二苯乙烯(芪)的一些药理作用

芪(二苯乙烯)通常用于化学工业,对其药理活性的研究很少。通过动物实验我们发现芪能明显保护CCl_4引起的小鼠肝损害,表现在使高的SGPT及SGOT降低、BSP潴留减少、肝组织病变减轻等。芪明显促进肝糖元生成,此作用强度与可的松相近,但芪没有可的松那样的抗炎作用。在去肾上腺小鼠,芪仍能明显促进肝糖元生成,故此作用似乎不通过体内的垂体-肾上腺系统。芪对小鼠戊巴比妥睡眠时间影响不明显。根据实验资料分析,芪对CCl_4肝损害的保护机制大概不是通过酶诱导,也不象某些抗氧化剂那样直接对抗CCl_4的作用,但有可能与其促进肝糖元生成有某种关系。 芪有微弱的雌激素作用(约为己烯雌酚的数万分之一)。 芪的毒性很低,小鼠一次腹腔注射LD_(50)为6.5 g/kg,灌胃LD_(50)大于8 g/kg,但油溶液毒性较大(灌胃LD_(50)为0.92g/kg)。长期大量给予芪,对雄小鼠的生长及睾丸发育有抑制作用,给狗服芪50 mg/kg/天连续一个月以上未见明显异常反应。     

龙葵碱对小鼠睾丸生殖细胞线粒体损伤的研究

目的：研究龙葵碱对小鼠睾丸的毒性作用。方法：30只雄性小鼠,体质量20～24 g。随机分成5组,每组6只。采用ip龙葵碱对小鼠进行染毒,染毒剂量分别是1/8 LD₅₀（5.25 mg/kg）、1/4 LD₅₀（10.5 mg/kg）、1/2LD₅₀（21 mg/kg）。另设阴性对照组（生理盐水组）,阳性对照组（环磷酰胺,CP,给药剂量40 mg/kg）,龙葵碱不同浓度组连续染毒14 d。应用紫外分光光度法测定睾丸中SDH、MDA、SOD、GSH的活力。结果：龙葵碱染毒两周后,GSH的量仅1/2LD₅₀染毒剂量组与空白组相比较呈非常显著性差异（P＜0.01）;随着染毒剂量的增加, MDA含量增加,1/2 LD₅₀、1/4 LD₅₀、1/8 LD₅₀染毒剂量组与空白组比较呈非常显著性差异（P＜0.01）;随着染毒剂量的增加SOD的活性降低明显,1/2 LD₅₀、1/4LD₅₀染毒剂量时,SOD活性的降低与空白组比较呈非常显著性差异（P＜0.01）;随着染毒剂量的增加SDH的活性降低明显,1/2LD₅₀、1/4LD₅₀染毒剂量时,SDH活性的降低与空白组比较呈非常显著性差异（P＜0.01）。结论：龙葵碱能够使SDH、MDA、SOD、GSH活力降低,从而导致自由基增多,呼吸链和氧化磷酸化脱偶联,三羧酸循环被阻断,线粒体基质渗透压升高,内膜肿胀,使线粒体的功能发生障碍,线粒体氧化损伤。     

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。     

补骨脂素和异补骨脂素的急性毒性和相互作用

目的 探究补骨脂素、异补骨脂素的急性毒性及两者（1∶1）混合使用后的相互作用。方法 补骨脂素（1 125、843、633、475 mg/kg）、异补骨脂素（475、404、343、292 mg/kg）以及两者1∶1的混合物（633、538、457、389、330 mg/kg）1次性ig给予小鼠,连续观察并记录14 d小鼠的毒性反应和死亡情况,用SPSS计算补骨脂素、异补骨脂素以及两者混合使用后的半数致死量（LD₅₀）,用等效线图解法判断两者的相互作用。结果 给药组小鼠均出现僵直、腹部贴地、活动力减弱,甚至抽搐、口眼周有分泌物,心率减慢直至死亡的现象,与助溶剂组比较,体质量呈降低趋势;补骨脂素LD₅₀为638.69 mg/kg,95%可信限为526.91～785.78mg/kg;异补骨脂素LD₅₀为351.72 mg/kg,95%可信限为248.17～394.57 mg/kg;两者1∶1混合给药的LD₅₀为454.66 mg/kg,95%可信限为422.58～489.59;两者合用的LD₅₀在补骨脂素和异补骨脂素相加等效线上。结论 补骨脂素和异补骨脂素大剂量给予小鼠时,引起药物急性毒性反应,1∶1混合给药具有相加作用。     

克班宁急性毒性与抗心律失常活性的初步研究

目的研究克班宁(crebanine,Cre)的急性毒性与抗心律失常作用。方法以改良寇氏法考察小鼠静注LD₅₀,以BaCl₂致大鼠心律失常模型观察Cre的治疗与预防作用。结果LD₅₀为9.382mg/kg,95%可信限为8.314～10.600mg/kg;治疗组与预防组iv Cre2.5mg/kg可使大鼠恢复窦律,与对照(生理盐水)组相比,差异有显著性意义。结论Cre有一定的毒性,对大鼠实验性心律失常具有治疗与预防作用。     

枳梖子对实验性肝损伤的防护作用

CCl₄性肝损伤小鼠血清GPT活处、血消和肝MDA含量显著性升高,但血糖和白蛋白浓度显著性下降,表明肝脏结构与功能的严重损伤,用枳子匀浆灌胃14d,然后用CCl₄时,上述指标变化幅度明显变小,提示枳子对CCl₄引起的肝损伤具有防护作用。枳子能显著升高正常小鼠体内SOD活性,降低MDA含量,这种明显的抗脂质过氧化作用,可能是其抗CCl4性肝损伤的代谢机制。     

盐酸关附甲素注射液对实验性心律失常的作用

关附甲素是从关白附子块根中提取的一种新生物碱。实验表明IGFAH(50　g/ml)对大鼠离体心脏结扎冠脉诱发的室性心律失常有明显的保护作用,IGFAH3、6、12mg/kgiv能显著提高电刺激麻醉兔心室致颤阈值,IGPAH13.4,16.8,21.0mg/kgiv能明显对抗Cal₂-Ach液诱发小鼠房扑(颤),其ED₂为12.4±1.5mg/kg。IGFAH10,25,40mg/kgiv对乌头碱诱发的大鼠室性心律失常有明显的保护作用。IGFAH小鼠iv的LD₅₀为163.9mg/kg,其96%可信限为151.9—176.7mg/kg。     

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。     

麝香的药理研究 Ⅱ.麝香及其有效成分的抗炎作用

麝香水提物对小鼠巴豆油耳部炎症,大鼠琼脂性关节肿、酵母性关节肿、佐剂型多发性关节炎均具非常显著的抑制作用。对大鼠烫伤性血管渗透性增加、羧甲基纤维素引起的腹腔白细胞游走亦具非常明显的抑制作用。静脉注射麝香1号对巴豆油小鼠耳炎症的50%抑制剂量为0.63 mg/kg,为氢化可的松作用强度的36倍,如以克分子剂量相比,则为氢化可的松的500倍以上。静脉注射麝香水提物对小鼠的LD₅₀及95%可信限为848±104 mg/kg。     

4种川乌类药材急性毒性的差异性研究

目的 比较同源饮片川乌、黑附片、白附片与天雄之间急性毒性及其所引发毒性表现的差异性。方法 采用急毒实验方法测定小鼠灌胃生川乌和黑附片提取物的半数致死量（LD₅₀）和天雄提取物的药物最大耐受量（MTD）,同时对白附片提取物做限度实验并观察小鼠毒性表现。结果 生川乌和黑附片半数致死量测定结果分别为4.55 g饮片/kg和78.71 g饮片/kg;天雄药物最大耐受量测定结果为34.19 g饮片/kg;白附片提取物以5 g·kg^-1的剂量灌胃小鼠,引起严重毒性反应,但不能引起小鼠死亡。4种饮片引起的毒性表现十分相似,可能累及神经、呼吸和循环等多个系统,不同的是除白附片外,其他3种饮片均可使小鼠发生眼球突出、惊厥甚至死亡反应。结论 4种饮片的急性毒性由大到小依次为生川乌、黑附片、天雄和白附片。虽然其引发的毒性表现十分类似,但是在严重程度上略有差异。     

Protective effects of Coriandrum sativum extracts on carbon tetrachloride-induced hepatotoxicity in rats

Oxidative damage is implicated in the pathogenesis of various liver injuries. The study was aimed to investigate the antioxidant activity of Coriandrum sativum on CCl₄ treated oxidative stress in Wistar albino rats. CCl₄ injection induced oxidative stress by a significant rise in serum marker enzymes and thiobarbituric acid reactive substances (TBARS) along with the reduction of antioxidant enzymes. In serum, the activities of enzymes like ALP, ACP and protein and bilirubin were evaluated. Pretreatment of rats with different doses of plant extract (100 and 200 mg/kg) significantly lowered SGOT, SGPT and TBARS levels against CCl₄ treated rats. Hepatic enzymes like SOD, CAT, GPx were significantly increased by treatment with plant extract, against CCl₄ treated rats. Histopathological examinations showed extensive liver injuries, characterized by extensive hepatocellular degeneration/necrosis, inflammatory cell infiltration, congestion, and sinusoidal dilatation. Oral administration of the leaf extract at a dose of 200 mg/kg body weight significantly reduced the toxic effects of CCl₄. The activity of leaf extract at the dose of 200 mg/kg was comparable to the standard drug, silymarin. Based on these results, it was observed that C. sativum extract protects liver from oxidative stress induced by CCl₄ and thus helps in evaluation of traditional claim on this plant.     

Biochemical and histopathological effects on liver due to acute oral toxicity of aqueous leaf extract of Ecliptaalba on female Swiss albino mice

Background:

Limited data is available about the toxicity of herbal remedies used for self-medication. Since a popular medicinal plant Ecliptaalba contains various bioactive molecules, the present study aimed to observe the biochemical and histological changes in liver associated with acute oral toxicity (LD₅₀) of aqueous extract of E. alba (L.) Hassk. in female Swiss albino mice.

Materials and Methods:

For the acute oral toxicity study, the animals were divided into six groups of 6 mice each. Group– I was normal control and the treatment groups were administered aqueous leaf extract of E. alba orally at different doses of 500 mg (group – I),1750 mg (group–III), 2000 mg (group- IV), 2500 mg (group- V) and 3000 mg/ kg/b.wt.(group- VI) for seven consecutive days. The mice were sacrificed on the eighth day and blood was collected for the analysis of ALP (alkaline phosphatase), SGPT (serum glutamic pyruvic transferase), total protein and albumin. The liver was dissected, weighed, and processed for histopathological analysis.

Results:

The LD₅₀ was found to be 2316.626 mg/kg /body weight in female mice. Serum SGPT, total protein and albumin increased in treated group- IV (P < 0.05), V (P < 0.01), and VI (P < 0.01) as compared to the control (group- I). ALP level significantly decreased in the treated group- IV (P < 0.05), V (P < 0.01) and VI (P < 0.01). Histopathological changes were observed at dose of 2000 mg (group- IV), 2500 mg (group- V) and 3000 mg (group- VI).

Conclusion:

It was concluded that oral administration of aqueous leaf extract of E. alba had detrimental effects on biochemical parameters and induced histopathological alterations in liver of female Swiss albino mice at doses higher than 2000 mg/kg/day indicating that its indiscriminate use should be avoided.KEY WORDS: Biochemical, Ecliptaalba, hepatotoxicity, histopathological     

Potentiation of the hepatotoxicity of carbon tetrachloride following preexposure to chlordecone (kepone) in the male rat.

The effect of carbon tetrachloride (CCl₄) challenge on several parameters of hepatic injury was determined in chlordecone (CD)-pretreated male rats. Following a 15-day feeding of 0 or 10 ppm CD, rats received a single intraperitoneal challenge of 0, 25, 50, 100, or 200 μl CCl₄/kg. Twenty-four hours after CCl₄, biliary excretion of phenolphthalein glucuronide (PG), bile secretion, and serum transaminase (SGPT, SGOT) activities were examined as functional indices of hepatic injury. Feeding of 10 ppm CD alone resulted in decreased biliary excretion of PG (59% of control) but had no effect on bile flow or on serum transaminases. Twenty-four hours after CCl₄ alone, the two high doses caused decreased biliary excretion of PG in the absence of any effect on bile flow and doubled serum transaminases at the highest dose (200 μl/kg). A single challenge of CCl₄ to CD-fed rats resulted in a dose-dependent impairment of PG excretion at a dose of 50 μl/kg and higher. Bile secretory function was severely impaired in the CD-fed animals receiving CCl₄ at the doses of 100 and 200 μl/kg. Decreased bile flow was not seen in any other groups. Greatly potentiated hepatotoxicity was reflected in the form of elevated SGPT and SGOT activities which increased in excess of 30- and 10-fold, respectively, in CD-fed rats challenged with CCl₄ at 100 and 200 μl/kg. Parenchymal liposis (cytoplasmic sudanophilic droplets) developed in all CD-fed rats receiving CCl₄, while necrosis occurred after CCl₄ at 50 μl/kg and increased in a dosedependent manner. CCl₄ controls exhibited parenchymal liposis and limited centrilobular necrosis only at the two highest doses of CCl₄. These data indicate a great potential for production of severe liver damage resulting from interactions of CCl₄ and CD exposure at levels which may be independently nontoxic.     

联苯双酯、二苯乙烯、五仁醇及灵芝对小鼠实验性肝损伤保护作用的比较

联苯双酯系合成五味子丙素的一种中间产物。二苯乙烯系合成五味子丙素所用的一种化工原料,我们对这两种化合物与五味子和灵芝对小鼠肝脏的作用进行了比较,结果表明,对于四氯化碳、硫代乙酰胺引起的血清谷丙转氨酶(SGPT)升高,联苯双酯、五味子、灵芝及二苯乙烯均有降低作用。对强的松龙所致的SGPT升高,仅联苯双酯有降低作用,其余三种无效。对于四氯化碳和硫代乙酰胺引起的小鼠肝脏甘油三酯的蓄积,除联苯双酯无效外,五味子、灵芝及二苯乙烯均有明显降低作用。对强的松龙引起小鼠肝脏甘油三酯的蓄积,仅二苯乙烯能使其降低,而灵芝使其蓄积更多,联苯双酯和五味子则无明显影响,对DL-乙硫氨酸引起的脂肪肝,灵芝和二苯乙烯有明显预防作用,五味子无效,联苯双酯使蓄积更明显。此外,五味子和二苯乙烯能促进小鼠肝糖原的生成,联苯双酯对四氯化碳中毒小鼠有缩短戊巴比妥钠睡眠的作用。总之,上述四种药物对小鼠肝脏的作用,有的相似,有的不同。从临床治疗角度考虑,试用药物时,合并用药可能更好,这样各药可以取长补短。     

Some Studies on the Rodenticidal Action of Indomethacin

ABSTRACT

The oral LD₅₀ of indomethacin for a seven-day observation was found to be 12.58μpM1.15 mg/kg. At LD₁₀ of 6.61 mg/kg, a dose to weight ratio of 28 was obtained for a 240g rat, while at a maximum single dose of 3 mg/kg in man it is only 0.04. Neither diazepam nor phenobarbital influenced death at the doses of both drugs used. However, cholestyramine 2g/kg/day was found to protect by 50% from the LD₁₀₀ of indomethacin. Gross pathological studies showed dose-dependent ulceration and perforation (P < 0.001, 12 vs 24 mg/kg) and such lesions occurred in starved rats, were low in bile duct-ligated compared to sham-operated rats (P < 0.001) and were also low in cholestyramine-treated rats. Indomethacin-induced lethality in rats was found to be dose-dependent.     

Prevention of Carbon Tetrachloride-Induced Hepatotoxicity by the Ethanol Extract of Capparis moonii Fruits in Rats

The effect of the ethanol extract of Capparis moonii Hook. f. Thoms. (Capparidaceae) fruits was studied in carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. The hepatotoxicity was induced in rats with the administration of 1 : 1 (v/v) mixture of CCl₄ in olive oil at the dose of 1 ml/kg subcutaneously on day 7. The ethanol extract of C. moonii (200 mg/kg) and the standard drug silymarin (25 mg/kg) were given orally from day 1 to day 9. The extract of C. moonii produced significant (p &lt; 0.001) lowering of the elevated Serum glutamic oxaloacetic transaminace (SGOT) Serum glutamicpyraric transaminase (SGPT), alkaline phosphatase (ALP), and a rise of depleted total protein when compared with the toxic control. The results were comparable with the standard drug silymarin.     

Effectiveness of metyrapone in the treatment of acetaminophen toxicity in mice

Metyrapone tartrate, 400 mg/kg i.p. raised the LD₅₀ for acetaminophen from 340 mg/kg i.p. to 540 mg/kg i.p. in fasting male Swiss white mice. The minimum protective dose of metyrapone was 200 mg/kg. Metyrapone was effective in preventing death when given up to 2 h after acetaminophen administration. The LD₅₀ for metyrapone tartrate was 760 mg/kg i.p. Metyrapone decreased or prevented acetaminophen induced hepatic damage measured either by histology or plasma glutamate pyruvate transaminase activity. Metyrapone tartrate, 400 mg/kg i.p., inbibited the severe liver glutathione depletion seen with acetaminophen alone. It is proposed that metyrapone protects mice from acetaminophen induced liver toxicity and death by inhibiting the oxidation of acetaminophen to a toxic intermediate.     

A safety study on single intravenous dose of tetrachloro-diphenyl glycoluril [iodogen] dissolved in dimethyl sulphoxide (DMSO)

Abstract

1. Iodogen (tetrachloro-diphenyl glycoluril) dissolved in DMSO (dimethyl sulphoxide) appears indispensable in radioiodination of hypericin for a new anticancer strategy. We studied the safety of intravenously administered iodogen/DMSO in mice (n?=?132).

2. Median lethal dose (LD₅₀) of iodogen/DMSO was determined with doses of 40.0, 50.0, 55.0, 60.0, 65.0 and 70.0?mg/kg. Next, toxicity of iodogen/DMSO at 30.0?mg/kg was evaluated using saline and DMSO as controls. Changes in behaviour, body weight and serum biochemistry were evaluated. Histopathology of lungs, heart, liver and kidney was performed.

3. LD₅₀ values of iodogen/DMSO were 59.5?mg/kg (95% confidence limits (CI): 54.1–65.4?mg/kg) and 61.0?mg/kg (95%CI: 56.2–66.2?mg/kg) for female and male mice, respectively. Similar to that of control groups, no animal deaths were encountered after iodogen/DMSO administration at 30.0?mg/kg. Body weights over 24?h were not altered in all groups, but significantly higher in iodogen/DMSO and DMSO groups (p?<?0.05) 14?d post-injection. Blood urea nitrogen and alkaline phosphatase increased (p?<?0.05) in iodogen/DMSO group without clinical symptoms. No pathologies were found by gross and microscopic inspection.

4. A single dose of iodogen/DMSO up to 30.0?mg/kg, over 3000 times the dose in potential human applications, appears safe, with an LD₅₀ doubling that dose in mice.     

Suppression of Humoral and Cell-Mediated Immune Responses by Carbon Tetrachloride

Suppression of Humoral and Cell-Mediated Immune Responses byCarbon Tetrachloride. KAMINSKI, N. E., JORDAN, S. D., HotSAPPIM. P. (1989). Fundam Appl. Toxicol 12, 117–128. The effectsof carbon tetrachloride (CCl₄. following 7 consecutive daysof exposure ip at 500, 1000, and 1500 mg/kg, were determinedon murine humoral and cell-mediated immune responses, body andorgan weights, spleen cell blastogenesis following mitogenicstimulation, and clinical serum parameters for liver injury.In vivo sensitization of CCl₄ B6C3F1 mice resulted in a dose-dependentsuppression of the T-dependent antibody response to sheep redblood cells (sRBC) at all doses-36, 48, and 53%, respectively.The T-independent in vivo antibody response to DNP-Ficoll wassuppressed only at 1500 mg/kg, and only by approximately 16%.This dosing regimen also resulted in a significant decreasein thymus weights; however, there were no significant effectson liver, kidney, lung, or body weights. The serum chemistryprofile indicated a dose-dependent increase in serum glutamic-pyruvictransaminase (SGPT) levels (34-, 47-, and 55-fold) and a non-dose-dependentincrease in serum bilirubin and total protein. Serum glucoseand albumin levels were unaffected. Splenocytes from mice treatedwith 1500 mg/kg and sensitized in vitro with antigen demonstrateda comparably suppressed antibody response to the antigens sRBCand DNP-Ficoll as observed in vivo-66 and 28% respectively.This dose of CCl₄ had no effect on the in vitro antibody responseto the polyclonal antigen lipopolysaccharide. The mixed lymphocyteresponse was dose dependently suppressed following CCl₄ exposure;however, the delayed-type hypersensitivity response was unaffected.Lymphocyte blastogenesis following mitogenic stimulation withlipopolysaccharide or concanavahn A was also inhibited by CCl₄exposure. These studies demonstrate that exposure to CCl₄ resultsin marked suppression in both humoral and cell-mediated immuneresponses at concentrations which also affect the liver as evidencedby the marked increase in SGPT levels.