[Possibilities of using a new binding substance in barbital and sodium barbital tablets].
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Some aspects of the changes induced by chronic barbital treatments in the male rat.
Oral barbital treatments consisting of average daily doses of 200 mg/kg with durations of 15-50 weeks have been used to induce functional tolerance and physical dependence. Tolerance is usually studied with a hexobarbital threshold while increased excitation has been studied by various means, such as induction of convulsions with pilocarpine or choline. After barbital treatments for 30 weeks brain weights are reduced by approximately 10 per cent. This reduction is not due to changes in body weight or water content of the brain. The decrease is still found 30 days after the end of the barbital treatment. Supersensitivity to pilocarpine and reduced acetylcholine content in the brain are some earlier published indications that cholinergic mechanisms are involved in abstinence. Further studies have shown that atropine (8 mg/kg given intraperitoneally on the third day of abstinence) can reduce the tolerance to hexobarbital. An atropine treatment (4 mg/kg per day for 2 weeks) given late in the period of abstinence following a barbital treatment can induce a tolerance to hexobarbital. A prerequisite for this tolerance is the earlier barbital treatment. A steric selectivity in the action of hexobarbital is indicated by the interaction between atropine (8 mg/kg) and the isomers of hexobarbital. In normal rats only the potent isomer of hexobarbital is influenced by atropine. If the convulsive effect of choline is utilized in a threshold test, an increased sensitivity indicating increased excitation is found on day 10-11 of the period of abstinence when other signs of excitation are returning to normal. When these signs are maximal, on day 3, no increased sensitivity to choline is found. Choline seems to act on a selective mechanism which is revealed only late in the abstinence period. Hexobarbital thresholds performed on two phases of the blood ethanol concentration curve were used to study the interaction between ethanol and hexobarbital during abstinence following a barbital treatment. Immediately after the end of the barbital treatment, a general tolerance was present. A week later, ethanol eliminated the tolerance to hexobarbital. On day 15 of abstinence, no tolerance to hexobarbital was found, but there was a tolerance to ethanol on the increasing portion of the blood ethanol concentration curve. Thus, it is unlikely that physical dependence and functional tolerance constitute a single phenomenon in abstinence after barbital treatments. Cholinergic mechanisms seem to be involved in the presumably adaptive changes that can be recorded.
Acetylcholine↗
Barbital overdose and abuse.
Bailey, David N., and Jatlow, Peter I.: Barbital overdose and abuse. A new problem. Am J Clin Pathol 64:291-296, 1975. The unusual epidemiology and toxicology of barbital overdose and abuse are demonstrated by eight recent cases. Since barbital is used primarily in laboratory buffers and is not available as a prescription or over-the-counter drug in the United States, barbital overdose and abuse have until recently been rare. In several instances the barbital was stolen from a clinical or research laboratory. Serum concentrations were often "astronomically" high compared with those of other barbiturates, including phenobarbital. Concentrations severalfold greater than would be considered lethal for other barbiturates were consistent with survival, and all patients, including one with a serum concentration of 120.2 mg per dl. (higher than any previously reported), recovered with only conservative therapy (no peritoneal or hemodialysis). Patients could be awakened when the concentration was less than 16.0 mg per dl. Serum barbiturate concentrations greater than 20.0 mg. per dl. in a living patient should warrant serious consideration of barbital ingestion. In addition to the eight overdoses, 16 abusers of barbital were detected during 1974 by drug-abuse screening of urine.
Acute Disease↗
The interaction between electrically induced convulsions and tolerance in the abstinence period after chronic barbital treatments in the rat.
The effect of electrically induced convulsions was tested on the tolerance to hexobarbital after chronic barbital treatment in male rats. In two experiments barbital was given in the drinking water for more than 20 weeks. The dose was around 200 mg/kg/day. Tolerance was tested with an EEG threshold method where hexobarbital is infused intravenously to obtain a criterion of burst suppression. If on the third abstinent day an electrical convulsion was induced 1 h prior to the threshold determination then the hexobarbital thresholds were reduced compared with barbital-treated animals where no convulsion had been induced (Fig.2). The distribution of hexobarbital threshold doses tended to be biphasic in the barbital-treated animals where a convulsion had been induced. The animals with the most "normal" thresholds in this distribution did not show any increase in threshold on the 24th abstinent day and had a larger mortality during the observation period after the first barbital treatment. Long-term effects of the convulsion thus cannot be excluded in rats if the tolerance on the third abstinent day after a barbital treatment was influenced. No effect of the convulsion was found in untreated controls. The hypothesis that convulsions are means to reduce the changes of physical dependence in the central nervous system was not refuted by the present experiments. A survey of the literature indicates that acetylcholine might be one central nervous transmittor that is involved in these changes.
Animals↗
Delirium tremens: a double-blind comparison of diazepam and barbital treatment.
The effect of diazepam and barbital in the treatment of delirium tremens and other acute conditions related to alcohol abuse was evaluated in a double-blind trial. 91 patients participated in the study, 44 in the diazepam group, 47 in the barbital group. The choice of diazepam rather than chlordiazepoxide was motivated by its major anticonvulsive properties. Barbital was given by the oral route, diazepam as intramuscular injections. Different ways of drug administration to patients with delirium tremens are discussed. It is concluded that the two different ways used in the study probably did not have a noteworthy influence on the results. All patients were excluded who had taken psychoactive drugs before admission. Nevertheless a considerable part of the patients had diazepam, but not barbital, in the blood before treatment was initiated. This may give support to the use of barbital as a "special purpose drug" in the treatment of these conditions. The patients were divided into three diagnostic categories, according to the severity of the clinical condition. No difference between the two drugs tested was found in the milder conditions, but barbital was found superior to diazepam in the treatment of fully developed delirium tremens.
Administration, Oral↗
Increased penetration of barbital through the bloodbrain barrier in the rat after pretreatment with probenecid.
Some weak organic acids are eliminated from the brain by an acid transport system. The question arose is this system also used to transport drugs out of the brain? In that case probenecid pretreatment (100 mg/kg subcutaneously) should influence the induction time of a slightly lipid soluble barbiturate (barbital) which penetrates into the brain slowly, more than the induction time of a very lipid soluble barbiturate (hexobarbital). In the first experiment barbital (200 mg/kg) was given intraperitoneally and in the second experiment barbital (150 mg/kg) was infused intravenously during 10 min. In both experiments loss of righting reflex occurred more rapidly after pretreatment with probenecid compared with pretreatment with saline. Only in the second experiment did probenecid significantly increase the time during which the righting reflex was lost. In the next experiment hexobarbital was infused intravenously at a rate of 0.25 mg/kg/sec. until a burst suppression which lasted 1 sec. or more was seen in a concomitant EEG-record. When this "silent second" occurred the infusion was stopped and the ensuing anaesthesia times recorded. Probenecid had no effect on the induction when studied with this method, but the ensuing anaesthesia times were increased. The hypothesis of an acid transport system out of the brain was thus not refuted by these experimental results. Studies of brain concentrations of barbital also supported this finding. After 200 mg/kg intraperitoneally the concentration of barbital in the brain was higher after pretreatment with probenecid as compared to saline pretreated controls i.e. at times corresponding to the induction times in the in vivo experiments. No difference was found in the serum levels of barbital.
Anesthesia↗
Absorption and distribution of sodium [2-14C]barbital in tissues of normal and dystrophic mice.
The absorption and distribution of [2-14C]barbital after oral administration was studied in various tissues, including skeletal muscle, of normal and dystrophic mice. There appeared to be a more rapid gastric emptying in the mutant homozygote as reflected in lower levels of the drug recuperated from the gastrointestinal tract. This resulted in initially higher plasma and tissue concentrations of barbital in the dystrophic mice. Two hours after oral administration, this kinetic profile was reversed so that less barbital remained in the tissues of the dystrophic mouse. The tissue:plasma concentration ratios were consistently, but not significantly, higher in all tissues of the dystrophic animals. Analysis of the half-life of the drug in both groups suggests that there is an increase in the distribution volume of barbital in the dystrophic mice. The phenomenon of more rapid absorption of the barbiturate seems to be more consistent as the symptoms of the disease progress. The altered absorption and disposition of barbital in various tissues of the dystrophic mouse support the concept that a generalized multisystemic disorder may be crucial to the pathogenesis of murine muscular dystrophy, in contradistinction to a purely myogenic origin.
Animals↗
Regional distribution of barbital in the brain of mice during the development of tolerance and physical dependence.
ICR male mice each receiving a 16 mg barbital pellet implanted subcutaneously for three days developed about 40 percent tolerance to barbital and more than 50 percent tolerance to pentobarbital as measured by sleeping time. The development of physical dependence in these mice was demonstrated by an increased sensitivity to convulsions with pentylenetetrazol. The concentration of barbital rose to high levels in the subcortex and the cerebellum during the time between the implantation of the pellet and the loss of the righting reflex and distributed uniformly thereafter. After a challenge dose of the drug, higher barbital concentrations were found in these two areas as well as in the pons-medulla at 30 minutes and in all areas at the time of the loss of righting reflex, in withdrawn mice. The latter finding would indicate an increase in threshold for barbital anesthesia. The mechanisms of the higher uptake in the brain of withdrawn mice are discussed.
Animals↗
Physical dependence to barbital compared to pentobarbital. IV. Influence of elimination kinetics.
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.
Animals↗
Assessment of tolerance to barbital by means of drug discrimination procedures.
This study was designed to determine the relative development of tolerance to the discriminative-stimulus and hypnotic properties of barbital. By selectively reinforcing lever presses only in the presence of one of the drug stated, rats were trained in a Skinner Box to discriminate the effect of sodium barbital (80 mg/kg) injection from that of saline injection. After the rats were well trained, the administration of daily hypnotic doses of barbital (240 mg/kg) for 8 days produced marked tolerance to the hypnotic effect of the barviturate in all animals. The ability of the 80 mg/kg dose to serve as a discriminative stimulus was not impaired in animals which had been trained with the drug as the condition during which bar presses had been reinforced (SD condition). Animals for which bar presses had gone unrewarded under barbital (Sdelta condition) displayed a tendency to develop tolerance to the stimulus properties of barbital. These findings are interpreted in the light of dose-effect studies, and it is suggested that the acquired polarity of the drug condition determined by its assignment as Sd or Sdelta may influence the discriminability of the drug in future exposures.
Animals↗
Differences in the stimulus properties of barbital and hallucinogens.
The present investigation sought to determine whether drugs which produce markedly different perceptual effects in man, barbital and mescaline or LSD produce different stimuli in rats. In a standard 2 lever operant test chamber, rats received sweetened milk for correct responses according to a variable interval schedule. All sessions were preceded by 1 of 2 treatments; following Treatment A, only responses on Lever A were reinforced and, in a similar fashion, Lever B was correct following Treatment B. No responses were reinforced during the first 5 min of a daily 30 min session. It was found that barbital can serve as a discriminative stimulus when this drug is paired with saline. Previously, we had demonstrated that mescaline or LSD can serve as discriminative stimuli. When barbital was administered to animals trained to discriminate mescaline or LSD and saline, they made either random responses or responses appropriate to saline treatment. This observation suggests that the stimulus properties of barbital are difference from those of the hallucinogens. A subsequent demonstration of discriminated responding when barbital and mescaline or LSD were paired as discriminative stimuli supports this conclusion. The present results extend previous findings which suggest that the degree of similarity or difference of drug stimuli in rats is congruent with the degree of similarity or difference of perceptual drug effects in man.
Animals↗
The effects of atropine on the tolerance and the convulsions seen after withdrawal from forced barbital drinking in the rat.
Male rats were forced to drink a barbital solution as their only drinking fluid for 33 weeks. During the last part of the treatment the average dose of barbital was around 200 mg/kg/day. In the abstinence period after barbital treatment, tolerance was recorded with a hexobarbital anaesthesia threshold utilizing an EEG criterium. Convulsions were recorded in jiggle cages. On days 3 and 28 of the abstinence period, i.p. pretreatment with atropine (2, 4, and 8 mg/kg) was given 1.5 h before threshold determinations. The barbital treatment induced a clear tolerance to the hexobarbital, which still could be detected on day 28 of abstinence. Atropine (8 mg/kg) reduced the hexobarbital threshold in tolerant and in control animals at both the time of maximum tolerance (day 3) and later during abstinence (day 28). The magnitude of the response was greater in tolerant animals, but no parallel shift in the dose-response curve was seen. The convulsions during abstinence were reduced for at least 8 h after atropine treatment (8mg/kg) on day 3. These results support the hypothesis that cholinergic mechanisms are involved in the changes induced by chronic barbiturate treatments.
Animals↗
Effect of long-term forced oral barbital administration on endogenous acetylcholine in different regions of rat brain.
Rats received a solution of sodium barbital as their only drinking fluid for 25 and 30 weeks. Four groups were studied: (1) control; (2) barbital until sacrifice; (3) barbital withheld (abstinent) for 3 days; (4) abstinent for 12 days. Abstinence convulsions in groups 3 and 4 were recorded with jiggle cages. The rats were killed by decapitation and the concentration of acetylcholine (ACh) was measured in 3 parts of the brain: striatum, hippocampus + cerebral cortex, cerebellum + medulla oblongata + midbrain. In animals receiving barbital until sacrifice, no significant change in ACh content was found in any of the brain regions compared with controls. In animals abstinent for 3 days and with a maximal frequency of spontaneous convulsions a decreased content of ACh (--35%) was found in the striatum. On the 12th day of abstinence, when the convulsive activity clearly had decreased, the ACh content was still decreased (--30%) in the striatum and a significant decrease compared with controls was also found in the cerebellum + medulla oblongata + midbrain.
Acetylcholine↗
Barbital and diazepam plasma levels during treatment of delirium tremens.
Plasma concentrations of barbital and diazepam were measured daily during a double-blind study of the efficacy of the two drugs in the treatment of delirium tremens and less severe clinical states. Treatment was estimated as satisfactory in the majority of cases; the present study deals with the satisfactory groups only. Both in the barbital group and in the diazepam group the same plasma level was seen in different clinical states. This result is discussed in relation to the theories about the aetiology of delirium tremens, and it is concluded that the data fits best with the assumption that delirium tremens is released from a withdrawal state, but once established, the delirious state is not interrupted by the drugs. The barbital concentrations were rather high, many at a level where non-alcoholics would show pronounced intoxication symptoms not seen in the present material. The diazepam concentrations on the other hand were low, often below a level where a cerebral effect is measurable in normal subjects. On this basis it is concluded, that the two drugs have different modes of action. Barbital may act by its cross-dependence properties with alcohol and thus diminish the withdrawal reaction, whereas diazepam may act by its anti-anxiety effect, but not in the doses here applied, by cross-dependence properties with alcohol. Finally, this hypothesis is discussed in relation to clinical experience in the treatment of delirium tremens.
Alcohol Withdrawal Delirium↗
Disulfiram enhances pharmacological activity of barbital and impairs its urinary elimination.
Disulfiram or diethyldithiocarbamate significantly enhanced the sleeping time induced by barbital in rats. At identical time intervals after rats were injected with barbital the concentration of barbital in the blood or brain of animals that had previously received disulfiram was significantly higher than the concentrations in the corresponding tissues of control animals. Urinary excretion of barbital was significantly reduced in disulfiram-treated animals.
Animals↗
Physical dependence to barbital compared to pentobarbital. II. Tolerance characteristics.
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.
Animals↗
Physical dependence to barbital compared to pentobarbital. III. Withdrawal characteristics.
After "chronically equivalent" barbital and pentobarbital dosing for 5 weeks, treatments were abruptly stopped and the animals were carefully observed for signs of barbiturate withdrawal. The severity of withdrawal was assessed at preset times by counting the number of grand mal type convulsions and subjectively rating 20 additional motor, autonomic and behavioral signs including tremors, twitches, myoclonic jerks, postural disturbances and motor incoordination. Ratings achieved at peak intensity (raw scores) and their incidences were used to compute "total intensity scores" for each graded sign. For all quantitative measures, withdrawal signs were less severe for barbital than for pentobarbital, with strikingly lower (P less than .05) incidences of convulsions (6.3% vs. 100%), bizarre (hallucinatory) behavior (6.3% vs. 41.3), and death (0% vs. 100%). The withdrawal signs for barbital appeared later, developed more slowly and persisted longer than those for pentobarbital. That the onset and then peak of withdrawal signs occurred when the extents of decline from peak blood concentration of barbital and pentobarbital were similiar suggests that the time course of withdrawal might be inversely related to residual concentrations of drug, i.e., negative dose-response.
Animals↗
Osmotic minipumps for administration of barbital to mice: demonstration of functional tolerance and physical dependence.
Sodium barbital was administered to mice at a constant rate by miniature osmotic pumps implanted subcutaneously. Each pump delivered approximately 0.25 mg/hr. With two pumps per mouse, blood barbital levels of 20 to 30 microgram/ml could be maintained for various periods. Barbital was assayed by gas chromatography. Functional tolerance was shown by a significant decrease in sleep time after a challenge dose of barbital administered 24 hours after withdrawal. Physical dependence was demonstrated by withdrawal hyperexcitability as measured either with pentylenetetrazol or by convulsions elicited by handling.
Animals↗