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PubMed1990

Calcium-dependent actions of the convulsant barbiturate, CHEB, on transmitter release at the rat neuromuscular junction.

1. The effect of convulsant barbiturates on spontaneous and evoked acetylcholine release was studied at the rat neuromuscular junction in vitro. 2. The convulsant barbiturates (+)-5-(1,3-dimethylbutyl)-5-ethyl barbituric acid [(+)-DMBB], 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB), 5-ethyl-5-(3-methylbut-2'-enyl) barbituric acid (3M2B) and 5-ethyl-5-(1,3-dimethylbut-1'-enyl) barbituric acid (1,3M1B) all produced a concentration-dependent increase in miniature end-plate potential (MEPP) frequency. 3. With CHEB (100 microM) this increase in MEPP frequency was found to be dependent on the [Ca2+]o. CHEB in 0.5 mM [Ca2+]o did not alter MEPP amplitude, but in 1.3 and 2.5 mM [Ca2+]o CHEB significantly reduced the amplitude. 4. At a [Ca2+]o of 0.5 mM, CHEB produced an increase in both EPP amplitude and quantal content, while at 1.3 mM [Ca2+]o CHEB did not alter EPP amplitude or quantal content. 5. The plot of log quantal content vs log [Ca2+]o showed a parallel shift to the left in the presence of 100 microM CHEB. This change occurred without any alteration in the maximum quantal content. This suggests that the enhancement of transmitter release may be mediated by an effect on calcium fluxes in the pre-junctional nerve terminal.

Acetylcholine↗
PubMed1981

Analytical aspects of barbiturate abuse: identification of drugs by the effective combination of gas-liquid, high-performance liquid and thin-layer chromatographic techniques.

Chromatographic retention data for a group of barbiturates have been measured on seven chromatographic systems (two gas--liquid chromatographic (GLC), three high-performance liquid chromatographic (HPLC) and two thin-layer chromatographic systems) and the value of these for barbiturate identification has been discussed. The overall correlations observed between pairs of systems are generally low; however, specific groups of barbiturates show very high correlations and this determines the approach to the selection of two or more systems to increase chromatographic discrimination of the barbiturate group. Column chromatographic techniques with lipophilic phases (GLC using SE-30, HPLC using ODS-silica) are most suitable for barbiturate identification. Changes of eluent pH in reversed-phase HPLC proved very effective for the separation of barbiturates with closely related structures.

Barbiturates↗
PubMed1991

Analysis of barbiturates in human serum and urine by high-performance capillary electrophoresis-micellar electrokinetic capillary chromatography with on-column multi-wavelength detection.

The analysis of barbiturates in human serum (or plasma) and urine by high-performance capillary electrophoresis-electrokinetic capillary chromatography with on-column fast-scanning multi-wavelength detection is discussed. The use of a buffer of ca. pH 8 and containing sodium dodecyl sulphate provides a medium suitable for fast and high-resolution separations of barbiturates. Seven barbiturates are characterized by their retention and absorption spectra between 195 and 320 nm. Comparison of these computer-stored data with those of unknown samples is shown to allow the identification of barbiturates in samples of patients undergoing pharmacotherapy and in toxicological urine and serum specimens. Three-dimensional electropherograms provide reliable information on the requirement and suitability of sample pretreatment procedures. With urine, extraction of barbiturates prior to analysis is necessary. With human serum several barbiturates, including phenobarbital, are shown to elute in an interference-free window in front of uric acid and the proteins, allowing these substances to be determined by direct sample injection. The need for multi-wavelength detection over a relatively wide wavelength range as a means of peak confirmation in electrokinetic capillary analyses is demonstrated and limitations of this technique for compounds with similar retention behaviour and absorption spectra are discussed.

Barbiturates↗
PubMed2000

Barbiturates inhibit K(+)-evoked noradrenaline and dopamine release from rat striatal slices--involvement of voltage sensitive Ca(2+) channels.

The cellular target site(s) for anaesthetic action remain unclear. In rat striatal slices we have previously demonstrated that K(+)-evoked noradrenaline (NA) and dopamine (DA) release is mediated predominantly via P/Q-type voltage sensitive Ca(2+) channels (VSCC). Using this model of Ca(2+) dependent transmitter release we have evaluated the effects of anaesthetic and non-anaesthetic barbiturates. Rat brain striatal slices were incubated in the absence and presence of barbiturate for 10 min at 37 degrees C. The slices were then incubated for 6 min with 40 mM KCl. All anaesthetic barbiturates produced a concentration-dependent inhibition of K(+)-evoked NA and DA release. Non-anaesthetic barbiturate, barbituric acid was ineffective. The pIC(50) for NA and DA release (thiopental: 4.90+/-0.13 and 5.00+/-0.10, pentobarbital: 4.39+/-0.07 and 4.43+/-0.14, phenobarbital: 3.85+/-0.08 and 3.59+/-0.10, respectively) correlated with lipid solubility (NA: r(2)=0.999, DA: r(2)=0.987). We therefore suggest that barbiturates inhibit catecholamine release via an interaction with P/Q VSCC further implicating this channel in anaesthetic action.

Anesthetics↗
PubMed2002

Determination of barbituric acid, utilizing a rapid and simple colorimetric assay.

Barbituric acid is widely used in the manufacturing of plastics, textiles, polymers, and pharmaceuticals. Three assay methods are presented, which can utilize either aqueous or solid samples. The detection of as little as 10 microg of barbituric acid can be accomplished, either as an aqueous or solid sample, when using micro reaction tubes. The red-violet endpoint is easily discerned and results upon the formation of a violuric acid derivative. A Spot Test protocol is described which allows for a positive/negative indication of barbituric acid presence. The Spot Test is sensitive to as little as 18.75 microg/ml of barbituric acid. The construction of a Standard Curve for assaying multiple samples and over longer time periods is demonstrated, and is shown to be linear from 18.75 microg/ml to 2.25 mg/ml of barbituric acid. Spectrophotometer readings are made from an absorption peak appearing at 530 nm. The molar absorptivity of the violuric acid derivative is calculated to be 31.4 per mol/l per cm. The micro reaction tube assay will quantitate as little as 10 microg of barbituric acid through interpolation with controls containing a known amount of analyte. Inorganic salts such as NaCl, NaN(3), LiBr, and CaCO(3) do not interfere with endpoint determination. Many organic compounds (also pharmaceuticals) do not inhibit the reaction.

Barbiturates↗
PubMed1996

Barbiturate inhibition of GLUT-1 mediated hexose transport in human erythrocytes exhibits substrate dependence for equilibrium exchange but not unidirectional sugar flux.

Barbiturates inhibit GLUT-1 mediated hexose transport both in vivo [Gjedde & Rasmussen (1980) J. Neurochem. 35, 1382-1387; Otsuka et al. (1991) Am. J. Physiol. 261, R265-R275] and in vitro [Honkanen et al. (1995) Biochemistry 34, 535-544]. In the present study, the mechanism by which barbiturates inhibit GLUT-1 mediated hexose transport was examined by measuring both unidirectional zero trans and equilibrium exchange fluxes of hexoses in the functionally well-characterized, GLUT-1 rich human erythrocyte system. Unidirectional influx were both inhibited (> 80%) by 10 mM pentobarbital (PB). This symmetrical inhibition of unidirectional flux by PB was virtually independent of cis sugar concentration (2-130 mM) and exhibited an IC50 of approximately 2 mM. In contrast to unidirectional sugar flux, PB inhibition of equilibrium exchange sugar flux is attenuated by increased substrate concentration (e.g., 88% inhibition at 1 mM Glc versus 40% inhibition at 130 mM Glc in the presence of 10 mM PB) and exhibits an IC50 of approximately 10 mM at 100 mM Glc. Other barbiturates were found to inhibit sugar flux in human erythrocytes in this differential manner. These findings, when viewed with kinetic models proposed for GLUT-1 mediated transport [Carruthers (1990) Physiol. Rev. 70, 1135-1176], are consistent with barbiturates being noncompetitive inhibitors of Glc translocation and preferentially inhibiting the unoccupied form of the carrier protein. We propose, therefore, that barbiturates may prevent or alter the conformational changes associated with the reorientation of the carrier protein within the membrane. Overall, these results imply that barbiturates may more strongly inhibit GLUT-1 mediated Glc flux in vivo when the trans Glc is near zero as a result of either metabolism or another transport process.

Barbiturates↗
PubMed1980

Convulsant and anticonvulsant barbiturates. 1. Molecular conformations from classical potential-energy calculations.

Conformational energy calculations are reported for a series of convulsant and anticonvulsant barbiturates derived from 5-ethyl-5-(1'-methylbutyl)barbituric acid (pentobarbital) by minor structural changes to the butyl side chain. A number of low-energy conformations are identified for each barbiturate. In each case substantial barriers to rotation exist between the alternative conformations, and the magnitudes of these barriers suggest that the barbiturates may be conformationally restricted even at physiological temperatures. Fully extended conformations, with both side chains perpendicular to the plane of the barbiturate ring, are favored. In the 1'-methyl derivatives, conformations with the 1'-methyl group located directly above the barbiturate ring are equally low in energy.

Anticonvulsants↗
PubMed1989

Promotion by sodium barbital of renal cortical and transitional cell tumors, but not intestinal tumors, in F344 rats given methyl(acetoxymethyl)nitrosamine, and lack of effect of phenobarbital, amobarbital, or barbituric acid on development of either renal or intestinal tumors.

Comparative effects of four barbiturates, phenobarbital (PB), amobarbital (AB), sodium barbital (NaBB), and barbituric acid (BA) on the development of neoplasms in the intestinal tract and other organs were investigated in rats following initiation with methyl(acetoxymethyl)nitrosamine (DMN-OAc). Four-week-old F344/NCr male rats were given a single i.p. injection of 0.05 nmol DMN.OAc in 5 ml sterile phosphate buffered saline/kg body weight. Two weeks after DMN.OAc treatment, the animals were provided with either tap water or drinking water containing 500 p.p.m. of PB, NaBB, AB, or BA for the remaining experimental period. Control groups received a single i.p. injection of 5 ml of sterile phosphate buffer/kg body weight and 2 weeks later were given either tap water or drinking water containing 500 p.p.m. of one of the barbiturates listed above. Rats were killed at 52 weeks or 80 weeks after DMN.OAc injection. DMN.OAc induced multiple intestinal tumors that occurred mostly in the mucosa of the small intestine, especially the terminal ileum. None of the barbiturates had any effect on either incidence or multiplicity of intestinal tumors. PB significantly enhanced the development of hepatocellular tumors as well as thyroid follicular cell neoplasms in DMN.OAc initiated rats, while the subsequent administration of NaBB, but not other barbiturates, resulted in the development of renal cortical and pelvic transitional cell tumors. This is the first demonstration of promotion of carcinogenesis in renal pelvic transitional epithelium, a cell type not previously recognized as vulnerable to initiation by DMN.OAc given i.p. NaBB without prior administration of DMN.OAc induced severe nephropathy and focal hyperplasia of both renal cortical tubular and pelvic transitional cell epithelium. No such effects were observed with either PB, AB, or BA. Our results failed to confirm the earlier findings of others that intestinal epithelial carcinogenesis could be promoted by continuous oral administration of NaBB. However, these results strongly support and extend our previous conclusions that some barbiturates have broad organ specificities and promote epithelial carcinogenesis in more than one organ and tissue.

Adenoma↗
PubMedDate not supplied

New fluorescence polarization immunoassays for analysis of barbiturates and benzodiazepines in serum and urine: performance characteristics.

The performance of the new fluorescence polarization immunoassay reagents Cassette COBAS INTEGRA Serum Benzodiazepines assay (SBENZ) and Cassette Serum Barbiturates assay (SBARB) was evaluated as compared to other immunoassays (Abbott TDx Serum Benzodiazepines, Abbott TDx Urine Benzodiazepines, Behring EMIT Serum Benzodiazepines, Abbott ADx Serum Barbiturates, Behring EMIT Serum Barbiturates, and the COBAS INTEGRA Barbiturates (BARB) urine assay) and gas chromatography-mass spectrometry (GC-MS). Recoveries of nordiazepam and secobarbital using the SBENZ and SBARB assays, respectively, were equivalent for serum, plasma, and urine. Cross-reactivities of structurally related benzodiazepines, barbiturates, and their metabolites were very similar in serum and urine for the SBENZ and SBARB assays. Precision was within 5.4% for SBENZ serum and within 11% from 10 to 100 ng/mL for urine. Precision was within 5% for SBARB serum and within 7% from 136 to 277 ng/mL for the urine application. The standard curves for SBENZ and SBARB were stable for at least 16 weeks with the reagents stored open on the COBAS INTEGRA analyzer. Clinical comparison of the SBENZ serum assay indicated an increased pickup rate, as confirmed by GC-MS, compared to TDx and EMIT. The diagnostic sensitivities of the SBENZ serum application, TDx, and EMIT versus GC-MS were 100%, 89%, and 36%, respectively. The diagnostic specificities were 71%, 79%, and 100%, respectively. The diagnostic sensitivities of the SBENZ urine application and TDx versus GC-MS were 100% and the diagnostic specificities were 88%. The increased positive pick-up of the SBENZ assay compared to the other immunoassays is most probably due to the difference in the limit of detection (LOD) and the increased cross-reactivity for the low-dose benzodiazepines. Clinical comparison of the SBARB serum assay indicated an increased positive pick-up rate, as confirmed by GC-MS. The diagnostic sensitivities of the SBARB serum application, ADx, and EMIT versus GC-MS were 96%, 65%, and 35%, respectively. The diagnostic specificities were all 100%. The diagnostic sensitivities for the SBARB urine application and BARB versus GC-MS were all 100%, and the diagnostic specificities were all 91%. The SBENZ and SBARB kits demonstrated increased sensitivity for the detection of benzodiazepines and barbiturates in both serum and urine compared to the other immunoassays.

Barbiturates↗
PubMedDate not supplied

The response of spinal cord blood flow to high-dose barbiturates.

The response of spinal cord blood flow (SCBF) to high-dose barbiturate therapy is documented. In nine mongrel dogs with an arterial pCO2 (PaCO2) of 40 mm Hg, sodium thiopental was administered to produce 30, 60, 120, and 240 seconds of electroencephalographic (EEG) burst suppression. At 30-second intervals of EEG suppression, cervical and thoracic cord segments demonstrated a decrease in SCBF of 47% and 39%, respectively, from control values. Isoelectric EEG intervals longer than 30 seconds were not associated with any further significant decrease in SCBF. In 13 other dogs and in the absence of barbiturates, hypocapnia to 20 mm Hg from PaCO2 of 60 mm Hg produced reductions in SCBF of 89% for the cervical and 82% for the thoracic segments. In the presence of thiopental-induced 30- to 60-second intervals of EEG silence, the decrement in SCBF in response to the same degree of hypocapnia was 83% and 75%, respectively, although the absolute value of this reduction was half that without barbiturates. These findings of a significant reduction in SCBF in response to high-dose barbiturate therapy are suggestive of a protective effect of barbiturates upon spinal cord injury as occurs in the brain. Further studies of the influence of barbiturates upon spinal cord compressive syndromes are indicated.

Animals↗
PubMed1985

Barbiturates are selective antagonists at A1 adenosine receptors.

Barbiturates in pharmacologically relevant concentrations inhibit binding of (R)-N6-phenylisopropyl[3H]adenosine ([3H]PIA) to solubilized A1 adenosine receptors in a concentration-dependent, stereospecific, and competitive manner. Ki values are similar to those obtained for membrane-bound receptors and are 31 microM for (+/-)-5-(1,3-dimethyl)-5-ethylbarbituric acid [(+/-)-DMBB] and 89 microM for (+/-)-pentobarbital. Kinetic experiments demonstrate that barbiturates compete directly for the binding site of the receptor. The inhibition of rat striatal adenylate cyclase by unlabelled (R)-N6-phenylisopropyladenosine [(R)-PIA] is antagonized by barbiturates in the same concentrations that inhibit radioligand binding. The stimulation of adenylate cyclase via A2 adenosine receptors in membranes from N1E 115 neuroblastoma cells is antagonized only by 10-30 times higher concentrations of barbiturates. It is concluded that barbiturates are selective antagonists at the A1 receptor subtype. In analogy to the excitatory effects of methylxanthines it is suggested that A1 adenosine receptor antagonism may convey excitatory properties to barbiturates.

Adenylyl Cyclases↗
PubMedDate not supplied

Quantum pharmacologic studies applicable to the design of anticonvulsants: theoretical conformational analysis and structure-activity studies of barbiturates.

We report the first large-scale systematic quantitative structure-activity relationship (QSAR) study of barbiturates, correlating molecular structures with anticonvulsant activity. To achieve this QSAR study, we devised a four-step strategy. In step 1, an optimal quantum mechanical technique for determining the geometry and shape (conformation) of barbiturates was ascertained; this is the AM1 semiempirical molecular orbital method. In step 2, the AM1 method was used to optimize the structures and molecular properties of 48 barbiturates with varying anticonvulsant activity. In step 3, discriminant analysis and regression analysis statistical calculations were used to correlate the molecular properties of the 48 analogues against maximal electroshock (MES) and subcutaneous metrazol (s.c.Met)-induced seizures. In step 4, the contribution of molecular electrostatic properties to barbiturate anticonvulsant activity was further refined by quantum mechanical derived molecular electrostatic potential (MEP) maps. Using this four-step strategy, we defined the pharmacophore, the portion of a molecule responsible for bioactivity, for anti-MES and anti-s.c.Met activity. For anti-s.c.Met activity, barbiturate lipophilicity and geometry are important considerations; for anti-MES activity, barbiturate topologic and electronic properties have increased relevance.

Anticonvulsants↗
PubMed1984

Reevaluation of potency and pharmacokinetic properties of some lipid-soluble barbiturates with an EEG-threshold method.

Five lipid-soluble anaesthetic barbiturates amobarbital, (pentymalum NFN), hexobarbital (enhexymalum NFN), pentobarbital (mebumalum NFN), thiopental (thiomebumalum NFN), methohexital (enallynymalum NFN) were investigated for potency and kinetic properties with an EEG-threshold method. By constant infusion of barbiturate at different dose rates to a well specified EEG-criterion, the "silent second", a dose rate curve can be made. This curve has a minimum, "optimal dose rate", and the amount of barbiturate used to reach the criterion at this dose rate can be used as an accurate measure of potency. The dose to reach the "silent second" at the optimal dose rate was highly correlated to brain concentrations at the criterion for the barbiturates in contrast to the plasma concentrations. This measure of potency is superior to other used measures such as anaesthesia times or AD50, since it is less affected by differences in pharmacokinetic properties. The anaesthesia times after threshold determinations show large variations between different barbiturates which can be dependent both on dose administered and on dose rate. The quotient between brain concentration at the EEG-criterion and at the time of return of righting reflex for these barbiturates shows variations that can be due to differences in acute tolerance.

Anesthesia↗
PubMed1984

The interaction between atropine and some lipid-soluble barbiturates in rats.

The effect of atropine pretreatment on the CNS sensitivity to five lipid-soluble barbiturates was studied in rats. Atropine in a dose of 8 mg/kg intraperitoneally or saline was given 1.5 hr before an EEG-threshold determination with the tested barbiturates. The barbiturate was infused by constant rate through a tail vein. The dose of barbiturate needed to induce a burst suppression period in the EEG which is one second or longer was used as the threshold dose. Atropine pretreatment decreased the threshold dose significantly for two N-methylated barbiturates, hexobarbital (enhexymalum NFN) and methohexital (enallynymalum NFN), but not for thiopental (thiomebumalum NFN), pentobarbital (mebumalum NFN) or amobarbital (pentymalum NFN). No clear effects of atropine pretreatment could be found in the ensuing anaesthesia times after threshold determinations. These results indicate that there are differences in mechanisms of action between barbiturates. One of these mechanisms is related to the cholinergic system in the CNS.

Anesthesia↗
PubMed1977

Self-poisoning with barbiturates in England and Wales during 1959-74.

Hospital admissions due to acute barbiturate poisoning per million population in England and Wales have decreased since 1965 at about the same rate as NHS prescriptions for barbiturates. Admissions due to poisoning with other drugs have increased, but, largely because the benzodiazepine hypnotics and tranquillisers are much less toxic than the barbiturates that they are replacing, deaths from poisoning with all solids and liquids have decreased. The risk of death from self-poisoning associated with each barbiturate prescription has increased two and a half times since 1961, perhaps partly because greater quantities of barbiturate are being dispensed with each prescription and partly because patients for whom these drugs are still being prescribed would, in the event of an overdose, be unlikely to be found and admitted to hospital in time owing to their age and social circumstances. There is now little to justify prescribing barbiturate hypnotics or sedatives for anyone.

Barbiturates↗
PubMed1977

Nocturnal femoral fracture and continuing widespread use of barbiturate hypnotics.

A survey of 390 patients aged over 65 with fractured femurs showed that nearly all the fractures that had been caused by nocturnal falls had occurred among the many patients who were still taking barbiturate hypnotics. Barbiturates were also strongly associated with a history of frequent falls. Barbiturates are still prescribed surprisingly often for the elderly. An analysis of 1622 elderly patients referred to a geriatric clinic in Nottingham showed that 41% were taking barbiturates in 1973. By 1976 this fugure had actually increased to 51%, despite the substantial campaign against barbiturate prescribing. This campaign thus appears to have made little or no impact on prescriptions for the elderly in at least one large town. The dangers of barbiturates may well need constant reemphasis.

Accidents, Home↗
PubMedDate not supplied

Tolerance and efficacy of enteral nutrition in traumatic brain-injured patients induced into barbiturate coma.

BACKGROUND: There is a paucity of data evaluating the efficacy of nutrition support in traumatic brain-injured patients induced into barbiturate coma for refractory intracranial hypertension. Our objective was to evaluate the efficacy of enteral nutrition in a select group of trauma patients. METHODS: Prospective data were collected on severe traumatic brain-injured patients over a 4-year period. Patients were stratified by whether or not they were induced into a barbiturate coma. Barbiturate coma was defined as per American Association of Neurological Surgeons (AANS) guidelines. All patients were initially fed via the enteral route via a nasogastric feeding tube. Patients who did not tolerate feedings within 48 hours started receiving prokinetic agents. Feeding tolerance was defined as ability to tolerate enteral feedings with <150 mL of gastric residuals every 6 hours for >72 hours. RESULTS: Fifty-seven patients were induced into a barbiturate coma. All were victims of blunt-force trauma. Forty-two of 57 (74%) patients were men, with a mean age of 37+/-12 years and a mean injury severity score of 24+/-10. Thirty-eight of the 57 (67%) patients had an isolated traumatic brain injury. All 57 patients failed enteral nutrition via the nasogastric route after the first 48 hours of nutrition initiation after barbiturate coma was fully achieved by protocol criteria. Prokinetic agents demonstrated no improvement in feeding tolerance after the subsequent 48-72 hours. Of the 12 patients who had a postpyloric feeding tube placed, only 25% tolerated enteral nutrition for >48 hours. CONCLUSIONS: Patients with traumatic brain injury induced into barbiturate coma develop a significant ileus that is refractory to prokinetic agents. Only a marginal improvement is seen when the postpyloric route is obtained. Early parenteral nutrition should be considered in this patient population.

Adult↗
PubMed1980

The effect of barbiturates on 24-h water intake and renal excretion of sodium and water in dogs.

The effects of barbiturates on 24-h intakes of water and food and urinary excretion of sodium and potassium as well as on plasma concentration of sodium and potassium and osmolality were examined in dogs placed in metabolism cages and fed with a semiliquid diet. Administration of barbiturates stimulated drinking in a Series of 8 dogs having free access to water. Twenty four-h water intake and water balance increased significantly. Food intake, urinary output and urinary excretion of solutes, sodium and water did not change in this Series. A significant decrease in urine output as well as in osmolal clearance and urinary excretion of sodium was observed in a Series of 7 dogs having water restricted for 24 h following administration of barbiturates. Water balance increased in this Series. The same restriction of water in the dogs which had not received barbiturates did not modify renal excretion of water and electrolytes. Plasma osmolality, sodium and potassium concentrations did not change in either Series of experiments. It is concluded that barbiturates induce positive water balance either by stimulation of drinking when water is freely available or by reduction in urine output when water is restricted. The results suggest that expansion of the body fluids following the increased water intake may abolish reduction in urine output and sodium excretion which otherwise occur after administration of barbiturates.

Animals↗