Enhancement of pharmacologic responses of pentobarbital by dopram

The effect of Dopram (doxapram hydrochloride, A. H. Robins Co.) on the pharmacologic responses to pentobarbital was evaluated. In naive and pentobarbital-tolerant mice, Dopram was shown to enhance significantly sodium pentobarbital-induced narcosis in a dose-related manner. The effect of the duration of action of Dopram on pentobarbital narcosis also was assessed. It was observed that Dopram (40 mg/kg, i.p.) significantly increased pentobarbital-induced narcosis even when administered 2 hr prior to challenge with sodium pentobarbital (60 mg/kg, i.p.) A significantly increased hypothermic response to sodium pentobarbital was seen in Dopram-treated animals. The half-life of pentobarbital in brain and serum was shown to be increased significantly in animals receiving Dopram, 40 mg/kg, i.p. The waking brain and serum pentobarbital concentrations were not significantly different in either group. These studies show that Dopram potentiates pentobarbital's effects. Further study is necessary to determine the sites of operation and mechanism of this potentiation.     

Effects of acute and continuous pentobarbital administration on the gamma-aminobutyric acid system

Effects of acute anesthetic doses and chronic administration of pentobarbital on γ-aminobutyric acid (GABA) and glutamic acid levels in mouse brain have been investigated. Acute administration of pentobarbital caused an increase in the brain level of GABA which was associated with pentobarbital-induced narcosis. This was further substantiated by the finding that pentobarbital-induced sleeping time was prolonged when brain GABA level was elevated by the administration of either amino-oxyacetic acid (AOAA), an inhibitor of GABA-2-oxoglutarate aminotransferase (GABA-T), or glutamate, the precursor of GABA. In addition, the activity of l-glutamate-1-carboxylase (GAD) measured during pentobarbital-induced narcosis was higher than that of the control group. On the other hand, chronic administration of pentobarbital resulted in a decrease of both GABA and glutamate levels. There was a concomitant 30 per cent decrease in the activity of GAD. This was confirmed by the finding that the rate of brain GABA accumulation induced by AOAA administration in tolerant mice was slower than that of the non-tolerant animals. Brain GABA remained at significantly lower levels after an abrupt withdrawal from pentobarbital; however, brain glutamate levels showed no significant difference as compared to the control group. It appears that the GABA system in the central nervous system may be involved in barbiturate narcosis and further linked with the development of tolerance to barbiturate.     

Comparison of the effects of acute and subchronic administration of Aroclor 1254, a commercial mixture of polychlorinated biphenyls, on pentobarbital-induced sleep time and [14C]pentobarbital disposition in mice

We have reported previously that polychlorinated biphenyls (PCBs) alter neurochemistry and suppress spontaneous locomotor activity in mice. The present study was initiated to determine whether orally administered (Aroclor 1254) would potentiate pentobarbital-induced sleep time. Sleep time was enhanced significantly by Aroclor 1254 (500 mg/kg) given 0 to 8 h prior to pentobarbital, with the peak effect occurring at 2 h. This effect was demonstrated to be dose-responsive in the range of 5 to 25 mg/kg given 2 h prior to pentobarbital, but only slightly larger increments in sleep time were observed with higher doses of PCBs (50, 100, 250, and 500 mg/kg). Administration of vehicle or Aroclor 1254 (30 or 100 mg/kg) for 14 successive days reduced sleep time when pentobarbital was given 45 min after the last dose of vehicle or Aroclor 1254, with a further reduction when pentobarbital was given 24 h after the last dose. As a correlate to the sleep-time studies, levels of pentobarbital and metabolites were measured in brain, liver, and plasma of mice that had received varying doses of Aroclor 1254 2 h prior to [14C]pentobarbital. Elevated levels of pentobarbital and decreased levels of metabolites were found after acute administration of Aroclor 1254 during a period of time when Aroclor 1254-treated mice were still asleep. These effects of Aroclor 1254 on pentobarbital disposition were found to be dose-dependent. Brain levels of pentobarbital in mice after 14 d of Aroclor 1254 treatment (30 mg/kg) were less than those in vehicle-treated animals, and these levels were consistent with the reduced sleep times. Thus, a correlation between pentobarbital brain levels and sleep time in both Aroclor 1254-treated and nontreated animals suggests that Aroclor 1254 does not alter pentobarbital narcosis by a direct action on the brain. Rather, acutely administered Aroclor 1254 may be augmenting sleep time by competing with pentobarbital for metabolic sites in the liver, while chronically administered Aroclor 1254 induces pentobarbital metabolism.     

Genotype-dependent effects of GABAergic agents on sedative properties of ethanol

Two lines of mice, selectively bred for differential sensitivity to the soporific effects of ethanol (ETOH), were administered GABAergic drugs in an effort to evaluate a role for GABA in ETOH sensitivity. ETOH sensitive Long-Sleep mice (LS) showed potentiated ETOH sedation when administered bicuculline, muscimol and aminooxyacetic acid (AOAA). ETOH-insensitive SS mice exhibited reduced ETOH sedation in the presence of the antagonists, bicuculline and picrotoxin, and potentiated sedation in the presence of muscimol and AOAA. These changes in narcosis duration were interpreted as central effects, since blood ethanol levels at waking from ETOH sedation varied with GABAergic drug treatment. Picrotoxin antagonized pentobarbital-induced nacrosis in both lines, but to a greater extent in SS mice. These and other experiments with a genetically heterogeneous stock suggest GABA involvement in genotype-dependent ETOH sensitivity, but do not support a simple role of GABA receptor involvement.     

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。     

Tolerance to ethanol and cross-tolerance to pentobarbital and barbital

A chronic regimen of ethanol by intubation, which produced clear tolerance to ethanol-induced hypothermia, ataxia and narcosis, produced only a marginal degree of cross-tolerance to these effects of pentobarbital. The lack of appreciable cross-tolerance to pentobarbital-induced hypothermia and ataxia was also observed over a wide range of test doses. However, cross-tolerance to barbital was observed after chronic treatment with ethanol. Increased rate of drug biotransformation did not contribute significantly to the observed tolerance and cross-tolerance. The difference in the extent of cross-tolerance between ethanol and the two barbiturates is consistent with the hypothesis that there is a degree of specificity in the sites of action of ethanol and other sedative-hypnotic drugs.     

Influence of thyrotropin releasing hormone (TRH) on drug-induced narcosis and hypothermia in rabbits

Thyrotropin releasing homone (TRH) administered via the intracerebroventricular (icv) route in doses ranging between 0.1 and 100 g decreased the duration of pentobarbital-induced narcosis in rabbits. Antagonism of narcosis occurred whether TRH was administered before or after the barbiturate. TRH doses above 10 g produced, in addition, behavioral excitation and hyperthermia. The antagonism of phenobarbital-induced narcosis was not as profound; animals were aroused only for a short period of time, after which the narcotized state returned. However, TRH exerted a prolonged antagonism or reversal of the phenobarbital-induced hypothermia. The central nervous system depression and analgesia produced by morphine were unaffected by TRH, but hypothermia and respiratory depression were reversed. TRH may represent an arousal factor in mammalian brain.     

Effect of synthetic estrogens and estrogen-progestin combinations on the hepatic microsomal enzyme system

Pretreatment of male rats with mestranol or ethynyl estradiol 10 min prior to the administration of pentobarbital had no effect on the duration of pentobarbital-induced sleep. Although the estrogens are alternate substrates for the microsomal enzyme system which metabolizes pentobarbital, the concentrations used in this study did not affect pentobarbital metabolism. Chronic pretreatment with mestranol or ethynyl estradiol did not induce the hepatic microsomal enzyme system, as determined by measuring the concentration of cytochrome P-450, the rate of activity of cytochrome P-450 reductase and the amount of microsomal protein/g of rat liver. However, chronic pretreatment with ethynyl estradiol or mestranol markedly decreased the daily body weight gain of the rats, but did not significantly alter the weight of their livers.     

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.     

Chronic treatment with haloperidol affect the response of the brain to pentobarbital

Treatment of mice with haloperidol increased the number of dopamine D2 receptors (Bmax). The animals were given 40 or 50 mg of pentobarbital. Animals treated with haloperidol had a shorter duration of narcosis induced by pentobarbital than the controls, suggesting a decreased sensitivity to pentobarbital which was functional (CNS), since the animals treated with haloperidol had higher levels of pentobarbital in the brain upon awakening than the controls. The results suggest that increased Bmax reduces the sensitivity of the brain to pentobarbital.     

Tetrandrine, a bisbenzylisoquinoline alkaloid from Chinese herb Radix, augmented the hypnotic effect of pentobarbital through serotonergic system

This is the first study of hypnotic activity of tetrandrine (a major component of Stephania tetrandrae) in mice by using synergism with pentobarbital as an index for the hypnotic effect. The results showed that tetrandrine potentiated pentobarbital (45 mg/kg, i.p.)-induced hypnosis significantly by reducing sleep latency and increasing sleeping time in a dose-dependent manner, and this effect was potentiated by 5-hydroxytryptophan (5-HTP). In the subhypnotic dosage of pentobarbital (28 mg/kg, i.p.)-treated mice, tetrandrine (60 and 30 mg/kg, p.o.) significantly increased the rate of sleep onset and also showed synergic effect with 5-HTP. Pretreatment of p-chlorophenylalanine (PCPA, 300 mg/kg, s.c.), an inhibitor of tryptophan hydroxylase, significantly decreased pentobarbital-induced sleeping time and tetrandrine abolished this effect. From these results, it should be presumed that serotonergic system may be involved in the augmentative effect of tetrandrine on pentobarbital-induced sleep.     

Sex-related Differences in Rat Liver Microsomal Enzymes and Their Induction by Doxapram

Abstract— The effects of doxapram on the hepatic microsomal mono-oxygenase system of male and female rats were investigated. Male and female rats were administered doxapram (10–120 mg kg^?1 day^?1, i.p.) for 4 days. In female rats, administration of doxapram (20, 40, 60, 80, 100 and 120 mg kg^?1) elevated the parameters in a dose-dependent manner while doxapram (100 and 120 mg kg^?1) elevated the levels of cytochrome P450 and hexobarbitone hydroxylase in male rats. Doxapram (40 mg kg^?1) caused induction of hepatic drug metabolism typified by an increase of hepatic microsomal cytochrome P450 content and activities of hexobarbitone hydroxylase, benzphetamine N-demethylase and ethylmorphine N-demethylase in female rats, but no change in male rats. These findings were supported by the results of SDS/polyacrylamide-gel electrophoresis. However, 7-ethoxycoumarin O-de-ethylase and arylhydrocarbon hydroxylase activities were significantly increased in male rats. NADPH-cytochrome c reductase and NADH-cytochrome c reductase activities, and cytochrome b₅ content were unaffected in rats of both sexes. The sex-dependent cytochrome P450 species may be selectively sensitive to the action of doxapram.     

Effects of 1-ethyl-4-(2-morpholinoethyl)-3, 3-diphenyl-2-pyrrolidinone hydrochloride hydrate (doxapram) on the transmural stimulation and reactiontonicotine of the isolated guinea pig heart atrium]

It has been reported that doxapram exhibits a remarkable stimulating effect on respiration in humans and various experimental animals. The present experiment was an attempt to investigate whether or not doxapram inhibits an atrial arrest induced by transmural stimulation and exogenously applied nicotine. Doxapram and dimorpholamine used as comparative agents showed transient and slightly positive responses followed by a negative one in the atrium preparation. Transmural stimulation under a condition of 30 V intensity with 0.3 msec duration at a frequency of 10 Hz for 2 sec caused an atrial arrest for about 3 sec followed by negative chronotropic and inotropic responses, and a positive one. All responses caused by transmural stimulation were hardly affected by pretreatment with doxapram at a concentration of 10(-5) g/ml or less, while dimorpholamine at a high concentration (10(-5)g/ml) showed an inhibition of atrial arrest and following negative responses. Negative chronotropic and inotropic responses caused by an application of nicotine were significantly inhibited by pretreatment with doxapram or dimorpholamine. Both doxapram and dimorpholamine at higher concentrations also inhibited the positive responses of the atrium caused by nicotine. Neither doxapram nor dimorpholamine affected the ACh-induced responses. NA-induced responses were uneffected by pretreatment with doxapram, while the responses were slightly potentiated by dimorpholamine. The action mechanisms of doxapram and dimorpholamine are discussed.     

Species difference in the inhibition of pentobarbital metabolism by empenthrin

Empenthrin, synthetic pyrethroid, prolonged the pentobarbital-induced sleeping time in mice, but not in rats, guinea pigs or hamsters. Empenthrin did not delay the clearance of pentobarbital from serum in dogs. In addition, empenthrin dose-dependently inhibited in vitro metabolism of pentobarbital in mice, but not in rats, guinea pigs, hamsters or rabbits. Lineweaver-Burk plots indicated that the inhibition was competitive in mice. Microsomal fractions of recombinant yeast expressing human cytochrome P-450 (CYP)s were used to determine the inhibitory effect of empenthrin on pentobarbital metabolism in humans. CYP2B6 and CYP2D6 were responsible for biotransformation of pentobarbital to a pentobarbital alcohol identified as 5-ethyl-5-(1′-methyl-3′-hydroxybutyl) barbituric acid. The structure of pentobarbital fit the criteria for a CYP2D6 substrate on computational analysis. Empenthrin did not inhibit the pentobarbital metabolism catalyzed by these two CYPs. These findings suggest that the inhibition of pentobarbital metabolism by empenthrin in mice does not occur in other species including humans.     

A pharmacokinetic study of doxapram in patients and volunteers.

1. Following intravenous bolus injections or brief infusions in healthy volunteers, plasma concentrations of doxapram declined in a multi-exponential fashion. The mean half-life from 4-12 h was 3.4 h (range 2.4-4.1h), the mean apparent volume of distribution was 1.5 1 kg-1 and the whole body clearance was 370 ml min-1. 2. Enteric-coated capsules of doxapram base were absorbed rapidly after an initial delay, and the systemic availability was about 60%. 3. Doxapram is extensively metabolized and less than 5% of an i.v. dose was excreted unchanged in the urine in 24 h. A metabolite (AHR 5955) was present in plasma in amounts comparable to the parent compound and had a similar half-life. 4. The disposition of doxapram appears to be similar in healthy volunteers and patients with respiratory failure. 5. The previously held belief that plasma concentrations fall rapidly when an infusion is stopped is only true following short duration infusions. The pharmacokinetic properties of doxapram are such that steady-state plasma concentrations will not be achieved for many hours with the recommended constant rate infusion régime.     

Pharmacological effects in mice of anandamide and its related fatty acid ethanolamides, and enhancement of cataleptogenic effect of anandamide by phenylmethylsulfonyl fluoride.

Anandamide (N-arachidonoylethanolamine) and six fatty acid ethanolamides were synthesized and their pharmacological effects in mice were assessed using catalepsy, hypothermia and pentobarbital-induced sleep prolongation as indices. The effects of phenylmethylsulfonyl fluoride (PMSF) pretreatment on anandamide effects were also evaluated and discussed in relation to inhibition of anandamide amidohydrolase in mouse brain and liver. The cataleptogenic effect of anandamide (ED50=6.0 mg/kg, i.v.) was 4 to 6 times more active than those of N-oleoyl- (ED50=26.5 mg/kg, i.v.) and N-linoleoylethanolamine (ED50=37.5 mg/kg, i.v.), although the peak time in the effect was observed within 1 min after i.v. administration. None of the saturated fatty acid ethanolamides (N-myristoyl-, N-palmitoyl-, N-stearoyl- and N-arachidoylethanolamine) showed a positive response in the cataleptogenic effect even at a dose up to 40 mg/kg i.v. Anandamide, N-linoleoyl-, N-oleoyl- and N-myristoylethanolamine (10 mg/kg, i.v.) produced a significant hypothermia (0.19 to 0.59 degrees C) at 5 to 15 min after administration. The duration of the effects of these ethanolamides was also relatively short. Anandamide, N-linoleoyl-, N-oleoyl- and N-palmitoylethanolamine (5 or 10 mg/kg, i.v.) significantly prolonged pentobarbital-induced sleeping time by 148-207% of control sleeping time. The cataleptogenic effect of anandamide was markedly potentiated by pretreatment of mice with PMSF (100 mg/kg, i.p.). The ED50 (mg/kg, i.v.) of anandamide was 0.48 (0.24-0.96) in PMSF-pretreated mice. The pretreatment of mice with PMSF significantly decreased the metabolic clearance rate of anandamide in microsomal fractions of liver and brain. Thus, the Vmax/Km values of brain and hepatic microsomes were 26 and 10%, respectively, as compared with those of control mice. The present study demonstrated that anandamide and N-acylethanolamines of unsaturated fatty acids exhibited cannabinoid-like effects in mice, and that anandamide amidohydrolase has an important role in the pharmacological effects of anandamide in vivo.     

Effects of naloxone and naltrexone on drug-induced hypothermia in mice

The hypothermia produced by injecting apomorphine into mice was potentiated by morphine; it was antagonized by haloperidol, by naloxone and by naltrexone. The hypothermic responses to morphine, chlorpromazine and ethanol were also blocked by naltrexone. However, naltrexone potentiated the hypothermic response to pentobarbital. Tolerance to morphine, produced by subcutaneous implantation of a morphine pellet, was accompanied by cross-tolerance to apomorphine-induced hypothermia. Animals made tolerant to apomorphine were not tolerant to morphine-induced hypothermia. The dopamine supersensitivity resulting from chronic treatment with haloperidol potentiated the hypothermic response to apomorphine but not to morphine. These results suggest that endogenous opioids may serve as mediators in the control of thermoregulation by dopamine.     

Effects of ethanol and pentobarbital on neuronal hexose uptake in inbred mice

The effect of ethanol and pentobarbital narcosis on 2-deoxyglucose uptake into brain synaptosomes prepared from inbred C57BL/6J and DBA/2J mice which exhibit differential central sensitivity to ethanol and heterogeneous ICR mice was examined. A reversible depression of synaptosomal uptake was exhibited in all strains administered ethanol acutely, occurring at 2 min in ICR and C57BL/6J mice and 15 min in DBA/2J. Uptake returned to control values in all strains at 30 min although the mice remained intoxicated. Brain glucose concentration was significantly elevated at this time. Pentobarbital administration was without effect on synaptosomal hexose transport in DBA/2J and C57BL/6J mice but increased it significantly in ICR mice at 30 min. Pentobarbital anesthesia did not alter brain glucose concentration. No correlation was apparent between synaptosomal 2-deoxyglucose uptake and differential CNS sensitivity to ethanol and pentobarbital. The effects of ethanol and pentobarbital on neuronal hexose transport is discussed with respect to reported changes in glycolytic metabolism produced by these agents.     

Differential pharmacological responses to ethanol,pentobarbital and morphine in rats selectively bred for ethanol sensitivity

The hypothermic and analgesic effects of ethanol, pentobarbital and morphine were examined in two lines of rats that had been selectively bred for their differential sensitivity to ethanol. Males and females of the least-affected (LA) line were observed to be less sensitive than their most-affected (MA) counterparts to hypothermia and analgesia induced by ethanol and morphine. By contrast, no differences were observed with respect to pentobarbital-induced hypothermia. At the dose used, pentobarbital had no significant analgesic effect in either animal line.     

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.