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PubMed1979

Changes in brain levels of cyclic nucleotides and gamma-aminobutyric acid in barbiturate dependence and withdrawal.

Rats exposed to chronic intake of sodium barbital maintained high circulating levels of barbital in blood and brain and exhibited increased sensitivity ot audiogenic convulsions during the withdrawal period. Levels of gamma-aminobutyric acid (GABA), glutamate, guanosine 3',5'-monophosphate (cyclic GMP) and adenosine 3',5'-monophosphate (cyclic AMP) were measured in selected brain regions after sacrifice with high power microwave inactivation. Cyclic GMP during chronic barbital administration was significantly lower than controls in most brain regions, especially the hindbrain. During the withdrawal period cyclic GMP in the cerebellum was significantly increased, while returning at least to control levels in all other regions. GABA throughout the brain tended to be reduced during barbital dependence, while cyclic AMP and glutamate levels remained unchanged in all groups. These results indicate a possible role for cyclic GMP in the mediation of the central nervous system response during barbiturate dependence and withdrawal.

Acoustic Stimulation↗
PubMed1989

Isolation of Streptomyces tendae mutants with an altered nikkomycin spectrum.

To isolate Streptomyces tendae mutants blocked in the biosynthesis of the nikkomycin nucleoside base 4-formyl-4-imidazoline-2-one, an assay was developed to detect the formation of nikkomycins containing this base during growth on solid medium. The assay is based on the reaction of the 4-formylimidazolone structure of nikkomycins with the aldehyde reagent barbituric acid leading to red-colored products. Among 18,000 N-methyl-N'-nitro-N-nitrosoguanidine treated clones tested in the barbituric acid assay, we isolated one mutant which was incapable of forming any nikkomycins containing the 4-formylimidazolone base (nikkomycins Cx, X and I) but instead produced nikkomycins containing uracil (nikkomycins C, Z and J). In addition, we isolated strains with mutations affecting the biosynthesis of 2-amino-4-hydroxy-4-(5-hydroxy-2-pyridyl)-3-methylbutyric acid, the unusual amino acid of nikkomycins Z, X, J and I. By analyzing colonies derived from single spores or protoplasts of S. tendae Tü901/395, a mutant producing besides nikkomycins Z, X, J and I, also nikkomycins Kz/Kx and Oz/Ox, we obtained strains which only formed nikkomycins Kz/Kx and Oz/Ox with 2-amino-4-hydroxy-4-(2-pyridyl)butyric acid and 2-amino-4-hydroxy-4-(5-hydroxy-2-pyridyl)-butyric acid as amino acids. Mutation of such a strain (Tü901/395-11) by UV365nm in the presence of 8-methoxypsoralen and selection of S-2-aminoethyl-L-cysteine-resistant clones led to the isolation of Tü901/AEC1 and AEC2 which produced exclusively nikkomycins Kz and Kx. According to their nikkomycin spectrum, these strains were blocked at the hydroxylation step occurring at the pyridyl residue during biosynthesis of the nikkomycin amino acid.

Aminoglycosides↗
PubMedDate not supplied

[Study of the nature of interactions between narcotic analgesics and barbiturates and biological membranes by the method of fluorescent probes].

By employing the method of fluorescent probes the interaction of the barbituric acid derivatives and phenanthrene with biological membranes was analyzed. An association of phenanthrene derivatives with the probe molecules was uncovered. As a result of hydrophobic interaction the barbituric acid derivatives dislodge the probes from the sites of their bonding with biological membranes. This effect correlates with the distribution coefficient of narcotics in the octanol-water system.

1-Naphthylamine↗
PubMed1997

Barbiturate induced benzophenanthridine alkaloid formation proceeds by gene transcript accumulation in the California poppy.

Four barbiturates, barbituric acid, butethal, phenobarbital, and 2-thiobarbituric acid, of fourteen tested were found to induce accumulation of benzophenanthridine alkaloids in cell suspension cultures of the California poppy Eschscholzia california. When the plant cell suspension cultures were treated with 1 mM barbiturate, alkaloids accumulated to 100 mg/l within four days. This is a level comparable to that achieved with 300 microM concentration of the established secondary metabolite inducer methyl jasmonate. In contrast to methyl jasmonate, barbituric acid, and 2-thiobarbituric acid, butethal and phenobarbital treatment resulted in a different alkaloid profile, suggesting that only select cytochrome P-450 genes were activated by these latter two barbiturates. RNA gel blot analysis of barbiturate induced cell cultures confirmed that transcripts of at least two benzophenanthridine alkaloid biosynthetic genes cyp80b1 (encoding the cytochrome P-450-dependent monooxygenase (S)-N-methylcoclaurine 3'-hydroxylase) and bbe1 (encoding the covalently flavinylated berberine bridge enzyme) increased up to 5- to 7-fold over control values.

Alkaloids↗
PubMed1985

The colorimetric determination of cyanide in human food and animal feed.

The well-known Kröller method for the determination of cyanide requires the use of the harmful chemicals benzidine (carcinogenic) and bromine (toxic) in the colorimetric part; the analytical result depends strongly on the conduct of the liberation procedure. The substitution of barbituric acid and N-chlorosuccinimide for benzidine and bromine has been investigated. The reproducibility of both colorimetric reactions is similar, but the sensitivity of the barbituric acid colorimetry is approximately 50% higher. A reproducible liberation yield can be obtained by a proper control of the heating programme. The detection limit for cyanide in a solution is approximately equal to 10 micrograms/l.

Animal Feed↗
PubMed1980

Synthesis and cyclization of dialkylmalonuric esters.

A novel method for the synthesis of methyl dialkylmalonuric esters was developed using the base-catalyzed ring opening of an isopropylidene malonic ester with urea as the key step. The rates of cyclization of these malonuric esters to the corresponding barbituric acids then were studied at buffer concentrations ranging from 0.01 to 1.00 M. The reaction was shown to be general base catalyzed, and the reaction rate was found to be subject to a deuterium isotope effect, kH2O/kD2O=1.3. The thermodynamic activation parameters also were determined. A three-step mechanism for the conversion of malonuric esters to barbituric acids was proposed; it involved a rapid cyclization step, followed by proton removal by a general base catalyst and a rate-determining collapse of the resulting tetrahedral intermediate aided by a general acid.

Barbiturates↗
PubMed1997

Quantitative structure-pharmacokinetics relationships: I. Development of a whole-body physiologically based model to characterize changes in pharmacokinetics across a homologous series of barbiturates in the rat.

As part of an overall program to develop a framework for evaluating the contribution of structural and physicochemical properties to pharmacokinetics, the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) was examined after i.v. bolus administration in rats. The barbituric acids studied form a true homologous series; therefore any differences in pharmacokinetics, noted between congeners, can be directly linked to the increase in lipophilicity, resulting from the addition of a methylene group. A whole-body physiologically based pharmacokinetic model has been developed, assuming most of the tissues to be well-stirred compartments. Brain and testes, in which distribution for the lower homologues was permeability rate-limited, were represented by two compartments. For each homologue, the model parameters have been optimized, using the tissue concentration-time data. The initial distribution processes in the system were very rapid, making it quite stiff, and essentially over before the first samples were taken. A progressively increasing redistribution from lean tissues into adipose on ascending the homologous series was observed, characterized by a tendency for a progressive decrease in the magnitude of the concentration-time profiles for some of the lean and well-perfused tissues, an increase in the adipose concentration-time profile, and an increase in the time to reach the maximum adipose concentration. A shift from permeability rate limitation to perfusion rate limitation of the distribution processes for brain and testes, as well as an increase in the intrinsic hepatic clearance and decrease in the renal clearance with the increase of lipophilicity of the homologues, were quantified. An increase in the total unbound volume of distribution on ascending the homologous series was also observed. Muscle was found to be the major drug depot at steady state, accounting for approximately 50% of the total unbound volume of distribution, regardless of the lipophilicity of the homologue; the unbound volume of distribution of adipose increases more than 10-fold with the increase of lipophilicity.

Adipose Tissue↗
PubMed1989

Effect of barbiturates on polyphosphoinositide biosynthesis and protein kinase C activity in synaptosomes.

Previously, it has been found that phenobarbital inhibited protein kinase C (PKC) and the enzymes of the metabolism of polyphosphoinositide, especially phosphatidylinositol 4-phosphate (PIP) kinase (PIP-kinase). As a continuation of these studies, a number of barbiturates (barbituric acid, barbital, butabarbital, pentobarbital, amobarbital, phenobarbital, secobarbital and hexobarbital) were tested for inhibition of these enzymes and also of phosphatidylinositol (PI) kinase (PI-kinase), in a synaptosomal preparation at pH 7.8 from the brain of rat. All compounds, except barbituric acid (and Na-barbital for PI-kinase) inhibited the three kinases. However, PKC was approximately 3-5 fold more sensitive to inhibition by the drugs (measured by Ki values) than PIP-kinase, which was 2- to 4-fold more sensitive than PI-kinase. The inhibitory potency of the drugs increased with their lipophilicity, although to a lesser degree than expected from the differences in partition coefficients; the largest deviation from a positive correlation (i.e. hexobarbital) may be the result of the blockade of an imide (-NH) group at one position of the barbituric ring. Concentrations of drugs (after correction for the greater than normal ionization (pH 7.8) of the drugs in the assays) necessary for half-maximal inhibition were well within, or smaller than, those reported necessary for in vitro blocking of nerves. The possibility, therefore, exists that the physiological effects of the barbiturates are, in part, the result of an inhibition of protein kinase C and PIP-kinase.

1-Phosphatidylinositol 4-Kinase↗
PubMedDate not supplied

Metabolism of butalbital, 5-allyl-5-isobutylbarbituric acid, in the dog.

Butalbital, 5-allyl-5-isobutylbarbituric acid, labeled in the 2-position with 14C, was administered to dogs. Ninety-two percent of the radioactivity of the dose was excreted in the urine. The drug and three major urinary metabolites were identified in the urinary excretion of the dog. The major metabolite was 5-isobutyl-5-(2,3-dihydroxypropyl)barbituric acid, which accounted for 50.2% of the dose. Smaller amounts of the unchanged drug (2.6% of the dose) and urea (8.6% of the dose) were present. 5-Allyl-5-(3-hydroxy-2-methyl-1-propyl)barbituric acid, formed by omega-hydroxylation, accounted for 10.1% of the dose; the optical rotation of the 1,3-diethyl derivative was [alpha]D20 = +10.5. Five minor and unidentified metabolities accounted for an additional 10.7% of the dose. A total of 82.2% of the dose was accounted for.

Animals↗
PubMed1990

Hypolipidemic activity in rodents of phenobarbital and related derivatives.

A series of 5-alkyl-5-phenylbarbituric acid analogues were shown to be potent hypolipidemic agents in rats and mice at 20 mg/kg/day. This dose is lower than that required for hypolipidemic activity for clofibrate and nicotinic acid derivatives in rodents and man. These new derivatives reduced both serum cholesterol and triglyceride levels in rodents by either the oral or intraperitoneal route of administration. Previous studies have demonstrated that similar heterocyclic compounds, i.e. cyclic imides, glutarimides and hydantoins are potent hypolipidemic agents in rodents. The barbituric acid derivatives probably interfered with de novo synthesis of cholesterol and fatty acids in the early steps since the agents inhibit the activities of ATP-dependent citrate lyase and acetyl-CoA synthetase. Triglyceride synthesis may be blocked since the agents inhibited the rate limiting enzyme, sn-glycerol-3-phosphate-acyl-transferase. Rat tissue lipids especially cholesterol and triglycerides were reduced after 14 days treatment. Fecal lipids were increased in cholesterol and phospholipid content by selected compounds. The rat serum lipoprotein after 14 days drug administration showed reduced VLDL-cholesterol and HDL-triglyceride contents. The modulation of the lipid content of the serum lipoproteins by the barbituric acids suggest that these agents may be helpful in treating clinical hyperlipidemic disease states.

Animals↗
PubMed1985

Differential effect of anionic and cationic drugs on the synaptosome-associated acetylcholinesterase activity of dog brain.

The evoked effects of the negatively charged drugs phenobarbital and barbituric acid, the positively charged imipramine, perphenazine and trifluoperazine, and the neutral primidone, on the synaptosome-associated acetylcholinesterase activity were studied. A marked increase in the enzyme activity was exhibited in the presence of low concentrations (up to 3 mM) of phenobarbital, barbituric acid and primidone. Higher concentrations (up to 10 mM), however, led to a progressive inhibition of the enzyme activity. However, the activity of the enzyme was not affected by imipramine, but it was decreased by perphenazine and trifluoperazine. Arrhenius plots of acetylcholinesterase activity exhibited a break point at 23.4 degrees C for the untreated (control) synaptosomes, which was shifted to around 16 degrees C in the synaptosomes treated with the charged drugs. The allosteric inhibition by F- of acetylcholinesterase was studied in control synaptosomes and in those treated with the charged drugs. Changes in the Hill coefficients in combination with changes in Arrhenius activation energy produced by the charged drugs would be expected if it is assumed that charged drugs 'fluidize' the synaptosomal plasma membranes.

Acetylcholinesterase↗
PubMed1984

Proline dehydrogenase from Escherichia coli K12. Reconstitution of a functional membrane association.

Soluble and membrane associated proline dehydrogenase differ in catalytic properties. The soluble enzyme transfers electrons from L-proline to exogenous electron acceptors. It has a high Km for L-proline (105 mM) and is insensitive to the respiratory chain inhibitors 5-ethyl-5-isopentyl-barbituric acid and cyanide. The membrane-associated enzyme transfers electrons from L-proline to O2 via the respiratory chain, with coupled transmembrane proton translocation. It has a low Km for L-proline (3 mM) and is inhibited by 5-ethyl-5-isopentyl-barbituric acid and cyanide. Proline:O2 oxidoreductase activity identical to that of native membranes can be reconstituted using enzyme purified in the absence of detergent and enzyme deficient membranes from a putA mutant strain. Reassociation of the enzyme with the membrane is an autocatalytic process that requires the simultaneous presence of L-proline, MgCl2, enzyme, and membranes. It can be monitored by observing the chromogenic reaction of delta 1-pyrroline carboxylic acid with o-aminobenzaldehyde. Reduction of membrane components or generation of a protonmotive force is apparently required to promote enzyme-membrane association or to activate electron transfer. The reconstituted activity is a saturable function of enzyme concentration at constant membrane concentration and the activity approached is 20-fold higher than that of native membranes isolated from bacteria that have been induced for proline utilization. It is therefore unlikely that saturation of the available membrane binding sites is achieved during induction of the put genes in vivo.

Cell Membrane↗
PubMed1976

Crystallization of human placental estradiol 17beta-dehydrogenase. A new method for crystallizing labile enzymes.

Estradiol 17beta-dehydrogenase from human placenta has been crystallized by a new technique, herein referred to as electrophoretic diffusion. This is the first crystallization of an enzyme from human placenta as well as the first crystallization of any steroid-converting enzyme of human source. A solution of the enzyme (specific activity 7.1 units/mg) in 1.5 ml of Tris-barbituric acid buffer, pH 7.0, containing 20% glycerol as stabilizer, was placed in an electrophoresis tube and the tube was closed at both ends with a dialysis membrane which permits the passage of substances of molecular weight less than 18,000. The tube was placed in a gel electrophoresis apparatus and the reservoirs filled with the Tris-barbituric acid buffer. A potential of 100 V was applied for 12 hours, then raised to 200 V for another 12 hours, and finally to 300 V until opalescence appeared at the bottom of the tube. Activity measurements showed that more than 90% of the enzyme had concentrated in the bottom 0.15-ml portion of the solution. When this section of the solution was removed and kept overnight at 4 degrees, gross and microscopic examination revealed a heavy crop of crystals which possessed a specific activity of 7.2 units/mg. The specific activity remained constant throughout three recrystallizations. The crystalline enzyme displayed a single band by analytical and sodium dodecyl sulfate-polyacrylamide gel analysis. Crystals of enzyme of high specific activity could also be obtained from an enzyme sample initially possessing a specific activity of only 4.5 units/mg. The new technique should be appliable for the crystallization of other labile enzymes and receptor proteins which have so far resisted crystallization by conventional methods.

Crystallization↗
PubMed2001

Metabolism of bucolome in rats. Stability and biliary excretion of bucolome N-glucuronide.

Bucolome (BCP) is a non-steroidal anti-inflammatory drug, which is used in the treatment of chronic articular rheumatism. Bucolome N-glucuronide (BCP-NG), a metabolite of BCP, is the first unique N-glucuronide of barbituric acid derivatives. First, the stability of BCP-NG in various pH aqueous solutions was studied. BCP-NG was quite unstable under neutral and acidic conditions, and is easily hydrolyzed to BCP. Based on these characteristics of BCP-NG, a simple, rapid and highly sensitive method for the simultaneous determination of BCP and BCP-NG with phenylbutazone (I.S.) in biological fluids was developed using high-performance liquid chromatography (HPLC). A reversed-phase ODS column was used for the separation of BCP, BCP-NG and I.S. A pharmacokinetic study for BCP and BCP-NG was carried out in male Wistar/ST rats following i.v. administration of BCP at a dose of 10 mg/kg body weight. The slow plasma elimination of BCP with time was shown. A major metabolite of BCP in bile was N-glucuronide. The cumulative amounts of BCP and BCP-NG in the bile over 8 h were approximately 2.4 +/- 1.4% and 12.6 +/- 2.3% of the dose, respectively. BCP and BCP-NG in the urine were 2.7 +/- 0.7% and 3.2 +/- 0.3% of the dose. Although BCP had a long half-life (over 8.5 h), the preliminary pharmacokinetic parameters (0-8 h) were determined: t 1/2, 8.52 +/- 1.96 h; AUC, 419.9 +/- 45.2 microg x h/ml; MRT, 3.29 +/- 0.11 h; CLtot, 5.93 +/- 0.54 ml/h; and Vdss, 19.5 +/- 1.3 l. These observations are the first pharmacokinetic findings for the N-glucuronide of the barbituric acid derivatives.

Animals↗
PubMed1983

Optimization of a novel two-phase potentiometric titration method of barbiturates with mercury (II). Part I: Theory.

A two-phase potentiometric titration procedure for barbiturates with mercury(II) was developed. In the new titration procedure the barbituric acid derivative is dissolved in an aqueous borate buffer. An organic phase consisting of chloroform and benzyl alcohol is added, and the vigourously stirred contents of the titration vessel are titrated by a mercury(II) nitrate solution. The theory of the conditional formation constant in a two-phase system is derived to provide a basis for the selection of optimal titration conditions. It is shown that the new conditional formation constant of the two-phase system, K, increases if the mercury-barbiturate complex is extracted into the organic layer. By extraction of the barbituric acid derivative into the organic layer K is diminished, but this effect can be minimized by a correct choice of the pH of the aqueous layer. The influence of these factors on the pM jump in the equivalence point is demonstrated by calculation of the corresponding theoretical titration curves.

Barbiturates↗
PubMed1980

[Drug distribution during convulsive seizure in comparison with narcosis].

3 min after simultaneous i.v. administration of phenazone (200 mg/kg) and of pentetrazole (50 mg/kg) or of phenazone and of the convulsively active S-(+)-1-methyl-5-phenyl-5-propyl barbituric acid = (+)-MPPB (75 mg/kg), respectively, phenazone concentrations in liver, spleen and fat tissue of rats are lower, in brain tissue, however, it is higher than those of the control (rats receiving phenazone only); the distribution pattern of (+)-MPPB between the tissues corresponds to that of phenazone after simultaneous administration of pentetrazole. In rats anaesthetized by hexobarbital (35 mg/kg) or by the anaesthetically active R-(-)- 1-methyl-5-phenyl-5-propyl barbituric acid = (-)-MPPB (75 mg/kg), respectively, phenazone tissue distribution is at the same time (3 min) not different from that of the control; the tissue distribution pattern of (-)-MPPB corresponds to that of phenazone after simultaneous administration of hexobarbital. Following pretreatment with diazepam, reserpine and phenoxybenzamine, respectively, the tissue distribution pattern of (+)-MPPB, in the rats approaches that of (-)-MPPB. The distribution of (-)-MPPB in the tissues corresponds to that of (+)-MPPB, if the animals receive simultaneously pentetrazole or are electrically stimulated, respectively, to cause a convulsive seizure.

Adipose Tissue↗
PubMed1983

Increased release of [3H]acetylcholine in vitro from the mouse hippocampus by a convulsant barbiturate.

The effects of the convulsant barbiturate, 5-(2-cyclohexylidene-ethyl)-5-ethyl barbituric acid (CHEB), on the spontaneous release of [3H]acetylcholine (ACh) from mouse hippocampal slices in an in vitro superfusion system have been evaluated. The pattern of the release of [3H]ACh by a single treatment with CHEB or an elevated potassium concentration was similar, with the peak release occurring in the same fraction. A maximally effective concentration of CHEB (500 microM) caused a 177% stimulation of spontaneous release of [3H]ACh, while 50 mM KCl increased the release by 2100% above the baseline. The stimulation of the spontaneous release of [3H]ACh by CHEB was concentration-dependent with an EC50 of 180 microM. The pattern of release of [3H]ACh induced by multiple treatment with CHEB and elevated potassium appeared to differ, suggesting that different pools of [3H]ACh in the cholinergic neurons might be affected by these treatments. The action of CHEB on the spontaneous release of [3H]ACh was unique among some other convulsant drugs that were studied. Another convulsant barbiturate, S(+)-1-methyl-5-phenyl-5-propyl barbituric acid [S(+)-MPPB], pentylenetetrazol and a convulsant benzodiazepine 1,3-dihydro-5-methyl-2H-1,4-benzodiazepine-2-one (Ro-5-3663) did not affect the spontaneous release of [3H]ACh. The relationship between the stimulation of release of ACh and the convulsant action of the barbiturates is discussed.

Acetylcholine↗