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PubMed1999

GLUT1-deficiency: barbiturates potentiate haploinsufficiency in vitro.

Barbiturates are known to inhibit glucose transport mediated by the facilitative sugar transporter GLUTI. We have studied such inhibition in children with GLUT1-deficiency. Zero-trans influx of 14C-labeled 3-O-methyl glucose (3OMG) into erythrocytes of patients (n = 3) was 35% of controls (n = 6). Preincubation with 10 mM phenobarbital or pentobarbital reduced patients' 30MG influx to 17%. In patients and controls, preincubation with barbiturates significantly decreased Vmax in a dose-dependent manner (for pentobarbital, IC50 = 0.84 mM, patient 2). The apparent Km in individuals remained largely unchanged. Three-OMG influx without preincubation resulted in a stronger inhibition at lower barbiturate concentrations. The patients' data are discussed in the light of individual missense mutations (patient 1: R126L and K256V; patient 2: T310I; patient 3: S66F) in the GLUTI gene. In conclusion, in controls and patients with GLUT1-deficiency barbiturates interact with GLUT1, lowering its intrinsic activity. The use of barbiturates in this condition for anesthesia or as anticonvulsants could therefore potentially aggravate the existing glucose transport defect and may put these patients at increased risk.

Adolescent↗
PubMed1988

Barbiturates and nifedipine have different and selective effects on calcium currents of mouse DRG neurons in culture: a possible basis for differing clinical actions. The 1987 S. Weir Mitchell award.

Barbiturates and dihydropyridines have been shown to block voltage-dependent calcium channels, but have differing sites of action and clinical effects. We have investigated the effects of the barbiturates, pentobarbital and phenobarbital, and the dihydropyridine, nifedipine, on isolated calcium currents in mouse dorsal root ganglion neurons in culture. Three different calcium channels exist in neurons, designated T, N, and L. None of the drugs affected the T calcium current, but all blocked the activation of the L calcium current. Nifedipine had no effect on the N calcium current. The activation of the N calcium current from holding potentials more negative than--80 mV was not affected by either barbiturate, though both caused a more rapid inactivation of the current at test potentials of--20 to 0 mV. To determine the possible functional significance of these different and selective effects on calcium currents, we studied synaptically driven spontaneous activity in spinal cord neurons in culture. Nifedipine had no effect on spontaneous activity, whereas pentobarbital completely suppressed it. This suggests that block of the L calcium channel alone is not sufficient to suppress spontaneous activity. The additional action of pentobarbital on N calcium current may explain in part the complete suppression of spontaneous activity; other possibilities are discussed. These data suggest a basis for the separate sites of action of barbiturates and dihydropyridines as well as a possible mechanism for the hypnotic and anesthetic effects of the barbiturates.

Animals↗
PubMed1993

Barbiturate-benzodiazepine interactions at the gamma-aminobutyric acidA receptor in rat cerebral cortical synaptoneurosomes.

Combinations of benzodiazepines (midazolam and diazepam) with barbiturates (pentobarbital and phenobarbital) exhibit synergistic (supra-additive) hypnotic interactions in rats. Because both benzodiazepines and barbiturates interact with the gamma-aminobutyric acidA (GABAA) receptor complex, we have tested the hypothesis that these supra-additive hypnotic interactions are due to a synergistic effect on Cl- conductance subsequent to binding at allosterically coupled sites on the GABAA receptor ionophore complex. Equilibrium binding and 36Cl- flux measurements were performed under nearly identical conditions using rat brain cerebrocortical synaptoneurosomes. The benzodiazepines and barbiturates alone both allosterically enhance binding of [3H]muscimol to comparable, but modest, extents (range = 18%-32% enhancement). Isobolographic analysis reveals that combinations of benzodiazepines and barbiturates do in fact produce a synergistic enhancement of [3H]muscimol binding. Paradoxically, this effect is not translated into a synergistic enhancement of muscimol-stimulated 36Cl- flux. Because the positively cooperative interactions between benzodiazepines and barbiturates, as demonstrated both behaviorally and by binding measurements, are not reflected in enhanced Cl- conductance, the mechanistic basis for hypnotic synergism may involve other non-GABAergic components.

Animals↗
PubMed1990

Abuse liability of barbiturates and other sedative-hypnotics.

The principal action of the sedative-hypnotic drugs, of whom the barbiturates are the most widely known and utilized, is to produce drowsiness and promote sleep. At one time these were also the only drugs available to calm seriously anxious or disturbed people. Unfortunately, in addition to their clinical applications these drugs manifest a very high abuse potential. Experienced drug abusers report feelings of well-being and euphoria while under the influence of these drugs. Self-administration experiments conducted in animals have shown that the barbiturates are potent reinforcing agents. In controlled studies in humans, former drug abusers express a preference for barbiturates over benzodiazepines and will "work" to receive barbiturates. Long term consumption of the sedative-hypnotics, particularly barbiturates, leads to dependence characterized by a severe, potentially life-threatening abstinence syndrome following the abrupt withdrawal of the drug. Withdrawal manifestations include delirium and grand mal seizures. Because of the high abuse potential of these drugs, their manufacture and distribution has been greatly curtailed, and for most clinical applications they have been largely replaced by drugs, e.g., the benzodiazepines, which appear to have much less abuse liability.

Animals↗
PubMed1997

Barbiturates.

Barbiturate use by adolescents has increased gradually in the past several years, but few adolescents use this class of drugs regularly. Instead, these sedatives are used most often to treat unpleasant effects of illicit stimulants, to reduce anxiety, and to get "high". Short-acting barbiturates such as pentobarbital and secobarbital are the preferred drugs of abuse. Barbiturates are dangerous drugs, with a narrow therapeutic index between the dose required for sedation and the dose that will cause coma and death. They are physiologically addicting if taken in high doses over 1 month or more, and the abstinence syndrome can be life-threatening. Pregnant women who take barbiturates during the third trimester can give birth to addicted infants who undergo an extended withdrawal syndrome. It is important to educate adolescent patients about the hazards of sedative/hypnotic use, particularly frequent barbiturate use. As indicated in the findings from the 1995 annual survey of United States high school seniors, many young people are not aware of the significant danger and toxicity of this class of drugs.

Adolescent↗
PubMed1978

Mechanism of barbituric-acid protection against inhibition by alloxan of glucose-induced insulin release.

Isolated rat islets were maintained in a simple static incubation system and were exposed to alloxan for a period of five minutes. Alloxan inhibited subsequent glucose-induced insulin release in a dose-dependent manner at 37 degrees C., with 650 muM alloxan producing 94 per cent inhibition of insulin release. Barbituric acid, a compound structurally related to alloxan, provided complete protection (at 37 degrees C.) against this inhibition of insulin release when present during the alloxan exposure. At 23 degrees C., barbituric acid was shown to be absent from the intracellular space of the islet yet still protected completely against alloxan inhibition of insulin release. Thus, barbituric acid apparently provided protection against alloxan in the extracellular medium. By fluorometric and chromatographic analyses, it was determined that barbituric acid reacted rapidly with alloxan to produce a new compound. These findings indicate that barbituric acid protected against alloxan by a chemical reaction in the medium.

Alloxan↗
PubMed1982

EMIT-st drug detection system for screening of barbiturates and benzodiazepines in serum.

The determination of barbiturates and benzodiazepines in serum using the EMIT-st drug detection system is reported. The within-day and the day-to-day precision of this assay was investigated by replicate analysis (n = 20) of the serum negative (no drug) and serum positive control of secobarbital (8.0 micrograms/mL) and diazepam (1.0 microgram/mL), respectively. In all cases the coefficients of variation for intra- and interday analysis for both drugs were between 9 and 15%. No temperature influence on the benzodiazepine assay could be observed by running the tests at temperatures ranging from 20 to 25 degrees C as well as at a temperature of 23 degrees C. The specificity and sensitivity of the EMIT-st assay was investigated by measuring various serum concentrations of 14 different barbiturates and 15 different benzodiazepines. A definitive positive response was obtained at a level of 10 micrograms/mL for 5 out of the 14 barbiturates. A positive result at a concentration of 1 microgram/mL was obtained for 10 of the 15 benzodiazepines. A good correlation in response was found for the barbiturates and benzodiazepines compared to the HPLC and GC procedures at concentrations above the detection limit of the assay. In our opinion the EMIT-st tests are useful to clinical toxicological practice. However, the applicability of the screenings test for barbiturates is limited since only a number of these compounds can be detected.

Barbiturates↗
PubMed2003

A bifunctional alkylating nitrogen mustard agent that utilizes barbituric acid as carrier drug with the potential for crossing the brain-blood barrier.

Barbituric acid is the parent compound of a large family of hypnotic barbiturates. A nitrogen mustard (N-mustard) group (-CH2CH2N[CH2CH2Cl]2) was placed onto the two nitrogen atoms at positions 1 and 3 of the pyrimidine ring. This N-mustard agent is a solid at 25 degrees C, stable at -10 degrees C for >10 weeks, and soluble in aqueous solvent at 37 degrees C and 25 degrees C. The partition coefficients miLog P and CLog P were calculated to be -0.93 and -1.441 for barbituric acid. The miLog P and CLog P for the N-mustard agent were 1.82 and 2.707, respectively. The N-mustard substituents significantly increased solubility in lipid by-layers. The N-mustard agent alkylated a nucleophilic primary amine (p-chloroaniline) at physiological conditions of pH 7.4 and 37 degrees C. Aliquots of reaction mixtures were withdrawn at known time periods to react with fluorescamine for determination of unreacted p-chloroaniline and calculation of rate constants. The alkylation of the primary amine was second order with rate = k2[Nu]2, (Nu is nucleophile) and rate constant k2 = 0.01358 L/(mole.min). The molecular dipole of barbituric acid and the N-mustard agent was calculated by SPARTAN software (wavefunction, Irvine, CA) to be 0.681 and 2.153 Debye, respectively. The brain/blood partition coefficient (Log BB) of the N-mustard agent was -0.399. Values of molecular polar surface area (TPSA) for barbituric acid and the N-mustard agent was 75.27 and 64.17, respectively. TPSA values indicate an expected intestinal absorbance to be 79% and 90%, respectively. The N-mustard agent showed zero violations of the Rule of 5, indicating good bioavailability.

Barbiturates↗
PubMed1982

The effects of deep barbiturate coma on multimodality evoked potentials.

The authors report their investigation of the effects of high-dose barbiturates on the multimodality evoked response in 9 cats. After baseline evoked responses were obtained, boluses of pentobarbital were infused intravenously at regular intervals, amounting to cumulative total doses of 9, 18, 27, 45, 63, 123, and 183 mg/kg at respective infusions. This resulted in gradually increasing serum pentobarbital levels, reaching therapeutic coma levels (4 to 5 mg/dl) after the fifth infusion. At this point, the electroencephalogram was flat, and pressor agents were required to maintain cardiovascular stability. Evoked responses were obtained 15 minutes after each infusion. Brain-stem auditory evoked response (BAER) showed little change in wave latencies at therapeutic coma levels of pentobarbital. Further barbiturates resulted in delay of the late components of this response. In the somatosensory evoked responses (SER), early brain-stem components were relatively unaffected by therapeutic coma levels. Late brain-stem components and the initial cortical response showed progressive latency increase. Late cortical (association cortex) waves were abolished at relatively low doses. The central conduction time was relatively unaffected. The late waves of the visual evoked responses (VER) were abolished with low-dose barbiturates (9 mg/kg). A single positive-negative complex persisted despite massive infusions. It is concluded that evoked responses may prove useful in monitoring patients in deep barbiturate coma, but barbiturate effects must be kept in mind.

Animals↗
PubMed1995

Effects of a barbituric acid/CuCl2 initiator system on resin adhesion to dentin.

The effectiveness of a barbituric acid/copper (II) chloride initiator system in dentin was examined in terms of the effects of barbituric acid structures and dentin conditioners on bond strength. Curing times and tensile bond strengths to bovine dentin were measured for PMMA/MMA resins in conjunction with initiators consisting of a combination of CuCl2 and four barbituric acids having different substituents. The dentin surfaces were treated with six conditioners consisting of 10% citric acid or phosphoric acid with or without 3% FeCl3 and CuCl2. Among the four barbituric acid systems studied, curing times varied significantly (p < 0.002), but the bond strengths to dentin, conditioned with 10% citric acid containing 3% CuCl2, did not (p > 0.60). The dentin conditioners influenced bond strength significantly (p < 0.02). The phosphoric acid based conditioners produced higher bond strengths than those based on citric acid. The bond strengths obtained under optimal conditions were comparable to those reported for MMA-TBB resin. Thus, the resin applied using the barbituric acid/CuCl2 system worked as well as one of the most effective bonding resins available.

Acid Etching, Dental↗
PubMed2002

[Quantitative analysis of plasma concentration of barbiturate for diagnosis of brain death].

Organ transplantation from brain death patients started in Japan in 1997. However it is difficult to diagnose brain death in patients treated with barbiturate therapy. In this study, the influence of long continuous administration of barbiturate on diagnosis of brain death was investigated by measuring plasma concentration of barbiturate. In 15 patients treated with barbiturate therapy, plasma concentrations of thiamylal were measured by liquid chromatographic apparatus every day until it's level decreased below 0.1 microgram/ml after cessation of continuous administration. At the same time, plasma thiamylal levels were checked on the day when burst-suppression (b-s) pattern had disappeared in 9 cases, light reflex of pupil appeared in 7 cases and spontaneous respiration had been detected by trigger lamp in 11 cases. The plasma concentrations of thiamylal on the day when b-s pattern had disappeared differed clearly among the cases in the range of 8.8 to 37.9 micrograms/ml. Those cases in which light reflex of the pupil had been recognized were also different in the range of 17.8 to 57.8 micrograms/ml. The cases in which spontaneous respiration had been detected were in the range of 4.4 to 23.0 micrograms/ml. These concentrations varied about 4, 3 and 5 times among the cases examined. The intervals between cessation of continuous administration of thiamylal and the decrease of plasma concentration to below 0.1 microgram/ml also varied from 2 to 14 days from case to case. The minimum concentration of thiamylal on the day when b-s pattern had disappeared, light reflex of the pupil had been recognized and spontaneous respiration had been detected was 8.8, 17.8 and 4.4 micrograms/ml respectively. These results suggest that diagnosis of brain death in patients treated with barbiturate therapy is able to be made when the plasma thiamylal level is below 4.4 micrograms/ml.

Adolescent↗
PubMed1991

Barbiturates in neuroanesthesia and neuro-intensive care.

Barbiturates reduce cerebral activity which again reduce the cerebral metabolic rate probably by activating chloride channels and potentiating GABA's effects on these channels. Protection of the brain against hypoxia might theoretically occur by this mechanism, by vasoconstriction or by inhibiting calcium or glutamate. The barbiturates appear to have a positive effect in head-injury patients with high ICP uncontrollable by conventional therapy (in one study 5% of patients with a GCS < or = 7), and in animal studies of regional ischemia. No effect has been established in complete cerebral ischemia (cardiac arrest). The barbiturates have a depressant effect on the cardiovascular and respiratory systems, and the patients require intensive care. Thus there are some indications in the literature that the barbiturate treatment itself causes complications, and it is possible that this might cancel a potential beneficial effect in some patients. Clinically, the barbiturates are effective anticonvulsants, can be used in an attempt to control an elevated ICP uncontrollable by conventional means, and during transient ischemic episodes in the operating room with adequate monitoring and support systems already in place.

Anesthesia, Intravenous↗
PubMed1978

Increased risk of brain tumors in children exposed to barbiturates.

The possible etiologic role of barbiturates in the development of brain tumors in children was examined. Interviews were conducted with mothers of children with brain tumors and results compared with those from interviews with mothers of normal children and mothers of children with other cancers. Mothers of children with brain tumors more frequently reported having used barbiturates during their pregnancy with the index child than did mothers of normal children or mothers of children with other cancers. In addition, more children with brain tumors were reported to have used barbiturates than were normal children or children with other malignant diseases, with most of such uses appearing to be unrelated to symptoms resulting from the brain tumor itself. The results suggested that barbiturates may play an etiologic role, and it is estimated that as many as 8% of brain tumors in children may be attributable to use of barbiturates either by the child or prenatally by the mother.

Adolescent↗
PubMed1986

Inhibition of canine platelet aggregation by barbiturates.

The ability of barbiturates to affect in vitro platelet aggregation of canine platelets was examined. Platelet-rich plasma was incubated with thiamylal, pentobarbital, and barbital for 10 minutes before the addition of the aggregating stimulus. All three barbiturates produced a concentration-related inhibition of platelet aggregation induced by adenosine diphosphate (ADP) and collagen. The inhibitory effect of the barbiturates could not be overcome by increasing the concentration of extracellular calcium. In contrast to ADP- and collagen-induced aggregation, no inhibitory effect was observed on aggregation initiated by A23187, 12-O-tetradecanoylphorbol-13-acetate, or phospholipase C. In further studies, the ADP-induced rise in free cytosolic calcium was blocked by the barbiturates. These findings suggest that barbiturates may interfere with the rise in internal calcium associated with agonist-receptor stimulation of platelets.

Adenosine Diphosphate↗
PubMed1986

Barbiturate anesthesia in greyhound and mixed-breed dogs: comparative cardiopulmonary effects, anesthetic effects, and recovery rates.

The cardiovascular effects, anesthetic effects, and recovery rates were evaluated in racing Greyhounds under barbiturate anesthesia. Greyhounds and mixed-breed dogs of similar body weights were given (by IV route) thiopental (15 mg/kg), thiamylal (15 mg/kg), methohexital (10 mg/kg), and pentobarbital (20 mg/kg). The anesthesia lasted longer in Greyhound than in non-Greyhound mixed-breed dogs given thiopental, thiamylal, and methohexital. The mean times from recumbency to standing were 3 to 4 times longer for Greyhounds anesthetized with thiobarbiturates than for non-Greyhound mixed-breed dogs anesthetized with the same drugs, with recovery times for some Greyhounds lasting more than 8 hours. With thiobarbiturate anesthesia, Greyhounds had long periods of respiratory depression, struggled, and relapsed into sleep, whereas in the other dogs, the recovery was quiet. Respiratory depression related to the stage of anesthesia was produced by all barbiturates, but did not result in significant changes in blood gas values. Rectal temperature decreased in all dogs, but did not result in significant hypothermia. Cardiovascular variables and acid-base estimations in Greyhounds were not significantly different from those in mixed-breed dogs before and during barbiturate anesthesia. Packed cell volumes in Greyhounds were significantly higher than those in non-Greyhound mixed-breed dogs after the thiobarbiturates and methohexital were administered. Total plasma protein concentrations were significantly lower in Greyhounds, compared with those in the other dogs before and during barbiturate anesthesia. Methohexital is a useful alternative to thiobarbiturates for short-duration barbiturate anesthesia in Greyhounds.

Anesthesia, General↗
PubMed1985

Energy expenditure in acute trauma to the head with and without barbiturate therapy.

The increased energy expenditure associated with severe trauma to the head appears genuine but exhibits wide variation in its magnitude. Patients with severe acute trauma to the head without barbiturate treatment are hypermetabolic with an average energy expenditure 26 per cent over predicted. Barbiturate therapy abolishes this hypermetabolism and decreases energy expenditure to 14 per cent below predicted. In the individual patient, there appears to be a close relationship between the degree of suppression of energy expenditure and the serum barbiturate level. However, this relationship would appear to be different in each patient, and therefore, for this group, a significant correlation between energy expenditure and serum barbiturate level does not exist. The wide variability of energy expenditure in individual patients makes the estimation of energy expenditure by population predictive formulas imprecise. This may lead to incorrect estimates of caloric requirements and inappropriate provision of exogenous energy substrates. Although for those patients receiving energy expenditure and serum barbiturate levels in the individual may further aid in estimating the caloric expenditure for each individual, in order to provide appropriate amounts of calories to the patient with trauma to the head, energy expenditure should be measured in each instance.

Adolescent↗
PubMed1985

Investigation of clonidine and lofexidine for the treatment of barbiturate withdrawal in mice.

This study was designed to determine the effectiveness of clonidine (CL) and CL analogue, lofexidine (LF), in reducing the incidence and/or severity of convulsion associated with barbiturate withdrawal in mice. CL and LF have been shown to be useful in blocking opioid withdrawal symptoms in rodents and man. Some of the symptoms and possibly the mechanism(s) of the barbiturate withdrawal syndrome are similar to those of the opioid withdrawal syndrome. Therefore, we hypothesized that LF and CL may be efficacious in treating barbiturate withdrawal. The method of Belknap et al as modified by Blum et al for inducing barbiturate dependence in mice was used. Phenobarbital was thoroughly mixed with the animals' milled diet. After 10 days 45 pre-treated mice were divided into withdrawal, control, clonidine- and lofexidine-treated groups. Withdrawal scores were graded as 0 = no effect, 1 = tremor, 2 = wild running, 3 = tonic-clonic seizures, 4 = death, and were collected for each group every 5 hr for 2.5 days. The data in this model suggest that CL and LF offer no protective effect in treating barbiturate withdrawal-induced seizures in mice.

Animals↗
PubMed1978

[Tumor-inhibiting agents. 8. 5-Aminomethylated barbituric acid derivatives].

In view of the tumor inhibitory activity of various pyrimidine derivatives, investigations aimed at the structure modification of barbituric acids were performed. In accordance with the aminomethinylation principle, barbituric acids (2) are converted into 5-formimidoylbarbituric acids (4) by s-triazine (1). Aside from the free barbituric acid (2a), both 1-substituted (2b, d, and f) and 1,3-di-substituted (2c, e, and g) barbituric acids are amenable to this reaction. After introduction of the formimidoyl group into 5-position of the barbituric acid ring system, marked tumor inhibitory effects against lymphoma, lymphocytical leukemia, and luekemia L-1210, are ascertainable.

Animals↗