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.     

Inhibition of drug-metabolizing enzymes in the mouse after treatment with host-mediating antitumor drugs

The effect of host-mediating antitumor drugs on drug-metabolizing enzymes and cytochrome P-450 of the mouse liver was studied. Treatment of mice with a streptococcal preparation (OK-432), Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS), or protein-bound polysaccharide (PSK) depressed aniline hydroxylase and aminopyrine N-demethylase activities in a dose-responding fashion. Cytochrome P-450 content of the hepatic microsomes was also decreased by the treatment. Time of sleeping induced by pentobarbital was prolonged by the drug treatment.     

Effect of a new sleep inducer, 1H-1,2,4-triazolyl benzophenone derivative 450191-S on rat liver drug-metabolizing enzyme system

The effect of a new sleep inducer, 450191-S, on the hepatic drug-metabolizing enzyme system was examined using rats and compared with those of nitrazepam and phenobarbital. Cytochrome P-450-dependent 7-alkoxycoumarin O-dealkylation activity determined using liver homogenate and isolated microsomes increased after successive oral administrations of 450191-S, and induction of the enzyme system was observed by administration of 150 approximately 200 mg/kg of the drug for at least 3 approximately 5 days. Normal activity was recovered with withdrawal of the drug for 3 approximately 5 days after induction of the hepatic enzyme system. Administration of higher amounts of 450191-S (200 approximately 600 mg/kg/day) for 3 days caused remarkable increases in the O-dealkylase and UDPGA-glucuronyltransferase activities and cytochrome P-450 and b5 contents. Similar changes in the hepatic enzyme system were observed with administration of nitrazepam (200 approximately 600 mg/kg for 3 days, p.o.) or phenobarbital (10 approximately 40 mg/kg for 3 days, i.p.). We concluded that the inducing activity of 450191-S is almost the same as that of nitrazepam, but weaker than that of phenobarbital. When the hepatic enzyme system was induced by the administration of either 450191-S or phenobarbital, the pentobarbital-induced sleeping time was shortened with increasing doses of the drugs. On the other hand, sleeping time was prolonged by the administration of another type of inducer, beta-naphthoflavone. The results suggest that the inductive pattern of 450191-S is similar to that of phenobarbital.     

A study of the factors affecting the sleeping time following intracerebroventricular administration of pentobarbitone sodium: Effect of prior administration of centrally active drugs

1 Injection of pentobarbitone sodium into a lateral cerebral ventricle of rats produced a loss of righting reflex. The duration of anaesthesia was dose-dependent.

2 The optimum dose of pentobarbitone to allow study of the factors affecting the sleeping time was considered to be 650 μg injected in 25 μl water.

3 In a study of the effect of age and sex on the sleeping time, the youngest rats used (88 g body weight) were found to be the most sensitive to barbiturate. Female rats were more sensitive than male animals.

4 The duration of anaesthesia was not affected by induction or inhibition of hepatic drug-metabolizing enzyme activity.

5 Prior administration (acute) of central nervous system depressant drugs shortened the latent period and prolonged the duration of sleep. Prior administration of stimulant drugs antagonized the effect of pentobarbitone.

6 Animals withdrawn following chronic administration of a number of drugs, barbitone, barbitone/bemegride mixture, Mandrax (methaqualone: diphenhydramine; 10: 1), chlordiazepoxide, nitrazepam, chlorpromazine or ethanol, exhibited a significant tolerance to intracerebroventricularly administered pentobarbitone.

7 Withdrawal of amphetamine, morphine, methyprylon or diazepam did not result in tolerance to intracerebroventricularly administered pentobarbitone.

8 Chronic administration of all drugs except amphetamine and morphine induced a tolerance to intraperitoneally administered hexobarbitone (100 mg/kg).

9 The usefulness of sleeping time determination following intracerebroventricular administration of pentobarbitone as an assessment of central nervous system excitability is discussed. It is concluded that this method gives a valid indication of the sensitivity of the central nervous system to barbiturate and of the level of excitability in general. The method is particularly applicable in situations where the activity of hepatic drug-metabolizing enzyme activity may be altered.

     

Morphological and enzymatic alterations in the rat liver caused by administration of a hypocholesterolemic agent AT-308 and its related compounds

The administration of a hypocholesterolemic agent, 3-[4-(1-ethoxycarbonyl-1-methylethoxy)phenyl]-5-(3-pyridyl)-1, 2, 4-oxadiazole (AT-308), to rats induced hepatomegaly accompanying a significant proliferation of microbodies. AT-308 and some related compounds were given to rats to investigate the relationship between chemical structures of the test compounds and their several biological effects including hypocholesterolemic effect, proliferation of hepatic microbodies, induction of liver catalase activity and drug-metabolizing enzyme activity as manifested by pentobarbital sleeping time. The results obtained are as follows. First the administration of AT-308 or clofibrate to rats fed a basal or high cholesterol diet produced a significant increase in the number of hepatic microbodies. especially of anucleoid type. The administration of 3-[4-(2-diethyl-aminoethoxy)phenyl]-5-(3-pyridyl)-1, 2, 4-oxadiazole (AT-293) induced a slight increase in the number of hepatic microbodies, and 3, 5-di-(3-pyridyl)-1, 2, 4-oxadiazole (AT-232) did not produce such an increase at all. Second, the liver catalase activity increased in the AT-308- and clofibrate-treated groups, but the increase of the latter was less prominent than that of the former. Third, the administration of AT-308 or clofibrate. but not of AT-293 or AT-232, shortened the duration of pentobarbital anesthesia. These results suggest that the proliferation of hepatic microbodies with AT-308 administration may be ascribable to a clofibrate-like side chain in the molecule of AT-308 and not to its 1, 2, 4-oxadiazole moiety.     

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.     

Hexobarbital sleeping time and drug metabolism in rats with ligated bile ducts—A lack of correlation

Hexobarbital sleeping time is commonly used as an index of the activity of hepatic microsomal drug-metabolizing enzymes in animals. This report describes anomalies between hexobarbital sleeping time and the rate of metabolism in vitro by microsomal enzymes in rats after bile duct ligation (BDL). The duration of hexobarbital sleeping time, 2–24 hr after BDL, was approximately twice that of sham-operated controls. No significant decrease in the activity of microsomal aminopyrine demethylase, aniline hydroxylase, hexobarbital oxidase or the amount of cytochrome P-450 was detected during this period. A further prolongation of hexobarbital sleeping time was observed 48–72 hr after BDL, and this was accompanied by a significant impairment of drug metabolism in vitro. The effect of BDL on hexobarbital sleeping time was independent of the route of administration. Thiopental sleeping time was prolonged at 12 and 72 hr after BDL. Zoxazolamine paralysis time was prolonged at 72 hr after BDL, but not at 12 hr. Plasma protein binding of hexobarbital and thiopental was not altered by hyperbilirubinemia. These data suggest that changes in drug metabolism are not responsible for the prolongation of hexobarbital sleeping time during the early phase of cholestasis caused by BDL.     

Effect of thiol compounds on experimental liver damage (III). Effect of tiopronin (2-mercaptopropionylglycine) and glutathione on drug metabolizing activity (author's transl)]

In our previous papers, tiopronin (2-mercaptopropionylglycine) and glutathione were reported to suppress the liver damage induced by ethionine. In the damage induced by ethionine. In the present study, we evaluated such suppressive effect from the aspect of drug metabolizing activity. Aniline hydroxylating enzyme activity and aminopyrine N-demethylating enzyme activity of the liver microsome of rats 24 hr after administration of 1 g/kg ethionine were decreased to 53.2% and 61.7% respectively as compared with those of the normal rats. Administration of tiopronin or glutathione to the ethionine treated rats suppressed the decrease of both enzyme activities induced by ethionine. Ethionine did not influence NADH-cytochrome c reductase (fp1) but brought about increase of the activity of NADPH-cytochrome c reductase (fp2) and decrease of the cytochrome P-450 content. These thiol compounds did not influence fp1 and fp2 but tended to suppress the cytochrome P-450 content decreased by administration of ethionine. In particular, tiopronin suppressed the content significantly. Disappearance of aminopyrine, hexobarbital and pentobarbital from the blood was markedly delayed by ethionine administration. It was revealed, however, that such delay was recovered by tiopronin or glutathione. The sleeping time induced by hexobarbital and pentobarbital was also prolonged by ethionine, but this tended to be shortened by tiopronin or glutathione.     

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。     

The role of opiate receptors in the potentiation of pentobarbital sleeping time by the acute and chronic administration of opiates

Male rats injected with pentobarbital (50.0 mg/kg i.p.) showed increased sleeping time after the acute administration of morphine (5.0 or 10.0 mg/kg s.c.). This effect was antagonized by naltrexone (2.0 mg/kg s.c.). The enhancement displayed stereoselectivity as levorphanol greatly lengthened the sleeping time induced by pentobarbital while dextrophan only produced a slight increase. Rats implanted for 3 days with pellets of morphine base (75.0 mg) were tolerant to the analgesic effects of morphine (2.5 mg/kg s.c.) but showed an even greater increase in pentobarbital-induced sleeping time than rats treated acutely. No potentiation was observed in subjects that were also implanted with a pellet of naltrexone (30.0 mg). It is concluded that the potentiation of pentobarbital-induced sleeping time produced by opiates is mediated by opiate receptors, but fails to show the development of tolerance.     

Effect of 1-(m-chlorophenyl)-3-N,N-dimethyl-carbamoyl-5-methoxypyrazole (PZ-177) on drug-metabolizing enzyme on rat liver.

Effect of 1-(m-chlorphenyl)-3-N,N-dimethylcarbamoyl-5-methoxypyrazole (PZ-177) (62.5 and 250 mg/kg) on rat liver was investigated by measuring liver weight and drug-metabolizing enzyme activity. The effects of PZ-177 were compared with those of phenobarbital, phenylbutazone, and tiaramide hydrochloride. Increase of liver weight and liver/body weight ratio was observed in the rats treated with PZ-177 or phenobarbital, however, normal values were reverted to 1--2 weeks after treatment. PZ-177 similar to phenobarbital, significantly enhanced the activity of aminopyrine demethylase and aniline hydroxylase after 1,2, and 4 weeks of treatment. In contrast, tiaramide hydrochloride decreased the activity of aminopyrine demethylase and aniline hydroxylase after 1 week of treatment, and significantly enhanced the activity of these enzymes after 4 weeks. The content of cytochrome P-450 and the activity of NADPH cytochrome C reductase were also increased by treatment with PZ-177. The sleeping time by hexobarbital was shortened significantly by the administration of PZ-177. Vmax for both aminopyrine demethylase and aniline hydroxylase increased by treatment with PZ-177. However, only the Km for aniline hydroxylase was increased by treatment with PZ-177. From the results of these experiments, PZ-177 may be classified as a phenobarbital-type inducer.     

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。     

Effect of endosulfan pretreatment on organ weights and on pentobarbital hypnosis in rats

The effects of ebdosulfan on the weights of the liver, adrenal and ovary, on pentobarbital blood and brain levels and on sleeping time (ST) have been investigated in female rats after daily oral doses of 0, 1.0, 2.5 and 5.0 mg/kg for a period of 7 or 15 days. No significant change in body weight was observed. With higher doses (2.5–5.0 mg/kg) the liver weight was significantly increased, but ovary and adrenal weights did not increase. Endosulfan treatment shortened sleeping time, while induction time was significantly increased. The concentration of pentobarbital in the blood and brain of rats after 30 min and upon awakening indicated that there was a significant decrease at 30 min. No change at awakening was observed in endosulfan-treated rats as compared to controls. It is suggested that endosulfan may shorten the duration of pentobarbital-induced sleep, perhaps by induction of hepatic microsomal enzyme activity.     

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。     

Interaction of doxapram and pentobarbital in mice

We found a statistically significant increase in duration of pentobarbital-induced narcosis in doxapram-treated mice. The influence of doxapram (a respiratory stimulant) pretreatment on pentobarbital metabolism in mice was assessed by measurements of sleeping times, hypothermia, LD50 values, hepatic microsomal metabolism and relative plasma and brain levels of pentobarbital. When doxapram was given intraperitoneally 60 min. prior to administration of pentobarbital, doxapram potentiated pentobarbital-induced narcosis in a dose- and time-dependent manner, but had no effect on onset time. Doxapram potentiated hypothermia, increased acute toxicity, and prolonged the pentobarbital half-life in brain and plasma, but measurement of the concentration of pentobarbital in the brain and plasma immediately upon recovery from narcosis showed that there were no differences in any of the groups examined. Also, brain-to-plasma ratios of pentobarbital did not differ between the control and doxapram-treated groups. Doxapram competitively inhibited the hepatic metabolism of pentobarbital in 9000 x g supernatant incubation mixtures. The results obtained from these experiments indicate that inhibition of drug-metabolizing enzymes by doxapram may account for its enhancement of the duration of pentobarbital-induced narcosis.     

Inhibition and induction of hepatic drug metabolism in rats and mice by nafimidone and its major metabolite nafimidone alcohol

Nafimidone, a candidate anticonvulsant agent, and its metabolite (nafimidone alcohol) demonstrated potent inhibition of hepatic drug metabolism in male rats. Inhibition occurred both in vivo following acute administration as a prolongation of hexobarbital sleeping time and as an elevation of plasma hexobarbital levels, and in vitro following addition to hepatic microsomes as a disruption of ethyl-morphine N-demethylation and aniline p-hydroxylation. Inhibition of ethylmorphine N-demethylation was of a mixed type, whereas aniline p-hydroxylation was inhibited in a noncompetitive manner; the micromolar Ki values obtained for both enzymes were severalfold lower than those obtained for imidazole. Nafimidone alcohol produced a type II difference spectrum when added to rat hepatic microsomes. The Ks value was 2.1 microM. Chronic administration of nafimidone alcohol caused induction of hepatic drug metabolism typified by shortening of pentobarbital sleeping time in vivo in male mice and a doubling of hepatic microsomal cytochrome P-450 content in male rats. In rats, these changes were associated with a 30-fold elevation in the Vmax for microsomal ethoxyresorufin O-deethylase and a moderate increase in the Vmax for microsomal ethylmorphine N-demethylase, but no change in either the rate of aniline p-hydroxylation, 4-hydroxybiphenyl- or 4-methylumbelliferone UDP-glucuronosyltransferase, or the activity of the flavoprotein reductase component. These data suggest induction of a predominating cytochrome P-448-type of Phase I drug-metabolizing activity by nafimidone alcohol.     

Effect of cimetidine or ranitidine pretreatment on hepatic mixed function oxidase activity in the rat

This study compared the effect of single equimolar oral doses of cimetidine (100 mg/kg) or ranitidine (139 mg/kg) on rat hepatic mixed function oxidases. Cimetidine significantly (p less than 0.05) increased hexobarbital sleeping time and prolonged aminopyrine and theophylline elimination. In contrast, ranitidine did not significantly affect hexobarbital sleeping time and theophylline elimination but significantly (p less than 0.025) increased aminopyrine elimination. Aminopyrine N-demethylase activity in vitro was significantly (p less than 0.05) inhibited by cimetidine pretreatment but significantly (p less than 0.025) increased by ranitidine pretreatment. The direct addition of cimetidine or SKF 525A to the 10,000g supernatant fraction from controlled liver homogenates decreased aminopyrine N-demethylase activity, whereas the direct addition of ranitidine tended to increase aminopyrine N-demethylase activity. A significant correlation (r = 0.65, p less than or equal to 0.005) was observed between hexobarbital sleeping time in vivo and aminopyrine N-demethylase activity in vitro in the same rat. The results of this study showed that cimetidine inhibited mixed function oxidases, whereas ranitidine had no effect or tended to stimulate mixed function oxidases.     

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.     

Effects of the antitumor agents from various natural sources on drug-metabolizing system, phagocytic activity and complement system in sarcoma 180-bearing mice

Correlation between antitumor activity and effects on some biological properties, such as phagocytic activity of the reticuloendothelial system, the third component of complement (C3) activation, hepatic drug-metabolizing activities and pentobarbital-induced narcosis, of antitumor agents from various natural sources such as B B (Broncasma Berna), GU-P (Grifora umbellata polysaccharide), OK-432, PS-K (Polysaccharide Kureha), and RA-P (Rumex acetosa polysaccharide) were studied with female ICR mice implanted with Sarcoma 180 solid tumor. All of these agents depressed aniline hydroxylase and aminopyrine demethylase activities, prolonged the duration of pentobarbital-induced narcosis, and significantly enhanced the phagocytic activity and C3 activity. Especially, RA-P which has the strongest antitumor activity was the most effective in changing these activities. The biological activities of GU-P at a dose of 10 mg/kg reached the same level as that found with PS-K at a dose of 100 mg/kg. a possible mechanism of inhibition of Sarcoma 180 solid tumor growth by the treatment with the antitumor agents could be interpreted as due to the C3 activation, the stimulation of phagocytic activity and depression of the hepatic microsomal drug-metabolizing system in tumor-bearing mice.     

Effect of monensin on liver glutathione, glutathione S-transferase and monooxygenases in rats.

Monensin administered ip to male rats at a dosage of 2.5 mg/kg/d for 3 consecutive days did not change the liver levels of glutathione, but depressed significantly the amount of cytochrome P-450 and the activities of aniline hydroxylase and a cytosolic CDNB-specific glutathione S-transferase. There was a marked decrease in the aminopyrine N-demethylase activity and a significant increase in the pentobarbital sleeping time in rats treated with monensin. In contrast, no change in these parameters was found 2 h after a single ip dose (7.5 mg/kg) of monensin. The results suggest that monensin-induced inhibition of the liver cytosolic glutathione S-transferase and microsomal monooxygenases is non-specific.