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PubMed1974

Interaction of Escherichia coli 30S ribosomal subunits with MS2 phage RNA in the absence of initiation factors.

MS2 RNA binds at 0 degrees to 30S subunits from E. coli and, to a smaller extent, to those of a Pseudomonas species, as judged by filtration on nitrocellulose membranes; this mRNA does not bind to 30S subunits from Bacillus brevis or Caulobacter crescentus. Binding does not depend on the presence of initiation factors; it is sensitive to aurintricarboxylic acid but insensitive to edeine and is competitive with such synthetic polynucleotides as poly(U) and poly(AUG). Complex formation can also be detected by electrophoresis on polyacrylamide-agarose gels. By this procedure, E. coli 30S subunits are separated into two major components. Only the more slowly moving component, which contains the ribosomal protein S1, interacts with the RNA.

Anti-Bacterial Agents↗
PubMed2003

Brain uptake of the acid metabolites of F-18-labeled WAY 100635 analogs.

The 5-HT1A ligands [ 18F]FPWAY and [ 18F]FCWAY are metabolized to [ 18F]fluorobenzoic acid (FB) and [ 18F]fluorocyclohexanecarboxylic acid (FC), respectively. To quantify the penetration of these acids into the brain, dynamic positron emission tomography studies were performed in rhesus monkeys with [ 18F]FB and [ 18F]FC. High-performance liquid chromatography analysis of arterial blood samples showed no metabolites for [ 18F]FB, whereas [ 18F]FC was rapidly metabolized to [ 18F]fluoride. A model with one tissue compartment and vascular radioactivity was used to analyze gray matter time-activity curves. For [ 18F]FC, an additional term was added to account for [ 18F]fluoride skull spillover into the brain; this term accounted for 70% to 90% of the measured radioactivity concentration at 90 minutes. For [ 18F]FB, mean gray matter parameters were as follows: K1, 10 +/- 3 micro L. min(-1). mL(-1); distribution volume, 0.052 +/- 0.006 (mL/mL). For [ 18F]FC, the values were as follows: K1, 15 +/- 4 micro L. min(-1). mL(-1); V, 0.29 +/- 0.06 mL/mL. The values were consistent with a physiologic model that included brain-to-blood pH difference and the plasma free fraction of the acid. Simulations based on [ 18F]FCWAY human data showed that [ 18F]FC uptake produces significant biases in estimates in regions with low specific binding. These results can be used to correct the tissue [ 18F]FCWAY time-activity data for brain uptake of [ 18F]FC using the measured [ 18F]FC input function.

Animals↗
PubMed1989

Regulation of the gamma-aminobutyric acidA receptor by gamma-aminobutyric acid levels within the postsynaptic cell.

Synaptosomes and synaptoneurosomes were prepared from rat cerebral cortex. Comparison of the amino acid levels in the two types of organelles and of the effects of gabaculine thereon indicated that the neurosome portion of synaptoneurosomes constituted the major influencing component of the organelles. Administration to rats of inhibitors of gamma-aminobutyric acid (GABA) degradation, such as gabaculine and L-cycloserine, resulted in elevated GABA levels in synaptoneurosomes and a decrease in muscimol-stimulated Cl- up-take by the organelles. Addition of gabaculine directly to the incubation medium for the uptake assay had no effect on the Cl- transport. In contrast, administration to rats of isonicotinic acid hydrazide, an inhibitor of GABA synthesis, decreased the GABA level in synaptoneurosomes and increased the muscimol-stimulated Cl- uptake by the organelles. Although the evidence is not unequivocal, it does support the concept of GABA released from nerve endings being taken up by the postsynaptic cell, from where it exerts a regulatory influence on the functioning of the GABA receptor/ion channel complex.

Animals↗
PubMed2006

Pregabalin exerts oppositional effects on different inhibitory circuits in human motor cortex: a double-blind, placebo-controlled transcranial magnetic stimulation study.

PURPOSE: To explore acute effects of pregabalin (PGB) on human motor cortex excitability with transcranial magnetic stimulation (TMS). METHODS: PGB, 600 mg/day, was orally administered in 19 healthy subjects twice daily in a randomized, double-blind, placebo-controlled crossover design. Several measures of motor cortex excitability were tested with single- and paired-pulse TMS. RESULTS: Mean short-interval intracortical inhibition (SICI) was reduced after PGB (74 +/- 7% of unconditioned response) compared with placebo (60 +/- 6% of unconditioned response). In contrast, mean long-interval intracortical inhibition (LICI) was increased by PGB (26 +/- 4% of unconditioned response) compared with placebo (45 +/- 8% of unconditioned response), and mean cortical silent period (CSP) showed an increase from 139 +/- 8 ms or 145 +/- 8 ms after placebo to 162 +/- 7 ms or 161 +/- 10 ms after PGB. Motor thresholds, intracortical facilitation, and corticospinal excitability were unaffected. CONCLUSIONS: The observed excitability changes with oppositional effects on SICI and LICI or CSP suggest gamma-aminobutyric acid (GABA)B-receptor activation. They are markedly distinct from those induced by gabapentin, although both PGB and gabapentin are thought to mediate their function by binding to the alpha2-delta subunit of voltage-gated calcium channels. Conversely, the TMS profile of PGB shows striking similarities with the pattern evoked by the GABA-reuptake inhibitor tiagabine.

Adult↗
PubMed2000

Upregulation of hepatic glucose 6-phosphatase gene expression in rats treated with an inhibitor of glucose-6-phosphate translocase.

The multicomponent hepatic glucose 6-phosphatase (Glc-6-Pase) system catalyzes the terminal step of hepatic glucose production and plays a key role in the regulation of blood glucose. We used the chlorogenic acid derivative S 3483, a reversible inhibitor of the glucose-6-phosphate (Glc-6-P) translocase component, to demonstrate for the first time upregulation of Glc-6-Pase expression in rat liver in vivo after inhibition of Glc-6-P translocase. In accordance with its mode of action, S 3483-treatment of overnight-fasted rats induced hypoglycemia and increased blood lactate, hepatic Glc-6-P, and glycogen. The metabolic changes were accompanied by rapid and marked increases in Glc-6-Pase mRNA (above 35-fold), protein (about 2-fold), and enzymatic activity (about 2-fold). Maximal mRNA levels were reached after 4 h of treatment. Glycemia, blood lactate, and Glc-6-Pase mRNA levels returned to control values, whereas Glc-6-P and glycogen levels decreased but were still elevated 2 h after S 3483 withdrawal. The capacity for Glc-6-P influx was only marginally increased after 8.5 h of treatment. Prevention of hypoglycemia by euglycemic clamp did not abolish the increase in Glc-6-Pase mRNA induced by S 3483 treatment. A similar pattern of hypoglycemia and possibly of associated counterregulatory responses elicited by treatment with the phosphoenolpyruvate carboxykinase inhibitor 3-mercaptopicolinic acid could account for only a 2-fold induction of Glc-6-Pase mRNA. These findings suggest that the significant upregulation of Glc-6-Pase gene expression observed after treatment of rats in vivo with an inhibitor of Glc-6-P translocase is caused predominantly either by S 3483 per se or by the compound-induced changes of intracellular carbohydrate metabolism.

Animals↗
PubMed2006

New antiepileptic drugs that are second generation to existing antiepileptic drugs.

In the last decade, 10 new antiepileptic drugs (AEDs) have been introduced that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug interactions. However, despite the large therapeutic range of old and new AEDs, approximately 30% of the patients with epilepsy are still not seizure free and, consequently, there is a substantial need to develop new AEDs. The new AEDs currently in development can be divided into two categories: drugs with completely new chemical structures such as lacosamide (formally harkoseride), retigabine, rufinamide and talampanel; and drugs that are derivatives or analogues of existing AEDs that can be regarded as second-generation or follow-up compounds of established AEDs. This article focuses on the second category and thus critically reviews the following second-generation compounds: eslicarbazepine acetate or BIA-2-093 and 10-hydroxy carbazepine (carbamazepine derivatives); valrocemide and NPS 1776 (isovaleramide; valproic acid derivatives); pregabalin and XP13512 (gabapentin derivatives); brivaracetam (ucb 34714) and seletracetam (ucb 44212; levetiracetam derivatives); and fluorofelbamate (a felbamate derivative). In addition, a series of valproic acid derivatives that are currently in preclinical stage has also been evaluated because some lead compounds of this series have a promising potential to become new antiepileptics and CNS drugs. For any of these follow-up compounds to become a successful second generation to an existing AED, it has to be more potent, safer and possess favourable pharmacokinetics, including low potential for pharmacokinetic and pharmacodynamic drug interactions.

Amines↗
PubMed1997

Endogenous synthesis of arginine plays an important role in maintaining arginine homeostasis in postweaning growing pigs.

This study was conducted to determine whether endogenous synthesis of arginine plays a role in regulating arginine homeostasis in postweaning pigs. Pigs were fed a sorghum-based diet containing 0. 98% arginine and were used for studies at 75 d of age (28.4 kg body weight). Mitochondria were prepared from the jejunum and other major tissues for measuring the activities of Delta1-pyrroline-5-carboxylate (P5C) synthase and proline oxidase (enzymes catalyzing P5C synthesis from glutamate and proline, respectively) and of ornithine aminotransferase (OAT) (the enzyme catalyzing the interconversion of P5C into ornithine). For metabolic studies, jejunal enterocytes were incubated at 37 degrees C for 30 min in Krebs-Henseleit bicarbonate buffer containing 2 mmol/L L-glutamine, 2 mmol/L L-[U-14C]proline, and 0-200 micromol/L gabaculine (an inhibitor of OAT). The activities of P5C synthase, proline oxidase and OAT were greatest in enterocytes among all of the tissues studied. Incubation of enterocytes with gabaculine resulted in decreases (P < 0.05) in the synthesis of ornithine and citrulline from glutamine and proline. When gabaculine was orally administered to pigs (0.83 mg/kg body weight) to inhibit intestinal synthesis of citrulline from glutamine and proline, plasma concentrations of citrulline (-26%) and arginine (-22%) decreased (P < 0.05), whereas those of alanine (+21%), ornithine (+17%), proline (+107%), taurine (+56%) and branched-chain amino acids (+21-40%) increased (P < 0.05). On the basis of dietary arginine intake and estimated arginine utilization, the endogenous synthesis of arginine in the 28-kg pig provided >/=50.2% of total daily arginine requirement. Taken together, our results suggest an important role for endogenous synthesis of arginine in regulating arginine homeostasis in postweaning growing pigs, as previously shown in neonatal pigs.

Animals↗
PubMed1972

Inhibition of tryptophan synthetase by indoleacrylic acid.

Indoleacrylic acid (5 x 10(-4)m in the growth medium) inhibits the growth of mycelia of Neurospora crassa and causes the cells to accumulate indoleglycerol phosphate. Measurement of kinetic parameters of partially purified tryptophan synthetase in the presence of indoleacrylic acid showed the following patterns of inhibition: in Reaction 1, the physiological reaction, indoleglycerol phosphate + serine [Formula: see text] tryptophan + glyceraldehyde-3-phosphate (unusual with respect to indoleglycerol phosphate, partially competitive with respect to serine); in Reaction 2, indole + serine [Formula: see text] tryptophan (unusual with respect to indole, partially competitive with respect to serine); in Reaction 3, indoleglycerol phosphate [Formula: see text] indole + glyceraldehyde-3-phosphate (no inhibition observed). The effects of indoleacrylic acid on whole cells were completely reversed by equimolar concentrations of tryptophan but not by indole. The addition of a 10-fold molar excess of serine to the medium completely reversed the effects. The accumulation of indoleglycerol phosphate appears to be the result of the partial blockage of tryptophan synthetase, the resulting deprivation of tryptophan, and the consequent release of its physiological feedback control on anthranilate synthetase.

Acrylates↗
PubMed2005

Pharmacokinetics of gabapentin during delivery, in the neonatal period, and lactation: does a fetal accumulation occur during pregnancy?

PURPOSE: To study the pharmacokinetics of gabapentin (GBP) during delivery, lactation, and in the neonatal period. METHODS: GBP concentrations in plasma and breast milk were determined with high-performance liquid chromatography in samples from six women treated with GBP and in their offspring. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from the newborns on three occasions during 2 days after delivery. GBP concentration also was determined in breast milk and in blood collected from five of the mothers and suckling infants 2 weeks to 3 months after birth. RESULTS: The umbilical cord/maternal plasma concentration ratios ranged from 1.3 to 2.1 (mean, 1.7). GBP plasma concentrations in the neonates declined with an estimated half-life of 14 h. Mean GBP plasma concentrations in the infants were 27% of the cord plasma levels (range, 12-36%) 24 h postpartum. The mean milk/maternal plasma concentration ratio was 1.0 (range, 0.7-1.3) from 2 weeks to 3 months. The infant dose of GBP was estimated to 0.2-1.3 mg/kg/day, equivalent to 1.3-3.8% of the weight-normalized dose received by the mother. The plasma concentrations in the breast-fed infants were approximately 12% of the mother's plasma levels, but no adverse effects were observed. CONCLUSIONS: Our limited observations suggest an active transplacental transport of GBP, with accumulation in the fetus as a consequence. We suggest that this could be by the specific L-type amino acid transporter 1 (LAT-1), which is expressed in the placenta. Newborns seem to have a slightly lower capacity to eliminate GBP than do adults. Transfer of GBP to breast milk is extensive, but plasma concentrations appear to be low in suckling infants. No adverse effects were observed in the newborn. Although more data are needed, our observations suggest that breastfeeding in conjunction with GBP treatment is safe.

Amines↗
PubMed1993

Comparative pharmacokinetics of the newer antiepileptic drugs.

During the past few years a major increase has taken place in the number of drugs which have become available in the antiepileptic arsenal. In fact, 3 new antiepileptic drugs, vigabatrin, oxcarbazepine and lamotrigine, were recently approved in several European countries. Two other drugs, felbamate and gabapentin, are expected to be approved in the US in the near future. This review comparatively evaluates the pharmacokinetics of the following 10 new antiepileptic drugs: felbamate, flunarizine, gabapentin, lamotrigine, oxcarbazepine, remacemide, stiripentol, tiagabine, topiramate and vigabatrin. Three of the new drugs, gabapentin, topiramate and vigabatrin, are more promising on the basis of their pharmacokinetic features. They are well absorbed, excreted mainly unchanged in the urine, and are not susceptible to enzyme induction or inhibition. Their drug interaction potential appears to be minimal. About 50% of felbamate is excreted unchanged, with the rest eliminated by metabolism. The remaining drugs are eliminated by metabolic processes such as glucuronidation (lamotrigine), deglycine formation (remacemide) or oxidative metabolism (flunarizine and stiripentol). Oxcarbazepine and remacemide have high hepatic clearance and are biotransformed to hydroxy and deglycine metabolites, respectively, with the activity of their metabolites contributing to the antiepileptic activity of the parent drug after oral administration, despite high first-pass effect metabolism. Gabapentin and oxcarbazepine do not behave pharmacokinetically as their original design intended. Gabapentin is not effective as a chemical drug delivery system for gamma-aminobutyric acid (GABA), and oxcarbazepine serves as a prodrug to its hydroxy metabolite, but does not act as a drug on its own. Nevertheless, these 2 agents demonstrate efficacy in extensive preclinical and clinical trials. Although the pharmacokinetics features of these drugs are important, these features are secondary to their pharmacodynamic properties--i.e. to the requirement that new antiepileptic drugs have to have proven clinical efficacy and safety in epileptic patients.

Acetamides↗
PubMed1988

Structure of D-prephenyllactate. A carboxycyclohexadienyl metabolite from Neurospora crassa.

A novel natural product structurally related to prephenate and arogenate was isolated from a mutant of Neurospora crassa. This D-beta-(1-carboxy-4-hydroxy-2,5-cyclohexadiene-1-yl)-lactic acid is herein given the trivial name of D-prephenyllactate. The new metabolite is even more acid labile than is prephenate and is quantitatively converted to phenyllactate at mildly acidic pH. The structure characterization of prephenyllactate was performed using spectroscopic techniques (ultraviolet, 1H NMR, 13C NMR, two-dimensional heteronuclear experiments and mass spectrometry). Circular dichroism proved conclusively the R configuration of the asymmetric carbon at C-8 of prephenyllactate. Enzymatic utilization of prephenyllactate by cyclohexadienyl dehydratase and by cyclohexadienyl dehydrogenase from Klebsiella pneumoniae was demonstrated.

Chromatography, High Pressure Liquid↗
PubMed1977

Acute gastrointestinal haemorrhage. Experience with early panendoscopy and tranexamic acid in a rural hospital.

One hundred and fifty-nine consecutive patients admitted to a small rural hospital because of acute gastrointestinal haemorrhage were studied. Patients with haematemesis and/or melaena were treated with antacids and tranexamic acid from the very beginning and were examined by means of early panendoscopy. All patients were closely observed on a general medical ward by a staff especially trained to deal with acute gastrointestinal bleeding. Eight patients required acute surgery. The overall mortality rate was 4.4%. It is concluded that acute gastrointestinal haemorrhage can be successfully handled with modern diagnosis and treatment even in a small hospital.

Acute Disease↗
PubMed1985

Use of cloned genes of Pseudomonas TOL plasmid to effect biotransformation of benzoates to cis-dihydrodiols and catechols by Escherichia coli cells.

DNA fragments containing the xylD and xylL genes, which specify the broad-specificity enzymes toluate-1,2-dioxygenase and 3,5-cyclohexadiene-1,2-diol-1-carboxylic acid dehydrogenase, respectively, of TOL plasmid pWW0-161 of Pseudomonas putida have previously been cloned in the pBR322 vector plasmid (P.R. Lehrbach, J. Zeyer, W. Reinecke, H.-J. Knackmuss, and K. N. Timmis, J. Bacteriol. 158:1025-1032, 1984). In this study, Escherichia coli cells containing hybrid plasmids carrying the cloned xylD or xylDL genes quantitatively transformed 14C-ring- and 14C-carboxy-labeled benzoate to the pathway intermediates 3,5-cyclohexadiene-1,2-diol-1-carboxylic acid (cis-dihydrodiol) and catechol, respectively. Like P. putida cells, E. coli cells containing the xylD gene transformed a variety of chloro- and hydrocarbon-substituted benzoates. The toluate-1,2-dioxygenase produced in E. coli thus exhibited the broad-substrate-specificity properties of the enzyme in P. putida. Turnover rates by the enzymes in these two bacteria are compared.

Benzoates↗
PubMed1979

[Morphological differentiation of neuroblastoma by 1 methyl cyclohexane carboxylic acid (CCA) and some C1 derivatives].

We describe the induction of neuroblastoma morphological differentiation by 1 methyl cyclohexane carboxylic acid (CCA) and by some C1 derivatives of CCA. This induction proceeds in a medium which allows, in the absence of inducer, a normal growth of neuroblastoma cells and contains 7.5% fetal Calf serum. In order to establish a clear-dose response relationship and to compare the relative potencies of different drugs, the morphological changes were assessed by examining "long neurite-bearing cells".

Animals↗
PubMed2006

Determination of gabapentin in human plasma and urine by high-performance liquid chromatography with UV-vis detection.

A simple and reliable high-performance liquid chromatographic (HPLC) method with UV-vis detection has been developed and validated for the determination of gabapentin (GBP) in human plasma and urine. The clean up of the sample was carried out by solid-phase extraction with C18-cartridge. After the clean up procedure, the samples were pre-column derivatizated with 1,2-naphthoquinone-4-sulphonic acid sodium salt (NQS). A chromatographic separation was achieved on a C18 column with a mobile phase consisting of acetonitrile and 10mM orthophosphoric acid (pH 2.5) with isocratic elution (35:65). Baclofen was used as an internal standard (I.S.). The method developed for GBP was linear over the concentration range of 0.05-5.0 microg/ml and 0.1-10.0 microg/ml for plasma and urine, respectively. The method is precise (relative standard deviation, R.S.D. <4.05%) and accurate (relative mean error, RME <0.15%); mean absolute recoveries were 72.21% for plasma and 72.73% for urine.

Amines↗
PubMed1987

Oral nimodipine reduces prostaglandin and thromboxane production by arteries chronically exposed to a periarterial haematoma and the antifibrinolytic agent tranexamic acid.

The calcium antagonist nimodipine blocks the effects of many vasoconstrictors of cerebrovascular smooth muscle and may reduce the incidence of delayed cerebral ischaemia following subarachnoid haemorrhage though not necessarily by inhibiting the development of angiographic cerebral vasospasm. Post-haemorrhagic CSF contains abnormally large quantities of various eicosanoids that partly reflect enhanced production by cerebral arteries. Does nimodipine affect this process? The extra-arterial and intra-arterial production of PG6 keto-F1 alpha, PGE2, PGF2 alpha and TXB2 were measured in perfused common carotid arteries taken from rabbits in which the arteries had been ensheathed by blood clot in vivo for 7 days. All rabbits were given the antifibrinolytic agent tranexamic acid to retard resolution of the clot, and half were given oral nimodipine (2 mg/kg/day) for 10 days. Nimodipine significantly reduced the extra-arterial production of TXB2 during the third and fourth hours of perfusion and, less consistently, the production of PGF2 alpha, PGE2 and PG6 keto-F1 alpha. Lutrol, the solvent for nimodipine, had no such effect.

6-Ketoprostaglandin F1 alpha↗
PubMed1978

Anti-fibrinolytic therapy of giant hypertrophic gastritis (Menetrier's disease).

In five cases of giant hypertrophic gastritis (Menetrier's disease) biopsied gastric mucosa was examined for fibrinolytic activity; in all cases there was marked elevation of the activity due mainly to tissue plasminogen activator. The patients were given antifibrinolytic therapy with oral tranexamic acid (trans-4-aminomethyl cyclohexane carboxylic acid; trans-AMCHA), and four of the patients showed marked improvement of their hypoproteinemia as well as their mucosal disorders. One patient, who showed moderate increase of serum protein level but no reduction of the mucosal disorder, finally received gastrectomy. It was concluded that antifibrinolytic therapy seemed to block the vicious circle of 'membrane disorders', 'increased tissue fibrinolysis', 'increased vascular permeability' and 'hypoproteinemia' in Menetrier's disease.

Adult↗