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G Toth

Publications and source records attributed to G Toth.

67 records · Page 4Linked to original sources
PubMed1988

No evidence of a genetic polymorphism in the oxidative metabolism of midazolam.

The benzodiazepine midazolam is rapidly eliminated by oxidative metabolism. In young healthy volunteers elimination half-life (t1/2) is about 2.4 hours. A recent study showed a prolonged t1/2 from 8 to 22 hours in 6.5% of surgical patients, and a genetic polymorphism of midazolam's metabolism has been suggested. Therefore, we measured in 168 surgical patients the elimination of midazolam and its major hydroxylated metabolite (alpha-OH-midazolam) in blood and urine. Co-medication, disease status, smoking habits and alcohol intake were recorded; normal liver and kidney functions were assessed by routine laboratory tests. Midazolam was administered intravenously (0.1 to 0.2 mg/kg) for the induction of anaesthesia. Blood was drawn 1.5, 3, 4.5 and 6 hours after application and urine was collected for 6 hours. Plasma protein binding of midazolam was determined by equilibrium dialysis. Midazolam and alpha-OH-midazolam were measured in plasma by specific gas-liquid chromatography and in urine by high performance liquid chromatography. Data for the dose-corrected area under plasma-level curve of midazolam (AUC-midazolam/dose: 1.23 +/- 961 x 10(5) h/ml; mean +/- SD) and for the metabolic plasma ratio (AUC of alpha-OH-midazolam/AUC-midazolam: 0.52 +/- 0.28) demonstrated a log-normal distribution. Likewise, the percentage of the unbound fraction of midazolam in plasma (5.0 +/- 2.4%), urinary excretion of alpha-OH-midazolam (55.9 +/- 22.7% of dose) and the values for t1/2 (2.9 +/- 1.1 hours) did indicate a unimodal distribution. Age, comedication and smoking habits did not affect the disposition of midazolam. However, patients with regular intake of alcohol had a higher (p less than 0.05) metabolic ratio. Only in 3 patients could a prolonged t1/2 of midazolam from 7.5 to 10.2 hours be detected, but plasma levels and urinary excretion of alpha-OH-midazolam in those individuals were found to be normal. Therefore it is very unlikely that the oxidative metabolism of midazolam exhibits a genetic polymorphism.

Age Factors↗
PubMed1987

Synthesis and binding of 3H-oxymorphazone to rat brain membranes.

Oxymorphazone is a 14-hydroxydihydromorphinone derivative which contains a C-6 hydrazone group and hence could serve as an irreversible label for opioid receptors. 3H-oxymorphazone was synthesized by the reaction of 3H-oxymorphone with excess hydrazine. A specific radioactivity of 640 GBq/mmol (17,3 Ci/mmol) was achieved. Both the unlabelled compound and the tritiated ligand show high affinity to mu and kappa opiate receptor subtypes in rat brain membranes. Two binding sites were detected by equilibrium binding studies, with apparent Kd values of 0.62 nM and 28 nM. About 20% of the H-oxymorphazone specific binding is irreversible after reaction at 1 nM ligand concentration, and this can be enhanced by a higher concentration of tritiated ligand. No azine formation was detected. Preincubation of the membranes with unlabelled oxymorphazone resulted in an irreversible blockade of the high affinity 3H-naloxone binding sites.

Animals↗
PubMed1986

Storage and release of acetylcholine in rat cortical synaptosomes: effects of D,L-2-(4-phenylpiperidino)cyclohexanol (AH5183).

A post-stimulation synthesis of acetylcholine (ACh), its incorporation into a 'stable-bound' (vesicular) compartment and subsequent release, were compared in K+-stimulated synaptosomes, in the absence and presence of 10 microM AH5183. The drug depressed by 16% the net intrasynaptosomal formation of ACh from 1 microM [3H]choline (Ch) in the medium, by competitively inhibiting (Ki approximately equal to 20 microM) the high-affinity Ch transport, but it had no direct effect on the intraterminal synthesis of ACh per se. The drug reduced incorporation of newly synthesized [3H]ACh into synaptic vesicles by 55% and subsequent K+-depolarization-induced release of [3H]ACh by 83%, although it had no effect on Ca2+ influx into synaptosomes. These results are consistent with the hypothesis that AH5183 blocks cholinergic neurotransmission presynaptically by interfering with recharging of synaptic vesicles with ACh. Since the reduction of ACh release in the presence of AH5183 had no direct effect on ACh synthesis, these results also suggest that the transmitter release is not prerequisite for enhancement of Ch uptake and ACh synthesis in stimulated nerve terminals.

Acetylcholine↗
PubMed1986

Microtubule disassembly increases the number of opioid receptor binding sites in rat cerebrum membranes.

The role of microtubules in opioid receptor binding was studied by using microtubule assembly inhibitors. Preincubation of rat cerebrum membranes with podophyllotoxin or colchicine provoked a marked increase in the number of binding sites as judged by [3H]-naloxone, [3H]-morphine and [3H]-D-Ala2-Leu5-enkephalin binding experiments. These results indicate microtubule involvement in regulation of opioid receptor expression.

Animals↗
PubMed1986

Preparation of [3H]-oxymorphazone and its binding to rat brain membranes.

Oxymorphazone is a 14-hydroxydihydromorphinone derivative which contains C-6 hydrazone group and hence could serve as an irreversible label for opioid receptors. 3H-oxymorphazone was synthesized by the reaction of 3H-oxymorphone with excess hydrazine, with 640 GBq/mmol specific radioactivity. Both the unlabelled compound and the tritiated ligand show high affinity to mu and kappa opiate receptor subtypes in rat brain membranes. Two binding sites were detected by equilibrium binding studies. About 60% of the 3H-oxymorphazone specific binding is irreversible at 10nM ligand concentration. Preincubation of the membranes with unlabelled oxymorphazone resulted in an irreversible blockade of the high affinity 3H-naloxone binding sites.

Animals↗
PubMed1984

Effects of Pb2+ and Cd2+ on acetylcholine release and Ca2+ movements in synaptosomes and subcellular fractions from rat brain and Torpedo electric organ.

In this work we examined the effects of Pb2+ and Cd2+ on (a) [3H]ACh release and voltage-sensitive Ca2+ channels in rat brain synaptosomes, and (b) 45Ca2+ binding to isolated brain mitochondria and microsomes, and synaptic vesicles isolated from Torpedo electric organs. Pb2+ (Ki approximately 1.1 microM) and Cd2+ (Ki approximately 2.2) competitively block the K+-evoked influx of 45Ca2+ through the 'fast' calcium channels in synaptosomes. The Kis obtained with synaptosomes are in good agreement with the Ki values obtained from electrophysiological experiments at the frog neuromuscular junction (KPb:0.99 microM, KCd: 1.7 microM)7. The Ki for the inhibition of ACh release from synaptosomes by Cd2+ is 4.5 microM. Pb2+ is a less effective inhibitor of transmitter release (Ki approximately 16 microM) because it secondarily augments spontaneous transmitter efflux. Cd2+ has no effect on spontaneous release at concentrations less than or equal to 100 microM. The enhancing effect of Pb2+ on spontaneous release is (a) not abolished by omission of Ca2+ from the bathing medium, (b) is delayed by 1-2 min after the beginning of Pb2+ exposure, (c) is reversed upon the removal of Pb2+. In the presence of physiological concentrations of ATP (1 mM), Mg2+ (1 mM) and Pi (2 mM), 1-10 microM Pb2+ inhibits calcium uptake but Pb2+ greater than 10 microM causes a several-fold stimulation of passive binding of calcium to the organelles. This effect is associated with Pb2+-induced enhancement of Pi uptake. Cd2+ inhibits Ca2+ binding at all concentrations tested (1-50 microM) and reduces the Pb2+-induced Ca2+-binding to organelles. Neither Pb2+ nor Cd2+ have any discernible effects on spontaneous loss of calcium from mitochondria or microsomes preloaded with 45Ca. In summary, these data are consistent with the notion that Pb2+ and Cd2+ are potent blockers of presynaptic voltage-sensitive Ca2+ channels and the evoked release of transmitter which is contingent on Ca2+ influx through these channels. Our results are not consistent with the hypothesis that Pb2+ augments spontaneous release by interfering with intraterminal Ca2+-buffering by mitochondria, endoplasmic reticulum, or synaptic vesicles.

Acetylcholine↗
PubMed1983

Purification and characterization of beta-adrenoreceptor rich heart plasma membrane.

A new procedure utilizing saccharose density gradient centrifugation was developed for the purification of beta-adrenergic receptor rich plasma membrane from rabbit heart ventricle tissue. The separation of the plasma membrane fraction from the sarcoplasmic reticulum and mitochondria was verified by conducting binding studies, measuring the activities of marker enzymes, as well as by electron microscopy. It was found that the binding of [3H]-L-dihydroalprenolol is stereospecific in addition to being inhibited by beta-adrenoreceptor agonists and antagonists. Adenylate cyclase retained its responsiveness to beta-agonists and guanine nucleotides.

5'-Nucleotidase↗
PubMed1982

Effects of fluphenazine decanoate (a long-acting phenothiazine) on serum prolactin and amphetamine-induced behavioural changes.

A single injection of fluphenazine decanoate (FD) antagonized effects of acute d-amphetamine (2.5 mg/kg) for a variable period of time (4 to 28 days), depending upon the dosage of the neuroleptic used (2.5 or 5.0 mg/kg) and the behavioural parameter(s) monitored. Locomotion and rearing were antagonized for a longer duration than was sniffing. Normal locomotor response to amphetamine was attained 12 and 28 days following the administration of 2.5 and 5.0 mg/kg FD, respectively. However, the 2.5 mg/kg FD group displayed significantly more locomotor activity on days 20 and 24 post-treatment. A similar supersensitive response was not demonstrable with the higher dose of FD (5.0 mg/kg), or with the other behavioural measures. The prompt and pronounced elevation of serum prolactin returned to within the normal range by days 4 and 14, following administration of 2.5 and 5.0 mg/kg FD, respectively. These results indicate that the behavioural paradigm is more sensitive in monitoring the effects of FD and could serve as a useful model in investigating the dose- and time-related effects of other long-acting neuroleptics.

Amphetamine↗
PubMedDate not supplied

Mu-receptor specificity of the opioid peptide irreversible reagent, [3H]DALECK.

A novel affinity reagent DALECK, i.e. D-Ala2-Leu5-enkephalin with a C-terminal chloromethyl ketone group, was previously synthesized in normal and in tritiated form and shown to react irreversibly at opioid receptors, with some evidence for selectivity for the mu subtype. DALECK tritiated in its phenolic group has been synthesized at 13-fold higher specific radioactivity than in the previous study. In the irreversible reaction of this product at pH 8.1 with rat brain membranes it was confirmed that only one polypeptide there is labelled, of apparent Mr 58,000. Competition between this reaction and ligands highly selective for the mu, delta or kappa binding sites yielded curves demonstrating the very high selectivity of the DALECK irreversible reaction for the mu site. The results provide evidence that the mu opioid receptor protein contains only one type of binding subunit, whose apparent Mr is 58,000, this size being dependent upon the conditions used in the gel electrophoresis and being higher when stringent conditions which would reduce all internal disulphide bonds are applied.

Amino Acid Chloromethyl Ketones↗