Duration of hexobarbital-induced sleep and monoamine oxidase activities in rat brain: Focus on the behavioral activity and on the free-radical oxidation.

The present study is focused on the relationship between monoamine oxidase (MAO) activity and hepatic content of cytochrome P450 (CYP), which reflects the status of microsomal oxidation. For vital integrative evaluation of hepatic microsomal oxidation in rats, the hexobarbital sleep test was used, and content of CYP was measured in hepatic microsomes. Rats with short hexobarbital sleep time (SHST) had higher content of microsomal CYP than rats with long hexobarbital sleep time (LHST). Whole brain MAO-A and MAO-B activities, serotonin and carbonylated protein levels were higher in SHST than in LHST rats. MAO-A and MAO-B activities were higher in brain cortex of SHST rats; MAO-A activity was higher only in hypothalamus and medulla of LHST. The same brain regions of LHST rats had higher concentrations of carbonylated proteins and lipid peroxidation products than in SHST rats. MAO activity was correlated with microsomal oxidation phenotype. Rats with higher hepatic content of CYP had higher activities of MAO-A and MAO-B in the brain and higher plasma serotonin levels than rats with lower microsomal oxidation. In conclusion, data obtained in this study showed a correlation between MAO activity and microsomal oxidation phenotype.

Hepatoprotective studies on Hedyotis corymbosa (L.) Lam.

Hedyotis corymbosa is used in traditional medicine of India and China to treat various hepatic disorders. In the present study, the hepatoprotective effect of the methanolic extract of the whole plant of Hedyotis corymbosa against paracetamol overdose-induced liver damage in Wistar rats was studied. The methanolic extract of the plant produced significant hepatoprotective effects as evidenced by decreased serum enzyme activities, SGPT, SGOT, SAKP and serum bilirubin and an almost normal histological architecture of the liver, in treated groups, compared to the controls. Hedyotis corymbosa shortened hexobarbitone-induced sleeping time in mice, besides showing significant antilipid peroxidant effect in vitro. The results thus support the use of Hedyotis corymbosa as a hepatoprotective agent.

Metabolic and psychophysiologic studies of cannabidiol-hexobarbital interaction.

Cannabidiol (CBD), 600 mg/day orally for 5 to 12 days, inhibited hexobarbital metabolism in ten subjects. Hexobarbital oral clearance was 36% lower and apparent volume of distribution was 35% smaller, with no change in half-life during CBD. In four subjects who received intravenous and oral hexobarbital, systemic clearance was 36% lower while bioavailability was 10% greater during CBD. Hexobarbital increased fatigue and tremor, impaired eye-tracking performance, and altered the electroencephalogram. Hexobarbital effects were not affected by CBD. Inhibition of metabolism of other drugs should be considered when large amounts of CBD are taken or when CBD is used for therapy.

Effects of aldehyde dehydrogenase inhibitors on hexobarbital sensitivity and neuroamine metabolism in rat brain.

Several authors have found that the aldehyde dehydrogenase (ALDH) inhibitor, disulfiram, prolongs hexobarbital-induced anaesthesia. It was suggested that this effect was caused by an alteration of the serotonergic system in brain, mediated by elevated levels of biogenic aldehydes. In the present study, disulfiram (300 mg/kg) was found to cause a 4-fold prolongation of hexobarbital-induced anaesthesia, while coprine (another potent ALDH-inhibitor) had no effect. This strongly suggested that biogenic aldehydes were not involved in this effect of disulfiram. The hexobarbital concentration in brain, at the electroencephalogram (EEG) criteria used for measuring hexobarbital sensitivity, was unaffected in rats given 75-300 mg/kg disulfiram, indicating that factors other than an increased brain hexobarbital sensitivity were responsible for the prolonged anaesthesia. Also 10-100 mg/kg coprine did not affect hexobarbital sensitivity measured this way. No alteration of the dopamine level in brain was found in rats given disulfiram, and in both disulfiram- and coprine-treated rats, similar changes in the serotonergic system were found. However, the level of norepinephrine was decreased in brains of disulfiram-treated rats, but it was unaffected by coprine. Thus, norepinephrine may have been involved in the prolongation of hexobarbital-induced anaesthesia caused by disulfiram.

Route- and dose-dependent pharmacokinetics of hexobarbitone in the rat: a re-evaluation of the use of sleeping times in metabolic studies.

The metabolic clearance (CL) and half-life of racemic hexobarbitone and sleeping time were studied in rats following intra-arterial (i.a.), intraperitoneal (i.p.) and oral (p.o.) administration, at dose levels of 25 and 100 mg kg-1 of its sodium salt. CLp.o. was higher than CLi.a. at both 25 and 100 mg kg-1. CLi.a. and CLi.p. values were much lower, but CLi.p. was higher than CLi.a. at 25 mg kg-1 and lower than CLi.a. at 100 mg kg-1. There was no distinct dependency of the half-lives on route of administration, but a slight increase upon increasing the dose was observed. Hexobarbitone blood concentrations at which the rats awoke were significantly higher after 100 mg kg-1 i.p. than after 100 mg kg-1 i.a., although there was only a small difference in sleeping time. It is postulated that the rate of uptake of the barbiturates into the portal system after i.p. administration is so high that transient saturation of hepatic first-pass metabolism occurs. Therefore neither CLi.p. nor sleeping times can be used as an accurate reflection of drug-metabolizing enzyme activity in the rat; instead CLp.o. should be used.

Midazolam does not antagonize fentanyl-mediated analgesia in surgical patients.

STUDY OBJECTIVE: To determine whether midazolam possesses a clinically significant antianalgesic action in surgical patients. DESIGN: Randomized, controlled study. SETTING: Inpatient anesthesia at a university department of neurosurgery. PATIENTS: 2 groups of 10 patients each who were scheduled for supratentorial brain surgery, did not have elevated intracranial pressure, and were free from systemic disease. INTERVENTIONS: Patients underwent anesthesia induction with hexobarbital, succinylcholine, and pancuronium; anesthesia was maintained with injections of droperidol-fentanyl (Group 1) or with midazolam-fentanyl (Group 2) following a predetermined repetitive dosing schedule, such that fentanyl 0.1 mg was injected upon predominant increases in heart rate, whereas droperidol 2.5 mg or midazolam 2.5 mg was injected upon increases in blood pressure. MEASUREMENTS AND MAIN RESULTS: Duration of anesthesia and invasiveness of surgery were similar in both groups. The amount of fentanyl required was 0.55 +/- 0.18 mg/hr (mean +/- SD) in Group 1 and 0.53 +/- 0.17 mg/hr in Group 2. Injections of droperidol 7.5 +/- 3.4 mg/hr (Group 1) and midazolam 5.9 +/- 2.3 mg/hr (Group 2) were administered intraoperatively. This redosing regimen was associated with uninterrupted hemodynamic stability, indicating comparable and adequate anesthetic depth. Plasma concentrations of metabolites and hormones indicative of humoral stress activation did not differ between groups. CONCLUSION: Under these clinical conditions, the administration of midazolam, when compared with droperidol, was not associated with signs of any antagonistic or antianalgesic action toward fentanyl-mediated analgesia.

[Effect of Oren-gedoku-to on changes in hexobarbital-induced sleeping time in chlorpromazine-treated mice].

The effects of Oren-gedoku-to on the hypnotic duration induced by hexobarbital, and on the change of this duration in chlorpromazine-treated mice were investigated. Single dose of Oren-gedoku-to (1.0 or 2.0 g/kg, p.o.) or chlorpromazine (10 mg/kg, p.o.) prolonged the hexobarbital hypnosis time. And the simultaneous dose of chlorpromazine (6.0 mg/kg, p.o.) and Orengedoku-to (1.0 g/kg, p.o.) indicated the equal effect for the administration of chlorpromazine (10.0 mg/kg, p.o.) alone. Although the mechanism of the action remains to be unknown, administration of Oren-gedoku-to in combination with chlorpromazine seems to be useful from the standpoint of alleviation of the side-effects caused by less dose.

[Use of the Soviet preparation methindione for injections in convulsive conditions]. / Primenenie pri sudorozhnykh sostoianiiakh otechestvennogo preparata metindiona dlia in"ektsii

The author studied the action of a Soviet preparation Metindion in 22 patients with serial epileptic seizures and in 16 patients with an epileptic status. The studies demonstrated a high anticonvulsive activity in serial fits. In epileptical states the action of metindion was less expressed. Its combination with diazepam preparations and barbiturates appeared to have a more expressed and prolonged anticonvulsive action. Metindion is most effective when used at initial stages of a convulsive condition.

[Turnover of liver hemoproteins in guinea pigs with various resistance to hexenal after peroral sensitization]. / Obnovlenie gemoproteinov pecheni morskikh svinok s razlichnoi ustoichivost'iu k geksenalu pri peroral'noi sensibilizatsii.

Patterns of hemoproteins turnover were studied in microsomal and mitochondrial fractions of liver tissue of guinea pigs with various duration of hexenal sleep; these patterns were calculated by means of modified procedure involving incorporation of 14C-aminolevulinic acid. Increase in turnover of microsomal cytochromes corresponded to decrease of their content in animals with short-term sleep simultaneously with a decrease in the lethal index after sensitization by means of ovalbumin.

Intra-arterial administration of hexobarbital enantiomers to the rat: disposition and estimation of apparent extraction ratio.

The enantiomers of hexobarbital, designated as S(+)-HB and R(-)-HB, were administered intra-arterially to rats in a dose of 25 mg X kg-1. Blood pharmacokinetics of the parent compound and two metabolites as well as urinary excretion of three major metabolites were studied. Using previously obtained data following oral administration of S(+)-HB and R(-)-HB two different methods for calculation of the hepatic extraction ratio (E) were compared. The metabolite profile in the urine after intra-arterial administration was not basically different from corresponding data on oral administration. The clearance of low-dose, intra-arterially administered S(+)-HB is useful as an indicator of hepatic blood flow in the rat.

Pharmocokinetics of hexobarbital in man after intravenous infusion.

The plasma levels of hexobarbital in humans were determined during and after a 30-min or 60-min zero-order intravenous infusion. Hexobarbital kinetics could be described by conceiving the body to exhibit two compartments. The plasma concentrations were fitted to the postinfusion equation and the parameters intrinsic to the two-compartment open model were estimated. The elimination half-life varied considerably among the 14 individuals (160-441-min), which could mainly be explained by the greatly varying metabolic clearance of the compound (123-360 ml/min). The apparent volume of distribution per kilogram of body weight was relatively constant (1.10 plus or minus 0.12 liters/kg).