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PubMed1981

Calcium uptake mechanisms affected by some convulsant and anticonvulsant drugs.

An anticonvulsant (phenytoin) and a convulsant barbiturate (5-(2-cyclohexylidene ethyl)-5-ethyl-barbituric acid) (CHEB) reduced depolarization-coupled 45Ca uptake by synaptosomes from rat brain. CHEB reduced uptake to the level of undepolarized control samples. Phenobarbital failed to affect synaptosomal 45Ca uptake. Phenobarbital inhibited mitochondrial 45Ca uptake by 38%. CHEB was even more effective, lowering mitochondrial 45Ca uptake nearly to the levels induced by the mitochondrial inhibitors KCN, ruthenium red and dinitrophenol. Phenytoin, phenobarbital and CHEB did not affect ATP-dependent 45Ca uptake by the endoplasmic reticulum in lysed synaptosomes. In view of the effect of CHEB, a known convulsant, in limiting Ca uptake by depolarized synaptosomes, an effect which was greater than either that of phenytoin or phenobarbital, an identification of such a mechanism with anticonvulsant or sedative properties may be oversimplified.

Adenosine Triphosphate↗
PubMed2001

Solvent strength and selectivity on a porous graphitized carbon column separated by a spectral mapping technique using barbiturates as solutes.

A spectral mapping technique (SPM) was employed for separating the strength and selectivity of the retention of 41 barbituric acid derivatives and 5 organic modifiers on a porous graphitized carbon column (PGC). The potency values calculated by SPM were considered to be indicators of the capacity of drugs to bind to the surface of PGC and the capacity of organic modifiers to remove the drugs from the surface. The dimensionality of the multidimensional selectivity maps was reduced to two by a nonlinear mapping technique. Calculations indicated that molecular lipophilicity plays a negligible role in the strength and selectivity of retention, proving that the retention mechanism of PGC deviates from those of traditional reversed-phase stationary phases. Sterical and electronic parameters exerted the highest influence on the retention, emphasizing the importance of the polar interaction and the sterical correspondence between the surface of PGC and the solute molecules.

Algorithms↗
PubMed1983

Modulation of tumor promotion in liver carcinogenesis.

Earlier, we demonstrated that feeding to rats a diet devoid of choline, a lipotropic factor, markedly enhances hepatoma induction by several chemical carcinogens, and that the diet acts as a strong promoter of the evolution of initiated cells to foci of altered hepatocytes. The ability of several factors to modulate the action of the choline-devoid (CD) diet as a promoter was investigated by quantitating the foci of gamma-glutamyl transpeptidase-positive hepatocytes developed in rats exposed to a single injection of diethylnitrosamine. Addition to the diet of phenobarbital (PHB) resulted in a promoting action stronger than those of the CD diet or of PHB alone. Two other barbiturates, amobarbital (AMB) and pentobarbital (PTB) exerted an effect similar to that of PHB, while barbituric acid (BA) had no effect. In other studies, lowering the fat content of the CD diet reduced its efficacy as a promotor, while the addition of a hypolipidemic agent, BR931, 4-chloro-6-(2,3 xylidino)-2-pyrimidinylthio (N-beta-hydroxy-ethyl)acetamide, completely abolished the promoting action of the CD diet. In rats not exposed to carcinogen, feeding the CD diet caused a marked enhancement of liver DNA synthesis and of cell proliferation. Inclusion of PHB, PTB or AMB in the CD diet inhibited these effects, while BA exerted no inhibition. The increased rate of DNA synthesis and cell proliferation in the liver were not affected by the level of fat in the CD diet. These results suggest that beside a stimulation of liver cell proliferation, other factor(s) determine the efficacy with which a CD diet exerts its promoting action.

Animals↗
PubMed1998

Quantitative structure-pharmacokinetics relationships: II. A mechanistically based model to evaluate the relationship between tissue distribution parameters and compound lipophilicity.

The tissue-to-unbound plasma distribution coefficients (Kpus) of 14 rat tissues after i.v. administration of nine 5-n-alkyl-5-ethyl barbituric acids, determined in a previous study, were used to identify a model of the relationship between tissue distribution and lipophilicity of the homologs, expressed in terms of their octanol to water partition ratio, P. Based on mechanistic considerations and assumptions, the parameter model was expressed as Kpu tau = fw.tau [1 + a tau (nPt.tau)Pb tau], where fw.tau is the tissue water content. (nPt. tau) is the binding capacity of the tissue, n is the number of the binding sites, a tau and b tau are the parameters of the relationship Ka tau = a tau Pb tau; and Ka tau is the binding association constant of each tissue. The parameter model was linearized and fitted to the predetermined Kpu values, yielding correlation coefficients ranging between .940 and .997. The predictive performance of the parameter model was evaluated using a leave-one-out procedure with subsequent computation of the mean prediction error (ME = measurement of the prediction bias) and the square root of the mean squared prediction error (RMSE = measurement of the prediction accuracy). The ME varied between -22.48 and 61.14%, indicating a slight tendency for overpredicting. The RMSE was between 24.73 and 102% for the individual tissues across the different homologs; and between 28.33 and 85.2% for the individual homologs across the different tissues. The apparently high Kpu prediction errors, when translated through the low sensitivity of the barbiturate whole-body physiologically based pharmacokinetic model, established previously, leads to predicted tissue concentration-time profiles within 5 to 20% of the original ones. Therefore, it is concluded, that the identified mechanistically based model is a good predictor of the tissue-to-unbound Kpus in the rat tissues.

Animals↗
PubMed1987

An automated colorimetric assay for urine nicotine metabolites: a suitable alternative to cotinine assays for the assessment of smoking status.

We have modified the direct barbituric acid (DBA) test for urine nicotine metabolites so that it can be used on a continuous flow auto-analyser. The performance of the method was compared with a cotinine radio-immunoassay (RIA). The auto-analyser DBA method and cotinine RIA performed equally well in terms of assessing smoking status, yielding a false positive rate of 1.5% at a detection rate of 98% when compared to self-reported smoking information. The results obtained with the two methods were correlated, r = 0.91, although the DBA method results were consistently higher than the corresponding cotinine RIA results; the method detects cotinine and other nicotine metabolites. The coefficient of variation for the DBA method was 3.4% compared with 10% for the RIA. The DBA method has a throughput of about 250 samples per day compared to about 70 per day by RIA and the reagents are readily obtained and inexpensive.

Autoanalysis↗
PubMed1980

Effect of a membrane-stabilizing compound on calcium binding to the plasma membrane of Acanthamoeba castellanii.

Binding of calcium ions at the plasma membrane was studied in Acanthamoeba cells pretreated with ZIMET 3164, a benzimidazole nitrogen mustard derivative, which is known to show a potent immunosuppressive action combined with a membrane-stabilizing effect in mice. For reference, 2 compounds were applied: ZIMET 3393 (Cytostasan¿), another benzimidazole mustard derivative, which exerts only a moderate membrane effect and acts as a strong cytostatic, and ZIMET 176/68, a barbituric acid derivative, which acts as an inhibitor of humoral immune responses but without membrane-stabilizing effect. Application of any of the 3 compounds does not reduce the appearance of calcium binding sites, visualized by means of ultracytochemical reaction, notwithstanding their different action in the mammalian organism. On the contrary, it was estimated by morphometric analysis that the number of Ca-dependent deposits was augmented after treatment with low doses of any of the 3 compounds, what seems to be connected with the induced metabolic disturbances in low molecular phosphates level. High doses and/or prolongation of treatment of the cells resulted in diminution of the number of deposits and induces profound disturbances in cell ultrastructure, probably due to the toxic action of the applied doses. In these cases, band-like structures crosslinking the two leaflets of the plasma membrane may be observed; it is suggested that they represent integral membrane proteins.

Amoeba↗
PubMed2000

Apoptosis and cell proliferation in rat hepatocytes induced by barbiturates.

To examine the effect on cell population in hepatocytes of phenobarbital (PB) and other barbiturates, PB, allobarbital (ALB), barbital sodium (BS) and barbituric acid (BA) were given orally to male rats for 7 consecutive days. Although there was no apparent change in non-promoting BA, hepatomegaly was induced by PB, BS and ALB, which are promoters of hepatocarcinogenesis. In PB- and BS-treated livers, hepatomegaly was attributable to hepatocyte proliferation and enzyme induction. In ALB-treated liver, it was attributable to enzyme induction. The level of cell proliferation was reduced to less than the control values following withdrawal of PB, ALB and BS. It seemed that the degree of suppression of cell proliferation following withdrawal of these compounds correlated to the degree of cell proliferation (PB>BS>ALB) during treatment. In PB-treated liver, apoptosis was induced during treatment, serving to eliminate the excess of hepatocytes. This suggests that short-term administration of PB neither induced suppression of apoptosis nor disturbed homeostasis of hepatocyte populations.

Animals↗
PubMed1990

Liquid chromatographic measurement of hydrophobicity constants for N-arylsulfonylglycine aldose reductase inhibitors.

The hydrophobicity constants for a series of aldose reductase inhibitors (ARIs) are determined by reversed-phase liquid chromatography. A series of reference compounds consisting of 23 barbituric acid derivatives are separated on two phenylsilica stationary phases over a range of methanol concentrations (30-80%) in 0.05 M phosphate buffer. Linear regression analysis of the measured log k' data is used to estimate the capacity factor in 100% water (log k'w) for each compound. The log k'w values are regressed against the shake-flask-measured 1-octanol-water partition coefficients, producing a correlation of 0.953. The same procedure is then used to estimate the log k'w values for a large group of ARIs and their log P values, calculated from the established relationship between log k'w and log P from the reference compounds. An initial analysis of the aldose reductase inhibitory activity of these compounds as a function of hydrophobicity alone fails to reveal a clear relationship, demonstrating the need for a multivariant approach for quantitative structure-activity analysis in this series of compounds.

Aldehyde Reductase↗
PubMed1999

Empirical versus mechanistic modelling: comparison of an artificial neural network to a mechanistically based model for quantitative structure pharmacokinetic relationships of a homologous series of barbiturates.

The aim of the current study was to compare the predictive performance of a mechanistically based model and an empirical artificial neural network (ANN) model to describe the relationship between the tissue-to-unbound plasma concentration ratios (Kpu's) of 14 rat tissues and the lipophilicity (LogP) of a series of nine 5-n-alkyl-5-ethyl barbituric acids. The mechanistic model comprised the water content, binding capacity, number of the binding sites, and binding association constant of each tissue. A backpropagation ANN with 2 hidden layers (33 neurons in the first layer, 9 neurons in the second) was used for the comparison. The network was trained by an algorithm with adaptive momentum and learning rate, programmed using the ANN Toolbox of MATLAB. The predictive performance of both models was evaluated using a leave-one-out procedure and computation of both the mean prediction error (ME, showing the prediction bias) and the mean squared prediction error (MSE, showing the prediction accuracy). The ME of the mechanistic model was 18% (range, 20 to 57%), indicating a tendency for overprediction; the MSE is 32% (range, 6 to 104%). The ANN had almost no bias: the ME was 2% (range, 36 to 64%) and had greater precision than the mechanistic model, MSE 18% (range, 4 to 70%). Generally, neither model appeared to be a significantly better predictor of the Kpu's in the rat.

Algorithms↗
PubMed2002

Cytokine modulation and suppression of liver injury by a novel analogue of thalidomide.

Thalidomide has been shown to reduce the production of tumor necrosis factor-alpha (TNF-alpha), a cytokine with deleterious pathophysiologic effects in various diseases. In search of thalidomide analogues with improved TNF-alpha inhibiting properties, 5-ethyl-1-phenyl-5-(3,4,5,6-tetrafluorophthalimido)barbituric acid (TFBA) was found to be superior to thalidomide. Besides TNF-alpha, TFBA also suppressed interleukin-6 and interleukin-10 production of isolated monocytes. The possibility that TFBA exerts its action by increasing levels of cAMP via inhibition of phosphodiesterase-4 activity was excluded. TFBA had no influence on T cell proliferation; neither did it inhibit TNF-alpha production in peripheral blood mononuclear cells stimulated by anti-CD3 monoclonal antibody. When applied to mice treated with D-galactosamine and lipopolysaccharide, TFBA prevented a rise in serum TNF-alpha, had no effect on interleukin-6 levels and led to an increase in interleukin-10 production. The changes in cytokine production observed in vitro and in vivo were reflected by similar changes in the mRNA expression. Moreover, TFBA significantly reduced liver transaminase levels in D-galactosamine/lipopolysaccharide-treated mice and thus efficiently protected the animals from liver injury. Thus, according to its properties, TFBA has the potential of modulating an immune response by acting as an anti-inflammatory agent.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

The effects of lattice water on free radical yields in X-irradiated crystalline pyrimidines and purines: a low-temperature electron paramagnetic resonance investigation.

The hydration layer of DNA increases the target size of DNA with respect to the formation of direct-type damage by ionizing radiation. The mechanisms that give rise to this increase are being investigated by EPR spectroscopy. To determine these mechanisms, it is necessary to distinguish between the change in sample mass and changes in packing/conformation brought about by the change in the level of hydration. Certain model compounds that crystallize as hydrates provide a system where the effects of mass and packing can be discerned. Three such hydrate crystals were used in this work: barbituric acid dihydrate (BA:2H2O), inosine dihydrate (IR:2H2O) and thymine monohydrate (T:H2O). The free radical yields (+/-25%) in the native crystals at 7-11 K are 0.08, 0.03 and 0.02, respectively. Removal of the lattice water leaves behind an ordered lattice and results in free radical yields of 0.08, 0.03 and < 0.004, respectively. Thus removal of the lattice water does not affect the free radical yield in BA:2H2O or IR:2H2O but decreases the free radical yield in T:H2O by an order of magnitude. Based on these observations and the known crystal packing, we conclude that the hydrogen bonding network is a major factor in determining the distribution and yield of trapped free radicals. We ascribe this to the importance of proton transfer processes which act to reduce the probability of radical combination. Consistent with this conclusion are the types of free radicals trapped in these crystalline materials before and after dehydration. From these results, we argue that a major determinant of free radical yields in solidstate samples of DNA constituents is molecular packing. In addition, the absence of HO. radicals trapped in single crystals of BA:2H2O provides an upper limit for the yield of trapped HO. of less than 10(-4) mumol/J. This supports the thesis that at < 77 K direct ionization of those waters associated directly with a pyrimidine or purine results in hole transfer to that molecule. Hydroxyl radical formation on a water adjacent to a DNA base is predicted to be negligible.

Barbiturates↗
PubMed1972

Metabolism of amylobarbitone in patients with chronic liver disease.

1. A single dose of amylobarbitone (3.23 mg/kg) was given by intravenous injection to each of ten healthy controls and two groups of five patients with chronic liver disease. A curve of serum amylobarbitone concentration against time was prepared for each subject and the proportion of the serum amylobarbitone bound to protein determined. The urinary excretion of the metabolite hydroxyamylobarbitone, ethyl (3 hydroxyisoamyl) barbituric acid was measured.2. The degree of protein binding of serum amylobarbitone was reduced in the five patients (group I) with abnormally low concentrations of albumin in serum (<3.5 g/100 ml) but was normal in the five patients (group II) with normal serum albumin concentrations (>3.5 g/100 ml).3. The equation for a double exponential decay was fitted to the concentration/time curves for amylobarbitone free in the serum water. The mean intercepts and rate constants were used to calculate the dimensions of mathematical models based on a two compartment open system.4. The five patients (group I) who had abnormally low concentrations of albumin in serum showed impairment of amylobarbitone metabolism; the rate constant beta(h(-1)) for the second exponential decay of serum amylobarbitone concentration was reduced (P<0.01), the urinary excretion of hydroxyamylobarbitone was reduced (P<0.001) and the mean serum water clearance (C, ml/min) representing amylobarbitone elimination by metabolism was reduced.5. The five patients (group II) who had normal concentrations of albumin in serum showed no impairment of amylobarbitone metabolism. Within the total patient group there were strong and significant positive correlations between the serum albumin concentration and each of the indices of the rate of amylobarbitone metabolism.6. Both patient groups showed an increase in the first dispositional rate constant alpha(h(-1)) and in the clearance (C(t) ml/min) representing transfer between central and peripheral compartments. The physiological basis for this observation is uncertain.7. The clinical response to the single intravenous dose of amylobarbitone was not significantly greater (P=0.11) in the patient group (I) with slow amylobarbitone metabolism than in the patient group (II) with a normal rate of amylobarbitone metabolism.

Adult↗
PubMed1976

Pharmacokinetics and relative bioavailability of vinylbital in man after oral and rectal administration.

A sensitive and specific method for the quantitative determination of 5-vinyl-5-(1-methylbutyl)-barbituric acid (vinylbital) in plasma was developed, by using gas chromatography with alkali flame ionization detection. The method is suitable for measuring vinylbital plasma levels in man after administration of therapeutic doses. The pharmacokinetics and relative bioavailability of vinylbital after oral and rectal administration were studied in man. Tablets (Bykonox) containing 150 mg vinylbital, were used for the oral experiments and suppositories (Suppoptanox, polyethylene glycol base) containing 200 mg vinylbital, were used for rectal administration. Six volunteers participated in a cross-over way in the study. Vinylbital plasma concentrations were determined at regular intervals after drug administration. Absorption and elimination of vinylbital appeared to occur according to a single first-order process and the plasma concentrations were fitted by computer according to the equation intrinsic to the one-compartment open model after oral or rectal administration. The lag time was shorter for the suppository than for the tablet, whereas the absorption rate was faster for the tablet (mean absorption half-life 0.24 h compared with 0.64 h for the suppository). The elimination half-life of vinylbital varied from 17.6 to 33.5 h, with a mean value of 23.5 h for oral administration and 23.8 h for rectal administration. The half-lives were not considerably different on the two occasions for the individual volunteers. The average bioavailability of vinylbital for the suppository, relative to the tablet, was approximately 93%. Three volunteers collected their urine during 3--4 days after administration of a tablet. Unchanged vinylbital was determined and approximately 1.6% of the administered dose was excreted as unchanged drug. Some preliminary experiments of repetive vinylbital administration showed that self-induction of metabolism did not occur.

Administration, Oral↗
PubMed1996

Quantitating direct chlorine transfer from enzyme to substrate in chloroperoxidase-catalyzed reactions.

Substrate competition methods that were previously used to quantitate the involvement of free Cl2 in the chloride-dependent peroxidatic reactions catalyzed by chloroperoxidase (CPO) (Libby, R. D., Shedd, A. L., Phipps, K. A., Beachy, T. M., and Gerstberger, S. M., (1992) J. Biol. Chem. 267, 1769-1775) are extended to CPO-catalyzed halogenation reactions. Relative substrate specificities of halogen acceptor substrates (RHs) antipyrine (ap), NADH, 2-chlorodimedone (2cd), and barbituric acid (ba) are compared with previously studied peroxidatic substrates catechol (cat) and 2, 4,6-trimethylphenol (tmp) in their reactions with the CPO-H2O2-Cl system versus the hypochlorite-Cl system. Studies were carried out at pH 2.75 over a chloride concentration range of 1-100 mM and at pH 4.80 over a chloride concentration range of 100-400 mM. Competition studies involved successive pairwise comparisons of substrates of increasing enzyme specificity. The orders of specificities, ba > 2cd > ap > cat > tmp at pH 2.75 and ba > 2cd > NADH > ap > cat > tmp at pH 4.80, are the same for both the CPO-H2O2-Cl and hypochlorite-Cl systems. However, the magnitudes of the specificities are different between the two systems. In all comparisons except ap versus cat, the specificity of the CPO-H2O2-Cl system toward the preferred substrate is higher than that of the hypochlorite-Cl system. Quantitative comparisons between specificities of CPO-H2O2-Cl and hypochlorite-Cl systems indicate that at least 98% of the CPO-catalyzed halogenation reactions of ba, 2cd, NADH, and ap occur by mechanisms in which the substrate reacts directly with the enzyme. Thus, less than 2% of any of the CPO reactions could possibly involve a free oxidized halogen intermediate. All data are consistent with a mechanism in which RH binds to the CPO chlorinating intermediate (EOCl), and the chlorine atom is transferred directly from EOCl to RH. Further, the results indicate that any halogenation substrate with a higher CPO specificity than ap must also undergo direct chlorine transfer from the enzyme. These results underscore the critical need for quantitative kinetic evidence in establishing the extent of involvement of any potential reaction intermediate. Finally, this work calls into question the long held assumption of the obligatory involvement of hypochlorite as an intermediate in myeloperoxidase reactions. It supports the recent kinetic evidence presented by Marquet and Dunford for direct chlorine transfer in myeloperoxidase-catalyzed chlorination of tuarine (Marquet, L. A., and Dunford, H. B. (1994) J. Biol. Chem. 269, 7950-7956).

Antipyrine↗
PubMed1995

Electrophysiological and metabolic effects of a convulsant barbiturate on dissociated mouse primary sensory neurons.

1. The convulsant barbiturate 5-(2-cyclohexylidene-ethyl)-5-ethyl barbituric acid (CHEB) depolarizes dorsal root ganglion (DRG) neurons. We have applied microfluorimetric and whole-cell patch clamp techniques to investigate the mechanisms underlying this response in freshly dissociated mouse DRG cells. 2. Application of CHEB (2-200 microM) raised cytosolic calcium concentration ([Ca2+]i) rapidly and reversibly in 55% of eighty-three neurons tested. This population did not correlate with other classifications of sensory neurons based on either cell size or the expression of membrane currents. 3. The response was dependent on external calcium and was reduced by 81 +/- 22% by Ruthenium Red. A rise in [Ca2+]i was still seen with the membrane potential clamped at -70 mV, excluding membrane depolarization and activation of voltage-dependent Ca2+ channels as the principal mechanism for the response. 4. The rise in [Ca2+]i was associated with an increase in membrane conductance and a current, ICHEB, which was inward at -70 mV. Both the rise in [Ca2+]i and the current showed 'run-down' under whole-cell recording conditions. When K+ conductances were blocked, the reversal potential of ICHEB was close to 0 mV. This was independent of the Cl- reversal potential, suggesting that ICHEB is carried as a non-specific cation current. 5. In contrast to the change in [Ca2+]i, ICHEB was not dependent on external Ca2+ and the current was still seen when [Ca2+]i as strongly buffered by the pipette filling solution. These data suggest that CHEB opens a non-selective cation channel permeant to Ca2+, raising [Ca2+]i and further depolarizing the cell membrane potential. The exact nature of this conductance remains unknown. These actions could readily account for the convulsant actions of the drug, depolarizing neurons and increasing transmitter release. 6. It was also noted that CHEB increases autofluorescence derived from mitochondrial NAD(P)H. Further examination of this phenomenon using the dye rhodamine 123 to follow changes in mitochondrial potential (psi m) suggested that CHEB is a potent inhibitor of mitochondrial respiration, probably acting at complex I. These effects appeared to be quite distinct from the action of CHEB at the level of the plasma membrane.

Animals↗
PubMed1997

Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat: a sensitivity analysis.

Sensitivity analysis studies the effects of the inherent variability and uncertainty in model parameters on the model outputs and may be a useful tool at all stages of the pharmacokinetic modeling process. The present study examined the sensitivity of a whole-body physiologically based pharmacokinetic (PBPK) model for 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) after i.v. bolus administration to rats. The aims were to obtain new insights into the model used, to rank the model parameters involved according to their impact on the model outputs and to study the changes in the sensitivity induced by the increase in the lipophilicity of the homologues on ascending the series. Two approaches for sensitivity analysis have been implemented. The first, based on the Matrix Perturbation Theory, uses a sensitivity index defined as the normalized sensitivity of the 2-norm of the model compartmental matrix to perturbations in its entries. The second approach uses the traditional definition of the normalized sensitivity function as the relative change in a model state (a tissue concentration) corresponding to a relative change in a model parameter. Autosensitivity has been defined as sensitivity of a state to any of its parameters; cross-sensitivity as the sensitivity of a state to any other states' parameters. Using the two approaches, the sensitivity of representative tissue concentrations (lung, liver, kidney, stomach, gut, adipose, heart, and brain) to the following model parameters: tissue-to-unbound plasma partition coefficients, tissue blood flows, unbound renal and intrinsic hepatic clearance, permeability surface area product of the brain, have been analyzed. Both the tissues and the parameters were ranked according to their sensitivity and impact. The following general conclusions were drawn: (i) the overall sensitivity of the system to all parameters involved is small due to the weak connectivity of the system structure; (ii) the time course of both the auto- and cross-sensitivity functions for all tissues depends on the dynamics of the tissues themselves, e.g., the higher the perfusion of a tissue, the higher are both its cross-sensitivity to other tissues' parameters and the cross-sensitivities of other tissues to its parameters; and (iii) with a few exceptions, there is not a marked influence of the lipophilicity of the homologues on either the pattern or the values of the sensitivity functions. The estimates of the sensitivity and the subsequent tissue and parameter rankings may be extended to other drugs, sharing the same common structure of the whole body PBPK model, and having similar model parameters. Results show also that the computationally simple Matrix Perturbation Analysis should be used only when an initial idea about the sensitivity of a system is required. If comprehensive information regarding the sensitivity is needed, the numerically expensive Direct Sensitivity Analysis should be used.

Animals↗
PubMed1981

Adverse effects of phenobarbital on morphological and biochemical development of fetal mouse spinal cord neurons in culture.

The effects of chronic phenobarbital treatment on neuronal development were assessed in cell cultures of fetal rodent spinal cord. The activity of the principal enzyme involved in acetylcholine synthesis, choline acetyltransferase (CAT), and counts of large spinal cord neurons were used as indicators of neuronal development Phenobarbital (30 to 120 micrograms/ml) added to cultures for two- or six-week periods produced dose-dependent decreases in both CAT activity and neurons counts. Barbituric acid at doses equimolar to those at which phenobarbital produced these decreases had no effect.

Acetylcholine↗
PubMed1988

Effects of chronic phenobarbital exposure on cultured mouse spinal cord neurons.

The anticonvulsant phenobarbital (PB), at concentrations of 20, 40, and 90 micrograms/ml, was chronically applied to cell cultures of mouse spinal cord from day 2 or day 14 after initial plating, and the effects of this exposure on neuronal density and morphological characteristics were determined. Neuronal morphological characteristics were analyzed quantitatively following intracellular injection of the fluorescent dye Lucifer yellow. Cultures exposed to PB for 6 weeks, from day 14 after plating, showed concentration-dependent reductions in neuronal density; both large and small neurons were equally affected. PB exposure also reduced dendritic branching frequency, and the length of dendrites, of remaining large neurons. A higher percentage of these neurons had a bipolar branching pattern than was normally the case. Neurons in cultures exposed to PB from day 2 after plating, compared with those exposed from day 14, showed significantly less alteration in terms of density and morphological characteristics. Effects on neuronal morphological characteristics increased with duration of drug exposure. Equimolar concentrations of barbituric acid produced effects similar to those produced by PB. Chronic exposure to PB adversely affects survival and morphological characteristics of mammalian central neurons grown in cell culture. Curiously, exposure from the time of initial plating appears to be less deleterious than exposure initiated 2 weeks later. To the extent that neuronal development in vitro can be compared to the situation in vivo, these results, and those of other investigators, raise concerns about long-term exposure of the developing human nervous system to PB.

Animals↗