MICA: NTD Highlight Notice - Defining PK/PD relationships of anti-leishmanial drugs - a novel approach for anti-leishmanial drug development

MICA：NTD 亮点通知 - 定义抗利什曼病药物的 PK/PD 关系 - 抗利什曼病药物开发的新方法

• 批准号: MR/J008702/1
• 负责人: Simon Croft
• 金额: $ 97.46万
• 依托单位: London School of Hygiene & Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ008702%2F1
• 关键词: MICA; NTD; Highlight; Notice; Defining

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania. The disease has many forms, ranging from localized and self-healing cutaneous leishmaniasis (CL) to the systemic visceral leishmaniasis (VL), which is fatal if not treated. There are more than 12 million people at risk of disease worldwide and an estimated 50 000 deaths per year due to VL. There are no vaccines and there are few drugs available. All the drugs have limitations, for example, resistance, long treatment courses, toxicity, methods of administration and high cost. In humans the Leishmania parasites survive and multiply inside macrophage cells, which in case of VL are found in the liver, spleen and bone marrow. For a drug to be effective it should ideally reach a concentration at the site of infection (it's pharmacokinetic property, PK) which can kill the parasite (it's pharmacodynamic property, PD) without being toxic to other parts of the body. The aim of a good dosing regimen is to deliver and keep effective drug levels at the site of infection to successfully kill all the parasites over several days. The aim of the chemists designing a new drug is to give it the properties that maximise its distribution to these sites of infection. The determination of the relationship between drug PKs and PDs is therefore important in both drug development and drug treatment. Currently we know very little about the PKs and PDs of any of the drugs used for leishmaniasis and nothing about drug action and drug concentration at the site of infection. The dosing regimens used in treatments today have not been optimised based upon this PK PD understanding, which could lead to improved efficacy, lower toxicity, and less chance of resistance; the same applies to the design of drug combinations. We aim to fill this knowledge gap by characterising the PK/PD relationships of established anti-leishmanial drugs and provision of predictive models that can be used in both drug development, by academic groups and the pharmaceutical industry, and in determining dose regimens and the best drug combinations. We will ensure that the successfully established methods and models are made available to the academic community and pharmaceutical and biotechnology companies with programmes in this field. We intend to make a contribution to the more cost-effective and efficient development of novel and much-needed therapeutic agents for this neglected tropical disease.

利什曼病是由利什曼原虫属寄生虫引起的一种被忽视的热带疾病。该疾病有多种形式，从局部和自愈的皮肤利什曼病（CL）到全身内脏利什曼病（VL），如果不治疗，这是致命的。全世界有超过1200万人面临疾病风险，估计每年有5万人死于VL。没有疫苗，可用的药物也很少。所有药物都有其局限性，如耐药性、疗程长、毒性、给药方法和成本高。在人类中，利什曼原虫在巨噬细胞内存活和繁殖，在VL的情况下，巨噬细胞存在于肝脏、脾脏和骨髓中。对于一种有效的药物，理想情况下它应该在感染部位达到一定的浓度（它的药代动力学特性，PK），可以杀死寄生虫（它的药效学特性，PD），而不会对身体的其他部位产生毒性。良好的给药方案的目的是在感染部位提供并保持有效的药物水平，以便在几天内成功杀死所有寄生虫。化学家设计新药的目的是赋予它最大限度地分布到这些感染部位的特性。因此，确定药物PK和PD之间的关系在药物开发和药物治疗中都很重要。目前，我们对治疗利什曼病的药物的PK和PD知之甚少，对感染部位的药物作用和药物浓度一无所知。目前治疗中使用的给药方案尚未基于这种PK PD理解进行优化，这可能导致疗效改善，毒性降低和耐药机会减少;这同样适用于药物组合的设计。我们的目标是通过描述已建立的抗利什曼病药物的PK/PD关系并提供可用于药物开发的预测模型来填补这一知识空白，学术团体和制药行业，以及确定剂量方案和最佳药物组合。我们将确保将成功建立的方法和模式提供给学术界以及在这一领域有方案的制药和生物技术公司。我们打算作出贡献，为这一被忽视的热带疾病更有成本效益和效率地开发新的和急需的治疗剂。

项目成果

Pharmacodynamics of single dose liposomal amphotericin B in a mouse model of visceral leishmaniasis

单剂量脂质体两性霉素 B 在内脏利什曼病小鼠模型中的药效学

• 发表时间: 2014
• 期刊: ICAAC Abstracts 54th Conference
• 作者: Seifert K.

[Design of treatments for cutaneous and visceral leishmaniasis].

[皮肤和内脏利什曼病的治疗设计]。

• DOI: 10.1254/fpj.149.220
• 发表时间: 2017
• 期刊: Nihon yakurigaku zasshi. Folia pharmacologica Japonica
• 作者: Croft S

Historical BCG vaccination combined with drug treatment enhances inhibition of mycobacterial growth ex vivo in human peripheral blood cells

历史上的卡介苗疫苗接种与药物治疗相结合增强了对人外周血细胞中分枝杆菌离体生长的抑制

• DOI: 10.1038/s41598-019-41008-4
• 发表时间: 2019
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: Prabowo S

Histopathological and immunohistochemical characterisation of hepatic granulomas in Leishmania donovani-infected BALB/c mice: a time-course study.

• DOI: 10.1186/s13071-018-2624-z
• 发表时间: 2018-01-31
• 期刊: Parasites & vectors
• 影响因子: 3.2
• 作者: Salguero FJ;Garcia-Jimenez WL;Lima I;Seifert K
• 通讯作者: Seifert K

Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular Leishmania donovani Amastigotes, with a Focus on Human-Derived Host Cells

• DOI: 10.1128/aac.01228-16
• 发表时间: 2017-01
• 期刊: Antimicrobial Agents and Chemotherapy
• 影响因子: 4.9
• 作者: Markela Koniordou;Stephen Patterson;S. Wyllie;K. Seifert