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Biomedical subjects

R Griffiths

Publications and source records attributed to R Griffiths.

At least 163 records · Page 9Linked to original sources
PubMed1986

Differential changes in the content of amino acid neurotransmitters in discrete regions of the rat brain prior to the onset and during the course of homocysteine-induced seizures.

Changes in amino acid concentrations were investigated in selected regions of rat brain prior to the onset and during the course of epileptiform seizures induced by L-homocysteine. The concentration of gamma-aminobutyric acid (GABA) decreased preictally in substantia nigra (-18%), caudate putamen (-26%), and inferior colliculus (-46%). After seizure onset, the GABA content was further reduced in substantia nigra (-31%) and additionally in hippocampus (-18%). Preictal taurine levels were elevated in globus pallidus (+26%) and caudate putamen (+13%) but returned to normal after seizure onset. However, in hippocampus, taurine decreased both preictally (-22%) and after seizure onset (-56%). Glycine was reduced preictally only in globus pallidus (-13%). After seizure onset the direction of its concentration change varied in the brain regions studied. Glutamate levels decreased preictally in hippocampus (-10%) and hypothalamus (-46%) but increased in globus pallidus (+14%). Normal levels were detectable after seizure onset in hypothalamus and globus pallidus but a further reduction in hippocampus (-59%) and significant reductions in substantia nigra (-15%) and caudate putamen (-17%) were detected. Aspartate was elevated in hippocampus, both preictally (+49%) and after seizure onset (+21%) while at the same phases in globus pallidus a consistent reduction (-30%) was observed. The glutamine content increased preictally in globus pallidus (+41%) and hypothalamus (+36%), and in all brain areas during the ictal phase of seizure, the hippocampus exhibiting a dramatic increase (approximately 300%). The contents of serine and alanine were altered in most regions studied only after seizure onset, with the exception of the hippocampus, where a decrease (-41%) of serine was observed preictally.

Alanine↗
PubMed1986

Mutual inhibition kinetic analysis of gamma-aminobutyric acid, taurine, and beta-alanine high-affinity transport into neurons and astrocytes: evidence for similarity between the taurine and beta-alanine carriers in both cell types.

The transport kinetics of gamma-aminobutyric acid (GABA), taurine, and beta-alanine in addition to the mutual inhibition patterns of these compounds were investigated in cultures of neurons and astrocytes derived from mouse cerebral cortex. A high-affinity uptake system for each amino acid was demonstrated both in neurons (Km GABA = 24.9 +/- 1.7 microM; Km Tau = 20.0 +/- 3.3 microM; Km beta-Ala = 73.0 +/- 3.6 microM) and astrocytes (Km GABA = 31.4 +/- 2.9 microM, Km Tau = 24.7 +/- 1.3 microM; Km beta-Ala = 70.8 +/- 3.6 microM). The maximal uptake rates (Vmax) determined were such that, in neurons, Vmax GABA greater than Vmax beta-Ala = Vmax Tau, whereas in astrocytes, Vmax beta-Ala greater than Vmax Tau = Vmax GABA. Taurine was found to inhibit beta-alanine uptake into neurons and astrocytes in a competitive manner, with Ki values of 217 microM in neurons and 24 microM in astrocytes. beta-Alanine was shown to inhibit taurine uptake in neurons and astrocytes, also in a competitive manner, with Ki values of 72 microM in neurons and 71 microM in astrocytes. However, beta-alanine was found to be a weak noncompetitive inhibitor of neuronal and astrocytic GABA uptake, whereas in reverse experiments, GABA displayed weak noncompetitive inhibition of neuronal and astrocytic uptake of beta-alanine. Likewise, taurine was a weak noncompetitive inhibitor of GABA uptake in neurons and similarly, GABA was a weak noncompetitive inhibitor of taurine uptake into neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1986

Pharmacological studies with SK&F 93944 (temelastine), a novel histamine H1-receptor antagonist with negligible ability to penetrate the central nervous system.

SK&F 93944 (temelastine), a novel histamine H1-receptor antagonist, has been studied in a variety of in vitro and in vivo test systems. SK&F 93944 was a competitive antagonist of histamine-induced contractions of guinea-pig ileum with a pA2 of 9.55 and a weak, non-competitive, inhibitor of the effects of histamine on guinea-pig atrium. In anaesthetized guinea-pigs SK&F 93944 displaced histamine bronchoconstriction dose-response curves at doses which had negligible effects on histamine tachycardia. In anaesthetized cats SK&F 93944 antagonized depressor responses to the histamine H1-receptor agonists, 2-(2-aminoethyl)pyridine and betahistine, at doses which had no effects on responses to the histamine H2-receptor agonist, dimaprit. Oral pretreatment with SK&F 93944 in conscious rats and guinea-pigs afforded protection versus the response to intradermal histamine injection. Comparative studies in each of the test systems showed that SK&F 93944 was of comparable or significantly greater potency than the standard compound, mepyramine. SK&F 93944 was found to be a weak, non-competitive antagonist of carbachol on the guinea-pig ileum but was devoid of measurable anticholinergic activity in vivo. Studies on the penetration of [14C]-SK&F 93944, labelled either in the isocytosine ring or in the butyl chain, showed that brain concentrations were very low when compared with the steady-state blood concentrations. In contrast, brain concentrations of [3H]-mepyramine exceeded blood concentrations by a factor of approximately 3. SK&F 93944 may have an advantage over classical histamine H1-receptor antagonists in that it is likely to be devoid of untoward effects on the central nervous system.

Animals↗
PubMed1985

A double inhibition kinetic analysis of [3H]-muscimol binding to the gamma-aminobutyric acid receptor on calf brain synaptic membranes. Further studies on the mechanism of homocysteine-induced seizures.

The simultaneous action of pyridoxal 5'-phosphate (PLP) and L-homocysteine on specific [3H]muscimol binding to the gamma-aminobutyric acid receptor on freeze-thawed, Triton-treated calf-brain synaptic membranes was examined kinetically by double inhibition analysis. PLP was found to be a pure inhibitor and L-homocysteine, a partial inhibitor, with respect to [3H]muscimol. Diagnostic analysis of the experimental data showed that the interaction constant (alpha) of the two inhibitors for the free receptor is between 0 and 1, confirming that the two inhibitors act synergistically. Further double inhibition analysis showed that no quaternary receptor-[3H]muscimol-homocysteine-PLP complex is formed although the ternary receptor-homocysteine-PLP complex is present. The localization and relationship of binding groups for both inhibitors is discussed as in their association with the ligand binding site.

Animals↗
PubMed1984

The pharmacokinetics in man of SK&F 93319--a new antagonist of histamine H1 and H2 receptors.

SK&F 93319, a potent histamine H1- and H2-receptor antagonist, is rapidly absorbed with a low rate of plasma clearance primarily by metabolism. Excretion is divided evenly between urine and faeces (probable biliary elimination) with little unchanged drug in the urine. Serum protein binding at low concentrations is very extensive and appears to restrict distribution of SK&F 93319. At higher concentrations (higher dose levels) reduced protein binding results in a marked proportional increase in available free drug with a consequent increase in distribution and clearance. Bioavailability is reduced at higher dose levels. The importance of factors contributing to non-linear pharmacokinetics and the potential clinical consequences are demonstrated.

Adult↗
PubMed1983

Synergistic inhibition of [3H]muscimol binding to calf-brain synaptic membranes in the presence of L-homocysteine and pyridoxal 5'-phosphate. A possible mechanism for homocysteine-induced seizures.

L-Homocysteine and pyridoxal 5'-phosphate (PxyP) inhibited [3H]muscimol binding to freeze-thawed, Triton-treated calf brain membranes (containing high-affinity muscimol-binding sites: Kd 9.5 +/- 0.6 nM, Bmax 5.2 +/- 0.2 pmol/mg protein). The homocysteine--pyridoxal-5'-phosphate (Hcy-PxyP) thiazine complex had no effect. L-Homocysteine was found to be a partially competitive inhibitor, thus demonstrating an allosteric inhibition with Ki value of 1.96 mM for free receptor and Ki of 13 mM for receptor-muscimol complex. PxyP was shown to be a two-site pure competitive inhibitor of [3H]muscimol binding with cooperativity of PxyP binding such that Ki values for PxyP of 20 mM and 2.1 mM were found. L-Homocysteine and PxyP when added simultaneously to binding assays, caused a greater degree of inhibition than that observed at the same total specific concentration of either inhibitor alone. This synergistic inhibitory effect was shown to be due to a homocysteine-induced increase in the affinity of PxyP-binding sites. Three alternative models are suggested to explain the observed synergistic effects whereby it is proposed that PxyP and [3H]muscimol binding is mutually exclusive, while L-homocysteine with PxyP and L-homocysteine with muscimol, exhibit non-exclusivity. Non-linear regression analysis of binding data was undertaken in order to substantiate conclusions drawn from graphical procedures and in an attempt to ascertain which mathematical model best fitted the experimental data describing the synergistic inhibitory effects of L-homocysteine and PxyP. This synergistic inhibitory effect of PxyP and L-homocysteine on the post-synaptic gamma-aminobutyric acid receptor may provide a basis for explanation of the mechanism of homocysteine-induced seizures.

Animals↗
PubMed1983

Hippocampal electrical activity and gamma-aminobutyrate metabolism in brain tissue following administration of homocysteine.

The concentration of gamma-aminobutyrate (GABA) and the activity of glutamate decarboxylase and GABA-transaminase were measured in extracts of mouse brain before the onset and during the course of generalized seizures induced by systemic administration of homocysteine thiolactone. The results indicate that whole brain GABA metabolism is unaffected by subconvulsive and convulsive doses of homocysteine at all stages of the generalized seizure. Electroencephalographic monitoring of rat brain electrical activity via hippocampal electrode implantation allowed the course homocysteine-induced seizures to be followed and afforded a means of quantifying such seizures.

4-Aminobutyrate Transaminase↗
PubMed1982

Trial of three-day and ten-day courses of amoxycillin in otitis media.

A randomised double-blind controlled trial compared three-day and 10-day courses of amoxycillin (25 mg/kg daily) in children with otitis media. Seventeen doctors from five centres admitted 84 children between the ages of 2 and 10 years. Symptoms and signs were measured on admission to the trial, on day 3, and on day 15. Mother's observations were recorded daily for 10 days. Audiograms were performed at four and 12 weeks after the end of the trial. The treatment groups showed little difference in the speed of resolution of symptoms and signs, the numbers of primary treatment failures, or the frequency of recurrent ear infections. There were no complications in either group. Most children with otitis media can probably be successfully and safely treated with no more than a three-day course of amoxycillin providing their progress is reviewed about the fifth or sixth day after treatment started. This policy could save over 1 million pounds annually in antibiotic costs.

Amoxicillin↗
PubMed1982

Oxmetidine: clinical pharmacological studies with a new H2-receptor antagonist.

The gastric antisecretory effects of oxmetidine, a new H2-receptor antagonist, have been studied in 33 healthy subjects. The relative potency of oxmetidine compared with that of cimetidine depended on the route of administration and the experimental conditions. Oxmetidine intravenously infused was approximately four times as potent as cimetidine, weight for weight, in inhibiting impromidine stimulated gastric acid secretion but was twice as potent when food was used as a stimulus. After oral administration there were no differences in the weight-for-weight potency of oxmetidine and cimetidine, although oxmetidine was twice as potent on a molar basis. These apparent differences according to the route of drug administration are probably due to first pass metabolism of oxmetidine. There were no differences in the duration of action of oxmetidine and cimetidine. Twenty-four hour monitoring of intragastric pH showed that oxmetidine 400 mg twice daily reduced mean hourly 24 hour intragastric pH by 59%, suggesting that a twice daily dosage regimen should be evaluated in the treatment of duodenal ulceration.

Adolescent↗
PubMed1981

Characterization of a structural glycoprotein from bovine ligamentum nuchae exhibiting dual amine oxidase activity.

A structural glycoprotein has been extracted from bovine ligamentum nuchae by using 5 M guanidine hydrochloride containing a disulfide bond reducing agent and purified by preparative gel electrophoresis. The isolated material appeared to be monodisperse, with a molecular weight of approximately 34000, as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by analytical ultracentrifugation. It contains 10% carbohydrate comprising mannose, N-acetylglucosamine, galactose, and sialic acid in a 6:5:3:3 molar ratio. The glycoprotein has been assayed for peptidyl-lysine oxidase activity by using [3H]lysine-aortic elastin, prepared from 15- to 17-day-old chick embryos, as a substrate. In the absence of free lysine, the specific activity of the preparation over a 2-h incubation was approximately 60 X 10(4) dpm/mg of purified protein. Addition of 10 mM lysine resulted in an approximately 50% decrease in the specific activity. Free lysine was shown to act as a substrate for the glycoprotein preparation as indicated by control experiments using [3H]lysine in place of the aortic substrate. These results demonstrate that the glycoprotein exhibits a dual amine oxidase activity. In the presence of 0.27 mM beta-aminopropionitrile fumarate, a concentration which completely inhibits peptidyl-lysine oxidase activity in other lysyl oxidases, the glycoprotein preparation was inhibited by approximately 14%. In the absence of 5 M guanidine hydrochloride and reducing agent, the glycoprotein undergoes aggregation which in the presences of copper ions results in the formation of cylindrical tactoids, the diameter of which (11 nm) corresponds closely to that of the fibrils which in the majority of connective tissue matrices constitute the microfibrillar component mainly associated with elastic fibers.

Amino Acid Oxidoreductases↗
PubMed1981

Cimetidine-a clinical and pharmacokinetic study.

1 The effect of six months therapy with cimetidine (800 mg or 1600 mg/day) and subsequent withdrawal was studied in 19 patients with duodenal ulceration. 2 The overall rates of healing were 63% and 79% of patients after 3 and after 6 months of treatment respectively. The longer course (6 months) or the higher dose (1600 mg) did not result in significantly increased rates of ulcer healing. 3 Abrupt withdrawal of cimetidine resulted in the recurrence of severe symptoms in 15 patients (79%). 4 Pharmacokinetic studies showed the mean elimination half-life of cimetidine to be 100 +/- 25 min, the total body cimetidine clearance 652 +/- 223 ml/min, the mean volume of distribution at steady state 65 +/- 181 and the overall bioavailability 78%. 5 Long term cimetidine treatment does not result in drug accumulation or changes in its pharmacokinetic profile. 6 Inter-individual differences in clinical and endoscopic response to cimetidine cannot be explained by pharmacokinetic differences.

Cimetidine↗