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PubMed1978

Glass formation in barbiturates and solid dispersion systems of barbiturates with citric acid.

Glasses were prepared from a number of barbiturates. The viscosities and glass transition temperatures of the glasses were dependent on the structure of the groups present on the C-5 and N-1 atoms. Solid dispersions were prepared from three selected barbiturates formulated with citric acid. The glass transition temperatures of these systems indicated that a 1:1 molar ratio complex was formed between the two components and that intermolecular bonding was stronger in the complex than in the individual components.

Barbiturates↗
PubMed1978

Transport of heterocyclic acids across rat small intestine in vitro.

A study has been made of the steady-state fluxes of barbituric acid, six of its substituted derivatives, and 5,5-dimethyloxazolidinedione (DMO) across the wall of rat jejunum in vitro. For each of the compounds tested the mucosal (M) to serosal (S) flux was significantly larger than the S to M flux. Both M to S and S to M fluxes increased linearly with concentration, and the transport of one acid was not influenced by the presence of a tenfold greater concentration of a second heterocyclic acid. The fluxes decreased as the pH of the incubation saline was increased, but neither the M to S, nor the S to M fluxes could be described in terms of simple nonionic diffusion. It was found that the relation between the flux ratios of the transported acids and their pKalpha values could be described by an equation derived from consideration of the transport of a weak acid in a series three compartment system, and it has been concluded that the three compartment system provides a good working hypothesis for the mechanism of heterocyclic acid transport across rat jejunum. It was found that the best fit of the theoretical curve to the experimental data was obtained when the ratio of permeabilities to the ionized and nonionized forms of a weak acid at one of the barriers was assigned the value 5 X 10(-1). It is suggested that this value may be characteristic of a noncellular restriction to diffusion, such as a layer of connective tissue, and substantiates previous suggestions that the intermediate compartment of the intestinal three compartment system is a component of the sub-epithelial extracellular space.

Amobarbital↗
PubMed2000

A second dihydroorotate dehydrogenase (Type A) of the human pathogen Enterococcus faecalis: expression, purification, and steady-state kinetic mechanism.

We report the identification, expression, and characterization of a second Dihydroorotate dehydrogenase (DHODase A) from the human pathogen Enterococcus faecalis. The enzyme consists of a polypeptide chain of 322 amino acids that shares 68% identity with the cognate type A enzyme from the bacterium Lactococcus lactis. E. faecalis DHODase A catalyzed the oxidation of l-dihydroorotate while reducing a number of substrates, including fumarate, coenzyme Q(0), and menadione. The steady-state kinetic mechanism has been determined with menadione as an oxidizing substrate at pH 7.5. Initial velocity and product inhibition data suggest that the enzyme follows a two-site nonclassical ping-pong kinetic mechanism. The absorbance of the active site FMN cofactor is quenched in a concentration-dependent manner by titration with orotate and barbituric acid, two competitive inhibitors with respect to dihydroorotate. In contrast, titration of the enzyme with menadione had no effect on FMN absorbance, consistent with nonoverlapping binding sites for dihyroorotate and menadione, as suggested from the kinetic mechanism. The reductive half-reaction has been shown to be only partially rate limiting, and an attempt to evaluate the slow step in the overall reaction has been made by simulating orotate production under steady-state conditions. Our data indicate that the oxidative half-reaction is a rate-limiting segment, while orotate, most likely, retains significant affinity for the reduced enzyme, as suggested by the product inhibition pattern.

Amino Acid Sequence↗
PubMed1985

Chemical reaction, diffusion, and ionization model for dissolution of oxygen acids and carbon acids.

A chemical reaction, diffusion, and ionization model, which assumes the establishment of ionization equilibrium at an equilibrium plane located within the diffusion layer, is tested by use of experimental dissolution rates for some oxygen acids and carbon acids. For oxygen acids both two- and three-zone models predict observed dissolution rates; however, for barbituric acid dihydrate and phenylbutazone neither model successfully depicts the dissolution behavior. Although the three-zone model approximately predicts dissolution rates of oxygen acids, its complexity does not add to the accuracy of the calculated rate. The three-zone model does support the frequent assumption that ionization is instantaneous and can be ignored in modeling.

Barbiturates↗
PubMed1983

Contrasting effects of a convulsant (CHEB) and an anticonvulsant barbiturate (phenobarbitone) on amino acid release from rat brain slices.

The effects of a convulsant barbiturate, 5(2-cyclohexylidine-ethyl)-5-ethyl barbituric acid (CHEB), and phenobarbitone (PhB) on the release of exogenous D-aspartate and GABA from slices of rat cerebral cortex were investigated. While PhB inhibited potassium-evoked release of D-aspartate more so than that of GABA, CHEB potently inhibited potassium-evoked GABA release and stimulated evoked D-aspartate release, in a concentration-dependent manner. These actions are consistent with the observed in vivo convulsant and anticonvulsant properties of these barbiturates. CHEB, but not PhB also elevated spontaneous efflux of both amino acids. The actions of these barbiturates were further studied in calcium- and sodium-free media, and in the presence of tetrodotoxin and ruthenium red, agents known to alter ion flux across neuronal membranes. The results obtained indicate that different ionic mechanisms may be involved in the release of excitatory and inhibitory amino acid transmitters.

Animals↗
PubMed1991

Paradoxical Modulation of Nociception in Mice by Barbiturate Agonism and Antagonism: Is a GABA Site Involved in Nociception?

In a battery of four acute and chronic nociceptive tests, the GABA antagonist picrotoxin produces a uniform and sustained analgesia in mice. By contrast, barbiturates which have been presumed to act at the same receptor produce mixed and paradoxical actions. At a standard time of 10 min after drug administration a convulsant barbiturate [5-ethyl-5-(3'-methyl-but-2'-enyl)-barbituric acid] produced analgesia in three tests but had no effect in the fourth; a pure hypnotic barbiturate (amylobarbitone) produced hyperalgesia in three tests but analgesia in the fourth; while the mixed hypnotic-convulsant pentobarbitone produced hyperalgesia in two of the tests and was without any effect in the other two. There was no pattern in these results with respect to acute or chronic nociceptive tests. Surprisingly, with extended observation using the tail-flick test both pentobarbitone and the pure hypnotic (amylobarbitone) gave early hyperalgesia followed by analgesia; the convulsant barbiturate gave only analgesia. The results suggest a role for GABAA receptors in the transmission of nociceptive information; they also suggest that barbiturates act at quite a different receptor.

Journal Article↗
PubMed1986

Tumor-promoting barbiturates act on DNA repair of cultured hepatocytes.

We have observed that two promoters of liver carcinogenesis, i.e. phenobarbital and barbital, markedly increase DNA-repair synthesis of cultured hepatocytes following treatment with the ultimate carcinogens methyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, N-acetoxy-2-acetylaminofluorene, and UV light of 254 nm. Phenobarbital also increased the incorporation rates of deoxynucleoside triphosphates into nuclear DNA of permeabilized hepatocytes following carcinogen treatment. The action of these barbiturates apparently correlates with their potential to promote hepatocarcinogenesis in vivo, since the non-promoting agent barbituric acid did not modify carcinogen-induced repair synthesis. Moreover, the mechanisms of action of tumor-promoting barbiturates is different from the known enhancing action on repair synthesis of inhibitors of nuclear poly(ADP-ribose) biosynthesis.

Adenosine Diphosphate Ribose↗
PubMed2003

Merocyanine dyes containing imide functional groups: synthesis and studies on hydrogen bonding to melamine receptors.

The condensation of the CH acidic heterocycles 4-alkyl-2,6-dioxo-1,2,5,6-tetrahydropyridine-3-carbonitrile (5a and b) and barbituric acid (15) with electron-rich thiophene aldehydes and benzaldehyde derivatives affords the respective monomethine dyes 10-13 and 17-19. The formylation of 5a,b and 15 with N,N'-diphenylformamidine or dibutylformamide in acetic anhydride and further reaction with 4-picolinium salts 9a,b provide the dimethine dyes 14 and 20a,b. Triple hydrogen bonding of the imide groups of merocyanine dyes 10-14 has been investigated by NMR titration experiments with melamine 21. Despite rather pronounced variations of the charge-transfer properties within the given series of dyes, minor changes of their binding constants have been observed. These results could be rationalized by semiempirical calculations that reveal small changes in the charge density at the oxygen functionalities involved in hydrogen bonding upon variation of the electron-donating carbocyclic or heterocyclic groups at the terminal double bond. Although the binding constants for triple hydrogen bonding between imides and melamines are rather weak in chloroform, they proved to be strong enough to facilitate dissolution of some of these dyes in aliphatic solvents by coordination to amphiphilic melamines and dipolar aggregation. UV-vis spectral changes observed in methylcyclohexane vs chloroform suggest the formation of colloidal assemblies through noncovalent polymerization.

Hydrogen Bonding↗
PubMed2001

Inhibitory effects of barbiturates on nicotinic acetylcholine receptors in rat central nervous system neurons.

BACKGROUND: Neuronal nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central and autonomic nervous systems. The authors have previously shown that depressant and convulsant barbiturates both inhibit the ganglion-type nAchRs in PC12 cells. However, the central and gangliontype receptors have different subunit composition and pharmacologic properties. In this study, the authors investigated the effects of thiopental, depressant [R(-)] and convulsant [S(+)] stereoisomers of 1-methyl-5 phenyl-5-propyl barbituric acid (MPPB) on neuronal nAChRs in the rat central nervous system to explore significance of these effects in barbiturate anesthesia. METHODS: Whole-cell currents were measured in acutely dissociated rat medial habenula (MHb) neurons by applying 10 or 100 microM nicotine in the absence or presence of thiopental 3-100 microM. Effects of R(-)- and S(+)-MPPB on the nicotine-induced current were also studied. RESULTS: Thiopental suppressed the nicotine-elicited inward current and accelerated the current decay dose-dependently at the clinical relevant concentrations. R(-)- and S(+)-MPPB both inhibited the nicotine-induced current dose-dependently without augmenting the current decay. There was no significant difference in the magnitudes of inhibition by R(-)- and S(+)-MPPB. CONCLUSIONS: Although thiopental suppressed the current mediated through native nAchRs in rat MHb neurons at the clinically relevant concentrations, the depressant and convulsant stereoisomers of MPPB both inhibited the current in the same extent. These findings are consistent with the results previously obtained in the ganglion-type receptors of PC12 cells and suggest that inhibition of nAChRs in MHb neurons is not directly relevant to the hypnotic or anticonvulsive actions of barbiturates.

Animals↗
PubMed1999

Gene sequence and properties of an s-triazine ring-cleavage enzyme from Pseudomonas sp. strain NRRLB-12227.

Pesticides based on the s-triazine ring structure are widely used in cultivation of food crops. Cleavage of the s-triazine ring is an important step in the mineralization of s-triazine compounds and hence in their complete removal from the environment. Cyanuric acid amidohydrolase cleaves cyanuric acid (2,4,6-trihydroxy-s-triazine), which yields carbon dioxide and biuret; the biuret is subject to further metabolism, which yields CO(2) and ammonia. The trzD gene encoding cyanuric acid amidohydrolase was cloned into pMMB277 from Pseudomonas sp. strain NRRLB-12227, a strain that is capable of utilizing s-triazines as nitrogen sources. Hydrolysis of cyanuric acid was detected in crude extracts of Escherichia coli containing the cloned gene by monitoring the disappearance of cyanuric acid and the appearance of biuret by high-performance liquid chromatography (HPLC). DEAE and hydrophobic interaction HPLC were used to purify cyanuric acid amidohydrolase to homogeneity, and a spectrophotometric assay for the purified enzyme was developed. The purified enzyme had an apparent K(m) of 0.05 mM for cyanuric acid at pH 8.0. The enzyme did not cleave any other s-triazine or hydroxypyrimidine compound, although barbituric acid (2,4, 6-trihydroxypyrimidine) was found to be a strong competitive inhibitor. Neither the nucleotide sequence of trzD nor the amino acid sequence of the gene product exhibited a significant level of similarity to any known gene or protein.

Amidohydrolases↗
PubMed1988

A simple method for determination of plasma thiocyanate.

We describe a method for the determination of thiocyanate in plasma from blood collected under field conditions in heparinised glass capillary tubes. After deproteinisation of plasma with perchloric acid, thiocyanate is directly determined colorimetrically by the König reaction with sodium hypochlorite as the chlorinating reagent and barbituric acid as the coupling agent. This simple method cannot be applied to urine as the latter contains interfering compounds.

Humans↗
PubMed1982

Liquid-chromatographic determination of pentobarbital in plasma with use of a resin column and an alkaline mobile phase.

We describe a liquid-chromatographic method involving a new, nonsilica column (XAD-2, Hamilton Co.) for pentobarbital in plasma. Plasma is extracted with chloroform after addition of the internal standard, 5-ethyl-5-p-tolyl-barbituric acid. Acidic drugs are back-extracted into alkali, then chromatographed on the resin-base reversed-phase column. The use of alkaline mobile phase allows enhanced sensitivity and detection of barbiturates at 240 nm. The within-run CV for 10 samples was 1.9%, the between-run CV 1.8%. Ten commonly used barbiturates are separated isocratically in less than 15 min. Other commonly prescribed acidic drugs do not interfere with determination of pentobarbital.

Chromatography, Liquid↗
PubMed1981

Barbiturates: active form and site of action at node of Ranvier sodium channels.

Barbiturate sodium channel block was investigated in the voltage-clamped amphibian node of Ranvier. Internal pH was manipulated by diffusion of buffers from the cut internodes. Like local anesthetics and volatile general anesthetics, barbiturates shift the voltage dependence of inactivation in the hyperpolarizing direction. A barbiturate anion, 5-phenyl barbituric acid, blocks sodium channels when applied externally or internally. On external application, block is of very slow onset. The barbiturate anion, like the local anesthetic cation, thus appears to bind to a receptor site on the axoplasmic side of the membrane. Unlike local anesthetics, however, phenobarbital exerts a frequency-dependent block which is modified by changes in internal pH and is not affected by changes in external pH. In addition, barbiturate frequency dependence is apparently more exclusively involved with channel inactivation. The results suggest a barbiturate sodium channel binding site closer to the axoplasm than the local anesthetic binding site is and also suggest that there is a proton barrier between the two sites.

Animals↗
PubMed1999

Barbiturates inhibit progesterone synthesis in cultured Leydig tumor cells and human granulosa cells.

Screening drugs used in obstetrical practice for effects on steroid hormone synthesis revealed that phenobarbital inhibited progesterone synthesis in MA-10 Leydig tumor cells. The inhibition was apparently a drug class effect since it could be reproduced by other barbiturates. Barbiturate blockade was reversible and could be bypassed in the MA-10 cells by using 22-hydroxycholesterol. Human granulosa cell progesterone synthesis was also inhibited in a dose dependent fashion by phenobarbital, secobarbital and barbituric acid. Significant inhibition occurred in dose ranges that would be therapeutic for treating epilepsy. From these data we conclude that barbiturates block steroidogenesis by inhibiting cholesterol transport to the cholesterol side chain cleavage enzyme.

Anticonvulsants↗
PubMed1981

Barbiturates and transmitter release at the frog neuromuscular junction.

The effects of the convulsant and anticonvulsant barbiturates, 5(2-cyclohexylidine ethyl)-5-ethyl barbituric acid (CHEB) an phenobarbital (PHB) were studied at the frog neuromuscular junction. Spontaneous transmitter liberation was augmented by both drugs irrespective of the external Ca2+ concentration, but CHEB was considerably more active than PHB. Miniature end plate potential amplitude was equally reduced by both drugs. The net effect of these agents on end plate potential (e.p.p.) amplitude varied depending on the external Ca2+ concentration. In Ca2+-deficient Ringer's solution both drugs increased the quantal content and the e.p.p. amplitude (CHEB more than PHB). In Ringer's solution containing a normal concentration of Ca2+ ions, both drugs depressed the evoked response and failed to alter the quantal content significantly.

Animals↗
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↗
PubMed1993

Calcium current block by (-)-pentobarbital, phenobarbital, and CHEB but not (+)-pentobarbital in acutely isolated hippocampal CA1 neurons: comparison with effects on GABA-activated Cl- current.

Block of a voltage-activated Ca2+ channel current by phenobarbital (PHB), 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB), and the optical R(-)- and S(+)-enantiomers of pentobarbital (PB) was examined in freshly dissociated adult guinea pig hippocampal CA1 neurons; the effects of the barbiturates on GABA-activated Cl- current were also characterized in the same preparation. (-)-PB, PHB, and CHEB produced a reversible, concentration-dependent block of the peak Ca2+ channel current (3 mM Ba2+ as the charge carrier) evoked by depolarization from -80 to -10 mV (IC50 values, 3.5, 72, and 118 microM, respectively). In contrast, (+)-PB was nearly inactive at concentrations up to 1 mM. The inhibitory action of PHB was decreased at acid pH, indicating that the dissociated (anionic) form of the molecule is the active species. Block by (-)-PB was voltage dependent with the fractional block increasing at positive membrane potentials; calculations according to the method of Woodhull indicated that the (-)-PB blocking site senses approximately 40% of the transmembrane electric field. The time course and voltage dependence of activation of the Ca2+ channel current were unaffected by (-)-PB, PHB, and CHEB. The rate of inactivation was enhanced by (-)-PB and CHEB, with the major effect being acceleration of the slow phase of the biexponential decay of the current. GABA-activated Cl- current was potently enhanced by (-)-PB and PHB (EC50 values, 3.4 and 12 microM), whereas (+)-PB was only weakly active. At concentrations of (-)-PB > 100 microM and PHB > 200-300 microM, Cl- current responses were activated even in the absence of GABA. These results demonstrate that in CA1 hippocampal neurons, PB causes a stereoselective block of a voltage-activated Ca2+ current; PHB is also effective, but at higher concentrations. For (-)-PB, the effect on Ca2+ channel current occurred at similar concentrations as potentiation of GABA responses. In contrast, PHB was more potent as a GABA enhancer than as blocker of Ca2+ current, but the maximal potentiation of GABA responses was 40% of that obtained with (-)-PB. Consequently, the anticonvulsant action of PHB at clinically relevant concentrations may relate to modest enhancement of GABA responses and partial blockade of Ca2+ current, whereas the sedative effects that occur at higher concentrations could reflect stronger Ca2+ current blockade. The powerful sedative-hypnotic action of (-)-PB may reflect greater maximal enhancement of GABA responses in conjunction with strong inhibition of Ca2+ current.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1979

Correlation of biological activity and high-pressure liquid chromatographic retention index for a series of propranolol, barbiturate, and anthranilic acid analogues.

The antiarrhythmic activity of propranolol analogues, the inotropic activity of propranolol analogues, the anti-inflammatory activity of anthranilic acids, the hypnotic activity of barbiturates, and the inhibition of cell division by barbiturates were correlated with either octanol--water partition coefficients or with high-pressure liquid chromatographic retention indices. The retention index, which was a scale based on the relative retention of the drug and a series of C3--C23 2-ketoalkanes, was found to give higher correlations with biological activity than was found between octanol--water partition coefficients and biological activity. Only in the case of the anthranilic acids was the retention index found to give the lower correlation.

Animals↗