Peters W, Ekong R, Robinson B L, Warhurst D C, Pan X Q
Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, U.K.
Ann Trop Med Parasitol. 1990 Dec;84(6):541-51. doi: 10.1080/00034983.1990.11812509.
The inherent blood schizontocidal activities of five antihistaminic compounds, cyproheptadine hydrochloride (CYP), ketotifen hydrogen fumarate (KET), pizotyline hydrogen maleate (PIZ), azatadine maleate (AZAT) and loratadine (LOR) were examined against the following organisms: chloroquine-sensitive (CS) Plasmodium berghei and chloroquine-resistant (CR) P. yoelii ssp. NS in mice; and CS Tak 9 clone 96 and CR K1 strain of P. falciparum in vitro. Chloroquine, verapamil and desipramine were used as comparison standards. CYP, KET, PIZ were active against the CS strain in vivo with ED90 levels between 20 and 30 mg kg-1 (given sc daily for four days). They were slightly more active against the CR strain. AZA was active, but much less so than the other compounds. LOR, verapamil and desipramine were inactive in vivo at the doses tested. Against CS P. falciparum in vitro, all five antihistaminics and desipramine were active at EC50 concentrations ranging from about 50-80 mumol l-1, while verapamil was only active at 175 mumol l-1. Against the CR strain of this parasite, CYP, PIZ and LOR were slightly more active than against the CS strain, but KET, AZAT, desipramine and verapamil were significantly less active. The action of all these compounds in combination with chloroquine was then examined both in vivo and in vitro. The ability of verapamil and desipramine to reverse chloroquine resistance in vitro was confirmed, but only a low level of reversal was seen with these compounds in vivo. However, CYP, KET, PIZ and AZAT produced a marked reversal of chloroquine resistance both in vivo and in vitro. The implications of these observations in relation to further laboratory and clinical research are discussed.
研究了5种抗组胺化合物，即盐酸赛庚啶（CYP）、富马酸酮替芬（KET）、马来酸吡唑替林（PIZ）、马来酸阿扎他定（AZAT）和氯雷他定（LOR）对以下生物体的固有血液裂殖体杀灭活性：对氯喹敏感（CS）的伯氏疟原虫和对氯喹耐药（CR）的约氏疟原虫亚种NS（在小鼠体内）；以及对氯喹敏感的恶性疟原虫Tak 9克隆96株和对氯喹耐药的K1株（在体外）。氯喹、维拉帕米和地昔帕明用作比较标准。CYP、KET、PIZ在体内对CS株有活性，ED90水平在20至30 mg kg-1之间（每天皮下注射给药4天）。它们对CR株的活性略高。AZA有活性，但比其他化合物活性低得多。LOR、维拉帕米和地昔帕明在测试剂量下在体内无活性。在体外，所有5种抗组胺药和地昔帕明对CS恶性疟原虫均有活性，EC50浓度范围约为50 - 80 μmol l-1，而维拉帕米仅在175 μmol l-1时有活性。对于该寄生虫的CR株，CYP、PIZ和LOR比对CS株的活性略高，但KET、AZAT、地昔帕明和维拉帕米的活性显著降低。然后在体内和体外研究了所有这些化合物与氯喹联合使用的作用。维拉帕米和地昔帕明在体外逆转氯喹耐药性的能力得到证实，但在体内这些化合物仅出现低水平的逆转。然而，CYP、KET、PIZ和AZAT在体内和体外均产生了显著的氯喹耐药性逆转。讨论了这些观察结果对进一步实验室和临床研究的意义。
