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。     

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。     

龙脑和异龙脑对小鼠和家兔的药理作用

对龙脑、异龙脑进行了急性毒性、局部刺激性、耐缺氧、镇痛、延长戊巴比妥睡眠时间等试验。观察到龙脑的毒性较异龙脑小。龙脑、异龙脑有镇痛、延长戊巴比妥引起的睡眠时间的作用。异龙脑能显著延长耐缺氧时间,龙脑的这一作用则不显著。龙脑、异龙脑的局部刺激性均较小,粘膜用药时异龙脑的刺激性略大于龙脑,肌注时则相反。     

柏子养心丸镇静催眠作用实验研究

目的:考察柏子养心丸对小鼠的镇静催眠作用。方法:采用戊巴比妥钠对小鼠睡眠的协同作用方法。结果:柏子养心丸可明显延长阈上剂量戊巴比妥纳所致小鼠睡眠时间,增加阈下剂量戊巴比妥钠睡眠动物数。结论: 提示柏子养心丸具有镇静催眠作用。     

灵芝孢子粉改善睡眠的实验研究

目的 探讨灵芝孢子粉改善睡眠的作用.方法 通过直接睡眠试验、延长戊巴比妥钠睡眠时间试验、戊巴比妥钠阈下剂量催眠试验、巴比妥钠睡眠潜伏期试验,观察灵芝孢子粉对睡眠的作用.结果 一定剂量的灵芝孢子粉能使戊巴比妥诱导的小鼠睡眠时间延长,睡眠发生率提高,巴比妥钠诱导的小鼠睡眠潜伏期呈现一定的剂量反应关系.结论 灵芝孢子粉对小鼠有改善睡眠的作用.     

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。     

醒脑静注射液的药效学研究

目的：对醒脑静注射液作为中药急救制剂的药效进行评估;方法：观察醒脑静注射液对小鼠耳廓肿胀、扭体、睡眠时间的影响;对四氯化碳致肝脏 损伤大鼠AST、ALT水平的影响;对细菌内毒素致热家兔体温的影响;对8种标准菌株的抑菌效果。结果：醒脑静注射液能明显缩短戊巴妥钠致小鼠睡眠时间;抑制二甲苯致小鼠耳廓肿胀;减少冰醋酸致小鼠扭体次数;明显抑制细菌内毒素致家兔体温升高;对实验菌株有不同程度的抑制效果;能降低四氯化碳致肝脏损伤大鼠的AST、ALT水平。结论：该药具有兴奋中枢、解热、镇痛、抑菌、抗炎、保肝的药效。     

薄荷醇对戊巴比妥中枢抑制作用的影响

研究薄荷醇经胃肠道给药戊巴比妥中枢抑制作用的影响，结果发现，薄荷对戊巴比妥的中枢抑制作具有一定的量效关系，含４．５％的薄荷醇溶中明显使小鼠的入睡时间短，并使急性死亡率增加，而含１．５％和０．５％的薄荷溶液对戊巴比妥的中枢抑制作用的无明显影响。     

静心助眠口服液改善睡眠功能试验

目的研究静心助眠口服液对小鼠睡眠功能的影响。方法采用改善睡眠功能检验方法,分别进行了直接睡眠实验、巴比妥钠睡眠潜伏期实验、戊巴比妥钠阈下剂量催眠实验、延长戊巴比妥钠睡眠时间实验。结果本品无明显直接睡眠作用,延长戊巴比妥睡眠时间实验结果为阳性、戊巴比妥钠阈下剂量催眠实验和巴比妥钠睡眠潜伏期实验结果为阴性。结论静心助眠口服液具有改善小鼠睡眠的作用。     

GABA合成酶抑制剂盐酸氨基脲对褪黑激素催眠作用的影响

目的:观察GABA合成酶抑制剂盐酸氨基脲对褪黑激素催眠作用的影响.方法:采用小鼠协同戊巴比妥钠睡眠法和大鼠脑电图描记法测定盐酸氨基脲对睡眠和褪黑激素催眠作用的影响.结果:褪黑激素对小鼠和大鼠均具有明显的催眠作用.盐酸氨基脲单独使用对小鼠和大鼠的睡眠无影响,但能明显阻断褪黑激素对戊巴比妥钠引起的小鼠睡眠时间的延长,并且明显抑制褪黑激素引起的大鼠总睡眠时间,慢波睡眠时间,快波睡眠时间的增加和觉醒时间的减少.结论:盐酸氨基脲能明显拮抗褪黑激素的催眠作用,提示褪黑素的催眠作用由GABA能系统介导.     

Einfluß von gewebsgespeichertem DDT auf die Wirkung von Pharmaka

Zusammenfassung Es wurde der Einfluß von akuter und chronischer DDT-Vergiftung auf die Wirkungen von Pentetrazol und Pentobarbital an Ratten untersucht.Die Krampfwirksamkeit von Pentetrazol war nach einmaliger akuter sowie nach chronischer Vergiftung nicht verändert. Erst nach dreimaliger akuter Vergiftung mit 100 mg/kg DDT oral stieg die ED₅₀ für Krämpfe signifikant von 54 auf 65 mg/kg an.Die Wirkungen von Pentobarbital wurden wesentlich stärker beeinflußt. Bei chronischer DDT-Zufuhr war die Schlafzeit nach Gabe von 30 mg/kg Pentobarbital um 80% verkürzt. Auch nach einmaliger akuter Vergiftu g mit 100 mg/kg DDT war schon nach 24 Std eine Schlafzeitabnahme um 55% zu beobachten, die nach 2 Tagen ihr Maximum mit ebenfalls 80% erreichte. Bei der weiteren Kontrolle des Vergiftungsablaufes zeigte die Schlafdauer allmählich wieder eine langsame Zunahme, war nach 70 Tagen aber immer noch um 40% vermindert. DDT-Konzentrationen im Fettgewebe und Schlafzeitverkürzung zeigen ein annähernd paralleles Verhalten.Als Ursache der Schlafzeitverkürzung wurde eine Beschleunigung des Pentobarbitalabbaus an Leberschnitten in vitro festgestellt. Bereits 1 mg/kg DDT i.p. bewirkte eine signifikante Schlafzeitverkürzung um 25%, 2 mg/kg um 50% DDT ist damit wirksamer als alle bisher bekannten Aktivatoren der oxydierenden Lebermikrosomenfermente.

---

Summary The effect of DDT poisoning on pentetrazol convulsions and pentobarbital sleeping time has been studied in rats. Both, a single acute poisoning and the chronic administration of DDT failed to alter the sensitivity towards pentetrazol convulsions. Repeated acute poisoning with an oral dose of 100 mg/kg DDT elevated the ED₅₀ for convulsions significantly from 54 to 65 mg/kg pentetrazol.A more pronounced effect of DDT was observed in pentobarbital sleeping time. In rats treated chronically with DDT the duration of sleep induced by 30 mg/kg pentobarbital was depressed to 20 percent of the control value. A single dose of DDT (100 mg/kg) lead to a reduction to 45 percent within 24 hours and to a minimal value of 20 percent within 2 days. In the further course of such DDT poisoning the duration of sleep showed a gradual increase, but after 70 days only 60 percent of the initial value was obtained. As the sleep induced by pentobarbital was restored the concentration of DDT in adipose tissue declined.The decrease in the duration of pentobarbital sleep can be explained by in vitro experiments on liver slices, showing that pretreatment with DDT caused an acceleration in the metabolism of pentobarbital. As 1 mg/kg DDT was sufficient to reduce the sleeping time to 75 percent of the control value this insecticide is more effective in activating drug metabolism in liver microsomes than any other compound.

---

---

Gefördert mit Hilfe von Forschungsmitteln des Landes Niedersachsen.     

Effect of chronic DDT exposure on pentobarbital tolerance and intolerance in the rat

Barbiturate tolerance and intolerance were studied in female albino rats. Three consecutive daily ip doses of pentobarbital (30 mg/kg) were shown to produce a significant tolerance in naive rats, with sleeping times significantly shortened on both day 2 (to 65% of control) and day 3 (to 53%). This tolerance was correlated with a significant increase in the in vitro rate of hepatic microsomal pentobarbital metabolism (235% at day 3). On day 23 (after 20 days of barbiturate abstinence) the animals exhibited an intolerance (sleeping time 126%) not associated with any change in hepatic enzyme activity. All parameters returned to control values by day 43. These results suggest that the intolerance is nonhepatogenic and likely related to enhanced CNS sensitivity. In parallel studies, chronic dietary exposure to DDT (p,p-DDT 13.1 ppm; o,p-DDT 5.3 ppm) caused increased liver enzyme activity which did not prevent the appearance of tolerance by day 3 (sleeping time 72%; barbiturate metabolism 139%) but did prevent the appearance of day 23 intolerance. The hepatic induction produced by DDT appears to offset any CNS sensitivity associated with delayed barbiturate intolerance.     

Changes in pentobarbital hypnosis and hepatic metabolism in streptozotocin-diabetic mice

The present study deals with the hypnotic effect of pentobarbital (Pento) in relation to its metabolism in hepatic microsomes in streptozotocin (STZ, 170 mg/kg, i.p.) injected mice. Liver weight (mg/10 g body wt.) of STZ-treated mice was larger than that of the controls throughout the experimental period. Although the shortening of sleeping time induced by Pento (60 mg/kg, i.p.) was always observed, Pento-metabolizing enzyme activity (by the method of Kato et al., 1964) increased in mice with diabetes for 2 and 4 weeks but decreased in mice with diabetes for 8 weeks. Induction following phenobarbital (100 mg/kg, s.c.) and inhibition by SKF 525-A (10 mg/kg, i.p.) of hepatic metabolizing enzyme were found in both control and mice with diabetes for 2, 4 and 8 weeks, but these were not definitely correlated to their hepatic Pento-metabolizing enzyme activities. STZ-induced hyperglycemia and shortening of sleeping time by Pento were completely prevented by the pretreatment with nicotinamide (500 mg/kg, i.p.). NPH-insulin injection partially decreased hyperglycemia in STZ-diabetic mice, but sleeping time by Pento was not significantly affected. These results suggest that the hyposensitivity to Pento in STZ-diabetic mice is partially related to an abnormality of metabolism in liver such as the hyperglycemic state.     

六氯对二甲苯对豚鼠肝药酶的抑制作用

六氯对二甲苯(HCX)单剂(50-100mg/kg)或多剂(100mg/kg,qd×6d或50mg/kg,qd×14d,ip)均能极显著延长豚鼠戊巴比妥钠催眠时间,HCX 100mg/kg ip使豚鼠血浆戊巴比妥t 1/2 β延长3.2倍,并使豚鼠肝匀浆内戊巴比妥侧链羟化酶和氨基比林N-脱甲基酶活性明显降低。表明HCX是豚鼠肝药酶的抑制剂。而大鼠ip HCX 100mg/kg对其血浆戊巴比妥t 1/2 β确无明显影响。     

Analysis of the vagal reflex tracheal constriction in the dog

The effect of an acute or a successive administration of endotoxin (lipopolysaccharide obtained from Escherichia coli, LPS) on the hepatic drug-metabolizing system in vivo and in vitro was examined in mice. An acute LPS (5 mg/kg, i.v.) administration or a successive LPS (5-20 mg/kg, i.p., a day for 6 days) administration prolonged the duration of pentobarbital sleeping time and reduced the rate of hepatic microsomal metabolism of pentobarbital, aminopyrine, aniline and cyclophosphamide and reduced cytochrome P-450 content as compared with those in the control mice. No change of these parameters, however, was observed by an acute treatment with LPS to the successively LPS-treated mice. In addition, the LD50's of aminopyrine and pentobarbital and the ED50 of aminopyrine were reduced by an acute administration of LPS in control mice. No change of both parameters, however, was observed in the successively LPS-treated mice with or without an acute administration of LPS.     

Comparative Effects of Medetomidine Enantiomers on in vitro and in vivo Microsomal Drug Metabolism

Abstract: The effects of dexmedetomidine, a selective α₂-adrenoceptor agonist, and its levo enantiomer (MPV-1441), on in vitro microsomal P450-dependent drug-metabolizing activities as well as on in vivo aminopyrine elimination and hexobarbital sleeping time were studied. Both enantiomers inhibited the oxidative metabolism of several model substrates and testosterone in rat liver microsomal incubations. Microsomal activities derived from control animals or rats pretreated with phenobarbital were more sensitive to inhibitory effects of dexmedetomidine than those from rats treated with 3-methylcholanthrene. Enzyme activities in human liver microsomes were also inhibited by dexmedetomidine. Retardation of the elimination of aminopyrine was dose-dependent; elimination was marginally retarded with doses up to 100 μg/kg (from 17 to 23 min.; both enantiomers). Higher doses of the levo enantiomer prolonged aminopyrine half-life to 78 (1 mg/kg) and 162 min. (10 mg/kg). The hexobarbital sleeping time was prolonged by the dose of 1 mg/kg of the levo enantiomer (128 min. versus 20 min. in controls), while the dose of 0.1 mg/kg had no effect (23 versus 20 min.). These studies indicate that both enantiomers of medetomidine are inhibitors of microsomal drug metabolism in vitro, but significant effects on aminopyrine elimination or hexobarbital sleeping time are apparent only at doses, which do not allow the use of dexmedetomidine because of excessive sedative effect.     

Influence of starvation and hepatic microsomal enzyme induction on the mobilization of DDT residues in rats.

Adult female Sprague-Dawley rats were treated with DDT (10 mg;kg po daily for 10 days) and were then treated with hepatic microsomal enzyme inducers and/or starved for various periods of time in order to study depletion of pesticide residues from the blood, brain, and abdominal fat tissue. The enzyme inducers used, and the daily doses administered over a period of 14 days, were: phenobarbital sodium 50 mg/kg, pregnene-16α-carbonitrile (PCN) 30 mg/kg, 9α-fluoro-11β, 17-dihydroxy-3-oxo-4-androstene-17α-propionic acid (CS-1) 40 mg/kg, and dexamethasone 4 mg/kg for 7 days and 2 mg/kg for 7 days. Starvation consisted in withholding solid food, but not water, for periods of 3 or 5 consecutive days, or 3 or 5 nonconsecutive days. At the end of the treatment period, the animals were sacrificed for determination of p,p′-DDT, p,p′-DDD, and p,p′-DDE. Phenobarbital and CS-1 reduced the concentration of the total residues in all three tissues examined, but phenobarbital was superior to the steroid. On the other hand, starvation for 5 consecutive days was more effective than any other period of starvation for reducing the concentration of the residues. Combination of a phenobarbital pretreatment with starvation for 5 consecutive days led to additive tissue depletion of the residues. The degree of effectiveness of the combined treatment was better when the animals were starved early during the period of phenobarbital administration. These results provide good evidence that the combination of enzyme induction and starvation is a superior means of clearing contaminated tissues of DDT than either treatment alone. However, maximal efficacy is obtained only when both treatments are interrelated optimally with respect to the time and the duration of admistration.     

Effect of p-amino-diphenyl ethers on hepatic microsomal cytochrome P450

The present paper aims to investigate whether p-amino-2',4'-dichlorodiphenyl ether and p-amino-4'-methyldiphenyl ether are inhibitors as well as inducers of P450. Mice were given daily intraperitoneal (ip) injections of p-amino-2',4'-dichlorodiphenyl ether (0.25 mmol/kg) or p-amino-4'-methyldiphenyl ether (0.25 mmol/kg) for 4 days and tested at 24 h and 48 h after the last dose injection. The results showed the mice pentobarbital sleeping time was shorter and the P450 content of hepatic microsome increased significantly in the group pretreated with p-amino-4'-methyldiphenyl ether when compared with the control group, while in mice pretreated with p-amino-2',4'-dichlorodiphenyl ether the hepatic microsome P450 content increased but the pentobarbital sleeping time was extended in clear contrast to the control group. The sleeping time of the phenobarbital group (80 mg/kg daily ip injection for 4 days) was shortened at 24 h after the last injection with increased P450 content of hepatic microsome, but it showed no difference at 48 h. The zoxazolamine-paralysis times of mice treated with p-amino-2',4'-dichlorodiphenyl ether were longer than those of the control mice, while the same dose of zoxazolamine did not lead to paralysis in mice pretreated with BNF. p-Amino-2',4'-dichlorodiphenyl ether and p-amino-4'-methyldiphenyl ether inhibited the activity of 7-ethoxyresorufin O-deethylase from rat hepatic microsome induced by BNF in vitro by 70.0% and 50.1% respectively. These results suggest that p-amino-2',4'-dichlorodiphenyl ether and p-amino-4'-methyldiphenyl ether are inhibitors as well as inducers of P450.     

The effect of pretreatment with dieldrin on certain in vivo parameters of enzyme induction in mice

The present investigation was undertaken in order to study under which conditions certain in vivo parameters (LD50, sleeping time, and tissue concentrations of a given drug) would best characterize the phenomenon of enzyme induction in mice pretreated with the organohalogenated insecticide dieldrin. Five barbiturates (barbital, hexobarbital, pentobarbital, thiopental and phenobarbital) possessing different metabolic pathways were selected as the test drugs, and the influence of the route of administration (iv, ip, sc and po) upon their ultimate pharmacologic effect was evaluated.The results obtained show that dieldrin given at a dose of 25 mg/kg/day sc for 5 days, is a liver microsomal enzyme inducer based on its effect on the amount of cytochrome P-450 and the enzymatic activity of 9000 g supernatant preparations with various barbiturates used as substrates. Dieldrin significantly increased the LD50 values of phenobarbital, regardless of the route of administration. Dieldrin also raised the LD50 of hexobarbital, thiopental and pentobarbital administered by all but the iv route; however, it did not modify the LD50 of barbital. The inducer was effective in significantly reducing the duration of sleep with hexobarbital, thiopental, pentobarbital and phenobarbital via all routes of administration. The sleeping time with barbital was significantly reduced when it was given by the po route; however, it was found that dieldrin-treated mice awoke with brain concentrations of barbital that were significantly higher than those in the control animals. Dieldrin was effective in reducing the concentrations of hexobarbital in the blood and brain following all routes of administration. The same was true for pentobarbital, except in blood after an iv injection.Under suitable experimental conditions, therefore, results of tests performed in intact animals correlate well with microsomal enzyme assays, thus reinforcing evidence for enzyme induction. However, the administration of an inducer, like dieldrin, could lead to “satellite” phenomena unrelated to microsomal enzyme induction.     

Effects of forced shaking stress at low temperature on pentobarbital-induced sleeping in mice

1. Effects of a new stressful manipulation, forced shaking stress at low temperature (4 degrees C) (FSLT stress), on sleeping induced by pentobarbital were investigated 70 min following its application. 2. Repeated application (7 times) decreased the duration of sleep induced by pentobarbital-Na (45 mg/kg, i.p.) in mice without affecting that induced by ketamine-HCl and chloral hydrate. This effect of FSLT stress disappeared 3 days after termination of application. 3. The latency of nociceptive response in hot-plate test increased in a naloxone-sensitive manner by single and repeated FSLT stress when tested immediately (2 min) after but not 70 min after the last stress application. 4. Diazepam (0.3 mg/kg, i.p.) significantly prolonged the duration of sleep induced by pentobarbital (45 mg/kg, i.p.) in stressed animals without changing that in unstressed animals. The effect of diazepam was blocked by Ro 15-1788 (10 mg/kg, i.p.), a specific benzodiazepine receptor antagonist. 5. Repeated FSLT stress thus appears to decrease pentobarbital sleep by inducing functional changes in the central nervous system and the GABAergic system may partially participate in FSLT stress-induced decrease in pentobarbital sleep.