Lin A J, Ager A L, Klayman D L
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, District of Columbia.
Am J Trop Med Hyg. 1994 Jun;50(6):777-83. doi: 10.4269/ajtmh.1994.50.777.
In addition to artelinic acid, which was demonstrated previously to possess good prophylactic as well as curative antimalarial activity against Plasmodium berghei by transdermal administration, seven artemisinin derivatives in a gel formulation were assessed for their antimalarial activities in this study. Artemisinin, the parent compound of the series, showed moderate prophylactic but poor curative activity. Although methyl artelinate was more active against P. berghei than artelinic acid and sodium artelinate by subcutaneous injection, its transdermal curative and prophylactic activity was only comparable with or weaker than that of artelinic acid. Conversely, both dihydroartemisinin trimethylsilyl ether and dehydrodihydroartemisinin showed weaker antimalarial activity than artelinic acid by the subcutaneous route, yet exhibited comparable activity by transdermal administration. Artemether, a prodrug of dihydroartemisinin, is as effective as the parent dihydroartemisinin, and both compounds were the most potent agents among the compounds studied, with total prophylactic and curative doses of 30 mg/kg and 60 mg/kg, respectively. Complete absorption of dihydroartemisinin appears to occur within 5 min after application. In general, we found that the prophylactic dose is about half that of the curative dose under the protocols used in this study. This novel drug delivery system may be an easy and safe way to administer artemisinin-type antimalarials and also a good alternative dosage form for active compounds with solubility problems.
除了先前已证明通过透皮给药对伯氏疟原虫具有良好预防和治疗抗疟活性的青蒿酸外，本研究还评估了凝胶制剂中的七种青蒿素衍生物的抗疟活性。该系列的母体化合物青蒿素显示出中等的预防活性，但治疗活性较差。虽然皮下注射时，青蒿甲酯对伯氏疟原虫的活性比青蒿酸和青蒿素钠更强，但其透皮治疗和预防活性仅与青蒿酸相当或比青蒿酸弱。相反，二氢青蒿素三甲基硅醚和脱氢二氢青蒿素通过皮下途径显示出比青蒿酸弱的抗疟活性，但通过透皮给药表现出相当的活性。双氢青蒿素的前药蒿甲醚与母体双氢青蒿素一样有效，这两种化合物是所研究化合物中最有效的药物，总预防剂量和治疗剂量分别为30mg/kg和60mg/kg。双氢青蒿素在给药后5分钟内似乎完全吸收。一般来说，我们发现在本研究使用的方案下，预防剂量约为治疗剂量的一半。这种新型药物递送系统可能是一种简单安全的青蒿素类抗疟药给药方式，也是具有溶解性问题的活性化合物的良好替代剂型。
