Efficacy evaluation of traditionally used antimalarial plants

描述(申请人提供)：每年报告的疟疾病例超过2.5亿例，其中100万例导致死亡。目前，由于广泛的耐药性，没有一种药物在治疗疟疾方面普遍成功；迫切需要新的抗疟疾药物。氯喹和青蒿素是最有效和最广泛使用的两种抗疟疾药物，它们都是从植物中提取的。植物很可能含有许多更有效且尚未被发现的抗疟疾化合物。默克公司在第二次世界大战期间(Spencer等人，1947)进行的大规模抗疟疾筛选计划为初步抗疟疾植物信息提供了宝贵的来源。在那项研究中，88种(在600种测试中)被证明对禽类疟疾株有效，但在随后的研究中，近一半(39种)被忽视。这些植物为进一步的抗疟疾研究提供了有希望的线索。我们的初步研究已经证实了默克公司确定的6种活性物种中的5种具有活性，验证了这项工作的拟议后续行动。 本申请中概述的工作评估了默克公司的科学家在1947年使用现代体外抑制培养的红细胞恶性疟原虫增殖试验和体内动物后续研究相结合的方法确定的未被研究但有前景的抗疟疾植物。将应用最先进的化学分离和表征技术来比较和阐明体外活性最高、毒性最低的抗疟疾植物提取物的组分、化学特性和生物活性。这些物质将在感染伯氏疟原虫品系的C57BL小鼠的疟疾动物模型中进行测试。该模型还将允许对有希望的提取物进行协同和药效学研究。 这一研究应用与公共卫生的相关性在于支持用于治疗疟疾的植物的传统使用，为未来新的抗疟疾疗法的开发提供关键的临床前数据，并有助于阐明关于疟原虫-宿主相互作用的新的生化和生理信息。通过评估可能在当地种植、在当地使用并在当地产生效益的植物治疗方法，这项科学工作将在全球范围内以及在社区范围内对防治疟疾产生广泛和长期的影响。 公共卫生相关性：这项研究应用与公共卫生的相关性是支持用于治疗疟疾的植物的传统使用，为未来新的抗疟疾疗法的发展提供关键的临床前数据，并帮助阐明关于疟原虫-宿主相互作用的新的生化和生理信息。通过评估可能在当地种植、在当地使用并在当地产生效益的植物治疗方法，这项科学工作将在全球范围内以及在社区范围内对防治疟疾产生广泛和长期的影响。

DESCRIPTION (provided by applicant): Over 250 million cases of malaria are reported each year, 1 million of which result in death. Currently, no drugs are universally successful in treating malaria due to widespread drug resistance; new antimalarials are desperately needed. Chloroquine and artemisinin, two of the most effective and widely used antimalarial drugs, are derived from plants. It is likely that plants harbor many more potent and as yet undiscovered antimalarial compounds. A massive antimalarial screening program conducted by Merck during the Second World War (Spencer et al 1947) provides a valuable source of preliminary antimalarial plant information. Eighty eight species (out of 600 tested) were proven active against avian strains of malaria in that study, but nearly half (39) have been neglected in subsequent studies. These plants represent promising leads for further antimalarial inquiry. Our preliminary research has confirmed the activity of 5 of 6 species identified as active by Merck, validating the proposed follow up of this work. The work outlined in this application evaluate the understudied, but promising antimalarial plants identified by Merck's scientists in 1947 using a combination of modern in vitro assay for inhibition of Plasmodium falciparum proliferation in cultured erythrocytes and follow-up in vivo animal studies. State-of-the- art chemical isolation and characterization techniques will be applied to compare and elucidate the composition, chemical identity, and bioactivity of fractions and compounds from antimalarial plant extracts with the highest in vitro activity and low toxicity. These substances will be tested in animal model of malaria using C57Bl mice infected with the Plasmodium berghei strain. This model will also allow synergistic and pharmacodynamic investigations of promising extracts. The relevance of this research application to public health is to support the traditional use of plants used to treat malaria, provide crucial preclinical data for future development of novel antimalarial therapies, and help to elucidate novel biochemical and physiological information about plasmodium-host interactions. By evaluating botanical treatments that might be cultivated locally, used locally, and have local benefits, this scientific work will have broad and long-term impacts both on the global scale as well on the communal scale in the fight against malaria. PUBLIC HEALTH RELEVANCE: The relevance of this research application to public health is to support the traditional use of plants used to treat malaria, provide crucial preclinical data for the future development of novel antimalarial therapies, and help to elucidate novel biochemical and physiological information about plasmodium- host interactions. By evaluating botanical treatments that might be cultivated locally, used locally, and have local benefits, this scientific work will have broad and long-term impacts both on the global scale as well on the communal scale in the fight against malaria.