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PubMed1983

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

A two-phase potentiometric titration procedure of barbiturates with mercury(II) was developed. The composition of the formed mercury-barbiturate complexes was elucidated by infrared spectrometry. 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 vigorously stirred contents of the titration vessel are titrated by a mercury(II) nitrate solution. In the potentiometric determination of the end-point a rotating mercury electrode is used as an indicator electrode that also serves as an efficient stirrer. The two-phase procedure was compared with a one-phase mercurimetric potentiometric titration in borate buffer and with the potentiometric titration by sodium hydroxide in an ethanol-water solution. The proposed two-phase procedure is superior to both methods because lower concentrations of barbiturates (10(-3) - 10(-4) M) can be determined successfully. The one-phase procedure suffers from systematic errors, while the titration with sodium hydroxide is less precise at concentration levels of the barbiturates prevailing in content uniformity studies. By the two-phase procedure the direct titration of phenobarbital and mephobarbital in a dry mix of tablet excipients was possible with a relative standard deviation smaller than 1.5 percent.

Barbital↗
PubMed1989

The pharmacology of quisqualate and AMPA in the cerebral cortex of the rat in vitro.

The depolarising population response to the excitatory amino acids, quisqualate and AMPA, in slices of cerebral cortex of the rat have been compared. Their respective dose-response curves had a similar maximum but the slope of the curve for AMPA was consistently steeper than that for quisqualate. The dose-response curves for AMPA had a mean log EC50 of -5.18 +/- 0.05, which was significantly different from -4.62 +/- 0.07 the mean log EC50 of the dose-response curves for quisqualate. Responses to both agonists were antagonised by kynurenic acid, barbiturates and gamma-DGT to a similar extent. The antagonism by kynurenate appeared to be competitive whilst the barbiturates were evidently noncompetitive antagonists. These results are in agreement with claims that quisqualate and AMPA act at a similar recognition site. The differences in the slopes of the dose-response curves for quisqualate and AMPA may be explained by the differences in the cellular uptake of the two agonists and/or by differences in efficacy.

Animals↗
PubMedDate not supplied

IR analysis of crystalline samples of some urea derivatives.

The dependence of an IR spectrum of crystal samples of allantoin, barbital, chloroethylaminouracil (dopan), carbromal, 5-allyl-5-(beta-hydroxypropyl)-barbituric acid (ipronal) and theophyllin upon the method of crystals preparation was found after 3 months storage of crystals. There were no differences in the case of mephenytoin. The results obtained here demonstrate the possibility of an occurence of the majority of the analyzed substances as metastable polymorphic modifications in solid dosage forms. Furthermore, the IR identification of drugs requires crystallization of a substance from a particular solvent just before analysis.

Allantoin↗
PubMed1975

Influence of pH on the contractor effect of convulsant barbiturate on frog lung.

Pentobarbial, thiopental and the convulsant 5-ethyl-5-(2-cyclohexylideneëthyl) barbituric acid (CHEB) were tested for contractor effect on the isolated lung of the fullfrog at pH 7.0 (7% CO2 and 20 mM HCO3-) and pH 8.4 (0.3% CO2 and 20mM HCO3-). CHEB was a potent contractor, thiopental a feeble contractor, and pentobarbital lacked contractor effect. The contractor potencies of both CHEB and thiopental were greater at the more acid pH. The potencies of formally charged agonists such as acetylcholine and K+ were not altered by the pH differences employed in these experiments. The pKa of CHEB was found to be 8.18 at 15 degrees C and 8.03 at 27 degrees C. Calculation of concentration-effect relationships of ionized and nonionized CHEB showed that only the nonionized CHEB was responsible for the contractor effect.

Acetylcholine↗
PubMed2000

Cyano-, nitro-, and alkoxycarbonyl-activated observable stable enols of carboxylic acid amides

A search for the enol structures of several amides YY'CHCONHPh with Y,Y' = electron-withdrawing groups (EWGs) was conducted. When Y = CN, Y' = CO(2)Me the solid structure is that of the enol (8b) MeO(2)CC(CN)=C(OH)NHPh, whereas in solution the NMR spectrum indicate the presence of both the amide MeO(2)CCH(CN)CONHPh (8a) and 8b. When Y = NO(2), Y' = CO(2)Et the main compound in CDCl(3) is the amide, but <10% of enol(s), presumably EtO(2)CC(NO(2))=C(OH)NHPh (9b), are also present. When Y = COEt, Y' = CO(2)Me or Y = COMe, Y' = CO(2)Et (10 and 11) enolization in solution and of 11 also in the solid state occurs at the carbonyl rather than at the ester site. With Y = Y' = CN a rapid exchange between the amide (NC)(2)CHCONHPh (12a) and a tautomer, presumably the enol, take place in several solvents on the NMR time scale. With YY' = barbituric acid moiety the species in DMSO-d(6) is an enol of an amide although which CONH group enolizes is unknown. B3LYP/6-31G calculations showed that the enol (NC)(2)C=C(OH)NH(2) (13b) is more stable by DeltaG of 0.4 kcal/mol than (NC)(2)CHCONH(2) (13a) due to a combination of stabilization of 13b and destabilization of 13a and both are much more stable than the hydroxyimine and ketene imine tautomers. The effect of Y,Y' and the solvent on the relative stabilization of enols of amides is discussed.

Journal Article↗
PubMed1988

Analysis of UMP synthase gene and mRNA structure in hereditary orotic aciduria fibroblasts.

Hereditary orotic aciduria is an autosomal recessive disease in which there is a severe deficiency in the activity of the de novo pyrimidine pathway enzyme uridine 5'-monophosphate (UMP) synthase. UMP synthase is a bifunctional enzyme containing the two activities orotate phosphoribosyltransferase and orotidine 5'-monophosphate decarboxylase, which catalyze the two-step conversion of orotic acid to UMP. Cell lines from three orotic aciduria patients have been characterized for UMP synthase gene and mRNA content. Restriction-enzyme analysis of DNA from the deficient cells revealed no changes in the gene structure compared with normal cell DNA structure. The amount of UMP synthase mRNA was not decreased, nor was there a detectable difference in the size of the UMP synthase mRNA in the deficient cells. Analysis of the mRNA by hybridization with a nearly full-length UMP synthase cDNA followed by S1 nuclease digestion showed no alteration in the mRNA structure. The UMP synthase activity of the deficient cells ranges from 2% to 7% of the normal cell level. The activity can be significantly increased by growing the deficient cells in barbituric acid. Our data indicate that UMP synthase gene transcription in the orotic aciduria cells produces the expected amount of a stable, correctly processed mRNA. The mRNA appears to code for a mutant enzyme that has reduced stability or altered kinetic properties.

Carboxy-Lyases↗
PubMed1985

[Experimental myocardial infarction in atherosclerosis--various methods of pharmacological correction].

The effect of the beta-blocker propranolol and of bensonal, a barbituric acid derivative stimulating microsomal oxidation of the liver monooxygenase, was evaluated using the model of experimental myocardial infarction (EMI) in the presence of 3-month cholesterol atherosclerosis. Using light and electron microscopy, polarography and weight planimetry atherosclerosis was shown to complicate considerably the course of EMI analyzed 1, 3, 7, 15 and 30 days after the coronary artery ligation. The drugs given at the same intervals improved the structure and metabolism of different myocardial zones while limiting necrotic areas for 7 days of EMI.

Administration, Oral↗
PubMed1973

Pentobarbitone inhibition of catecholamine secretion.

1. The perfused isolated cow adrenal gland was used to investigate the effect of barbituric acid, phenobarbitone and pentobarbitone on catecholamine secretion.2. Pentobarbitone reduced catecholamine secretion induced by a number of drugs which cause exocytosis. The concentration of pentobarbitone which caused a 50% inhibition of catecholamine secretion was for acetylcholine 5.6 x 10(-5)M, for carbachol 6.3 x 10(-5)M, for histamine 1.6 x 10(-4)M, for (+)-amphetamine 4.4 x 10(-5)M and for potassium chloride 1.5 x 10(-4)M. The degree of inhibition by pentobarbitone was not dependent on the concentration of the secretagogue.3. Pentobarbitone (up to 10(-3)M) did not inhibit the catecholamine release that was induced by acetyldehyde or by calcium chloride; it inhibited slightly (34%) the catecholamine secretion induced by tyramine.4. Catecholamine release induced by carbachol was also inhibited by phenobarbitone (50% inhibition at 2.8 x 10(-4)M (n=7)) but was unaffected by barbituric acid.5. Pentobarbitone had no effect on spontaneous or on (+)-amphetamine- or tyramine-induced release of catecholamines from isolated chromaffin vesicles of cow adrenal medulla.6. It is concluded that pentobarbitone inhibits catecholamine release by preventing a configurational change in the structure of the membrane of the chromaffin cell which is a necessary link between receptor activation and catecholamine release.

Acetylcholine↗
PubMed1979

Pathogenicity of Mengo virus to mice. III. Potentiation of infection by immunosuppressants.

Mengo virus has been described to cause, in dependence on the virus dose, lethal panencephalomyelitis and exocrine pancreatitis in mice after i.p. inoculation. Two immunosuppressive agents, cyclophosphamide and 1,3-bis(piperidinomethyl)-5-ethyl-5-phenyl-barbituric acid (ZIMET 176/68), were shown to potentiate Mengo virus infection as demonstrated by histopathology and enhanced mortality. Organotropism of Mengo virus did not change under the drug treatment. However, the histological lesions in brain, spinal cord and pancreas failed to exhibit any inflammatory reaction in case of cyclophosphamide, due to its antiphlogistic properties. Considering the mode of action of the drugs employed and the pathogenesis of Mengo virus infection in mice, it is concluded that in the system used both cyclophosphamide and ZIMET 176/68 exert their potentiating effects by interfering with primary virus-macrophage interaction.

Animals↗
PubMed1997

Neural network modeling for estimation of the aqueous solubility of structurally related drugs.

The ability of neural network models to predict aqueous solubility within series of structurally related drugs was evaluated. Three sets of compounds representing different drug classes (28 steroids, 31 barbituric acid derivatives, and 24 heterocyclic reverse transcriptase inhibitors) were studied. Topological descriptors (connectivity indices, kappa indices, and electrotopological state indices) were used to link the structures of compounds with their aqueous solubility. Separate models were built for each class of drugs using back-propagation neural networks with one hidden layer and five topological indices as input parameters. The effect of network size and training time on the prediction ability of the network was studied by the leave-one-out (LOO) procedure. In all three compound groups a neural network structure of 5-3-1 was optimal. To avoid chance effects, artificial neural network (ANN) ensembles (i.e.; averaging neural network predictions over several independent networks) were used. The cross-validated squared correlation coefficient (Q2) for 10 averaged predictions was 0.796 in the case of the steroid set. The corresponding standard error of prediction (SDEP) was 0.288 log units. For the barbiturates, Q2 and SDEP were 0.856 and 0.383, respectively, and for the RT inhibitors, these parameters were 0.721 and 0.401, respectively. The results indicate that neural networks can produce useful models of the aqueous solubility of a congeneric set of compounds, even with simple structural parameters.

Drug Design↗
PubMed2001

Transport of lipophilic drug molecules in a new mucus-secreting cell culture model based on HT29-MTX cells.

PURPOSE: A new mucus-secreting in vitro drug absorption model based on monolayers of goblet-cell like sub-clones of the human colon carcinoma cell line HT29 obtained by methotrexate (MTX) treatment was investigated. METHODS: Twelve sub-clones were isolated and characterized by light microscopy (LM), transelectron microscopy (TEM), confocal laser scanning microscopy (CLSM), transepithelial electrical resistance (TEER) and the transport of a paracellular marker FITC-Dextran (Mw 4400) (FD-4). RESULTS: Significant differences of microscopical appearance, TEER-values and permeability of FD-4 between the sub-clones were evident. However, two of them, namely MTX-D1 and MTX-E12. formed tight confluent monolayers with a thick mucus-layer on the apical surface. They were used to compare the apparent permeability coefficient (Papp) of a series of lipophilic drugs, which should be affected by the mucus-layer, namely barbiturates (barbituric acid, barbital, phenobarbital, methylphenobarbital and heptabarbital) and testosterone, as a reference, to mucus-free Caco-2 cells. The permeability of drugs with a partition coefficient (log P) > 1 was decreased in the mucus-producing cell lines. Testosterone, the most lipophilic compound, showed a decrease of up to 43%. CONCLUSIONS: We demonstrated that the mucus layer is a significant barrier to drug absorption for lipophilic drugs. In conclusion, our model may serve as a suitable in-vitro cell culture model to study the influence of the mucus layer on drug diffusion.

Algorithms↗
PubMed1998

Relationship between retention characteristics and physicochemical parameters of solutes on porous graphitized carbon column.

The retention of 44 barbituric acid derivatives was determined on porous graphitized carbon (PGC) column using dioxane water mixtures as eluents. Linear correlations were calculated between the logarithm of the capacity factor and the dioxane concentration in the eluent. Free Wilson analysis combined with stepwise regression analysis was used to elucidate the role of individual substituents in the retention behaviour. Calculations indicated that the apolar substituents lie parallel to the surface of PGC surface increasing in this manner the retention and--as opposed to the retention characteristics of traditional reversed-phase supports--the position of substituents also exerts a marked influence on the retention.

Barbiturates↗
PubMed2000

The role of voltage-gated chloride channels in type II pyrethroid insecticide poisoning.

Pyrethroids act on mammalian sodium channels, but we have previously shown that low concentrations of the type II pyrethroid deltamethrin also decrease the open channel probability (P(o)) of voltage-gated chloride channels. This effect would be expected to amplify the sodium channel-mediated signs of poisoning produced by pyrethroids. In the present study we evaluated potential chloride channel agonists in vitro, and then tested the most effective of these on pyrethroid-poisoned rats to determine the practical significance of chloride channel effects in vivo. Patch clamp experiments showed that, for voltage-gated maxi chloride channels in excised, inside-out patches from mouse N1E 115 neuroblastoma cells, ivermectin (10(-7) M) and pentobarbitone (10(-6) M) significantly increased open channel probability (p </= 0.01 and p </= 0.02, respectively), whereas phenobarbitone, hexobarbitone, mephobarbitone, thiopentone, and barbituric acid did not. This suggested that, if chloride channels were important in vivo, ivermectin and pentobarbitone should antagonize type II pyrethroid poisoning and phenobarbitone should not. Male F344 rats were then pretreated with ivermectin (4 mg/kg iv), equisedative doses of either pentobarbitone (15 mg/kg ip) or phenobarbitone (45 mg/kg ip), or solvent controls. This was followed by deltamethrin (1.5 or 2 mg/kg iv) or the type I pyrethroid cismethrin (4 mg/kg iv). Ivermectin produced a marked fall in deltamethrin-induced salivation (p </= 0.05) and also (in anesthetized rats) in repetitive electromyogram discharge and muscle twitch (p </= 0.01 and p </= 0.05, respectively). Pentobarbitone significantly reduced the motor signs score due to deltamethrin (p </= 0.01). Ivermectin therefore protected against the peripheral signs of deltamethrin poisoning and pentobarbitone protected against the central signs. As expected phenobarbitone had no protective effects. The motor signs produced by the type I pyrethroid cismethrin (which does not act on chloride channels) were not diminished by either barbiturate. The peripheral benzodiazepine receptor blocker PK11195 did not diminish the protective action of ivermectin on the muscle twitch (p </= 0.05), although it partially reversed the block of salivation (p </= 0.05). These results support the hypothesis that the voltage-dependent chloride channel is a toxicologically significant additional site of action for deltamethrin and that the use of chloride channel agonists can provide a rationale for a novel and effective therapy against type II pyrethroid poisoning.

Animals↗
PubMed2000

EGF receptors of hepatocytes from rats treated with phenobarbital are sensitized to down-regulation by phenobarbital in culture.

Hepatocytes from Fisher 344 rats treated with the liver tumor promoter phenobarbital (PhB; 0.1% in the drinking water, 2-3 months) exhibit reduced epidermal growth factor (EGF) binding and EGF-induced mitogenesis in culture. Similar responses are induced by >1 mM PhB added to the culture medium of hepatocytes from untreated rats. In this study, we demonstrated that hepatocyte EGFr protein, as determined by immunoblotting, was unchanged by treatment of rats with PhB. However, hepatocytes from PhB-treated rats are more sensitive to PhB in culture in that decreased EGF binding occurred with 0.05 mM PhB, a concentration also attained in plasma of rats exposed to PhB. Sensitization was reversible, as is tumor promotion, since hepatocytes from rats withdrawn from PhB for 1 month were unresponsive to <3 mM PhB. EGFr down-regulation by a series of barbiturates correlated well with their known activities as tumor promoters and CYP2B1/2 inducers, with pentobarbital and PhB yielding high activities, while barbital was intermediate and barbituric acid, 5-phenylbarbituric acid, and 5-ethylbarbituric acid were ineffective. Differentiated hepatocyte function was required for PhB-induced EGFr down-regulation since HepG2 and rat liver epithelial cells were unresponsive, but involvement of CYP2B1/2 activity was discounted by the failure of metyrapone to inhibit the response in PhB-induced hepatocytes. These studies support a role for impaired EGFr function in PhB liver tumor promotion due to effects on existing EGFr protein and suggest that EGFr down-regulation by PhB in culture is independent of CYP2B1/2 activity but shares mechanistic components involved in its transcriptional activation by PhB.

Animals↗
PubMed1994

Colocalized alterations in connexin32 and cytochrome P450IIB1/2 by phenobarbital and related liver tumor promoters.

Direct intercellular signal transduction is achieved by the passage of small molecules through gap junctions (GJ). Previous studies in our laboratory showed that the liver tumor promoter phenobarbital (PB) reversibly decreases the abundance of the GJ protein connexin32 (Cx32) in both preneoplastic-altered hepatic foci and centrolobular hepatocytes (M. J. Neveu et al., Cancer Commun., 2: 21-31, 1990). Because the inhibitory effects of PB on GJ intercellular communication are prevented by the nonspecific cytochrome P-450 inhibitor SKF-525A (J. E. Klauning, et al., Toxicol. Appl. Pharmacol., 102: 533-563, 1990), we investigated whether alterations in Cx32 are coincident with changes in the major PB-inducible cytochrome P-450, termed b/e or IIB1/2. Immunostaining of liver cryosections from rats fed dietary PB demonstrated that centrolobular hepatocytes that exhibit reduced Cx32 express enhanced cytochrome P450IIB1/2 protein. In contrast, no change in the periportal distribution of connexin26 immunoreactivity was found in PB-treated rats. In addition, rats were treated with the structurally related barbiturates pentobarbital, amobarbital, barbital, and barbituric acid. We found that the extent of the hepatic lobule occupied by coincident centrolobular alterations in Cx32 and P-450 staining correlates with the ability of the compounds to promote liver oncogenesis. To determine the molecular mechanisms responsible for the modification in Cx32 staining, we examined the mRNA and protein levels of Cx32 and P450IIB1/2 in total-tissue homogenates from PB-treated rats. Northern blotting demonstrated thatdietary PB dramatically induced P-450IIB1 mRNA, but the same RNA samples failed to show alterations in Cx32 steady-state transcripts. Consistent with these findings, the level of Cx32 protein in total liver homogenates did not change in rats chronically fed PB. Examination of Cx32 solubility in 20 mM NaOH demonstrated that PB treatment results in the generation of a NaOH-soluble form of Cx32 (i.e., 47 kDa). In addition, trypsinized paraffin-embedded liver sections from PB-treated rats exhibited diffuse cytoplasmic Cx32 staining that was restricted to centrolobular cells. Our results show that PB and related barbiturate tumor promoters reversibly down-regulate punctate Cx32 staining in centrolobular hepatocytes posttranslationally, possibly through modification(s) in the transport, assembly, and/or turnover of GJs.

Animals↗
PubMed1989

[Synthesis of potential metabolites of a barbiturate containing two branched side chains].

The two branched side chains of 5-(3-methylbutyl)-5-(2-methylpropyl)-barbituric acid present a tertiary carbon atom, which can be oxidized in vivo by hepatic enzymes. Potential metabolites of this compound are synthesised: the gamma-hydroxy metabolite can be oxidized directly by CrO3 while the beta-hydroxy metabolite can only be prepared by hydration of a double bond. This beta-hydroxybarbiturate then undergoes an alcoholysis leading to an allophanyl-gamma-lactone, which is hydrolysed into a carboxylic lactone, which can give a lactone by decarboxylation. On the other hand, a beta-gamma-dihydroxymetabolite is synthesised by double hydration of two double bonds using two different methods. A spirobilactone can also be synthesised from this dihydroxy compound.

Barbiturates↗
PubMed1986

Kinetic regulation of convulsant (TBPS) binding by GABAergic agents.

The kinetics of specific [35S]-t-butylbicyclophosphorothionate (TBPS) binding was studied in rat brain synaptosomal membrane preparations. The effects of a representative depressant barbiturate, R-(-)-N-(1)-Me-5-Phe-5-Pr-barbituric acid [R(-)MPPB, and gamma-aminobutyric acid (GABA) were biphasic on TBPS binding, but the enhancements of binding by low concentrations of R(-)MPPB or GABA disappeared when binding equilibrium was reached. The slope factors of TBPS displacement and the IC50 values of R(-)MPPB and GABA decreased when TBPS binding approached equilibrium. Up to 70 min, binding in the presence of 300 microM R(-)MPPB exceeded, then remained below, the level of the control. R(-)MPPB decreased the apparent association half-life of TBPS binding from 41.5 min to 11.9 min. The GABA agonist, muscimol, in the concentration range of 20 and 200 nM, progressively accelerated the rate of TBPS dissociation. This effect was completely reversed by 20 microM bicuculline methochloride. GABA antagonists, bicuculline methochloride (20 microM) and R 5135 (20 nM), alone decelerated the rate of TBPS dissociation. Dissociation of TBPS was also initiated by dilution in the presence of various salts. Replacement of Cl- by Br- ions (0.5 molar) accelerated the rate of dissociation, whereas replacement of K+ by Na+ ions had no effect. This indicates the role of Eccles anions, not of cations, in TBPS binding and the possible involvement of the chloride inophore. A kinetic model is discussed for the allosteric modulation of TBPS binding by various GABAergic agents. Interconvertible populations of TBPS sites are proposed with rapid and slow kinetics. Model calculations involving modulation in the same direction of the on and off rates of binding can reproduce observed phenomena. The model predicts that GABA agonists, barbiturate and pyrazolopyridine depressants, as well as 1,4-benzodiazepine agonists, would allosterically increase the proportion of a rapid kinetic population of TBPS sites. In contrast, the model predicts that a decrease in the contribution of the rapid phase might be brought about by GABA antagonists and beta-carboline inverse agonists. The slow and rapid kinetic populations of TBPS sites might represent the closed and open states of the chloride ionophores, respectively.

Animals↗
PubMed2001

Characterisation of retention in micellar high-performance liquid chromatography, in micellar electrokinetic chromatography and in micellar electrokinetic chromatography with reduced flow.

The retention (migration) behaviour of various barbiturates, phenylurea and triazine herbicides in micellar electrokinetic chromatography (MEKC) with uncoated fused-silica capillaries was compared with the behaviour in micellar electrokinetic chromatography with reduced electroosmotic flow (RF-MEKC) using capillaries modified with linear polyacrylamide. The error in the values of the retention factors caused by the neglection of the contribution of the electroosmotic flow in RF-MEKC was investigated and a method for correcting this error was suggested. The retention was characterised using the lipophilic and polar indices to characterise and to predict the retention as a function of the concentration of the surfactant (sodium dodecylsulphate) in the running buffer in MEKC and in RF-MEKC. Homologous series of n-alkylbenzenes and of n-alkan-2-ones were compared as the standard sets for the calibration of the retention (migration) index scale. The values of the lipophilic indices of a given solute measured in reversed-phase HPLC, MEKC and RF-MEKC are close to each other. Under ideal MEKC conditions, the values of the polarity indices are close to one for various sample solutes. However, for partially ionised compounds such as weakly acidic barbiturates, where the contribution of the electrophoretic migration is significant, the values of the polarity indices are significantly lower than one. Optimum conditions for separations of mixtures of triazine and phenylurea herbicides and of barbiturates using various techniques tested were compared.

Chromatography, High Pressure Liquid↗