Miki A, Tanabe K, Nakayama T, Kiryon C, Ohsawa K
Department of Medical Zoology, Osaka City University Medical School, Japan.
Exp Parasitol. 1992 Mar;74(2):134-42. doi: 10.1016/0014-4894(92)90040-h.
The effects of tricyclic antidepressants, desipramine and imipramine, and phenothiazines, chlorpromazine and trifluoperazine, on chloroquine (CQ)-resistant and CQ-sensitive lines of P. chabaudi were examined in vivo. In mice that received daily injections of these drugs the growth of CQ-resistant and CQ-sensitive parasites was unaffected or affected very slightly, if at all. A combination of CQ and each drug suppressed the growth of CQ-resistant parasites in a dose-dependent manner. In addition, in CQ-sensitive parasites each drug also increased the susceptibility to CQ. Measurements of CQ levels by high-performance liquid chromatography showed that CQ accumulated in sensitive parasites to more than twice the level in resistant parasites at 2 to 4 hr after an injection of CQ. Verapamil and desipramine substantially increased CQ levels in both CQ-resistant and CQ-sensitive parasites. These results suggest that not only Ca2+ antagonists but tricyclic antidepressants reverse CQ resistance in CQ-resistant parasites and enhance the inhibitory effect in sensitive parasites by increasing CQ levels in those parasites. The effects of Ca2+ antagonists, tricyclic antidepressants, and phenothiazines on a pyrimethamine-resistant line of P. chabaudi were also studied. None of the Ca2+ antagonists (verapamil, nicardipine, and diltiazem) affected the growth of the parasite in combination with 20 mg/kg pyrimethamine. Tricyclic antidepressants and phenothiazines suppressed pyrimethamine-resistant parasites to some extent. However, the extent of this suppression was less pronounced as compared with that of suppression of CQ resistance by the same drugs.
在体内研究了三环类抗抑郁药地昔帕明和丙咪嗪以及吩噻嗪类药物氯丙嗪和三氟拉嗪对查巴迪疟原虫氯喹（CQ）抗性和CQ敏感株的影响。在每日注射这些药物的小鼠中，CQ抗性和CQ敏感寄生虫的生长未受影响，或即使有影响也非常轻微。CQ与每种药物联合使用均以剂量依赖的方式抑制CQ抗性寄生虫的生长。此外，对于CQ敏感的寄生虫，每种药物还增加了其对CQ的敏感性。通过高效液相色谱法测量CQ水平表明，在注射CQ后2至4小时，敏感寄生虫中CQ的积累量是抗性寄生虫中CQ积累量的两倍以上。维拉帕米和地昔帕明显著提高了CQ抗性和CQ敏感寄生虫中的CQ水平。这些结果表明，不仅钙拮抗剂，而且三环类抗抑郁药可逆转CQ抗性寄生虫中的CQ抗性，并通过提高这些寄生虫中的CQ水平增强对敏感寄生虫的抑制作用。还研究了钙拮抗剂、三环类抗抑郁药和吩噻嗪类药物对查巴迪疟原虫乙胺嘧啶抗性株的影响。钙拮抗剂（维拉帕米、尼卡地平、地尔硫䓬）与20mg/kg乙胺嘧啶联合使用时均未影响寄生虫的生长。三环类抗抑郁药和吩噻嗪类药物在一定程度上抑制了乙胺嘧啶抗性寄生虫。然而，与相同药物对CQ抗性的抑制程度相比，这种抑制程度不太明显。
