病(最常见的形式)和内脏利什曼病(危及生命的形式)。到目前为止还没有批准用于人类的疫苗。传统药物的局限性包括低疗效和高成本以及全身毒性。低疗效的部分原因是药物难以接近寄生虫,寄生虫骑在巨噬细胞吞噬体内。这促使高剂量,随之增加的毒性。细胞内药物通路的困难可以用纳米药物来克服,如生物相容性脂质和聚合物纳米颗粒,它们可以被感染的巨噬细胞吞噬。除了细胞膜外,适当的药物纳米结构可能允许组织屏障穿透和药物给药通过更高的顺应性途径,如皮肤和肠道,而不是通常的静脉注射和肌肉注射途径。一般情况下,无论疾病严重程度如何,CL和VL均采用毒性全身注射治疗。本章将回顾和讨论已经进入市场的纳米药物的研究,如用于静脉给药的脂质体两性霉素B,以及旨在开发有效的皮肤和口服药物的创新临床前研究,重点是CL。
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引用次数: 5
Crossing Biological Barriers for Leishmaniasis Therapy: From Nanomedicinal Targeting Perspective 跨越生物屏障治疗利什曼病:从纳米药物靶向的角度
Pub Date : 2018-10-10 DOI: 10.5772/INTECHOPEN.75911
G. Shahnaz, H. S. Sarwar, M. Yasinzai
Despite past 60 years of extensive research in antileishmanial drug development, the successful therapy of this disease cannot be achieved at full potential. The biological barriers encountered by the therapeutic modalities favor the disseminations of the disease like intramacrophage location of parasite, lack of oral bioavailability, permeability across the cutaneous tissue, and active efflux of the drug. Nanomedicines are specifically engineered nano-sized delivery systems. The goal of designing a nanomedicine is to achieve the specific therapeutic objective via targeting the specific cells and intracellular locations, pharmacological receptors, enzymes and proteins, crossing biological barriers, and navigation through endocytic pathways. This chapter will cover various nanomedicinal approaches like targeting the macrophages, pathological organs, efflux pumps, metabolic enzymes, redox biology of Leishmania by using polymeric and metal nanocarriers to overcome all the biological barriers thus providing a successful alternative over the conventional therapies.
尽管过去60年来在抗利什曼病药物开发方面进行了广泛的研究,但这种疾病的成功治疗仍不能充分发挥其潜力。治疗方式遇到的生物屏障有利于疾病的传播,如寄生虫在巨噬细胞内的位置,缺乏口服生物利用度,穿过皮肤组织的渗透性,以及药物的主动外排。纳米药物是专门设计的纳米级输送系统。纳米药物的设计目标是通过靶向特定的细胞和细胞内位置、药理受体、酶和蛋白质、跨越生物屏障以及通过内吞途径导航来实现特定的治疗目的。本章将介绍各种纳米医学方法,如利用聚合物和金属纳米载体克服所有生物障碍,靶向巨噬细胞,病理器官,外排泵,代谢酶,利什曼原虫氧化还原生物学,从而为传统疗法提供成功的替代方案。
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引用次数: 4
Vaccines for Visceral Leishmaniasis: Hopes and Hurdles 内脏利什曼病疫苗:希望与障碍
Pub Date : 2018-10-10 DOI: 10.5772/INTECHOPEN.75184
E. Khalil
The leishmaniases are vector-borne parasitic diseases with multiple disease pheno- types that range from self-healing cutaneous ulcers to disfiguring post-kala-azar der mal leishmaniasis and fatal visceral leishmaniasis (VL). Infected individuals can develop subclinical infections or overt disease. Current treatments are toxic and expensive. The only successful control measure is case detection and drug treatment. Resistance to anti- leishmanial drugs are increasing with few drugs in the pipeline. The Leishmania parasites are good candidates for vaccine development, with no change in its antigenic coat and extensive cross-reactivity between species. First-generation vaccines are safe, immunogenic with inconclusive efficiency. These vaccines presented the leishmanin skin test (LST) as a potentially good surrogate marker of immunogenicity/protection that can help in future vaccine studies. First-generation vaccines are the only leishmaniasis vaccines that progressed to phase III. Second-generation vaccines are safe and immunogenic, but none progressed to phase III. Third-generation vaccines recently entered human testing. Alternative approaches include in silico prediction of immunogenic Leishmania epitopes with in vitro immunogenicity testing. New adjuvants can help in the quest to develop efficacious leishmaniasis vaccines. Failure of second- and third-generation vaccines to reach phase III, rising drug resistance and continued VL pandemics make it a necessity to revisit first-generation vaccines .
利什曼病是媒介传播的寄生虫病,具有多种疾病表型,从自愈的皮肤溃疡到毁容的黑热病后利什曼病和致命的内脏利什曼病(VL)。感染者可发展为亚临床感染或显性疾病。目前的治疗方法有毒且昂贵。唯一成功的控制措施是病例发现和药物治疗。抗利什曼原虫药物的耐药性正在增加,而正在开发的药物却很少。利什曼原虫是开发疫苗的良好候选者,其抗原外壳没有变化,物种之间具有广泛的交叉反应性。第一代疫苗是安全的,具有免疫原性,但有效性尚无定论。这些疫苗表明,利什曼素皮肤试验(LST)可能是免疫原性/保护性的良好替代标记物,有助于未来的疫苗研究。第一代疫苗是唯一进入第三阶段的利什曼病疫苗。第二代疫苗是安全且具有免疫原性的,但没有一种疫苗进展到第三期。第三代疫苗最近进入人体试验阶段。替代的方法包括体外免疫原性测试的免疫原性利什曼原虫表位的计算机预测。新的佐剂可以帮助研制有效的利什曼病疫苗。第二代和第三代疫苗未能达到第三阶段,耐药性上升以及VL流行病持续存在,使得有必要重新考虑第一代疫苗。
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引用次数: 3
Leishmaniases in West Africa: Past and Current 西非的利什曼病:过去和现在
Pub Date : 2018-10-10 DOI: 10.5772/INTECHOPEN.77009
A. Kone, M. Thera, B. Faye, O. Doumbo
Leishmaniases are vector-borne diseases. Cutaneous leishmaniasis (CL) is endemic in West Africa. Sporadic and anecdotal cases of visceral leishmaniasis (VL) have been reported in the past. Recent data showed the changing of epidemiology of leishmaniases in West Africa, with the occurrence of outbreak of CL due to Leishmania major in urban and rural areas. CL is transmitted by Phlebotomus duboscqi. The role of Sergentomyia (Spelaeomyia) darlingi as vector in rural areas has been evoked but not confirmed. Cases of VL due to Leishmania spp. have been described in West Africa; however, parasites species were not identified and dogs were suspected to be the reservoir. No humans’ case of symptomatic VL due to L. infantum has been described in West Africa. Recent data in rural areas of Senegal confirmed dog as reservoir of L. infantum. In the same study in Senegal, Sergentomyia sandflies were found infected with L. infantum, indicating a possible role in leishmaniasis transmission. Coinfection leishmaniases-HIV is reported but rare. In this chapter, we included most recent publications and propose an updated landscape of CL and VL epidemiology in West Africa.
利什曼病是媒介传播的疾病。皮肤利什曼病是西非的一种地方性疾病。过去曾报告过内脏利什曼病(VL)的零星和轶事病例。最近的数据显示西非利什曼病流行病学的变化,在城市和农村地区发生了由利什曼原虫引起的CL暴发。CL是由杜氏白蛉传播的。在农村地区,达林蛇精虫(Spelaeomyia)作为病媒的作用已引起关注,但尚未得到证实。西非已报告由利什曼原虫引起的VL病例;然而,寄生虫种类未被确定,狗被怀疑是宿主。在西非尚未报告由婴儿乳杆菌引起的人类有症状的VL病例。塞内加尔农村地区的最新数据证实狗是婴儿乳杆菌的宿主。在塞内加尔的同一项研究中,发现沙蝇感染了婴儿乳杆菌,这表明它可能在利什曼病传播中起作用。利什曼病- hiv合并感染有报道,但很少见。在本章中,我们纳入了最新的出版物,并提出了西非CL和VL流行病学的最新概况。
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引用次数: 1
The Polyamine Pathway as a Potential Target for Leishmaniases Chemotherapy 多胺途径作为利什曼病化疗的潜在靶点
Pub Date : 2018-10-10 DOI: 10.5772/INTECHOPEN.75867
J. I. Aoki, S. Muxel, Juliane Cristina RibeiroFernandes, L. Floeter-Winter
Considering the limitations of the current leishmaniases chemotherapy and the lack of effective vaccines, the identification of novel drugs and/or vaccine approaches for the leishmaniases treatment and control is urgently required. In fact, a rational strategy for the parasite control can be based on the identification of essential metabolic pathways of the parasite. One of the most important pathways is the polyamine biosynthesis. Leishmania is auxotrophic for many amino acids, such as l-arginine, a precursor of orni -thine, putrescine, and spermidine. These metabolites are essential for parasite replication and establishment of infection in the mammalian host. In addition, Leishmania has a specific and complex machinery to uptake and metabolize exogenous sources of those mol - ecules. In this chapter, we will focus on the main aspects of the polyamine pathway as a potential target for infection control aiming for new targets for Leishmania chemotherapy.
考虑到目前利什曼病化疗的局限性和缺乏有效的疫苗,迫切需要确定治疗和控制利什曼病的新药和/或疫苗方法。事实上,合理的寄生虫控制策略可以建立在寄生虫基本代谢途径的识别基础上。其中最重要的途径是多胺生物合成。利什曼原虫对许多氨基酸缺乏营养,如l-精氨酸,鸟氨酸、腐胺和亚精胺的前体。这些代谢物对寄生虫在哺乳动物宿主中的复制和感染的建立至关重要。此外,利什曼原虫有一种特殊而复杂的机制来吸收和代谢外源的这些分子。在本章中,我们将重点介绍多胺途径作为感染控制的潜在靶点的主要方面,旨在为利什曼原虫化疗提供新的靶点。
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引用次数: 2
Alternative Treatment for Leishmaniasis 利什曼病的替代治疗
Pub Date : 2018-10-10 DOI: 10.5772/INTECHOPEN.75895
R. M. Oliveira, S. A. Melo, Tatiane Aranha da Penha-Silva, Fernando Almeida-Souza, Ana LuciaAbreu-Silva
Leishmaniasis remains as one of the most important neglected diseases in the world and, after all these years, its treatment is still a problem, mainly because of the side effects caused by the first- and second-line drugs and the indiscriminate treatment, which leads to increasing cases of parasite resistance. The search for alternative therapies for the treatment of leishmaniasis is extremely important. In this context, the use of natural products arises as a promising alternative, combining the empirical knowledge dissemi nated in the population with researches that aim to scientifically prove the therapeutic effects of plants. Based on this, the use of medicinal plants is considered a desirable and accessible tool in the treatment of these diseases and considered by pharmacognosy as a valuable source for the development of new drugs and as adjuvant for conventional therapies.
利什曼病仍然是世界上最重要的被忽视疾病之一,经过这么多年,它的治疗仍然是一个问题,主要是因为一线和二线药物造成的副作用以及不分青红皂白的治疗,导致寄生虫耐药性病例增加。寻找治疗利什曼病的替代疗法极为重要。在这种情况下,天然产品的使用作为一种有希望的替代方案出现,将在人群中传播的经验知识与旨在科学证明植物治疗效果的研究相结合。基于此,药用植物被认为是治疗这些疾病的理想和可获得的工具,并且被生药学认为是开发新药的宝贵来源和传统疗法的辅助手段。
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引用次数: 7
Visceral Leishmaniasis 内脏利什曼病
Pub Date : 2018-10-10 DOI: 10.5772/intechopen.75907
S. Bhattacharya, Ajanta Ghosal, S. Ganguly, S. Ganguly, Sabahat Azim, S. Dutta
Clinically, leishmaniasis is of three types — visceral leishmaniasis (VL) or kala-azar, cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). Post-kala-azar dermal leishmaniasis (PKDL) is considered as a complication of VL. VL is characterized by fever, anemia and splenomegaly in a VL-endemic area (malaria excluded). A subject with such symptoms should be subjected to an rK39 strip test. Confirmation of diagnosis is made by demonstration of the parasite ( Leishmania donovani ) from samples obtained by aspiration of bone marrow or iliac crest puncture. Miltefosine, stibogluconate, amphotericin B, liposomal amphotericin B and paromomycin are effective available anti-leishmaniasis drugs. Vector ( Phleblotomus argentipes ) control for reduction of transmission and early diagnosis and complete treatment are essential elements of case management. There is no effective vaccine against VL. This review on VL aims at providing state-art knowledge on epide-miology, diagnosis and case-management and vaccine development.
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引用次数: 0
Introductory Chapter: Leishmaniasis: An Emerging Clinical Syndrome 导论章:利什曼病:一种新兴的临床综合征
Pub Date : 2018-10-10 DOI: 10.5772/INTECHOPEN.79662
F. Afrin, H. Hemeg
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引用次数: 0
期刊
Leishmaniases as Re-emerging Diseases
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