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Biomedical subjects

G Heinemeyer

Publications and source records attributed to G Heinemeyer.

28 records · Page 2Linked to original sources
PubMed1985

Oxidation and glucuronidation of valproic acid in male rats--influence of phenobarbital, 3-methylcholanthrene, beta-naphthoflavone and clofibrate.

The influence of phenobarbital, clofibrate, 3-methylcholanthrene and beta-naphthoflavone on omega- and beta-oxidation as well as on glucuronidation of valproic acid (n-dipropylacetic acid) was evaluated in male Sprague-Dawley rats by determination of urinary excretion of its metabolites by GC-MS after administration of 100 mg/kg. In controls 12% of the dose was excreted within 24 hours, primarily as glucuronides; metabolites formed by oxidation amounted to about 4%. Phenobarbital treatment led to stimulation of 4-hydroxyvalproic acid [(omega-1)-oxidation], 5-hydroxyvalproic acid and n-propylglutaric acid (omega-oxidation) excretion. Clofibrate enhanced the excretion of 4-hydroxyvalproic acid and 3-keto-valproic acid, a product of peroxisomal beta-oxidation. beta-Naphthoflavone slightly increased the excretion of 5-hydroxyvalproic acid. The most specific effect was found for 3-methylcholanthrene, which was effective in stimulating the formation of 3-hydroxyvalproic acid which might be formed by (omega-2)-oxidation. The addition of fatty acids (olive oil in which 3-methylcholanthrene and beta-naphthoflavone were suspended) led to increased excretion of 3-keto-valproic, 4-hydroxyvalproic and n-propylglutaric acid. The excretion of 3-hydroxyvalproic acid was completely suppressed by olive oil. Such specific effects were not observed for glucuronidation of valproic acid and its metabolites, although stimulation was attained after phenobarbital, clofibrate and 3-methylcholanthrene treatment, because of instability of glucuronide conjugates. Stimulation of valproic acid metabolism was also shown by increased plasma clearance after treatment with phenobarbital. In contrast, clofibrate given once 1 hr before valproic acid inhibited excretion of valproic acid, possibly by competition during renal tubular secretion. Determination of valproic acid metabolites in urine provides a useful tool for evaluation of inducer specificity of short chain fatty acid metabolism and differentiation between microsomal and peroxisomal enzyme activity.

Animals↗
PubMed1985

Comparison of midazolam, diazepam and placebo i.m. as premedication for regional anaesthesia. A randomized double-blind study.

In a randomized double-blind study, midazolam 0.1 mg kg-1 i.m. was compared with diazepam 0.2 mg kg-1 and placebo as premedication for patients undergoing urological interventions under spinal anaesthesia. The sedative and anxiolytic effects of midazolam were evident 5-10 min after administration, and were maximum between 30 and 90 min. After this, rapid recovery was observed. More than 90% of the patients receiving midazolam were totally or partially amnesic for the procedures in the induction room and the operation theatre. Amnesia was not seen in the patients receiving diazepam or placebo and, in contrast to midazolam, diazepam had almost no sleep-inducing effect. In a few patients, the depth of sleep achieved with midazolam 0.1 mg kg-1 was such that co-operation was impaired.

Aged↗
PubMed1983

[Respiratory and sleep-inducing effects of i.m. midazolam as premedication for regional anesthesia. Comparison with diazepam, promethazine/pethidine and placebo].

The effects of respiratory depression and sleep induction produced by 0.1 mg/kg and 0.15 mg/kg of midazolam i.m. were examined in patients in whom urological interventions had to be performed under spinal anesthesia. The same parameters were evaluated for 0.2 mg/kg of diazepam i.m. as well as 50 mg/50 mg of pethidine/promethazine i.m. and placebo i.m. The major difference between 0.1 mg and 0.15 mg/kg body weight of midazolam was a more pronounced PCO2-increase in the group with the higher dosage. Both dosages led to anterograde amnesia in 8 or 9 of 10 patients respectively. No amnesia developed in the control groups. Respiratory depression and sleep induction occurred later with promethazine/pethidine (at 60 min) or diazepam (at 120 min) than with midazolam. Noteworthy in the Diazepam and placebo group was a hyperventilation lasting 60 and 120 min respectively. The arterial PO2 decreased in all groups during the intervention. Under midazolam, the decrease was significantly higher statistically than in the control groups during the first 60 min at both dosages. Premedication with 0.1 mg/kg i.m. of midazolam proved to be sufficient in all patients. The rapid onset of action, the sleep during the intervention and the amnesia associated with it suggest that this form of premedication is more favorable than the other procedures examined. The dosage of 0.15 mg/kg of midazolam proved to be too high: in addition to producing a stronger respiratory depression, it had the effect of rendering cooperation with some patients more difficult.

Aged↗
PubMed1981

Studies on the mechanism of stimulation of microsomal H2O2 formation and benzo(a)pyrene hydroxylation by substrates and flavone.

The addition of activators like flavone and hexobarbital to hepatic microsomes markedly stimulates H2O2 formation. The similar increase observed with flavone of microsomal hydroxylation of benzo(a)pyrene and its inhibition by catalase and methanol suggests but does not prove a necessary interaction of microsomal H2O2 production with benzo(a)pyrene hydroxylation. Hexobarbital and flavone-stimulated H2O2 formation is optimal at a stoichiometric relationship of these activators and NADPH. This implies either their direct participation as electron donors or their indirect involvement in electron transport by facilitation of stoichiometric substrate cytochrome P-450/NADPH flavoprotein interactions. Steady state kinetics data are consistent with a scheme in which the formation in microsomes of a complex of 1 mole of NADPH with NADPH-cytochrome P-450 reductase and 1 mole hexobarbital with cytochrome P-450 regulates H2O2 formation.

Animals↗
PubMed1980

Hybrid information provided by the 14C-aminopyrine breath test. Studies with 14C-monomethylaminoantipyrine in the guinea pig.

N-Demethylation of 14C-aminopyrine (14C-AP), labelled at the methyl groups of the tertiary amino group, yields H14 CHO and 14C-monomethylaminoantipyrine (14C-MMAAP) which also undergoes N-demethylation, however, at a slower rate as measured in hepatic microsomes. As after intraperitoneal application to male guinea pigs of 14C-AP (75 mg/kg; 50 muCi/kg), exhalation rate of 14CO2 declines in a biphasic manner, the hypothesis was tested whether the terminal part might reflect N-demethylation of MMAAP. The application of 14C-MMAAP (70 mg/kg; 10 muCi/kg), resulted in monophasic curves of 14CO2 exhalation rate. Their half lives were, however, longer than terminal half lives obtained after 14CAP. Obviously, this terminal phase does not represent 14CO2 formation from the metabolite MMAAP only, but 14C-AP might still contribute to 14CO2 production. Confirmation was obtained by HPLC determination of AP and MMAAP in serum after injection of AP. Shortly after injection, high concentrations of AP and low ones of MMAAP were found in blood from the portal vein and systemic circulation. Thus, initial parts of 14CO2-exhalation rate curves reflect predominantly AP metabolism whereas later phases provided hybrid information.

Aminopyrine↗
PubMed1980

Hexobarbital-binding, hydroxylation and hexobarbital-dependent hydrogen peroxide production in hepatic microsomes of guinea pig, rat and rabbit.

Cytochrome P-450 dependent oxygenase (3'-hydroxy-hexobarbital) and oxidase activities (hydrogen peroxide) have been measured in hepatic microsomes from guinea pigs, rats and rabbits. A sensitive gas-chromatographic assay was developed to measure the hydroxylated product 3'-hydroxy-hexobarbital. The kinetics of its formation were determined and correlated to hexobarbital type I binding and compared with oxidase activity: in the rat, Vmax for 3'-hydroxyhexobarbital formation was 5.1 and 2.6 nmoles/mg/min, resp. This was increased by phenobarbital treated rabbits, Vmax was 15.0 nmoles/mg/min for hydroxylation and 40.8 for H2O2 formation. Spectral affinity constants (Ks) in control animals were 0.12 mM (rats) and 0.14 mM (rabbits). Phenobarbital treatment decreased these affinity constants, which were similar for each activity measured. In guinea pigs, however, hydroxylation of exobarbital was low (3.1 nmoles/mg/min) and hexobarbital-dependent formation of H2O2 was higher than hydroxylation (Vmax: 7.0 nmoles/mg/min). Phenobarbital treatment led here to two affinity constnts for each activity measured, which however, were alike. The existence of low in addition to high affinity constants observed here might explain the difficulties seen hitherto in correlating hexobarbital binding and metabolism in this species. Total oxidase activity was higher than oxygenase activity in all species tested. It is suggested that oxygenase activity of cytochrome P-450 is not limited by binding but by a competition with oxidase activity for a common intermediary species. This might be peroxy-P-450 (substrate-Fe3+O2(2-), rendering either substrate-Fe3+ O for hydroxylation reaction, or oxidized cytochrome P-450-substrate and hydrogen peroxide as product of oxidase function.

Animals↗
PubMed1979

Demonstration of drug-ethanol interactions by changes in activity of hepatic microsomal oxidase/oxygenase cytochrome P-450 function.

"Uncoupling" of microsomal hepatic oxygenases is characterized by a situation in which microsomal monooxygenases exhibit more oxidase than oxygenase activity with an increased formation of hydrogen peroxide at the expense of O2, NADPH and substrate hydroxylation. The importance of such in vitro observations with respect to physiological conditions "in vivo" has been tested by investigating elimination kinetics of ethanol. If hexobarbital, a substrate of mixed function oxygenase as well as an "uncoupler", is given to guinea pigs together with ethanol, changes in the elimination of ethanol occur. It is suggested that this is the consequence of an increased formation of H2O2 which contributes via peroxidatic reaction of catalase to the elimination of ethanol. The results also show additional interactions of hexobarbital as well as of ethylmorphine with ethanol elimination. Both compounds increased the initial blood levels of ethanol which precede accelerated elimination, probably by a first pass effect. At low concentrations of ethanol, ethylmorphine inhibits ethanol elimination by inhibition of ADH.

Alcohol Oxidoreductases↗