CAJ | 학술논문

目的寻找伯氏疟原虫氯喹抗性逆转剂.方法将健康昆明小鼠72只(雌、雄各半)每只腹腔注射0.2 ml伯氏疟原虫ANKA株氯喹敏感系(chloroquine sensitive,CS)或由其选育的高抗氯喹系(chloroquine resistance,CR),按下述随机分组后灌胃给药治疗,观察各组疗效.(1)小鼠感染CS疟原虫30 min后随机均分为4组,每组6只,给D-6182{(Z,Z)-N,N,N-三甲基-2,3-双[(1-氧代-9-十八碳烯酸)-氧代]-1-丙胺基盐酸盐|、C-2832[胆畄醇-3-N-(二甲胺基乙基)氨甲酸酯]、Ket(酮替酚)、0.1%西黄蓍胶(对照组),连续灌药5 d.于D1至D7每天每鼠取尾血涂片作常规镜检,确定各实验组的原虫血症.(2)小鼠感染CR疟原虫后第3天随机均分为8组,每组6只,给D-6182、C-2832、Ket组、氯喹组、0.1%西黄蓍胶对照组及给予D-6182、C-2832、Ket后2 h再加灌服小剂量12 mg/(kg·d)氯喹(5%ED90),连续5 d.每鼠于D4至D7每天取尾血涂片作常规镜检,确定各实验组的原虫血症,并计算各组的原虫减虫率.结果 (1)感染伯氏疟原虫CS株的小鼠,分别灌服80 mg/(kg·d)D-6182、120 mg/(kg·d)C-2832或10 mg/(kg·d)Ket连续5 d,各给药组与对照组小鼠的原虫感染率自D1至D4逐日上升,至D4达峰值,D5时对照组小鼠原虫感染率继续上升,而各给药组维持在D4的峰值水平.(2)感染伯氏疟原虫CR株的小鼠给适宜剂量的C-2832、D-6182或Ket后2 h加灌服小剂量氯喹12 mg/(kg·d)(5%ED90),此后连续5 d(D3-D7),于D4原虫减虫率可达到97.77%、99.28%或96.73%,而在D7可达到99.81%、98.87%或100.00%.结论 C-2832和D-6182两种化合物对伯氏疟原虫CR株感染小鼠的氯喹抗性具有逆转作用,其逆转能力与Ket相当.
목적 심조백씨학원충록규항성역전제.방법 장건강곤명소서72지(자、웅각반)매지복강주사0.2 ml백씨학원충ANKA주록규민감계(chloroquine sensitive,CS)혹유기선육적고항록규계(chloroquine resistance,CR),안하술수궤분조후관위급약치료,관찰각조료효.(1)소서감염CS학원충30 min후수궤균분위4조,매조6지,급D-6182{(Z,Z)-N,N,N-삼갑기-2,3-쌍[(1-양대-9-십팔탄희산)-양대]-1-병알기염산염|、C-2832[담류순-3-N-(이갑알기을기)안갑산지]、Ket(동체분)、0.1%서황시효(대조조),련속관약5 d.우D1지D7매천매서취미혈도편작상규경검,학정각실험조적원충혈증.(2)소서감염CR학원충후제3천수궤균분위8조,매조6지,급D-6182、C-2832、Ket조、록규조、0.1%서황시효대조조급급여D-6182、C-2832、Ket후2 h재가관복소제량12 mg/(kg·d)록규(5%ED90),련속5 d.매서우D4지D7매천취미혈도편작상규경검,학정각실험조적원충혈증,병계산각조적원충감충솔.결과 (1)감염백씨학원충CS주적소서,분별관복80 mg/(kg·d)D-6182、120 mg/(kg·d)C-2832혹10 mg/(kg·d)Ket련속5 d,각급약조여대조조소서적원충감염솔자D1지D4축일상승,지D4체봉치,D5시대조조소서원충감염솔계속상승,이각급약조유지재D4적봉치수평.(2)감염백씨학원충CR주적소서급괄의제량적C-2832、D-6182혹Ket후2 h가관복소제량록규12 mg/(kg·d)(5%ED90),차후련속5 d(D3-D7),우D4원충감충솔가체도97.77%、99.28%혹96.73%,이재D7가체도99.81%、98.87%혹100.00%.결론 C-2832화D-6182량충화합물대백씨학원충CR주감염소서적록규항성구유역전작용,기역전능력여Ket상당.
Objective To search for reverser of chloroquine-resistance in Plasmodium berghei (P.berghei) ANKA. Methods Seventy-two healthy Kunming mice were each infected with chloroquine sensitive (CS) or chloroquine resistance (CR) P. berghei ANKA respectively, then treated with various schedule of reversal agents C-2832 、D-6182 or ketotifen(Ket) respectively with or without co-administration of low dose (5%ED90) of chloroquine (CQ). Schedule 1: mice infected with CS were randomly distributed into 4 groups, 6 mice in each group, 30 min after infection,then treated i.g. with D-6182, C-2832, Ket or 0. 1% gum tragacanth(control) respectively for 5 consecutive days. The parasitemia of each experiment group was then determined by routine microscopic examination on blood smears from the tail blood of each mouse from D1 to D7.Schedule 2:mice infected with CR were randomly distriduted into 8 groups, 6 mice in each group, 3 d after infection, then treated i.g. with D-6182, C-2832, Ket, chloroquine or 0. 1% gum tragacanth (control) with or without co-administration of 12 mg/(kg · d) chloroquine (5% ED90) 2 h after the first administration for 5 consecutive days. The parasitemia of each experiment group was then determined microscopically by examination on blood smears from the tail blood of each mouse from D4 to D7. The reduction rates of each group were calculated and compared between the groups with or without treatment of reverser. Results 1. The parasitemia of mice infected with CS was going up daily from D1 to D4 and reached the peak on D4 in all groups administered with 80 mg/(kg · d) D-6182, 120 mg/(kg · d) C-2832 or 10 mg/(kg · d) Ket for5 d. From D5 the parasitemia kept going up in control group while it kept at the level of D4 in all treated groups. 2. Chloroquine 12 mg/(kg · d) administered i.g. 2 h after administration of C-2832 or D-6182 or Ket for 5 d(D3-D7) could reach 97.77%, 99.28% or 96.73% of reduction rate of parasitemia on D4 and 99.81%, 98.87% or 100.00% on D7 respectively in CR P. berghei infected mice. Conclusion Two compounds of C-2832 and D-6182 exhibited the reversal activity on CQ resistance in CR P. berghei infected mice at the same range of that of well-recognized reverser Ket.