六氯对二甲苯对豚鼠肝微粒体药物代谢酶的抑制特性

<正> 前文报道抗华支睾吸虫病药六氯对二甲苯(hexachloro—p—xylene,HCX)对豚鼠肝药酶的抑制作用,HCX能明显延长戊巴比妥催眠时间和血浆戊巴比妥t_(1/2β),并抑制肝匀浆中戊巴比妥侧链羟化酶(pentobarbital side—chain hydroxylase,PSCH)和氨基比林N—脱甲基酶(aminopyrine N—demethylase,ADM)活性。本文在肝微粒体和S9水平,进一步研究了HCX对肝微粒体药物代谢酶的作用,同时对其抑制特性进行了探讨。     

加锡果宁的中枢抑制作用

加锡果宁(Ed)在1/20～1/8 LD_(50)剂量下对小鼠可明显缩短巴比妥或安定的翻正反射消失潜伏期和延长睡眠时间,增强乙醚的麻醉作用,减少自发活动。对某些镇痛药也有增强作用,使家兔脑电呈高幅慢波。延长大鼠总睡眠和慢波睡眠时间,与ip 30mg/kg戊巴比妥钠的作用强度相似,但Ed抑制异相睡眠时间比戊巴妥钠更强。     

HPLC法测定机体中巴比妥酸盐类

在临床上或意外事故中常需对病人体液或组织中的巴比妥酸盐类进行测定,但过去的测定方法都不理想.本文用HPLC法对12种常用巴比妥酸盐进行定性或定量测定,方法快速、灵敏、复演性好.作者用μBondapak C_(18)柱子(15cm×3.9mm,id)测定血浆、尿、死者血液和组织中的巴比妥酸盐,该法已正式用于法庭和临床毒理学分析.材料:1mg/ml巴比妥酸盐甲醇液,血浆和血液的工作液(100和10μg/ml)用甲醇稀释;巴比妥酸盐标准液浓度分别为1、2、5、10、20、50和100μg/ml.50μg/ml阿普巴比妥和1mg/ml酚酞的甲醇液为内标.     

氧化苦参碱对小鼠的中枢抑制作用

氧化苦参碱(oxymartrine, OMT)系从豆科槐属植物苦豆子(Sophora alopecuroides, L)中提取的生物碱.为探讨OMT对小鼠中枢神经系统的影响.ip OMT 15～20min后,分别ip催眠阈剂量(40mg/kg)和阈下剂量(30mg/kg)戊巴比妥钠,观察OMT对戊巴比妥钠催眠作用的影响.应用GJ-1型光电计数仪观察ip OMT对小鼠外观行为活动及对小鼠自由活动的影响,观察OMT对戊四氮(100mg/kg,sc)惊厥及对最大电惊厥(2Hz,40V,10ms)的影响.结果表明,ip OMT 50,100,200mg/kg(LD50为800mg/kg,ip),对小鼠自由活动均有显著抑制作用.对戊巴比妥钠睡眠的影响为缩短入睡时间,显著延长睡眠时间,并能显著加强阈下剂量戊巴比妥钠的催眠作用.OMT 200,400mg/kg ip均不能对抗戊四氮惊厥和最大电惊厥.试验提示氧化苦参碱具有镇静、催眠等中枢抑制作用.     

国产扑喘息敏(Procaterol)的药理研究

扑喘息敏5×10~(-5)-2×10~(-3)mg/ml 对豚鼠离体气管有直接弛张作用,4×10~(-4)-4×10~(-3)mg/ml 可对抗组织胺收缩离体气管的作用,5mg/kg ip 可延长组织胺对豚鼠所致呼吸困难的潜伏期,20mg/kg iv 对麻醉兔有明显而暂时的降血压作用,2.5×10~(-3)mg/ml 可使豚鼠离体心脏收缩幅度增大,心率增加,1×10~(-2)mg/ml 可使灌流液流量和心率增加,3.6×10~(-2)mg/ml、9×10~(-2)mg/ml 可使部分豚鼠离体回肠收缩幅度增大,频率增加,张力增加。扑喘息敏给小白鼠ip,LD_(50)为390.5±20.3mg/kg。     

环孢菌素对麻醉药作用的影响

本文报道小鼠肌注单剂量环孢菌素对戊巴比妥引起的睡眠作用和芬太尼的镇痛作用的影晌.给小鼠肌注环孢菌素60mg/kg,2h后,腹腔注射戊巴比妥钠50mg/kg,测定小鼠翻正反射消失到恢复的时间,测得小鼠睡眠时间为70.4±4.2min(n=6),与给予相同剂量戊巴比妥钠对照组(睡眠时间为30.4±3.2min)相比较,其睡眠时间延长2.3倍.小鼠分组肌注     

镉、铅、汞对苯巴比妥诱导肝微粒体药物代谢酶的影响

一次ip醋酸镉2.4mg/kg、醋酸铅100mg/kg或氯化汞 2.0 mg/kg均可抑制大鼠肝微粒体药物代谢酶。上述处理还可明显降低苯巴比妥对肝微粒’乙基吗啡N-脱甲基化酶、氨基比林N-脱甲基化酶、苯胺羟化酶和环己巴比妥羟化酶活力的诱导作用,降低苯巴比妥对细胞色素P450和细胞色素 b_5以及微粒体蛋白合成的诱导作用。结果提示镉、铅、汞可能通过降低微粒体酶的新生合成,抑制肝微粒体药物代谢酶。     

南药药理的系列研究 (一)对小鼠睡眠时间及肝匀浆细胞色素P_(450)的影响

小鼠连续6d分别PO巴戟、砂仁、槟榔15g/kg,停药24h后,使戊巴比妥钠诱导的小鼠睡眠时间显著缩短,肝重增加;但肝匀浆细胞色素P_(450)含量无明显变化。大鼠结果与小鼠类似。说明三种南药与戊巴比妥间的相互作用与诱导细胞色素P_(450)间并不平衡。     

烟浪丁的抗心律失常作用

NICO 100 mg/kg iv,可明显对抗乌头碱和BaCl_2诱发大鼠及氯仿-肾上腺素引起兔的心律失常;降低CaCl_2所致的大鼠室颤率;提高豚鼠心脏哇巴因中毒时的耐量。50 mg/kg iv,也可预防结扎大鼠左冠状动脉引起的心律失常。50～100 mg/kg ip,能降低氯仿或ACh—CaCl_2引起的小鼠室颤率或房颤(扑)率。NICO可减慢豚鼠心率,且可拮抗异丙肾上腺素的正性变率作用。     

WB_(852)对移植性肝癌腹水型小鼠的抗癌活性和机制研究

小鼠ip WB_(852)LD_(50)为107.7mg/kg,iv LD_(50)为52.2mg/kg。体外实验,4～8×10~(-4)WB_(852)对HepA癌细胞的赤染率可达86～99%。体内实验,WB_(852)ip,40mg/kg/日,连用9日,平均可使生命延长率提高160.9%,25或60mg/kg均使生命延长率提高为124.2%,说明WB_(852)对HepA癌细胞体内外均有显著杀伤作用。采用同位素体外掺入法证明,WB_(852) 1-4×10~(-4)对~3H-TdR掺入HepA癌细胞DNA的合成均有抑制作用,培养1小时的掺入抑制率分别为64.9%和62.7%,5小时抑制率分别为66.3%和57.9%,说明WB_(852)对肝癌细胞DNA的合成有抑制作用。电镜观察表明,WB_(852)对肝癌细胞膜有损害作用,细胞膜破裂,细胞内容物溢出,但对细胞核、核膜及线粒体等则未见影响。     

Effect of the fungicide benomyl on xenobiotic metabolism in rats.

The effect of benomyl administered orally (p.o.) and intraperitoneally (i.p.) on the activity of hepatic microsomal mixed-function oxidases (MFOs) was studied in rats. A dose of 100 mg/kg given i.p. reduced the activities of several hepatic drug-metabolizing enzymes 24 h following the treatment. A similar reduction in the activities of the MFOs was also noted 24 h following oral benomyl administration at a dose of 500 mg/kg. Furthermore, in vivo inhibition of drug metabolism by benomyl was demonstrated by increased pentobarbital sleeping-time 24 h after p.o. as well as i.p. dosing. No alterations were found in the serum sorbitol dehydrogenase (SDH) at 24 h after i.p. or oral benomyl indicating a lack of hepatotoxic effect. These results indicate that benomyl shows a route-independent effect on MFOs and is not toxic to the liver.     

利福喷丁对小鼠肝微粒体药酶的诱导作用

连续给小鼠口服利福喷丁40mg/kg或20mg/kg14日后,用药鼠的戊巴比妥钠催眠时间显著缩短,利福喷丁血浓下降,鼠肝重增加,而SGPT活性无改变。鼠肝细胞中细胞色素P-450和细胞色素B_b含量明显增加,表明利福喷丁有诱导小鼠肝药酶的作用。     

Effects of combinational prophylactics composed of physostigmine and procyclidine on soman-induced lethality, seizures and brain injuries

The antidotal, anticonvulsant and neuroprotective effects of physostigmine (PhS) and procyclidine (PC), the combinational prophylactics for organophosphate poisoning, were evaluated. For the investigation of dose-response relationship in rats and guinea pigs, various doses (0-6 mg/kg) of PC in combination with a fixed dose (0.1 mg/kg) of PhS were pretreated subcutaneously 30 min prior to subcutaneous poisoning with soman. Procyclidine in combination with PhS exhibited remarkable synergistic effects in a dose-dependent manner, leading to 1.92-5.07 folds of protection ratio in rats and 3.00-4.70 folds in guinea pigs. On the other hand, a low effect (1.65 fold) was achieved with the traditional antidotes atropine (17.4 mg/kg) plus 2-pralidoxime (30 mg/kg) treated immediately after soman poisoning, compared with a marked protection (5.50 fold) with atropine (17.4 mg/kg) plus HI-6 (125 mg/kg) in unpretreated rats. Noteworthy, the combinational prophylactics greatly potentiated the effect of atropine plus 2-pralidoxime to 6.13 or 12.27 folds and that of atropine plus HI-6 to 12.00 or 21.50 folds with 1.0 or 3.0 mg/kg of PC, respectively. A high dose (100 μg/kg, 1.3×LD(50)) of soman induced severe epileptiform seizures in rats pretreated with HI-6 (125 mg/kg), resulting in brain injuries in discrete brain regions under histopathological examination in 24 h. Interestingly, such seizures and excitotoxic brain injuries were fully prevented by pretreatment with PhS (0.1 mg/kg) and PC (1 mg/kg). Taken together, it is proposed that the prophylactics composed of PhS and PC could be a promising regimen for the prevention of lethality, seizures and brain injuries induced by soman poisoning.     

Induction of cytochrome P-450 and related drug-oxidizing activities in muscone (3-methylcyclopentadecanone)-treated rats

In the present study, we investigated the effects of muscone on both in vitro and in vivo parameters of the hepatic microsomal drug-metabolizing enzyme system and other enzyme activities in rats. In the in vivo study, the serum dimethadione (DMO)/trimethadione (TMO) ratios at 2 hr after oral administration of TMO (100 mg/kg) were significantly increased in both male and female rats treated with 75 and 150 but not 40 mg muscone/kg. Antipyrine metabolite profile in 24 hr urine of rats pretreated with muscone (150 mg/kg) was examined. The results showed that the excretion of norantipyrine was significantly increased as compared to the control group. In the in vitro study, we found that the content of cytochrome P-450, and activities of aminopyrine, N-demethylase, aniline hydroxylase and delta-aminolevulinic acid (ALA) synthetase were significantly increased as compared to the controls in both male and female rats treated with muscone (75 and 150 mg/kg). This type of induction of the hepatic metabolizing enzymes was similar to that seen after treatment with a prototype drug, phenobarbital.     

Effect of pretreatment with some mixed-function oxidase enzyme inducers on the acute hepatotoxicity of coumarin in the rat

Male Sprague-Dawley rats were pretreated with saline, corn oil, sodium phenobarbitone (PB) (100 mg/kg body weight/day), 20-methylcholanthrene (20 MC) (20 mg/kg body weight/day) or Aroclor 1254 (ARO) (100 mg/kg body weight/day) by daily ip injections for 5 days. Animals were then given single oral doses of either 250 or 500 mg coumarin/kg body weight and hepatotoxicity was assessed after 24 hr. Coumarin produced hepatotoxicity, which comprised hepatocyte necrosis and elevation of plasma alanine aminotransferase and aspartate aminotransferase activities, in all pretreated groups. Hepatic microsomal cytochrome P-450 levels were reduced after coumarin administration. In rats pretreated with saline, corn oil or PB, coumarin produced centrilobular hepatic necrosis, whereas in rats pretreated with 20 MC or ARO, coumarin produced periportal hepatic necrosis. These results demonstrate that mixed-function oxidase enzyme inducers can modulate acute coumarin-induced hepatotoxicity in the rat. As coumarin is known to be bioactivated by cytochrome P-450-dependent enzymes, the change in the lobular distribution of toxicity after pretreatment with 20 MC or ARO is presumably due to the induction of particular cytochrome P-450 isoenzymes in periportal hepatocytes.     

Comparison of the effects of piperine administered intragastrically and intraperitoneally on the liver and liver mixed-function oxidases in rats

Piperine, a major pungent constituent of black and red peppers, was administered to rats intragastrically and intraperitoneally to study whether it alters the activities of hepatic mixed-function oxidases (MFO) and serum enzymes as specific markers of hepatotoxicity. An intragastric dose of 100 mg/kg of piperine to adult, male Sprague-Dawley rats caused an increase in hepatic microsomal cytochrome P-450 and cytochrome b5, NADPH-cytochrome c reductase, benzphetamine N-demethylase, aminopyrine N-demethylase and aniline hydroxylase 24 h following treatment. On the other hand, a 10 mg/kg dose given i.p. exhibited no effect on the activities of the aforementioned parameters of the hepatic drug-metabolizing enzyme system. However, when the intragastric and intraperitoneal doses were increased to 800 mg/kg and 100 mg/kg, respectively, the black pepper alkaloid produced a significant decrease in the levels of cytochrome P-450, benzphetamine N-demethylase, aminopyrine N-demethylase and aniline hydroxylase 24 h after treatment. None of the treatments significantly elevated the activities of serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and isocitrate dehydrogenase (ICD), suggesting that piperine is not a hepatotoxic agent.     

滴滴涕和六六六对戊巴比妥体内转化的双相影响

滴滴涕和六六六对大鼠肝脏转化戊巴比妥的作用都是双相的,卽先抑制而后刺激;对小鼠的作用,六六六是双相的,滴滴涕则只有抑制相,连续多次给与滴滴涕和六六六的所以能缩短大鼠戊巴比妥睡眠时间,除刺激药物转化酶外,部分由于肝脏重量的增加。苯巴比妥能进一步缩短滴滴涕处理大鼠的戊巴比妥睡眠时间,而对六六六处理动物则无明显影响。六六六和滴滴涕都能使大鼠尿中的维生素C排泄增加。     

Effect of the catecholamine-depleting agent 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624) on drug metabolism in the rat

Male rats injected with 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624) (25 mg/kg/day i.p.) for 3 days prior to induction of anesthesia with pentobarbital (40 mg/kg, i.p.) slept significantly (P < 0.05) longer than control animals. Plasma and brain half-lives of pentobarbital were also prolonged in the treated animals, but both control and treated groups awakened with similar brain levels of pentobarbital. In addition, the plasma half-life of antipyrine in treated animals was also prolonged significantly. Subacute administration of U-14,624 (50 mg/kg/day i.p.) to male rats for 5–7 days suppressed the activities of aminopyrine N-demethylase, aniline hydroxylase and p-nitroanisole O-demethylase enzymes in vitro; this effect could not be demonstrated at lower doses. Single doses of U-14,624 (100–200 mg/kg, i.p.) also suppressed the activities of the three oxidative enzymes. The suppression was positively correlated with reduced levels of hepatic microsomal cytochrome P-450. Levels of cytochrome b₅ and NADPH-cytochrome c reductase activity were not affected consistently by acute dosage with U-14,624. The inhibitory effects of single doses (100–400 mg/kg, i.p.) on all enzymatic systems were reversible, and recovery was complete within 48 hr. Whereas all three oxidative drug-metabolizing enzymes were inhibited in a mixed manner by in vitro exposure to U-14,624 (10^?5–10^?2 M), neotetrazolium diaphorase was not inhibited by U-14,624 at concentrations as high as 5 mM. Inhibition of oxidative drug metabolism by U-14,624 is mechanistically related to depletion of cytochrome P-450, but inhibition of these enzymes in vitro indicates that a second inhibitory mechanism may also be operative.     

Effect of DP-1904, a thromboxane synthetase inhibitor, on antigen- and spasmogen-induced bronchoconstriction in rodents

The effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetra-hydronaphthalene-2-car boxylic acid hydrochloride], a selective thromboxane synthetase inhibitor, was examined on antigen- and spasmogen-induced bronchoconstriction in rodents. Oral administration of DP-1904 (1, 3, 10 mg/kg) as well as OKY-046 (sodium (E)-3[4-(1-imidazolylmethyl)-phenyl]-2-propanoate, 100 mg/kg), significantly inhibited immunoglobulin G-mediated bronchoconstriction in actively sensitized guinea pigs. Immunoglobulin E-mediated bronchoconstriction in actively sensitized rats was also inhibited by both DP-1904 (1, 10 mg/kg) and OKY-046 (100 mg/kg). DP-1904 (3-30 mg/kg) and OKY-046 (30 mg/kg) suppressed leukotriene D4-induced bronchoconstriction in guinea pigs. In these models, the endogenous levels of thromboxanes significantly increased following the stimulus (antigen and leukotriene D4). DP-1904 (10 mg/kg) inhibited the increase in thromboxane level in both plasma and bronchial alveolar lavage fluid. These actions of DP-1904 persisted for more than 12 h, indicating a long-lasting effect of DP-1904 on bronchoconstriction. The results showed that the biological activity of DP-1904 in our rodents models is more potent than that of OKY-046 (Ozagrel), which is available as an anti-asthma agent in Japan.