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Göran Wahlström - One of the best experts on this subject based on the ideXlab platform.
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the interaction between physostigmine and Hexobarbital in male rats
Pharmacology & Toxicology, 2009Co-Authors: Göran WahlströmAbstract:The sensitivity to Hexobarbital was tested with an EEG-threshold. Hexobarbital was infused continuously in a tail vein of male rats and the dose needed to obtain a burst suppression of 1 sec. or more in the EEG (the “silent second”) was determined. In the first part of the experiments the dose response and time response of the effect of physostigmine on the Hexobarbital threshold was determined. The rats were pretreated with methylatropine 2.0 mg/kg subcutaneously. Testing of three different doses of physostigmine (0.5, 1.0 and 2.0 mg/kg intraperitoneally) showed that only the highest dose raised the Hexobarbital threshold. The optimal time interval between the dose of physostigmine and Hexobarbital threshold to obtain this effect was found to be around 1.5 hours. In the second part of the experiment the antagonistic effect of atropine was investigated. Methylatropine (2 mg/kg intraperitoneally) combined with physostigmine (2.0 mg/kg intraperitoneally) increased the Hexobarbital threshold to 117 ± 4 per cent of a pre-experimental value. Substitution of methylatropine with atropine (8 mg/kg intraperitoneally) gave a threshold value of 94 ± 4 per cent. Atropine combined with saline gave a threshold of 85 ± 2 per cent. The corresponding value after methylatropine was 100 ± 5 per cent. Thus pretreatment with atropine can reduce the increase in dose of Hexobarbital caused by the CNS- effects of physostigmine.
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unequal anaesthetic potency despite equal brain concentration of Hexobarbital antipodes
Pharmacology & Toxicology, 2009Co-Authors: Göran Wahlström, Horst Buch, Walter BuzelloAbstract:Confirming earlier results, approximately 100 mg/kg more (—)- than (+)-Hexobarbital (infused intravenously) was needed to obtain a “silent second” (= burst suppression of 1 sec. or more in the EEG) in male rats. After infusion of (+)-, (—)- and racemic Hexobarbital at exactly the same infusion rates and in doses which with the racemate gave a silent second, no difference was found in the brain concentrations. The amount of Hexobarbital infused was, however, in the case of the (+)-antipode approximately 20 mg/kg higher and in the case of the (—)-antipode, approximately 80 mg/kg lower than the dose which gave a silent second with the corresponding antipodes. It is thus highly unlikely that different rates of accumulation in the central nervous system during the infusion would explain the differences in potency between the two antipodes. The 28% lower concentration of (+)-Hexobarbital compared to (—)-Hexobarbital found in the liver could be explained by earlier findings i.e. that the (+)-antipode is more rapidly metabolized than the (—)-antipode.
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interactions between Hexobarbital and thiopental in male rats evaluated with an anaesthesia threshold
Pharmacology & Toxicology, 2009Co-Authors: Lennart Norberg, Göran WahlströmAbstract:: The anaesthetic interaction between Hexobarbital and thiopental in different combinations were investigated in male rats by using the isobolografic method. Data on dose, serum or brain concentrations at an EEG-criterion induced with a threshold method were utilized. The criterion was defined by a burst suppression in the EEG of 1 sec. or more (the “silent second”). With rats more than 115 days of age a synergistic interaction (potentiation) was obtained when a low dose of Hexobarbital and a high dose of thiopental were used. The relationship between serum and brain concentrations of Hexobarbital and thiopental in the different tested combinations gave no evidence for a pharmacokinetic interaction. Thus the synergistic interaction was located in the brain and probably related to the mechanisms of action. The same tests performed on rats at an age of approximately 90 days gave not only a potentiation when a low dose of Hexobarbital and a high dose of thiopental were used, but also a potentiation when a high dose of Hexobarbital and a low dose of thiopental were used. These results indicate an age-related change in sensitivity in the CNS between 90 and 115 days of age. Further investigations of this age-related change showed that this change from a potentiation to an additive interaction occurred between the age of 85 and 96 days.
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the interaction between Hexobarbital and atropine or methylatropine in male rats
Pharmacology & Toxicology, 2009Co-Authors: Göran WahlströmAbstract:The interaction of atropine or methylatropine with a barbiturate was studied in male rats. Different doses of the cholinergic blocking agents were given prior to an anaesthesia threshold determination with Hexobarbital. The dose of Hexobarbital needed to induce a burst suppression in the EEG which was 1 second or longer (the “silent second”) was used as the threshold. The ensuing anaesthesia times were also measured. Methylatropine in doses up to 8 mg/kg had no discernable effect on the threshold within 5 hrs after the dose. Atropine decreased the threshold 1.5 hr after the administration. The maximal effect was obtained with the largest dose given (8 mg/kg, fig. 2). Both cholinergic blocking agents decreased the body temperature. No measurable effects were obtained on the ensuing anaesthesia times. The synergistic effect found between atropine and Hexobarbital in the present experiments is probably brought about through actions in the central nervous system.
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interactions between 1 2 propanediol propylene glycol and Hexobarbital
Pharmacology & Toxicology, 2009Co-Authors: A Osterlind, A Akesson, Göran WahlströmAbstract:The interaction between 1,2--propanediol and Hexobarbital was studied with an anaesthesia threshold method, where Hexobarbital is infused intravenously. The dose needed to obtain a burst suppression of one second or more is determined and given as per cent of a pre-experimental value obtained in the same rat. The effect of varying the interval between the intraperitoneal injection of 1,2--propanediol (2.06 g/kg) and the threshold determination was investigated. In the intervals, 10--50 min., the Hexobarbital threshold doses were significantly decreased by 13--27% (n = 7--18). Four different doses between 0.25 and 2.06 g/kg of 1,2--propanediol were then tested after a fixed interval of 30 min. As in the time interval study the thresholds after 2.06 g/kg were significantly decreased. No certain depressant effect was seen with 1.03 and 0.52 g/kg. With the lowest tested dose of 1,2-propanediol (0.25 g/kg) there was instead a significant increase in the threshold dose (13%). This might be an excitatory effect, which could correspond to the well-known effect, seen with low doses of other depressants for instance ethanol.
Toshio Yasumori - One of the best experts on this subject based on the ideXlab platform.
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polymorphism in stereoselective hydroxylations of mephenytoin and Hexobarbital by japanese liver samples in relation to cytochrome p 450 human 2 iic9
Xenobiotica, 1992Co-Authors: Ryuichi Kato, Yasushi Yamazoe, Toshio YasumoriAbstract:1. Stereoselective 4'-hydroxylations of R-(--)-mephenytoin and S-(+)-mephenytoin were determined in liver microsomes of 19 Japanese subjects. 2. The content of P-450 human-2 assessed by Western-blots correlated with microsomal S-(+)-mephenytoin 4'-hydroxylation. Antibody raised against P-450 human-2 effectively inhibited microsomal S-(+)-mephenytoin 4'-hydroxylation, but was less efficient for inhibition of R-(--)-mephenytoin 4'-hydroxylation in extensive metabolizers, and 4'-hydroxylation of both mephenytoin enantiomers in poor metabolizers. 3. Similar results were observed on the stereoselective hydroxylations of R-(--)- and S-(+)-Hexobarbital. Clear correlations were observed for the content of P-450 human-2 and microsomal R-(--)-Hexobarbital 3'alpha-hydroxylation and S-(+)-Hexobarbital 3'beta-hydroxylation. 4. Moreover, yeast microsomes expressing P-450 human-2 cDNA showed high stereoselectivities for hydroxylations of mephenytoin and Hexobarbital similar to those observed in human liver. 5. Two other cytochromes P-450(IIC 9/10) expressed in yeast, whose cDNA were synthesized by site-directed mutagenesis from human-2 cDNA, showed no stereoselectivity for the hydroxylations of mephenytoin and Hexobarbital, in spite of the modification of only two amino acid substitutions or deletions in the whole sequence. 6. Only a cytochrome derived from P-450 human cDNA corresponding to P-450 human-2 was expressed in human livers, the two cytochromes of the three related IIC9/10 forms were not expressed. 7. These findings indicate that P-450 human-2 is the major cytochrome P-450 responsible for the polymorphisms in stereoselective hydroxylations of mephenytoin and Hexobarbital.
Satoshi Toki - One of the best experts on this subject based on the ideXlab platform.
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new aspects of Hexobarbital metabolism stereoselective metabolism new metabolic pathway via gsh conjugation and 3 hydroxyHexobarbital dehydrogenases
Yakugaku Zasshi-journal of The Pharmaceutical Society of Japan, 2004Co-Authors: Reiko Takenoshita, Satoshi TokiAbstract:Hexobarbital, a short-acting hypnotic, is metabolized to 3′-hydroxyHexobarbital by cytochrome P450, and then to 3′-oxoHexobarbital by liver cytosolic dehydrogenase. New methods of separation for Hexobarbital and its metabolites by TLC have been developed and applied to study the metabolism of Hexobarbital enantiomers and stereoselective metabolism of Hexobarbital. (+)-Hexobarbital preferentially was transformed into β-3′-hydroxyHexobarbital and the (−)-enantiomer preferentially transformed into α-3′-hydroxyHexobarbital by rat liver microsomes. Glucuronidation and dehydrogenation of 3′-hydroxyHexobarbital were also stereoselective and the S-configuration at the 3′-position was preferred. α-3′-HydroxyHexobarbital from (−)-Hexobarbital and the β-isomer from (+)-Hexobarbital were shown to be preferentially conjugated with glucuronic acid in rabbit urine, and to be preferentially dehydrogenated to form 3′-oxoHexobarbital by rabbit and guinea pig 3-hydroxyHexobarbital dehydrogenases. A new metabolic pathway of Hexobarbital was found in which 3′-oxoHexobarbital reacts with glutathione to form 1,5-dimethylbarbituric acid and a cyclohexenone-glutathione adduct, a novel metabolite. 1,5-Dimethylbarbituric acid was excreted into the urine and the cyclohexenone-glutathione adduct into the bile of rats dosed with Hexobarbital. 3-HydroxyHexobarbital dehydrogenases that dehydrogenate 3-hydroxyHexobarbital into 3′-oxoHexobarbital were purified from the liver cytosol of rabbits, guinea pigs, goats, rats, mice, hamsters, and humans and characterized. These enzymes were monomeric proteins and had molecular weights of about 34500—42000, and used NAD+ and NADP+ as cofactors, except for the human enzyme that had a molecular weight of about 58000 and used NAD+ alone. Each enzyme exhibited its own characteristics. Substrate specificity demonstrated that 3-hydroxyHexobarbital dehydrogenases dehydrogenate not only α,β-unsaturated cyclic and acyclic secondary alcohols but also some 17β-, 3α-hydroxysteroids or both, except for the human enzyme. The amino acid sequence of the hamster enzyme indicated that it belongs to the aldo-keto reductase superfamily and hydroxysteroid dehydrogenase subfamily.
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Hexobarbital metabolism a new metabolic pathway to produce 1 5 dimethylbarbituric acid and cyclohexenone glutathione adduct via 3 oxoHexobarbital
Xenobiotica, 1993Co-Authors: Reiko Takenoshita, T Nakamura, Satoshi TokiAbstract:1. In the presence of glutathione under physiological conditions, 3'-oxoHexobarbital was non-enzymically converted to 1,5-dimethylbarbituric acid and a cyclohexenone-glutathione adduct. 2. The two reaction products were characterized by mass spectrometry, 1H- and 13C-n.m.r. spectrometry, and UV spectral analyses. 3. 1,5-Dimethylbarbituric acid was excreted in urine of rat given Hexobarbital, 3'-oxoHexobarbital, or 1',2'-epoxyHexobarbital, and accounted for 13.4, 14.5 and 4.7% of dose, respectively. 4. The cyclohexenone-glutathione adduct, a novel metabolite of Hexobarbital, was excreted in the bile of rat given Hexobarbital. 5. The route of 1,5-dimethylbarbituric acid formation via 3'-oxoHexobarbital in the metabolism of Hexobarbital was discussed in comparison with the epoxide-diol pathway.
Ryuichi Kato - One of the best experts on this subject based on the ideXlab platform.
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polymorphism in stereoselective hydroxylations of mephenytoin and Hexobarbital by japanese liver samples in relation to cytochrome p 450 human 2 iic9
Xenobiotica, 1992Co-Authors: Ryuichi Kato, Yasushi Yamazoe, Toshio YasumoriAbstract:1. Stereoselective 4'-hydroxylations of R-(--)-mephenytoin and S-(+)-mephenytoin were determined in liver microsomes of 19 Japanese subjects. 2. The content of P-450 human-2 assessed by Western-blots correlated with microsomal S-(+)-mephenytoin 4'-hydroxylation. Antibody raised against P-450 human-2 effectively inhibited microsomal S-(+)-mephenytoin 4'-hydroxylation, but was less efficient for inhibition of R-(--)-mephenytoin 4'-hydroxylation in extensive metabolizers, and 4'-hydroxylation of both mephenytoin enantiomers in poor metabolizers. 3. Similar results were observed on the stereoselective hydroxylations of R-(--)- and S-(+)-Hexobarbital. Clear correlations were observed for the content of P-450 human-2 and microsomal R-(--)-Hexobarbital 3'alpha-hydroxylation and S-(+)-Hexobarbital 3'beta-hydroxylation. 4. Moreover, yeast microsomes expressing P-450 human-2 cDNA showed high stereoselectivities for hydroxylations of mephenytoin and Hexobarbital similar to those observed in human liver. 5. Two other cytochromes P-450(IIC 9/10) expressed in yeast, whose cDNA were synthesized by site-directed mutagenesis from human-2 cDNA, showed no stereoselectivity for the hydroxylations of mephenytoin and Hexobarbital, in spite of the modification of only two amino acid substitutions or deletions in the whole sequence. 6. Only a cytochrome derived from P-450 human cDNA corresponding to P-450 human-2 was expressed in human livers, the two cytochromes of the three related IIC9/10 forms were not expressed. 7. These findings indicate that P-450 human-2 is the major cytochrome P-450 responsible for the polymorphisms in stereoselective hydroxylations of mephenytoin and Hexobarbital.
D C Mays - One of the best experts on this subject based on the ideXlab platform.
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inhibition and induction of drug metabolism by psoralens alterations in duration of sleep induced by Hexobarbital and in clearance of caffeine and Hexobarbital in mice
Xenobiotica, 1991Co-Authors: Glen Apseloff, J B Hilliard, Nicholas Gerber, D C MaysAbstract:1. Hexobarbital (100 mg/kg i.p.) sleeping times in male CD-1 mice pretreated (-1 h) with a single i.p. injection of 150 μmol/kg of psoralen or coumarin analogues were increased, most markedly (6-fold) by linear, methoxy-substituted psoralens.2. Hexobarbital sleeping times of mice which received three daily injections (231 μmol/kg; 50 mg/kg) of 8-methoxypsoralen (8-MOP) were 44% of controls (corn oil).3. The whole-body half-life of caffeine (1 mg) in mice was 10˙2, 1˙2, and 0˙37 h following 8-MOP (50 mg/kg per day) × 1, vehicle, and 8-MOP × 3 respectively.4. The whole-body concentrations of Hexobarbital (100 mg/kg dose) in mice 30 min after dosing were 14˙3±0˙9, 8˙4±0˙3, and 5˙2±0˙5 μg/ml (1 mcuse = 150 ml) following 8-MOP (50 mg/kg per day) × 1, vehicle, and 8-MOP × 3 respectively.5. It is concluded that, administered acutely, psoralen analogues inhibit Hexobarbital metabolism in mice; and 8-MOP administered acutely inhibits the metabolism of caffeine and Hexobarbital, but administered repeatedly increase...