Rasoanaivo P, Ratsimamanga-Urverg S, Frappier F
Institut malgache de recherches appliquées, département de Phylochimie-Pharmacologie, Antananarivo, Madagascar.
Sante. 1996 Jul-Aug;6(4):249-53.
Investigation of Strychnos (Loganiaceae) shrubs and trees was initiated by their traditional uses of their inherent poisons on arrows: this led to the discovery of strychnine and curare alkaloids. Subsequently, phytochemical investigation of several Strychnos species has shown great structural diversity of the alkaloid constituent which also display various biological effects, i.e. convulsive and relaxant effects on muscles, and antimicrobial, antitumor and antihypertensive properties. Ethnobotanical field work conducted in different regions of Madagascar revealed that infusion of three Strychnos species, S. mostueoides, S. myrtoides and S. diplotricha, is used in association with subcurative doses of chloroquine to treat chronic malaria. Bioassayfractionation led to the isolation of two major bioactive components, strychnobrasiline and malagashanine. Whereas strychnobrasiline is a previously known chemical compound, malagashanine is the first in a series of a new subtype of Strychnos alkaloids. These two alkaloids are devoid of intrinsic antimalarial effects, both in vitro (IC50 = 73.0 micrograms/ml for strychnobrasiline and 69.1 micrograms/ml for malagashanine) and in vivo (10 mg/kg conferred a 5% suppression of parasitemia). When these alkaloids are combined with chloroquine at doses much lower than required for antiplasmodial effects, they greatly enhance the chloroquine action in a dose dependent manner as seen by the isobologram method. Several minor alkaloids structurally related to malagashanine were also isolated from Madagascan Strychnos. They all enhance, to greater or lesser degrees, the chloroquine effectiveness. Interestingly, there is a positive correlation between the ethnomedical use of the three Strychnos species as chloroquine adjuvants and the chloroquine-potentiating effects of malagashanine and strychnobrasiline isolated from them. After preliminary toxicological studies, infusion of stem barks of S. myrtoides in association with chloroquine was successfully evaluated in a clinical setting. Additional chemical, pharmacological and toxicological work is being conducted on these alkaloids with the aim of developing purified and standardized extracts for clinical trials. These trials will be carried out in the chloroquine-resistant regions of Madagascar which are in need of inexpensive and efficient drugs for the treatment of chloroquine-resistant malaria.
对马钱子属（马钱科）灌木和树木的研究始于它们在传统上被用于在箭头上涂抹其天然毒素：这导致了士的宁和箭毒生物碱的发现。随后，对几种马钱子属植物的植物化学研究表明，其生物碱成分具有极大的结构多样性，这些生物碱还表现出各种生物学效应，即对肌肉的惊厥和松弛作用，以及抗菌、抗肿瘤和抗高血压特性。在马达加斯加不同地区开展的民族植物学实地调查显示，将三种马钱子属植物，即莫氏马钱、桃叶马钱和双毛马钱的浸剂与低于治疗剂量的氯喹联用，用于治疗慢性疟疾。通过生物测定分级分离法，分离出了两种主要的生物活性成分，即马钱布拉西灵和马达加斯加宁。马钱布拉西灵是一种先前已知的化合物，而马达加斯加宁是马钱子生物碱新亚型系列中的首个化合物。这两种生物碱在体外（马钱布拉西灵的IC50 = 73.0微克/毫升，马达加斯加宁的IC50 = 69.1微克/毫升）和体内（10毫克/千克时可使疟原虫血症抑制5%）均无内在抗疟作用。当这些生物碱与氯喹以远低于抗疟所需剂量的方式联合使用时，通过等效应线图法可以看出，它们以剂量依赖的方式极大地增强了氯喹的作用。还从马达加斯加的马钱子属植物中分离出了几种与马达加斯加宁结构相关的次要生物碱。它们都或多或少地增强了氯喹的疗效。有趣的是，这三种马钱子属植物作为氯喹佐剂的民族医学用途与从中分离出的马达加斯加宁和马钱布拉西灵增强氯喹的作用之间存在正相关。经过初步毒理学研究后，桃叶马钱茎皮浸剂与氯喹联用在临床环境中得到了成功评估。目前正在对这些生物碱开展更多的化学、药理学和毒理学研究，目的是开发出用于临床试验的纯化和标准化提取物。这些试验将在马达加斯加对氯喹耐药的地区进行，这些地区需要廉价且有效的药物来治疗氯喹耐药性疟疾。
