Showing papers on "Barbiturate published in 1978"

Different actions of anticonvulsant and anesthetic barbiturates revealed by use of cultured mammalian neurons.

Abstract: Barbiturate anesthetics, but not anticonvulsants, abolish the spontaneous activity of cultured spinal cord neurons; directly increase membrane conductance, an effect which is suppressed by the gamma-aminobutyric acid (GABA) antagonists picrotoxin and penicillin; and are more potent than anticonvulsants in augmenting GABA and depressing glutamate responses. Barbiturate anticonvulsants abolish picrotoxin-induced convulsive activity. These results indicate qualitative and quantitative differences between anesthetic and anticonvulsant barbiturates, which may explain their different clinical effects.

Dose dependent reduction of glucose utilization by pentobarbital in rat brain.

Abstract: A new method of determining the rate of glucose utilization in brain regions of individual rats has been used to measure the dose dependency of the reduction of the metabolic activity of the cerebral cortex by pentobarbital. Cerebral cortical glucose utilization is depressed to a basal level of 44% of the control rate when cerebral pentobarbital levels exceed 50 microgram per g of tissue. The major portion of this effect occurs between the cerebral pentobarbital range of 10--20 microgram per g, which can be achieved by 1/5 to 1/10 the normal anesthetic intraperitoneal dosage. If a depression of brain metabolism is responsible for the previously reported protection of the brain from ischemic damage, these data suggest a substantial reduction of brain metabolic rate is achieved in the rat at a barbiturate dosage which may be therapeutically relevant in the human after acute brain ischemia.

Reversal of the action of amino acid antagonists by barbiturates and other hypnotic drugs

Abstract: 1 The effects of pentobarbitone (PB) and other sedative/hypnotic drugs have been examined in relation to γ-aminobutyric acid (GABA) in vitro on the superfused isolated superior cervical ganglion of the rat and in vivo on single units in the brain stem of the anaesthetized rat. 2 PB, and other barbiturates, depolarized the ganglion in a dose-dependent manner (threshold concentration 100–300 μm, cf. GABA depolarization threshold 1 μm). The depolarization was reduced in the presence of the selective GABA antagonist (+)-bicuculline methochloride (Bic). Other non-barbiturate sedatives e.g. chlordiazepoxide, amitriptyline, promethazine at concentrations up to 2mM produced no depolarization. 3 PB, tested at concentrations up to 80 μm, produced variable effects on the dose-response curve to GABA. On most occasions a slight potentiation occurred in responses to low concentrations of GABA (below 10 μm) coupled with a depression in the responses to concentrations of GABA greater than 10 μm. 4 Superfusion with PB in the presence of Bic reversed the depression in the response to GABA produced by Bic. This reversal phenomenon occurred at concentrations of PB too low to depolarize the ganglion and was dependent not only on the concentration of PB but also on that of Bic. 5 The reversal potency within an homologous series of barbiturates increased with the size of the alkyl substituent (R2) at C5 on the barbiturate ring. The most potent occurred when the substi-tuent contained 5 carbon atoms (pentobarbitone and amylobarbitone); above this, activity decreased. 6 PB reversed the effects of the other GABA antagonists, tetramethylenedisulphotetramine and isopropyl bicyclophosphate and also the non-selective antagonism produced by strychnine. A concomitant reduction by strychnine of responses to the cholinomimetic, carbachol, was not reversed by PB. 7 Non-barbiturate sedative/hypnotics also reversed the GABA antagonism produced by Bic. The benzodiazepines were effective at lower concentrations than PB (chlordiazepoxide threshold concentration 0.5 μm, cf. PB 5 μm), however, they only produced a partial reversal even at concentrations much higher than the maximally effective concentration of PB. 8 The Bic reversal effect of chlordiazepoxide (and other benzodiazepines) lasted many hours after removal from the superfusion solution. By contrast the effect of PB lasted only 15–30min after its removal. 9 Chlordiazepoxide (30 μm) applied in the absence of Bic did not affect the response to GABA but did reduce the depression produced by the subsequent application of Bic even though the chlordiazepoxide had been removed 40min earlier. 10 In the rat brain stem in vivo PB, applied iontophoretically in amounts which neither decreased the spontaneous neuronal firing rate nor affected the response to GABA or glycine, reversed the GABA antagonism induced by iontophoretic application of Bic (in all 23 neurones tested). PB also reversed the antagonism produced by strychnine of responses to glycine although this was less readily observed (5 out of 14 neurones tested). 11 Iontophoretic application of other barbiturates and chlordiazepoxide also reversed the effect of Bic. Chlordiazepoxide only produced a partial reversal, as in the isolated ganglion, and no reversal could be demonstrated with flurazepam. 12 Intravenous administration of thiopentone (1.3mg/kg) pentobarbitone (0.4–5.5 mg/kg) hexobar-bitone (0.4-0.8 mg/kg) and clonazepam (0.1-0.2 mg/kg) also reversed the effect of iontophoretically applied Bic. The reversal by clonazepam was of much longer duration than that produced by the barbiturates. 13 It is suggested that the reversal exhibited by PB and the other hypnotics may be explained by assuming that the amino acids and their antagonists bind to the membrane at separate sites. If the reversal agent has particular affinity only for the antagonist binding site then it may displace the antagonist without affecting the receptor.

Cerebral protection with barbiturates: relation to anesthetic effect.

Abstract: The effect of racemic mephobarbital and its optical isomers on survival time of mice exposed to 5% O2 was studied. There was an increase in survival time from 4.2 minutes to 12.6 minutes for 100 mg/kg of the anesthetically active (-) isomer and the racemic form, but no increase for 100 mg/kg of the inactive (+) isomer. Since it has been shown that there is no difference in brain concentrations between the isomers, we conclude that the barbiturate protective effect is bound to the anesthetic effect. All mice convulsed, and since the non-anesthetized animals convulsed earlier and stronger than the anesthetized, it was possible that barbiturate protection was accounted for by its anticonvulsant effects. Diazepam 7.5 mg/kg, while reducing convulsions to the same degree as barbiturates without producing anesthesia, only increased survival time to 6.2 minutes. Thus, the barbiturate protective effect is distinct from the anticonvulsant effect. It seems to be bound to a stereospecific receptor for both protection and anesthesia.

Cerebral Hypometabolism Obtained with Deep Pentobarbital Anesthesia and Hypothermia (30 C)

Abstract: Cerebral metabolic and vascular effects of hypothermia (30 C) and deep pentobarbital anesthesia, separately and combined, were evaluated in 15 mongrel dogs. External cardiovascular support was not used, and mean arterial blood pressures remained greater than 60 torr. Normothermic deep pentobarbital anesthesia, characterized by an electroencephalographic (EEG) frequency of less than 1 Hz, was associated with 30% decreases in cerebral metabolic rates for oxygen (CMRO2) and glucose (CMRG) from lightly anesthetized control values. Hypothermia (30 C) alone caused similar decreases in CMRO2 and CMRG in the presence of an active EEG. The use of pentobarbital anesthesia and hypothermia combined achieved significantly greater (P less than 0.05) decreases in CMRO2 (70%) and CMRG (72%) from the control state. Cerebral vascular resistance (CVR) increased by 70% (P less than 0.05) during hypothermia and about 20% when pentobarbital was administered to normothermic dogs. In hypothermic animals the addition of pentobarbital had a minimal effect on CVR. No alteration in the oxygen-glucose or lactate-glucose index indicative of cerebral hypoxia occurred in any experimental group. This study indicates that barbiturates combined with hypothermia decrease cerebral metabolism to a greater extent than hypothermia or barbiturate alone. When cerebral hypometabolism is therapeutically necessary, barbiturates may be indicated as an adjunct to moderate hypothermia.

Brain noradrenergic systems as a prerequisite for developing tolerance to barbiturates

Abstract: Mice treated with 6-hydroxydopamine before they were chronically fed phenobarbital did not develop functional barbiturate tolerance, measured by duration of the loss of righting reflex and hypothermia. Injection of 6-hydroxydopamine caused significant depletion of brain norepinephrine, while brain dopamine levels were not significantly depleted. Intact brain noradrenergic systems seem to be necessary for developing tolerance to the hypnotic and hypothermic effects of the barbiturates.

Experimental barbiturate dependence. I. Barbiturate dependence development in rats by drug-admixed food (DAF) method.

Abstract: A method for testing a rat's physical-dependence liability to sedaditive-hypnotic agents and for evaluating that dependence was studied by using the method. Rats received phenobarbital- or barbital-admixed food on a graded-increase dosage schedule over 30-40 days. Manifestations of CNS-suppressing action of either drug (e.g., systemic muscle relaxation, motor incoordination, staggering gait, and ptosis) persisted day and night during the drug medication. Twenty-four to 48 h after withdrawal of either drug, abstinence symptoms (e.g., muscle fasciculation, nuchal twitching, vocalization, increased irritability, ataxia, hyperthermia, and clonic-tonic and grand mal-type convulsions) were evidenced in all animals (N = 6), some of which died after convulsions. These withdrawal signs in rats were classified and found to be closely correlated with the magnitude of weight loss during the withdrawal. The calssification provides a basis for quantitatively assessing physical-dependence liability. The data obtained in the present study suggest that rats, like dogs and monkeys, are suitable experimental animals for tests in early stages of dependence liability, and that the administration of drug-admixed food is a useful method of developing dependence on both barbiturate and morphine-type drugs.

Physical dependence to barbital compared to pentobarbital. IV. Influence of elimination kinetics.

Abstract: The withdrawal characteristics of barbital and pentobarbital after "chronically equivalent" treatment suggested that the longer acting barbital was less liable to produce physical dependence. Therefore, to distinguish this potential pharmacodynamic difference from the known pharmacokinetic differences between the two drugs, the rate of elimination of each was adjusted to mimic that of the other. The rate of barbiturate elimination after chronically equivalent pentobarbital dosing was reduced by barbital substitution or by first-order pentobarbital dose reduction, with the result that withdrawal signs became mild and appeared later (3 days postdrug). The rate of barbiturate elimination after chronically equivalent barbital dosing was increased by pentobarbital substitution or by peritoneal dialysis of barbital, with the result that withdrawal signs became severe and appeared sooner (within 1 day). These findings conclusively support the key role of the rate of barbiturate elimination to expose underlying physical dependence to barbiturates. Furthermore, "physical dependence" and its expression in "withdrawal" must be regarded separately to evaluate and compare critically the dependence capability of different drugs.

Physical dependence to barbital compared to pentobarbital. II. Tolerance characteristics.

Abstract: This study describes the tolerance characteristics of barbital compared to pentobarbital, the standard drug, during "chronically equivalent" treatment. Barbiturate tolerance was assessed as the increase in dose from the beginning to the end of treatment required to achieve equieffective peak effect. Dispositional tolerance was assessed as a reduction in the elimination half-life of barbiturate from blood. Functional tolerance was assessed as the increase in blood concentration of barbiturate at the time of peak effect. Overall, greater tolerance was developed to pentobarbital than to barbital. For pentobarbital, tolerance was both dispositional and functional; the dispositional tolerance developed rapidly and was almost complete at 1 week. For barbital, tolerance was exclusively functional. A most interesting finding was that functional tolerance to barbital and pentobarbital developed at the same slow rate for chronically equivalent treatment. This finding suggests that functional tolerance development is independent of the particular barbiturate reflecting the adaptability of the central nervous system to chronic depression.

Effect of synthesis inhibition on the levels of brain catecholamines in barbital-dependent rats.

Abstract: Adult male Sprague-Dawley rats were made barbital dependent by the long-term consumption of increasing concentrations of this compound in their drinking water. At the end of the drug regimen, the rats were sacrificed immediately or 1 or 2 days following barbital withdrawal. Some animals in each of these groups as well as control animals were treated with α methyl-para-tyrosine (250 mg/kg) (αMPT) or FLA-63 (40 mg/kg) 2 h before sacrifice. Following sacrifice, the telencephalon and brain stem of each animal were collected for subsequent analysis of dopamine (DA) and noradrenaline (NA) concentration. No changes in NA concentration were observed in either brain area of any of the experimental groups. On the other hand, when compared to the same parameter in control rats, the depletion of NA produced by αMPT or by FLA-63 pretreatment was significantly greater in the telencephalons of rats following 1 day of barbital withdrawal. Compared to control animals, the depletion of NA after FLA-63 pretreatment was also significantly greater in the brain stems of rats 1 and 2 days following barbital withdrawal. The concentration of DA in the telencephalons of drug-dependent rats was significantly decreased when compared to the levels in control animals by the second day of barbital withdrawal. The present data are consistent with an increase in utilization of brain NA and perhaps DA following the abrupt withdrawal of barbital from dependent rats. Further studies are required to determine if these changes in the brain catecholamines are a significant factor in the manifestation of the barbiturate abstinence syndrome.

Sedative activity of celery oil constituents

Abstract: The central depressant activities of 3, n-butylphthalide and a new compound, sedanenolide, were studied in mice. While neither compound affects ethanol sedation, they exhibit similar activities in both prolonging pentobarbital narcosis by prior administration of the test compounds and in inducing sleep immediately following recovery from a prior treatment with barbiturate. Weak sedative activity is also shown to reside in both compounds without potentiation.

Inhibition of gamma-aminobutyric acid release from rat cerebral cortex slices by barbiturate anesthesia.

Abstract: Amobarbital and pentobarbital anesthesia inhibited the potassium-stimulated, Ca-dependent release of γ-aminobutyric acid (GABA) from rat cerebral cortex slices during incubation in vitro. Inhibition of GABA release was not found when slices were prepared from rats shortly after they awakened from amobarbital anesthesia. Phenobarbital anesthesia did not affect the release of GABA.

Barbiturate physical dependence in mice: Effects of neuroleptics and diazepam on the withdrawal syndrome

Abstract: Diazepam (8 mg/kg) quickly and effectively reduced the incidence of withdrawal symptoms in phenobarbital dependent C57BL/6J male mice. In contrast, the neuroleptic agents employed (chlorpromazine, haloperidol, or reserpine) or α-methyl-p-tyrosine tended to exacerbate the withdrawal syndrome. Chlorpromazine and haloperidol were approximately equally potent in their effects; this would suggest that their antidopaminergic effects were not the primary mechanism of action for the increased incidence of withdrawal symptoms.

Alcohol, prolonged isolation and barbiturate sedation in two strains of mice.

Abstract: Mice subjected to prolonged socioenvironmental deprivation gradually develop hyperirritability and hyperreactivity to physical stimuli. This heightened neuroexcitability may or may not debouch into aggressiveness according to strain and sex of the animals, and it is accompanied by a reduced sensitivity to CNS depressants. Socioenvironmental deprivation or isolation is shown to decrease the sensitivity either to pentobarbital or to ethanol potentiation of pentobarbital sleeping time in male mice from two different strains.

Dose dependent reduction of glucose utilization by pentobarbital in rat brain.

Abstract: A new method of determining the rate of glucose utilization in brain regions of individual rats has been used to measure the dose dependency of the reduction of the metabolic activity of the cerebral cortex by pentobarbital. Cerebral cortical glucose utilization is depressed to a basal level of 44% of the control rate when cerebral pentobarbital levels exceed 50 microgram per g of tissue. The major portion of this effect occurs between the cerebral pentobarbital range of 10--20 microgram per g, which can be achieved by 1/5 to 1/10 the normal anesthetic intraperitoneal dosage. If a depression of brain metabolism is responsible for the previously reported protection of the brain from ischemic damage, these data suggest a substantial reduction of brain metabolic rate is achieved in the rat at a barbiturate dosage which may be therapeutically relevant in the human after acute brain ischemia.

Individual differences in barbiturate-induced sleeping time in the mouse

Abstract: 1. 1. Differences in barbiturate induced onset and sleeping times were evident in three inbred strains of mice. 2. 2. Caffeine antagonized while promethazine enhanced the effects of pentobarbital. 3. 3. These effects are discussed in terms of arousal and neurochemical differences.

Effect of pentobarbital on the synaptosomal activity of acetylcholinesterase in Mongolian gerbils.

Abstract: The influence of Na pentobarbital anesthesia on the activity of specific and nonspecific cholinesterase was studied in the synaptosomal fraction of Mongolian gerbils' brains. These studies have shown that this barbiturate inhibits the specific activity of acetylcholinesterase only.