A BARBITURATE ANTIDOTE—Use of Methylethylglutarimide in Barbiturate Intoxication and in Terminating Barbiturate Anesthesia

Methylethylglutarimide was administered to 488 patients ranging in age from 7 to 89 years, in a study on sleep-reversal after harbiturate anesthesia. Sodium surital or sodium pentothal were the barbiturates used. The drug was administered intravenously in doses varying from 25 to 200 mg. Dosage below 25 mg. was found to be ineffective. Almost all patients showed signs of awakening as evidenced by the return of corneal and conjunctival reflexes, the opening of the eyes, and stirring or moving about. Many responded to questioning. Almost all showed evidence of greater responsiveness within five minutes. No untoward reactions were noted. No convulsions were produced.Five patients ranging in age from 24 to 70 years were treated for barbiturate poisoning with Mikedimide® given intravenously in doses varying from 550 mg. to 1950 mg. All recovered consciousness within 30 minutes to an hour. No convulsions were produced.While it is not known whether Mikedimide is a direct barbiturate antagonist, or whether it is an analeptic, it appears to be a useful drug in reversing the respiratory depression and the cerebral depression produced by harbiturate intoxication and barbiturate anesthesia.     

Barbiturate Intoxication: Morbidity and Mortality

The complications encountered in caring for 185 patients intoxicated with barbiturates were reviewed. The population consisted of 142 patients with long-acting barbiturate concentrations of 8 mg per 100 ml or greater, 20 patients with short-acting barbiturate concentrations of 3 mg per 100 ml or greater and 23 consecutive patients with short-acting barbiturate intoxication referred for monitoring. Pneumonia was the major cause of morbidity and mortality and correlated best with the initial depth of coma and the use of an endotracheal tube in treatment. Cardiovascular instability manifested by pulmonary edema was the next leading cause of morbidity and mortality and correlated best with the initial depth of coma and the quantity of intravenous fluid administered. In retrospect, use of eliminative measures such as dialysis would probably not have altered the outcome in most of the patients who died and attempts at forced diuresis may have contributed to several deaths. Particular emphasis should be placed on the problems of sepsis and fluid therapy in the management of these patients.     

Barbiturate Mortality as an Index of Barbiturate Use,Canada, 1950-1963

Changes in Canadian rates of mortality from barbiturates are examined, and their relation to barbiturate use in the general population is discussed. While the number of deaths attributed to barbiturates quadrupled, from 63 in 1950 to 232 in 1963, there has been a concomitant decrease in the number of deaths from inhalation of utility gas.Combined rates for deaths from utility gas and barbiturates declined steadily for most age groups between 1950-52, 1955-57, and 1959-63. It is possible that the increased mortality from barbiturates represents a change in fashion in regard to method of suicide. Changed mortality from barbiturates is not a valid measure of the extent to which consumption of barbiturates has increased in the Canadian population.     

Abnormal Drug Metabolism after Barbiturate and Paracetamol Overdose

Drug-metabolizing capacity has been assessed by serial measurements of the plasma antipyrine half life in 11 patients with severe barbiturate intoxication and in 17 patients with acute hepatic necrosis due to paracetamol overdosage. Drug metabolism was strikingly enhanced after barbiturate over-dosage, and this effect was still present six weeks later. In contrast the antipyrine half life was greatly prolonged in patients with paracetamol-induced acute hepatic necrosis but returned to normal or near-normal values within seven to 21 days.     

Interactions between phospholipids and barbiturates.

The effects of a number of barbiturates on the temperature of the lipid phase transition have been studied using chlorophyll a as a fluorescence probe. The barbiturates cause a reduction in the temperature of the phase transitions of dipalmitoyl phosphatidylcholine and dipalmitoyl phosphatidylethanolamine, the effects being greatest at lower pH values where more of the barbiturate is present in the uncharged form. There was no significant interaction between the barbiturates and dipalmitoyl phosphatidylserine. These and other observations on the actions of local anaesthetics are used to develop a model for local anaesthesia. It is suggested that the sodium channel is surrounded by an annulus of lipid in the gel state, this rigid microenvironment preventing the sodium channel relaxing from its active configuration to an inactive one. Local anaesthetics, which reduce the temperature of lipid phase transitions, trigger a change of the annular lipid from the gel to the liquid-crystalline state, with a consequent relaxation of the sodium channel to an inactive configuration, in which the sodium current is reduced or blocked.     

Effect of GABA ascorbinate on epileptiform reactions of cortical neurons and some metabolic consequences of hypoxia in the rat brain

In the first series of experiments on immobilized anesthetized rats we studied the effects of GABA ascorbinate (A-GABA) in combination with sodium thiopental on the epileptiform reactions of cortical neurons. It is demonstrated that when combined with a classic anticonvulsant, barbiturate, A-GABA effectively suppressed neuronal epileptiform reactions. This makes it possible to considerably decrease the dose of inected barbiturate. In the second experimental series, we studied the effects of acute cerebral hypoxia on the content of overall macroergic phosphates (MP) and Na, K-ATPase activity in the cortex. We also tested the possibility of corecting the hypoxia-related shifts of the above indices by treatment with GABA, A-GABA, or their combination with a vitamin complex (VC). A successive increase in the efficacy of the above agents from GABA to A-GABA+ VC was observed with respect to the above two indices. The mechanisms of the A-GABA effects on GABA receptor-channel complexes and the prospects for using A-GABA in combination with barbiturates and VC for treatment of various brain pathologies are discussed.     

Solubilization by CHAPS detergent of barbiturate-enhanced benzodiazepine-GABA receptor complex

Abstract: Barbiturates enhance the binding of [³H]flunitrazepam to benzodiazepine receptors solubilized with the detergent 3-[(3-cholamidopropyl)-dimethylammonio]propanesulfonate (CHAPS) from bovine cortex. The enhancement by the barbiturates is seen as a decrease in the dissociation constant, K _d , for specific benzodiazepine binding, with no effect on the number of binding sites. The effect of the barbiturates is facilitated by chloride ions, is concentration-dependent, and has a specificity that correlates well with the anesthetic potency of barbiturates. [³H]Flunitrazepam binding activity is stable with storage at 4°C., but barbiturate enhancement of soluble benzodiazepine binding activity decayed rapidly ( t _1/2= 48 h). [³H]Muscimol binding (GABA receptor) activity was also enhanced by barbiturates. Agarose gel filtration column chromatography of the CHAPS-solubilized receptor proteins showed the same elution profile as receptors solubilized with sodium deoxycholate, and enhancement by barbiturates was observed for both the benzodiazepine and GABA binding activities.     

Mannitol

Mannitol may be useful clinically both as a diuretic and as an obligate extracellular solute. As a diuretic it can be used to treat patients with intractable edema states, to increase urine flow and flush out debris from the renal tubules in patients with acute tubular necrosis, and to increase toxin excretion in patients with barbiturate, salicylate or bromide intoxication. As an obligate extracellular solute it may be useful to ameliorate symptoms of the dialysis disequilibrium syndrome, to decrease cerebral edema following trauma or cerebrovascular accident, and to prevent cell swelling related to renal ischemia following cross-clamping of the aorta. Largely unexplored uses for mannitol include its use as an osmotic agent in place of dextrose in peritoneal dialysis solutions, its use to maintain urine output in patients newly begun on hemodialysis, and its use to limit infarct size following acute myocardial infarction.     

Neurochemical Mechanisms Underlying Alcohol Addiction: Model Experiments on Rats

We measured the activities of the main alcohol-metabolizing enzymes (alcohol dehydrogenase, AlDH, and aldehyde dehydrogenase, AdhDH) in the blood serum, comparing these indices with the contents of ethanol and its main metabolite, acetaldehyde (AcAdh), in the blood, and also measured the contents of catecholamines (adrenaline, noradrenaline, and dopamine) in the blood and in different brain structures (hypothalamus, midbrain, and neocortex) of rats in the states of acute alcohol intoxication and chronic alcohol addiction. It was shown that, because of dissimilar changes in the activities of AlDH and AdhDH under conditions of alcohol intoxication, the dynamic balance between endogenous ethanol and AcAdh existing in the norm is disturbed, which results in an increase in the level of AcAdh. Such a phenomenon probably is one of the crucial factors underlying the development of alcohol addiction.     

Impaired Anthocyanin Production in Barbiturate treated Zea mays Seedlings

Anthocyanin production was impaired in both roots and shootsof Zea mays seedlings germinated on 1 and 2 mM concentrationsof four barbiturates having different lipid/aqueous partitioncoefficients. The severity of impaired anthocyanin productionwas greater in those seedlings treated with the higher lipidsoluble barbiturates irrespective of the concentrations used.Indirect evidence is presented which indicates that barbituratesinterfere with normal membrane physiology responsible for anthocyaninproduction. Anthocyanin, barbiturate, seedlings, Zea mays     

Changing pattern of drugs used for self-poisoning.

In 1967-76 the annual number of admissions to a poisoning treatment centre rose from 964 to 2134. The proportion of admissions caused by taking barbiturate hypnotics and methaqualone fell considerably while that caused by taking benzodiazepines and tricyclic antidepressants increased. As a result the proportion of patients admitted unconscious fell from 23% to 15%. The declining contributions of barbiturates and methaqualone and increased importance of tricyclic antidepressants were significant in all grades of coma. The change in drugs taken, however, has not yet reduced the percentage of unconscious patients needing endotracheal intubation or assisted ventilation, and hypothermia remains as common. Only hypotension has become less frequent as antidepressants replace barbiturates as the main cause of drug-induced coma. The use of salicylates for self-poisoning is declining slowly, and paracetamol poisoning is now as common.     

Effects of acute CS2 intoxication on protein metabolism in rat brain

The effect of acute CS₂ exposure on the rat brain protein metabolism was studied with control and phenobarbitone pretreated adult male rats 1, 4 and 46 h after exposure. Increased activity of acid proteinase was detected in both test groups 1 and 4 h after exposure and it was accompanied by changes in ¹⁴C-labelled leucine turnover as well as in RNA content. The changes were more conspicuous in cerebellum than in brain in both test groups while phenobarbitone pretreatment modified the brain response towards intoxication. This modification probably represents inherent effects of barbiturate on brain protein metabolism as well as altered metabolism of CS₂.The activities of creatine kinase and nonspecific cholinesterase displayed only subtle changes as assayed in cerebral homogenate and serum. Thus a single acute CS₂ intoxication apparently causes definitive transient changes in brain protein metabolism; serum enzyme determinations may not reflect the magnitude of these changes.     

Toxicological Statistics for Barbiturates,Other Sedatives,and Tranquillizers in Ontario: A 10-Year Survey

A steady increase in the number of cases of poisoning due to barbiturates, tranquillizers and non-barbiturate sedatives has been noted for Ontario by the Attorney-General''s Laboratory, Toronto, during the period 1955-1964 on the basis of submitted material. Five cases of poisoning by barbiturates were recorded in 1955 and 193 in 1964.Urine and blood samples from persons charged with driving motor vehicles while under the influence of drugs were also examined. In 1958 only one such case was reported to the Laboratory, whereas 25 cases were recorded in 1964; barbiturates were detected in 18 of these 25. Patients must be warned of the risks of ingesting alcohol while receiving barbiturate treatment.     

Respiration rate, heart rate, and body temperature values in cynomolgus monkeys (Macaca fascicularis) during barbiturate anesthesia

Respiration rate, heart rate, and body temperature values were obtained from 14 cynomolgus monkeys (Macaca fascicularis) during neurosurgery under barbiturate anesthesia. Vital sign values markedly declined below baseline during the early stages of surgery, steadily increased as surgery progressed and neared completion, and finally returned to baseline by the end of the postsurgical recovery period. There was considerable variability among the 14 monkeys, but the ranking of each monkey relative to the others remained constant across the period of observation. The findings suggested that the cynomolgus monkey may be more sensitive to barbiturates than the rhesus monkey, and cynomolgus monkeys may exhibit considerable individual differences in their sensitivity to barbiturates.     

Interaction of barbiturates with dihydropicrotoxinin binding sites related to the GABA receptor-ionophore system.

Barbiturate drugs of diverse chemical structure inhibited the binding of [³H] α-dihydropicrotoxinin to rat brain membranes. This biologically active analoque of picrotoxin labels membrane sites related to the convulsant action of these drugs in inhibiting GABA postsynaptic receptor-ionophore function at a site distinct from the GABA receptor. Depressant barbiturates such as pentobarbital inhibited dihydropicrotoxinin binding competitively at therapeutic concentrations (IC₅₀ = 50 μM) whereas the drug does not alter GABA receptors, uptake, or release at this concentration. Antiepileptics such as phenobarbital (IC₅₀=400 μM), were weaker inhibitors of binding. Convulsant barbiturates, however, such as dimethylbutylbarbiturate (IC₅₀=0.05 μM) and cyclohexylidene-ethyl barbiturate (IC₅₀=0.7 μM), were potent inhibitors. The displacement of radioactive dihydropicrotoxinin binding by the convulsant barbiturates had different slopes and Hill numnbers (0.4) compared to displacement by depressant barbiturates and picrotoxinin itself (Hill numbers = 1.0), indicating heterogeneity of binding sites or negative cooperativity. These potent intractions of barbiturates with dihydropicrotoxinin binding sites are consistent with neurophysiological evidence that depressant or convulsant action of barbiturates may involve modulation of CNS inhibitory synaptic transmission at the level of the postsynaptic GABA receptor-ionophores.     

Effect of xylocaine and carbachol applied to the caudate nucleus of rats on barbiturate sleeping time

Since lesion of subcortical structures may affect the barbiturate sleeping time (bST), we decided with the present study to elucidate the role of the caudate nucleus in the determination of central sensitivity to barbiturates. Rats implanted with a cannula in the caudate nucleus of one or both sides, as well as with a jugular cannula, were utilized. Intravenous injections of sodium pentobarbital (40 mg/kg), intracerebral injections of Xylocaine (0.04 microgram), carbachol (0.2 micrograms) or artificial cerebrospinal fluid (ACF) into the caudate nucleus were performed. Both Xylocaine and carbachol, but not ACF, increased the bST regardless of the preparation used, the only exception being Xylocaine which did not alter the bST, if injected into the left caudate nucleus. The results suggest that the caudate nucleus may act as a modulator of the central sensitivity to barbiturates.     

Biochemical pharmacology of the gamma-aminobutyric acid receptor/ionophore protein

The synaptic receptor sites for the neurotransmitter gamma-aminobutyric acid (GABA) can be assayed in vitro with several radiolabeled agonists and one antagonist. Numerous criteria of specificity have been met for these binding sites. All of the ligands show heterogeneity in binding affinities. The subpopulations thus defined have a remarkably similar specificity for GABA analogs, which suggests an intimate relationship and possible interconvertibility. Modulation of GABA receptor binding by barbiturates, anions, and other membrane treatments that affect agonists and antagonists in an opposite manner suggests a three-state model of interconvertible affinities. The complex of GABA receptor and chloride ion channel contains modulatory sites for barbiturates and benzodiazepines, drugs that enhance GABA responses in neurons. The receptor complex can be solubilized in detergent with the three mutually interacting receptor activities intact. The complex has an apparent molecular weight of 355,000 and has been partially purified. GABA agonist function has been assayed at the biochemical level by measuring the activation of 36Cl- efflux from preloaded hippocampal slices by GABA, muscimol, and barbiturates. This response is blocked by the antagonists of the GABA site (bicuculline) and the barbiturate site (picrotoxin). Comparison of binding and function on the same tissue should be useful in analyzing the mechanism of action of GABA.     

Stereoselective stimulus effects of 3-methylflunitrazepam and pentobarbital

Rats trained to discriminate 3.0 mg/kg of diazepam from saline in a two-lever operant choice task were challenged with the racemic mixture and optical isomers of 3- methylflunitrazepam or pentobarbital. Generalization of the diazepam stimulus was found to occur to (+/-)- and S(+)-3- methylflunitrazepam , with the S(+)-isomer being twice as active as the racemate. Diazepam stimulus generalization also occurred to (+/-)-, S(-)-, and R(+)-pentobarbital, with the S(-)-isomer being approximately twice as active as (+/-)- or R(+)-pentobarbital. In addition, the administration of the imidazobenzodiazepine Ro 15-1788, a selective benzodiazepine receptor antagonist, prior to benzodiazepine or barbiturate administration competitively antagonized the discriminative stimulus properties of the benzodiazepines but was completely ineffective in attenuating the discriminative stimulus effect of the barbiturates. The results of this study suggest that benzodiazepines exert their stimulus effects by a stereoselective interaction at a benzodiazepine receptor and that stereochemical factors are important in evaluating the stimulus properties of benzodiazepines or barbiturates.