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,IVd_2一次灌服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。     

抗疟药的研究 Ⅺ.4-甲基-5取代苯氧基伯喹的合成及其抗疟作用

本文报道了6个4-甲基-5取代苯氧基-6-甲氧基-8-(1-甲基-4-氨基丁氨基)喹啉(Ⅲ)的合成。除Ⅲ₃外,所有化合物对鼠疟P.berghei的抑制性治疗作用和对鼠疟P.yoelii的病因性预防作用均优干伯喹,其中以Ⅲ₁最强。Ⅲ₁口服治疗作用的SD₅₀和SD₉₀分别为0.65 mg/kg和1.60 mg/kg,口服预防作用的最小有效剂量(MED)和最小完全有效剂量(MFAD)分别为2.5mg/kg和5.0 mg/kg。对这类化合物的根治作用和毒性试验正在进行中。     

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。     

食蟹猴疟原虫——斯氏按蚊系统猴疟模型的一些生物学特性和对常用抗疟药物的生物效应

本文证明在一定条件下,斯氏按蚊对食蟹猴疟原虫的感染率为77±0.15％;恒河猴易感性强,对照组的感染率非常稳定,用10~5个以上子孢子静脉接种恒河猴可100％获得感染。在食蟹猴疟原虫—斯氏按蚊系统猴疟模型上,常用抗疟药如乙胺嘧啶、伯喹显示有病因性预防作用。伯喹剂量达到2.5mg(基质)/kg×5天,合并氯喹20mg(基质)/kg×3天显示有权治作用,氯喹20mg(基质)kg×3天则仅能显示抑制性治疗作用。     

抗疟药的研究Ⅳ——2,4-二氨基-6-取代氨基磺酰喹唑啉的合成

2,4-二氨基喹唑啉类化合物为叶酸代谢拮抗剂,文献曾报道了许多具有较好抗疟作用的这类化合物,2,4-二氨基-6-取代氨基磺酰喹唑啉亦属此类。我们曾于1974年合成了这一类化合物,其中2,4-二氨基-6-吡咯烷基磺酰喹唑啉(I_(11))皮下给药20mg/Kg对感染鸡疟(P. gallinaceum)的小鸡有病因性预防作用。2,4-二氨基-6-环己氨基磺酰喹唑啉(I_9)对感染鼠疟(P. berghei)的小鼠皮F给药10mg/Kg有治愈作用。最近发现I_9对鼠疟抗氯喹株的效果优于敏感株,皮下给药SD_(50)分别为1.7mg/Kg和2.9mg/Kg。为了继续观察这类化合物对鼠疟(P. berghei)抗氯喹株的治疗作用和对鼠疟(P. yoelii)的病因性预防作用,以及进一步研究其构效关系,作者等又合成了具有下列通式的取代氨基磺酰喹唑啉类化合物。     

食蟹猴疟原虫——斯氏按蚊系统猴疟模型的一些生物学特性和对常用抗疟药物的生物效应

本文证明在一定条件下,斯氏按蚊对食蟹猴疟原虫的感染率为77±0.15%;恒河猴易感性强,对照组的感染率非常稳定,用10⁵个以上子孢子静脉接种恒河猴可100%获得感染。在食蟹猴疟原虫—斯氏按蚊系统猴疟模型上,常用抗疟药如乙胺嘧啶、伯喹显示有病因性预防作用。伯喹剂量达到2.5mg(基质)/kg×5天,合并氯喹20mg(基质)/kg×3天显示有权治作用,氯喹20mg(基质)kg×3天则仅能显示抑制性治疗作用。     

三硝基甲苯对雌性大鼠生殖功能影响的研究

本文观察了雌鼠于交配前及妊娠期间TNT染毒对其子代生长发育和生殖能力的影响。雌性大鼠经灌胃染毒,TNT高剂量(130mg/kg)组、低剂量(65mg/kg)组,另设对照组。实验组每天给药一次,每周六天,共一个月。各组孕鼠于妊娠6—15天按实验设计剂量再次灌胃给药,部分于孕     

薯藤多糖降血脂作用实验研究

目的:观察薯藤多糖(STDT)在高脂动物模型上的降血脂作用。方法:SD大鼠、新西兰家兔采用高脂饲料喂养法、ICR小鼠采用腹腔注射蛋黄乳法复制高脂模型,分别灌胃给予不同剂量的STDT,测定给药前或给药后不同时间血清TC、TG、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)等指标。结果:STDT250、500、1000mg/kg剂量灌胃给药4周可明显抑制食糜性高脂大鼠血清TC、TG以及LDL-C的升高;100、200、400mg/kg剂量灌胃给药4周,能明显降低食糜性高脂家兔的血脂水平,使其血清TC、TG、LDL-C明显下降;STDT400、800、1600mg/kg剂量给药3d,对腹腔注射蛋黄乳所致的高脂模型小鼠血脂也有一定的降低趋势。结论:STDT无论是预防给药或是治疗给药,对多种高脂模型动物均体现出一定的降脂作用。     

~(14)C-磷酸喹哌和~(14)C-喹哌的合成

磷酸喹哌{1,3-双[4-(7′-氯代喹啉基-4′)哌哔嗪-1]丙烷四磷酸盐}是一种新的口服长效抗疟药,又是一种新的防治矽肺的药物。为了进一步探讨它在体内的作用机制及吸收分布、代谢情况,以便合理用药和指导长效药物的研究,我们合成了磷酸喹哌及喹哌的~(14)C标记     

参芪醒脑浸膏对阿尔茨海默病模型小鼠认知功能障碍的改善作用及机制研究

目的 探讨参芪醒脑浸膏对D-半乳糖诱导脑老化致阿尔茨海默病(AD)模型小鼠认知功能障碍的改善作用及机制。方法 选取无特定病原体级美国癌症研究所小鼠110只,随机分为对照组(16只)、大剂量对照组(15只)、模型组(17只)、小剂量组(16只)、中剂量组(16只)、大剂量组(16只)及多奈哌齐组(14只)。除对照组、大剂量对照组外,其余小鼠使用D-半乳糖溶液颈背部皮下注射,连续注射65 d制备AD小鼠模型。于造模当日开始灌胃给药,小剂量组予参芪醒脑浸膏3.5 g生药/kg,中剂量组予参芪醒脑浸膏7 g生药/kg,大剂量对照组、大剂量组予参芪醒脑浸膏14 g生药/kg,多奈哌齐组予多奈哌齐1 mg/kg,对照组、模型组予相同容积的蒸馏水,均为1次/d,连续给药65 d。采用Morris水迷宫实验及物体识别实验评价小鼠的空间学习记忆及识别记忆能力。采用蛋白质印迹法检测小鼠大脑皮质和海马组织内神经元核抗原(NeuN)、神经生长因子(NGF)的表达水平。结果 模型组第3～5天逃避潜伏期长于对照组(均P<0.05),小、中、大剂量组第3～5天及多奈哌齐组第3～4天逃避潜伏期均短于模型组(均P...     

Safety, tolerability, and single- and multiple-dose pharmacokinetics of piperaquine phosphate in healthy subjects

Piperaquine phosphate is an orally active bisquinolone antimalarial drug that has been used for the past 3 decades. The authors report the safety, tolerability, and pharmacokinetics of piperaquine from a classical controlled phase I study. It was a double-blind, randomized, parallel-group, placebo-controlled, and single- and multiple-dose study. During the rising single-dose study, single ascending oral doses of 500, 750, 1000, 1250, and 1500 mg of piperaquine phosphate were administered, whereas in rising multiple-dose study, once-daily ascending oral doses of 500, 750, 1000, and 1500 mg were administered for 3 consecutive days. Pharmacokinetic analysis for both the rising single- and multiple-dose studies was done using the noncompartmental approach. The mean apparent terminal half-life ranged from 11 to 23 days. Increase in exposure was less than dose proportional and linear. Piperaquine concentrations were measurable up to 60 days postdose. Multiple peaks were observed in the plasma piperaquine concentration-time profiles and exhibited 3- to 7-fold accumulation following multiple dosing. Piperaquine was well tolerated following single and multiple doses.     

Pharmacokinetics and metabolism of the antimalarial piperaquine after intravenous and oral single doses to the rat

This study aimed to evaluate the pharmacokinetic properties of piperaquine in the rat after intravenous and oral administration, and to identify and characterize the main piperaquine metabolites in rat plasma, urine, faeces and bile after intravenous administration. Male Sprague-Dawley rats were administered piperaquine as an emulsion orally or as a short-term intravenous infusion. Venous blood for pharmacokinetic evaluation was frequently withdrawn up to 90 h after dose. Urine, bile and faeces were collected after an infusion in rats kept in metabolic cages or in anesthetized rats. Pharmacokinetic characterization was done by compartmental modeling and non-compartmental analysis using WinNonlin. Piperaquine disposition was best described by a 3-compartment model with a rapid initial distribution phase after intravenous administration. The pharmacokinetics of piperaquine was characterized by a low clearance, a large volume of distribution and a long terminal half-life. Piperaquine displayed a low biliary clearance and less than 1% of the total dose was recovered in urine. The absolute oral bioavailability was approximately 50%. The main metabolite after intravenous administration of piperaquine was a carboxylic acid product identical to that reported in humans. The similarity with results in humans indicates the rat to be a suitable species for nonclinical in vivo piperaquine studies.     

Pharmacokinetics of piperaquine after repeated oral administration of the antimalarial combination CV8 in 12 healthy male subjects

Objective To investigate the pharmacokinetic properties of piperaquine after repeated oral administration of the antimalarial combination CV8 in healthy subjects.Methods Twelve healthy fasted Vietnamese males were administered four tablets CV8 (320 mg piperaquine phosphate, 32 mg dihydroartemisinin, 5 mg primaquine phosphate, 90 mg trimethoprim) on day 1, followed by two tablets every 24th hour, for a total of 3 days. Blood samples were frequently drawn on days 1 and 3 and sparsely drawn until day 29. Samples were analyzed for piperaquine using solid phase extraction followed by high-performance liquid chromatography. Population pharmacokinetic parameter estimates were obtained by nonlinear mixed effects modeling of the observed data using NONMEM.Results A two-compartment disposition model with an absorption lag time described the observed piperaquine concentrations. Absorption profiles were found to be irregular with double or multiple peaks. A dual pathway first-order absorption model improved the goodness of fit. Piperaquine pharmacokinetics were characterized by a large volume of distribution and a terminal half-life of several days. Estimates [95% confidence interval (CI)] of CL/F, V_ss/F and t½_z were found to be 56.4 (29–84) l/h, 6,000 (3,500–8,500) l and 11.7 (8.3–15.7) days, respectively.Conclusion Piperaquine pharmacokinetics after repeated oral doses were characterized by multiple concentration peaks and multiphasic disposition, resulting in a long terminal half-life. Sustained exposure to the drug after treatment should be taken into account when designing future clinical studies, e.g. duration of follow-up, and may also drive resistance development in areas of high malaria transmission.     

Synergistic anticonvulsant effects of a GABA agonist and glycine

Administration of muscimol to mice in subcutaneous doses between 0.34 and 1.25 mg/kg produced partial protection against 3-mercaptopropionic acid (MPA)-induced seizures. Glycine at a dose of 750 mg/kg (10 mmol/kg) protected 20% of the animals 45 min after its administration. Combined treatment with the two compounds gave a near to complete protection against MPA-induced seizures. These observations suggest that the concomitant enhancement of glycinergic and GABAergic activities amplify the anticonvulsant effect of these neuronal systems against seizures induced by impairment of GABA-mediated transmission.     

Evaluation of trimethoprim and sulphamethoxazole as monotherapy or in combination in the management of toxoplasmosis in murine models

The combination of trimethoprim (TMP) and sulphamethoxazole (SMX) is commonly used for the prevention of cerebral toxoplasmosis although there is no firm experimental basis to support this regimen. We used strain RH tachyzoites for challenge in the acute murine model of toxoplasmosis and found that TMP administered as a single agent, failed to eradicate toxoplasma even at the highest dose (70 mg/kg per day). SMX alone at 600 mg/kg per day, protected ten out of ten mice, although inoculation of brain from surviving animals to naive mice resulted in the development of an encephalitis. When combined, TMP (60 mg/kg per day) and SMX (300 mg/kg per day) protected ten out of ten mice and gave a 'cure' in four out of four mice. In the chronic cystogenic murine models, the combination TMP plus SMX administered from day 5 for 15 days or from day 28 for 288 days, gave protection and even apparent toxoplasmal eradication ('cure') at the highest dosing (60/300 mg/kg per day). However, microscopic severe encephalitis was found in mice classified as 'cured' after reinoculation. This result makes the interpretation of 'cure' very difficult. In conclusion TMP and SMX act synergistically, SMX being the more active arm of the combination. The combination was efficient in preventing the lethal development of chronic toxoplasma encephalitis, but did not guarantee complete recovery.     

Aspirin modulates the anticonvulsant effect of diazepam and sodium valproate in pentylenetetrazole and maximal electroshock induced seizures in mice

Release of prostaglandins in brain after spontaneous and experimentally induced seizures, has been demonstrated. The possible role of prostaglandins in modulation of seizure activity is still inconclusive. In the present study, the effects of aspirin and its interaction with the anticonvulsants (diazepam and sodium valproate) were studied in pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Aspirin 50, 100, and 500 mg/kg, i.p. was administered 45 min before the pentylenetetrazole (60 mg/kg, i.p.) and MES (60 mA, 0.2 s duration via car clip electrodes) challenge. In MES seizures significant protection was seen with aspirin 100 mg/kg where as higher dose of aspirin 500 mg/kg was required to elicit maximum protection against PTZ seizures. Sub anticonvulsant dose of sodium valproate 150 mg/kg, i.p. and aspirin 50 mg/kg i.p. showed complete protection in MES seizures and the same dose of sodium valproate offered superior protection in PTZ seizures than either drug used alone. When mice were pretreated with combination of diazepam 0.5 mg/kg and aspirin 50 mg/kg protection was significantly enhanced in PTZ seizures. However, aspirin did not show any significant protection with subanticonvulsant dose of diazepam against MES seizures. The present study suggests that prostaglandins may have anticonvulsant potential and also may have modulatory effect on anticonvulsant effect of conventional antiepileptic drugs.     

Antitumor effect of KW2149, a new mitomycin derivative, administered by different modalities

The effectiveness of a new mitomycin derivative, KW2149, against human tumors was evaluated by the 4 days subrenal capsule assay (SRCA) and the nude mice screening assay (NMSA). Evaluation by the SRCA showed a 50% response rate at a maximum dose of 3.8 mg/kg for 3 consecutive days. When evaluated by NMSA, the response rate was 100, 75 and 25% after the intermittent administration of 7.5, 5.6 and 4.5 mg/kg (q4dx3) respectively. Although the efficacy was reduced when mice were administered a single dose equivalent to the intermittent one, the new analog was along more effective than MMC administered by either modality.     

Influence of tiagabine on the antinociceptive action of morphine, metamizole and indomethacin in mice

The influence of tiagabine at a dose of 3.2 mg/kg (single administration) and at a dose of 1.2 mg/kg (multiple administration - 10 days) on the antinociceptive effect of morphine (10 mg/kg), metamizole (500 mg/kg) and indomethacin (10 mg/kg - single dose and 1.4 mg/kg - multiple doses) was investigated in mice using the hot-plate and tail-flick tests. All drugs were injected intraperitoneally. Tiagabine was administered to mice 30 min before the analgesic drugs. Measurement of the reaction to a noxious stimulus was performed 60, 90 and 120 min after administration of tiagabine. The study was further conducted for 10 days with repeated drug doses. Tiagabine and morphine administered in single doses demonstrate an additive antinociceptive effect in the hot-plate test and a slightly synergistic effect in the tail-flick test. A single administration of tiagabine slightly increased the antinoceptive action of metamizole and indomethacin in both tests, but that effect is less pronounced than the antinociceptive action of tiagabine alone. Repeated administration of tiagabine with morphine abolishes the tolerance to morphine analgesia. Both single and repeated administration of tiagabine alone exerted the antinociceptive effect in the hot-plate test.