伯氏鼠疟原虫(Plasmodium berghei)对咯萘啶抗药性的研究

用本所传代已二十余年、对药物敏感的伯氏鼠疟原虫作种源,每转种一代给小白鼠口服单次量咯萘啶。第1代剂量为8 mg/kg,其后剂量每代增加2 mg/kg。转种至第23代,剂量达2,400mg/kg时,虽部分小鼠死亡,存活小鼠的原虫血症仍不转阴,此时原虫的抗药性为亲代原虫的300倍以上。抗咯萘啶鼠疟原虫(RPB_2)对氯喹、喹哌、吡咯喹、M-6407、阿的平与青蒿素等有一定程度的交叉抗药性。用对亲代原虫有效量的3～10倍治疗RPB_2原虫时,不能使原虫血症转阴。如不再用药,连续转种5代,RPB_2可恢复对咯萘啶的敏感性。     

伯氏疟原虫K173株对喹哌抗药性的实验研究

用小剂量递增法培育伯氏疟原虫对喹哌的抗药性,起始剂量7 mg/kg×1,每传三代递增3.5 mg/kg,至20代,历时5个多月,培育出对喹哌有110倍以上抗性的虫系。抗喹哌伯氏疟原虫系对羟基喹哌、甲氟喹、青蒿酯、青蒿素都有明显的交叉抗性,对咯萘啶、氯喹和伯喹仅有微弱交叉抗性;对乙胺嘧啶和硝喹显示高敏效应。但该虫系的抗性尚不稳定,停药后连续血传12代,抗性水平由110多倍降至8倍.     

伯氏疟原虫K173株对喹哌抗药性的实验研究

用小剂量递增法培育伯氏疟原虫对喹哌的抗药性,起始剂量7 mg/kg×1,每传三代递增3.5 mg/kg,至20代,历时5个多月,培育出对喹哌有110倍以上抗性的虫系。抗喹哌伯氏疟原虫系对羟基喹哌、甲氟喹、青蒿酯、青蒿素都有明显的交叉抗性,对咯萘啶、氯喹和伯喹仅有微弱交叉抗性;对乙胺嘧啶和硝喹显示高敏效应。但该虫系的抗性尚不稳定,停药后连续血传12代,抗性水平由110多倍降至8倍.     

三氟甲基氨酚喹类似物的合成及其抗疟活性

本文报道了22个7-三氟甲基和2-甲基-7-三氟甲基氨酚喹类似物的合成。用伯氏疟原虫(plasmodium berghei)ANKA正常株感染小鼠作抑制性治疗试验,在剂量为(10 mg/kg)/d×4和(20 mg/kg)/d×4时,有11个化合物(Ⅰ_1～9,Ⅱ₃和Ⅱ₆)对疟原虫完全抑制。其中3个化合物(Ⅰ₂,Ⅰ₆和Ⅰ₇)在剂量为(5 mg/kg)/d×4时,就能对原虫完全抑制。12个化合物(Ⅰ_1～10,Ⅱ₃和Ⅱ₆)用伯氏疟原虫ANKA抗氯喹株感染小鼠作治疗试验,剂量为(20 mg/kg)/d×4,2个化合物(Ⅰ₄和Ⅱ₃)在受试的5只小鼠中,原虫完全被抑制的鼠分别为3和4只,用相同剂量的对照药物盐酸氨酚喹治疗,原虫仍为阳性。     

咯萘啶治疗恶性疟疾30例的疗效

本文报道用咯萘啶治疗恶性疟30例,其治疗剂量为2mg/kg,分别经2次或3次肌注;治疗剂量为3mg/kg,3次肌注。退热时间为26-36h,原虫转阴时间为41-57h。另用本品2mg/kg,肌注2次治疗间日疟12例,退热时间为18h,原虫转阴时间为37h。有脑型疟8例全部获得救治。有氯喹未治愈的2例患者改用本品后也能见效。本品对孕妇(2例)及婴儿(1例)均未出现不良反应。本研究证明咯萘啶抗疟效果好、副反应轻,值得在临床上继续试用。     

伯氏疟原虫对青蒿素抗药性的研究

仿Peters剂量递增法用伯氏疟原虫ANKA株及N株对QHS进行了抗药性的研究。经14个月的培育至第58代,QHS im注射“4日抑制性实验”的ED₅₀在RQ/ANKA系及RQ/N系分别为其亲代系的53.4及54.6倍,但经蚊传未获成功。在第40代(I₅₀=25)时,其50%的治愈剂量为其亲代系的5.4倍。停药传代其抗性会逐渐消失。该虫系对青蒿酯钠及蒿甲醚有明显的交叉抗性,其ED₅₀分别为其亲代系的13.1及11.7倍,对伯喹的抗性为2.9倍,对氯喹未见明显交叉抗性。     

抗疟新药咯萘啶对大鼠胚胎毒性的观察

抗疟新药咯萘啶以1100 mg/kg/d×1,330 mg/kg/d×3,165 mg/kg/d×3和84 mg/kg/d×3四个剂量组分别于母鼠妊娠第7天(D₇)开始每日灌胃一次。另设空白对照组及阳性对照组(敌枯双5 mg/kg/d×7)。妊娠D₂₀杀鼠检查胚胎。结果表明:咯萘啶各组均引起胚胎早期吸收率升高,并随剂量递增而增加。该药还能延迟大鼠胚胎胸骨与枕骨的骨化。各试验组中未见胎鼠外形、内脏及其它骨骼畸形。可见咯萘啶对大鼠有较明显的胚胎毒性。     

合成抗疟药研究 Ⅵ.三哌喹类化合物的合成及其抗疟活性

本文报道了根据羟基哌喹、12,278RP及M1020的结构和生物活性的特点设计合成的一类高效抑制性抗疟化合物。经鼠疟初筛,化合物Ⅳ_c,g,h 3 mg/kg连续灌服3天,原虫抑制率可达99.9～100%。鼠疟抑制性预防试验中,化合物Ⅳ_a和Ⅳ_d2 有明显的长效作用,IVd₂一次灌服600 mg/kg可在45天内保护小鼠不被红内期伯氏原虫感染,它对恒河猴输血感染食蟹猴疟原虫的保护期为20～25天。     

疟原虫组织期裂殖体杀灭剂的研究:2-取代苯氧基和4-甲基伯氨喹以及喹噁啉类衍生物的合成

合成了2-取代苯氧基伯氨喹及其类似物和4-甲基伯氨喹及其同系物以及7-甲氧基-5-(1-氨基烃基)氨基喹噁啉类化合物。其中以4-甲基伯氨喹的同分异构体25及其同系物24的作用最强。感染约氏疟原虫(Plasmodium yoelii)子孢子的小鼠,用10mg/kg单剂灌胃,全部小鼠的原虫血症均呈阴性,疗效高于对照组伯氨喹。     

抗疟新药的研究——苯骈[b]1,5-萘啶衍生物的合成

作者等用2-取代基-7,10-二氯苯骈[b]1,5-萘啶分别与取代氨基烃基胺和取代胺在苯酚中作用,合成了2-取代基-7-氯-10-(取代氨基烃基氨基)苯骈[b]1,5-萘啶(Ⅱ_1～10,表1)和相应的10-(取代氨基)-苯骈[b]1,5-萘啶(Ⅱ_11～14,表1);将2-取代基-7,10-二氯苯骈[b]1,5-萘啶与取代苯酚的钾盐作用,又合成了相应的10-(取代苯氧基)苯骈[b]1,5-萘啶(Ⅲ,表2)。在具有取代氨基烃基胺侧链的化合物中,以Ⅱ_2,6,10对血液转种的Plasmodium berghei和子孢子诱发感染的P.yoelii两种鼠疟原虫的作用最显著;具有N-甲基-N′-氨基哌嗪侧链的Ⅱ₁₁,经后一种鼠疟试验,也呈现了优于伯喹的显著的疗效;化合物Ⅲ_1,3,4,7,8仅对后一种模型呈现较弱的作用。     

感染食蟹猴疟原虫的恒河猴口服咯萘啶的疗效观察

When pyronaridine was given ig to 2 infected monkeys at a single dose of 6 mg (base)/kg, parasitemia was not cleared, but it was cleared in three of four monkeys treated at dosages of 6 mg/kg/d×3. With chloroquine at a single dose of 6 mg/kg, parasitemia of 2 monkeys turned negative, so did the parasitemia of 4 other monkeys treated at dosages of 6 mg/kg/d×3. Five of 6 monkeys treated with pyronaridine at 30 mg/kg recrudesced whereas only 1 of the 6 monkeys receiving the same dose of chloroquine recrudesced.     

In vivo Antimalarial Activities of Russelia Equisetiformis in Plasmodium Berghei Infected Mice

The rising problem of resistance to most commonly used antimalarials remains a major challenge in the control of malaria suggesting the need for new antimalarial agents. This work explores the antiplasmodial potential of ethanol extract of Russelia equisetiformis in chloroquine Plasmodium berghei infected mice. Swiss albino mice were intraperitoneally infected with chloroquine-resistant P. berghei (ANKA). Experimental mice were treated for four days consecutively with graded doses of plant extracts and standard antimalarial drugs (artesunate and chloroquine) at a dose of 10 mg/kg body weight used as control. The extract showed a dose-dependent activity in the chemosuppression of P. berghei parasites by 31.6, 44.7, 48.4 and 86.5% at doses of 100, 200, 400 and 800 mg/kg, while chloroquine (10 mg/kg) and artesunate produced 59.4 and 68.4%, respectively. The extract showed a significant decrease in parasitaemia (P<0.05). The level of parasitemia and decrease in weight in all the treated groups was significantly lower (P<0.05) compared with the infected but untreated mice. The plant extract was devoid of toxicity at the highest dose tested (5000 mg/kg). The study concluded that the ethanol extract of R. equisetiformis possesses antimalarial effect, which supports the folk medicine claim of its use in the treatment of malaria.     

抗疟药的研究——Ⅲ.2-(取代苯乙烯基)-4-氨基吡啶类的合成

本文报道2-(取代苯乙烯基)-4-(4′-二乙氨基-1′-甲基丁基氨基)-吡啶类的合成。动物筛选的初步结果表明:口服给药6.25mg/kg,化合物Ⅲ₂、Ⅲ₄和Ⅲ₇能完全抑制感染伯氏鼠疟原虫氯喹敏感株(Plalmodium berghei)小白鼠的原虫血症;皮下给药1.8mg/kg,化合物Ⅲ,即能达到完全抑制。     

Evaluation of herbal antimalarial MAMA decoction-amodiaquine combination in murine malaria model

Context: Co-administration of amodiaquine with MAMA decoction (MD), an herbal antimalarial drug comprising the leaves of Mangifera indica L. (Anacardiaceae), Alstonia boonei De Wild (Apocynaceae), Morinda lucida Benth (Rubiaceae) and Azadirachta indica A. Juss (Meliaceae) was investigated. The practice of concurrent administration of herbal medicines with orthodox drugs is currently on the increase globally.

Objective: The study was designed to investigate the possible enhancement of the antimalarial potency as well as possible herb–drug interaction resulting from concurrent administration of MAMA decoction with amodiaquine (AQ).

Materials and methods: Combinations of MD with AQ were investigated in chloroquine (CQ)-sensitive Plasmodium berghei NK 65 in varying oral doses (mg/kg) at: sub-therapeutic [MD30?+?AQ1.25], therapeutic [MD120?+?AQ10] and median effective [MD40?+?AQ3.8], using chemosuppressive and curative antimalarial test models. Secondly, P. berghei ANKA (CQ-resistant)-infected mice were orally treated with MD 120, 240, [MD120?+?AQ10] and [MD240?+?AQ10] mg/kg, using both models. The survival times of mice were monitored for 28 d.

Results: ED₅₀ values of MD and AQ were 48.8 and 4.1?mg/kg, respectively. A total parasite clearance of CQ-sensitive P. berghei NK65 was obtained with the therapeutic combination dose in the curative test giving an enhanced survival time. In CQ-resistant P. berghei ANKA-infected mice, [MD120?+?AQ10] and [MD240?+?AQ10] mg/kg gave comparable activities with AQ (10?mg/kg) in both models.

Conclusion: The therapeutic combination dose gave total parasite clearance of CQ-sensitive P. berghei NK65, whereas none of the doses tested showed notable activity against CQ-resistant P. berghei ANKA.     

The trypanocidal activity of various aromatic bisguanylhydrazones in vivo

Seven aromatic bisguanylhydrazones and two related compounds were screened against Trypanosoma brucei (EATRO 110M) in mice. The four most active were then screened against T. congolense (TREU 1183) in mice and rats. Eradication of parasitemia through 28 (T. brucei) or 42 days (T. congolense) resulting from a single dose of drug administered IP either 4 or 24 hours (respectively) after infection was used as the criterion of activity. 1,3-Diacetylbenzene bisguanylhydrazone dihydrochloride cleared T. congolense from 50% of the animals (ED₅₀) at a dose of approximately 10 mg/kg and from mice infected with T. brucei at approximately 15 mg/kg. This drug was also active when given 5 days after infection with T. congolense (ED₅₀ ? 15 mg/kg). The isomorphous pyridine derivative, 2,6-diacetylpyridine bisguanylhydrazone dihydrochloride, was active against T. brucei in mice (ED₅₀ ? 8 mg/kg), but noncurative against T. congolense. At therapeutic doses of these two compounds, reversal and clearance of parasitemia was often not observed for 2–4 days, suggesting a delayed mode of action. Moreover, 1–2 days after drug treatment, the infectivity of parasites obtained from treated animals was significantly reduced, if not abolished. These findings indicate that more intensive screening of aromatic bisguanylhydrazones against various species of trypanosomes is warranted.     

蒿甲醚对小鼠血清IgG及脾重的影响

青蒿素与青蒿酯钠的某些免疫作用已有报道。本文报道应用单向免疫扩散测定技术,测定了蒿甲醚对小鼠血清IgG含量的影响,还观察了蒿甲醚对脾脏重量的影响。动物用20～25g JCR纯种小鼠,按雌雄各半随机分组。蒿甲醚(桂林制药厂提供)与氯喹(重庆制药厂生产)均混悬于1％西黄蓍胶,供灌胃用。兔抗小鼠IgG抗血清及标准JCR小鼠血清抗原均为本实验室制备。