The chemotherapy of rodent malaria. LX. The importance of formulation in evaluating the blood schizontocidal activity of some endoperoxide antimalarials
The chemotherapy of rodent malaria. LX. The importance of formulation in evaluating the blood schizontocidal activity of some endoperoxide antimalarials
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DOI：
10.1179/000349802125001744
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发表时间：
2002-09-01
影响因子：
--
通讯作者：
Jefford, CW
中科院分区：
文献类型：
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作者：
Peters, W;Fleck, SL;Jefford, CW
比较了青蒿素（QHS）及其半合成类似物、合成1,2,4-三氧环化合物Fenozan B07（1307）和合成应召素替代物arteflene （ATF）在感染对药物敏感的伯氏疟原虫或耐氯喹的约氏疟原虫小鼠体内的活性。NS。这项研究是由观察到B07，在某些水制剂中，似乎通过皮下（sc）或口服（po）途径在啮齿动物模型中具有同等效力，但在猿类模型中没有。在啮齿类动物模型中，B07在用二甲基亚砜（DMSO）预溶药物制备的水原液中发生快速变化（半衰期< 24小时）。因此，在以后的所有水制剂实验中，试验材料每天都要重新配制。在作为“标准悬浮载体”（SSV）的羧甲基纤维素制剂中，B07和双氢青蒿素（DIHYD）的活性分别是将药物预先溶解在DMSO中然后用水稀释时的六分之一和十分之一。在啮齿类动物模型中，给予po的DMSO中的ATF活性不到sc时的二十分之一，而在SSV中，该药物几乎没有活性。这三种化合物（尤其是DIHYD和ATF）相对较低的口服活性可能归因于小鼠广泛的首过代谢。口服β-蒿甲醚（AM）和β-蒿甲醚（AE）在SSV中具有较高的活性。由于ATF的绝对生物利用度较差，在类人猿模型和临床试验中发现其活性较低。在啮齿动物疟疾模型中抗疟药物的血液分裂作用的体内研究中，在从化学系列中选择特定化合物进行进一步开发时，必须严格审查收集到的药物的结构-活性关系（SAR）数据。研究药物配方对其他新型抗疟药物活性的影响对药物评价至关重要，值得高度重视。
The activities of artemisinin (QHS) and a number of its semi-synthetic analogues, as well as Fenozan B07 (1307), a synthetic 1,2,4-trioxane, and arteflene (ATF), a synthetic surrogate of yingzhaosu, were compared in mice infected with drug-sensitive Plasmodium berghei or chloroquine-resistant P. yoelii ssp. NS. The studies were stimulated by the observation that B07, in certain aqueous preparations, appears to be equipotent by the subcutaneous (sc) or oral (po) routes in the rodent model but not in a simian model. In the rodent model, B07 was found to undergo rapid alteration (with a half-life of < 24 h) in an aqueous stock solution prepared using dimethyl sulphoxide (DMSO) to pre-dissolve the drug. Therefore, for all later experiments with aqueous preparations, the test material was newly formulated each day. In a carboxymethylcellulose formulation used as a 'standard suspending vehicle' (SSV), B07 and dihydroartemisinin (DIHYD) were found to be, respectively, one sixth and one 10th as active po as when the drugs were pre-dissolved in DMSO and then diluted with water. ATF in DMSO given po was less than one 20th as active as when used sc in the rodent model, and this drug in SSV was almost inactive po. The relatively low oral activity of these three compounds (especially DIHYD and ATF) may be attributable to extensive first-pass metabolism in the mouse. Oral β-artemether (AM) and β-arteether (AE) were highly active when used in SSV. ATF has been found to have low activity in simian models and clinical trials because of its poor absolute bio-availability. In in-vivo studies of the blood schizontocidal action of antimalarials, in rodent malaria models, the data collected on the structure-activity relationships (SAR) of the drugs must be viewed critically when selecting specific compounds from a chemical series for further development. A study of the influence of drug formulation on the activity of other, novel antimalarials is crucial to the evaluation of the drugs, and merits high priority.