抗癌新药-乙双吗啉(AT-1727)的药理研究

乙双吗啉(AT-1727)是我国合成的一种抗癌新药。它是一种双内酰亚胺化合物,实验证明,乙双吗啉对小鼠肉瘤S₃₇、S₁₈₀有显著抗肿瘤作用,对ECS,HCS,脑瘤B₂₂及L₆₁₅等移植性肿瘤亦有明显抗肿瘤作用。它对S₃₇的50%抑制剂量(ID₅₀)为1.88 mg/kg(ip)及6.61 mg/kg(po)。其抗肿瘤作用与给药方案有一定关系。乙双吗啉对小白鼠毒性LD₅₀为372.8±27.mg/kg(ip)及243.8±26.1 mg/kg(po)。因此,乙双吗啉腹腔注射及口服时,对S₃₇的化疗指数分别为47.5及36.9。给健康犬肌肉注射乙双吗啉25及50 mg/kg/天,连用10天,除出现食量减少,白细胞轻度下降外,对红细胞,血小板、肝、肾功能均无明显影响。乙双吗啉对以溶血素反应为指标的体液免疫有抑制作用;对以移植物抗宿主反应为指标的细胞免疫则无抑制作用。     

天花粉抗早孕作用的药理研究

小鼠妊娠第4、5日皮下注射天花粉,其抗早孕ED₅₀为1.78±0.28 mg/kg。天花粉的抗早孕作用可被甲地孕酮和HCG所部分拮抗,而为15-甲-PGF_2α所增强。抗早孕剂量天花粉对假孕小鼠的蜕膜有明显抑制作用。其抗早孕作用及抑制蜕膜作用均随剂量增加而增强。外源性甲地孕酮可对抗其抗早孕作用和抑制蜕膜作用。提示天花粉的抗早孕作用与其抑制蜕膜反应有关。外源性甲地孕酮有对抗天花粉抑制蜕膜反应的作用,提示天花粉有可能通过对抗假孕小鼠体内黄体激素作用而发挥抑制蜕膜反应的作用。本文初步探讨了这种对抗作用。     

吲哚拉新(Indolacin)的药理研究

吲哚拉新灌胃给药,对角叉菜胶所致大鼠踝关节肿胀具有抑制作用,其 ED_(50)为11.6±6.0mg/kg,对醋酸所致小鼠扭体反应具有抑制作用,其 ED_(50)为111.7±18.1mg/kg。吲哚拉新腹腔注射30mg/kg,对四联菌苗所致家兔体温升高具有降低作用。吲哚拉新灌胃给药80mg/kg 和100mg/kg,对部分大鼠有致胃溃疡作用;同时灌胃给予白芨—甘草和角叉菜胶,剂量均为1600mg/kg,均有抗吲哚拉新致胃溃疡作用。     

丙酸睾丸酮抗早孕作用的药理研究

本文研究表明丙酸睾丸酮在小鼠有明显的抗早孕作用。其抗早孕作用的ED₅₀=0.11±0.03 mg/kg。甲地孕酮、HCG明显对抗丙睾抗早孕作用。丙睾在抗早孕剂量时能明显抑制假孕小鼠蜕膜反应。甲地孕酮能明显对抗丙睾抑制假孕小鼠蜕膜反应的作用。但丙睾对去卵巢小鼠应用外源性雌、孕激素诱发的蜕膜反应无明显抑制作用。丙睾无溶黄体作用,也不增强子宫对催产素和15-甲基-PGF_2α的反应。实验结果提示丙睾抗早孕作用与其抑制蜕膜反应有关。丙睾对蜕膜反应的抑制作用是其抑制下丘脑—垂体—卵巢轴,而非直接拮抗雌、孕激素的结果。     

抗疟药咯萘啶在兔体内的药代动力学

本文报道抗疟药咯萘啶iv,im和ig给药后在兔体内的药代动力学。用NONLIN程序对血药—时间数据进行拟合。一次快速iv 6 mg/kg后的血药—时间过程符合线性三室开模型。药代动力学参数(±SD):t 1/2_β为59±10h;V_c2.418±0.287L/kg;V_d(ss),29±6 L/kg;总清除率Cl_T为0.442±0.131 L/kg·h。Im和ig给药后的动力学过程以线性二室开模型描述。im 6 mg/kg,吸收速率常数K_a为33.5±21.8 h^-1,t 1/2_β为52±8 h,吸收完全。Ig 30或60 mg/kg后的k_a为2.41±1.26 h^-1,t 1/2_β为55±5 h,吸收程度为34.6%。咯萘啶在血中呈不均一分布,im后1～96 h,球/浆浓度比为3～6。     

新型抗心梗药物果糖二磷酸镁的安全性研究

目的　探讨新型抗心肌缺血药———果糖二磷酸镁(FDP-Mg)的安全性。方法　采用Bliss法和QUANTAL程序测定和计算了FDP-Mg的LD₅₀和95%可信限并对其过敏性、溶血性和血管刺激性进行研究。结果　FDP-Mg小鼠静脉注射的LD₅₀为284.81mg/kg ,95%可使限为267.42～302.20mg/kg ;FDP-Mg大鼠静脉注射的LD₅₀为335.15mg/kg ,95%可信限为315.75～354.55mg/kg ;FDP-Mg大鼠静脉滴注[1000mg/(kg·h)]的MLD为(2509.9±226.8)mg/kg。FDP-Mg不引起全身过敏反应和溶血现象,对血管也无刺激性。结论　FDP-Mg用于静脉给药安全可靠。     

双氢青蒿素对小鼠抗疟作用的药效动力学

双氢青蒿素(DHA)是青蒿素的一种还原产物,对感染伯氏疟原虫ANKA株的小鼠一次im给药,其抗疟作用的量—效关系和时—效关系可分别用y=4.9960+2.9536x和y=7.2654-0.3414t表达,进而估算出其ED₅₀和ED₅₀分别为1.00±0.13 mg/kg和2.72±0.70 mg/kg以DHA 5.0 mg/kg im后其药效下降一半的时间为6.6 h,体内有效药量的消除速率常数k为0.2662 h^-1,效量半衰期为2.6 h。式中y为机率单位,是DHA对疟原虫抑制作用的估算值,x为对数剂量,t为DHA im后的间隔时间。     

西洋参茎叶总皂甙的药理、毒理研究

西洋参茎叶中提取的总皂甙,ip25和50mg/kg,可使小鼠自发活动次数由对照组的64.4±18.4减少为16.8±4.4和4.3±2.5(p<0.01);ig425和850mg/kg由73.3±19.7减少为30.8±14.6和18.4±4.8(p<0.01);ig850mg/kg能使阈下剂量的戊巴比妥钠催眠时间持续30.0±0.0min(p<0.01);ip20mg/kg和ig850mg/kg小鼠耐缺氧平均存活时间由对照组的37.6±8.2和37.5±7.7min延长为48.6±8.6和68.3±21.8min(p<0.01);ig30和60mg/kg,可对抗环磷酰胺引起的WBC减少。ip和ig给药,LD_(50)分别为204±SE2.6mg/kg和8511±SE1061mg/kg;长期毒性实验表明,动物体重、脏器重量、WBC、Hcmo各组间无显著差异,GPT、ZTT及TTT均在正常值范围,动物脏器经病理组织学检查属基本正常。     

达比加群在家兔中的药代动力学及其对实验室检查的影响

目的 通过在新西兰大白兔中单剂量服用达比加群酯,对比不同时间点的达比加群血药浓度变化、不同血药浓度时的实验室检查结果,探讨达比加群的药代动力学特征及其对实验室检查结果的影响。 方法 18只新西兰大白兔采用随机数字表法分为5 mg/kg组、10 mg/kg组和对照组三组,每组6只,分别灌胃5 mg/kg、10 mg/kg达比加群酯溶液和等体积的溶剂,于给药前,给药后0.5、1、1.5、2、3、4、6、8、12、24 h取血,通过液相色谱-串联质谱法(LC-MS/MS)检测达比加群血药浓度计算药代动力学参数并分析组间差异;通过检测达比加群浓度(蛇静脉酶发色底物法测定,ECA)、部分凝血酶原时间(APTT)、凝血酶时间(TT),与LC-MS/MS结果做相关性分析,同时对ECA与LC-MS/MS进行Bland-Altman偏倚性分析。 结果 达比加群在各实验组中药代动力学参数:5 mg/kg组:t_max=(2.42±0.66)h、C_max=(131.07±49.95)ng/mL、AUC0→t=(814.56±366.86)ng·h-1·mL-1、AUC0→∞=(902.79±426.86)ng·h-1·mL-1、MRT=(5.69±1.74)h、t1/2=(8.12±1.98)h;10 mg/kg组:t_max=(2.83±1.13)h、C_max=(309.99±189.12)ng/mL、AUC0→t=(1 732.26±605.15)ng·h-1·mL-1、AUC0→∞=(1887.63±616.99)ng·h-1·mL-1、MRT=(5.69±1.83)h、t1/2=(8.47±2.87)h,两实验组t_max、MRT和t1/2均差异无统计学意义(P>0.05)。实验室检查结果:与对照组相比,给药后TT-时间曲线随药-时曲线有类似的变化。APTT与达比加群呈低度相关(R²=0.224);TT与达比加群浓度呈高度相关(R²=0.780)但有过高的敏感性;ECA检测达比加群的血药浓度呈高度相关(R²=0.882),Bland-Altman偏倚性分析提示ECA低估药物浓度。     

怀牛藤总皂甙抗生育作用及其机理

给小鼠灌服怀牛藤总皂甙（ABS）75，150，300mg／kg，表明ABS具有明显的抗着床、抗早孕作用，且呈剂量依赖性关系，其ED50分别为96±27和145±51mg／kg。ABS的抗早孕作用，可被外源性黄体酮、人绒毛膜促性腺激素和泰必利部分拮抗。ABS300mg／kg可显著抑制假孕小鼠和去卵巢小鼠的子宫蜕膜细胞反应，但无雌激素样作用和抗雌激素样作用。     

芹菜甲素和乙素的抗惊厥作用

1-芹菜甲素(1-3-丁基苯酞)和1-芹菜乙素(1-3-丁基-4,5二氢苯酞)是从芹菜籽分离出的抗惊厥有效成分。在小于TD₅₀剂量下,对最大电休克(MES),最小电休克(MET),戊四唑(MST)和原发听源性惊厥(MAS)等四种动物模型有效,可认为有广泛的抗惊作用。其人工合成的dl-芹菜甲素(dl-3-丁基苯酞)更有抗惊作用强,毒性小和便于推广应用的优点。     

加锡果宁抗惊厥作用的机理

采用小鼠最大电休克惊厥法(MES),应用工具药物分析了加锡果宁(Ed)抗小鼠惊厥作用机理.结果,Ed具有较强的抗小鼠MES作用,其作用能被利血平、对氯苯丙胺、氟哌啶醇所对抗,被帕吉林、丙磺舒、L-色氨酸及L-多巴所增强.但α-甲基酪氨酸和酚妥拉明对其抗惊厥作用无明显影响。表明Ed抗惊厥作用与脑内5-MT,DA神经递质有关。     

Synthesis and potential anticonvulsant activity of new aryl sulfonyl semicarbazide derivatives

In the present study on the development of new anticonvulsants, twelve new aryl sulfonyl semicarbazide derivatives were synthesized and tested for anticonvulsant activity using maximal electroshock (MES), subcutaneous pentylenetetrazole screens. Their neurotoxicity was determined by the rotorod test. The most active compound 5i showed the MES-induced seizures with ED₅₀ value of 7.3 mg/kg and TD₅₀ value of 402.3 mg/kg after intraperitoneally injection to mice, which provided compound 5i with a protective index (TD₅₀/ED₅₀) of 55.1 in the MES test.     

Design,synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1,2,4‐triazolone moiety

A novel series of benzoxazole derivatives containing 1,2,4‐triazolone ( 5a‐m ) was designed. These compounds were synthesized in order to screen their anticonvulsant activities by the maximal electroshock seizure (MES) model and the subcutaneous pentylenetetrazole (sc‐PTZ) seizure model in mice. The rotarod test was used to evaluate their neurotoxicities. Most of the compounds showed anti‐MES activities at 100 and 300 mg/kg. Compound 5f , which showed potential anticonvulsant activity in the MES model with ED₅₀ values of 22.0 mg/kg, was considered as the most promising one in this study. It exhibited greater safety than that of carbamazepine and valproate regarding neurotoxicity. The efficacy of compound 5f in inhibiting the tonic seizures and death induced by the convulsants 3‐mercaptopropionic acid and BIC was also verified. In an enzyme‐linked immunosorbent assay, compound 5f and the positive drug phenytoin significantly increased the γ‐aminobutyric acid (GABA) level in the mouse brain. Further, pretreatment with an inhibitor of the GABA synthesizing enzyme dramatically raised the ED₅₀ value of 5f in the MES model. These results confirmed that the compound 5f plays its anticonvulsive action via regulating the GABA function in the brain. Also, a docking study of the compound 5f in the benzodiazepine (BZD) binding site of the GABA_A receptor confirmed possible binding of the compound 5f with BZD receptors.     

Anticonvulsant activity of 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose isolated from leaves of Mangifera indica

The present study was aimed to evaluate the anticonvulsant activity of 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG) isolated from methanolic leaf extracts of Mangifera indica in mice. Anticonvulsant activity of PGG was evaluated against pentylenetetrazole (PTZ)-induced and maximal electroshock (MES)-induced convulsions in mice. Additionally, locomotor activity and GABA levels in the brain were estimated to explore the possible CNS-depressant activity and mechanism behind the anticonvulsant activity, respectively. In these studies, PGG (2.5, 5, and 10 mg/kg, intraperitoneal (i.p.)) showed significant and dose-dependent inhibition of PTZ and MES-induced convulsions. Furthermore, PGG administration showed significant decrease in the locomotor activity as an indication of its CNS-depressant property; also, PGG has significantly increased the GABA levels in the cerebellum and whole brain other than the cerebellum. In conclusion, PGG isolated from M. indica showed potent anticonvulsant activity, and possible mechanism may be due to enhanced GABA levels in the brain.     

丹皮总甙抗实验性癫痫的研究

目的：了解丹皮总甙是否具有抗小鼠实验性癫痫作用。方法：采用最大电惊厥（ＭＥＳ）及戊四唑、士的宁、氨基脲等化学性惊厥模型，观察丹皮总甙（ｔｏｔａｌｇｌｕｃｏｓｉｄｅｓｏｆｍｏｕｔａｎｃｏｒｔｅｒ，ＴＧＭ）对动物惊厥发作数、发作潜伏期及动物存活时间等指标的影响，从而分析ＴＧＭ抗惊厥作用及其时量效关系。结果：ＴＧＭ（６０、８０ｍｇ·ｋｇ－１ｉｐ；８０ｍｇ·ｋｇ－１ｉｇ）可减少小鼠ＭＥＳ发作数，其峰时为药后０．５～１ｈ；ＴＧＭ（６０～８０ｍｇ·ｋｇ－１ｉｇ）可延长戊四唑、士的宁、氨基脲所致小鼠惊厥的潜伏期及动物存活时间；同时ＴＧＭ（４０ｍｇ·ｋｇ－１ｉｐ）可增强苯巴比妥抗上述惊厥之作用。结论：ＴＧＭ（６０～８０ｍｇ·ｋｇ－１）呈剂量依赖性对抗小鼠ＭＥＳ及戊四唑、士的宁、氨基脲所致小鼠化学性惊厥，并可增强苯巴比妥抗惊厥作用。     

中枢与外周α-肾上腺素能受体激动效应不一致性的原理分析

对戊巴比妥钠麻醉家兔,静脉注射α-肾上腺素能受体拮抗剂育亨宾(Yohimbine)或γ-氨基丁酸(GABA)受体拮抗剂苦味毒(picrotoxin)均可明显对抗侧脑室注射氯压定(clonidine)的降血压作用。但是育亨宾不能阻断侧脑室注射GABA的中枢降压作用,而苦味毒则能完全阻断其降压效应。家兔经GABA合成抑制剂氨基脲(Semicarbazide)静脉注射予处理后,动物于给药后3～4小时出现强烈惊厥,说明脑内GABA已降低到一定水平。此时用局部麻醉剂及肌松剂处理,在人工呼吸情况下,氯压定静脉注射的降压作用比不给氨基脲予处理的对照组动物显著减弱。以上结果启示,中枢肾上腺素能受体激动而产生的降压作用有可能是通过GABA能抑制性神经元而实现。     

岗松挥发油对实验性肝损害的防治作用

本研究表明,岗松油对四氯化碳、硫代乙酰胺、醋酸强的松龙引起的小鼠SGPT升高有明显的降低作用,使BSP潴留量减少,相应肝组织病变减轻。此外,岗松油对四氯化碳损害小鼠和正常小鼠戊巴比妥钠的睡眠时间均能明显缩短。对巴豆油引起小鼠耳部炎症有明显的抗炎作用。岗松油的毒性很低,口服半数致死量(LD₅₀为3,758±539mg/kg,给兔灌胃687～1030mg/kg每天一次,连续30天,一般表现、血象、肝肾功能及病理检查均未见明显的改变。     

Synthesis and anticonvulsant activity of N,N-phthaloyl derivatives of central nervous system inhibitory amino acids.

In order to study the influence of the length of the amino acid chain of N,N-phthaloyl-amino acid amides as analogues of the former anticonvulsant taltrimide on the seizure-antagonizing activity glycine, beta-alanine and gamma-aminobutyric acid (GABA) derivatives were synthesized. The corresponding taurine derivatives were also included. Generally, the glycine-derived amides showed a higher activity than the beta-alanine and GABA derivatives in the maximal electroshock seizure (MES) test in mice upon intraperitoneal administration. The activity was comparable to the respective taurine derivatives. The N,N-phthaloyl-glycine amides were also active in the MES test upon oral administration to rats. No significant activity was noted in the seizure threshold test with subcutaneous pentylene-tetrazole. The ED50 of N,N-phthaloyl-glycine ethyl amide (4b) in the MES test upon intraperitoneal administration to mice was 19.1 mg/kg. On a molar basis this activity is comparable to the activity of phenytoin with little toxicity in the rotorod test. In conclusion, N,N-phthaloyl-glycine amides might represent promising antiepileptic drugs.     

Synthesis and evaluation of 7-substituted-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones as anticonvulsant and hypnotic agents

A series of 7-substituted-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones was synthesized. The anticonvulsant effect and neurotoxicity of the compounds were evaluated with a maximal electroshock (MES) test and a rotated test in mice, respectively. Most of the compounds prepared exhibited anticonvulsant activities in the MES test, 7-(heptyloxy)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (10) was the most active. In the anti-MES potency test, it showed a median effective dose (ED₅₀) of 19.0 mg/kg. The hypnotic effect of the compound 10 was initially investigated by using a pentobarbital-induced-sleep test. Middle (30 mg/kg) and high doses (60 mg/kg) of the compound 10 both significantly increased the pentobarbital-induced sleep from 20.9 ± 5.28 to 26.9 ± 6.14 and 45.67 ± 7.94 min, respectively.