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Y Ohbora

Publications and source records attributed to Y Ohbora.

13 recordsLinked to original sources
PubMed2000

Michaelis-Menten elimination kinetics of acetate during ethanol oxidation.

BACKGROUND: The redistribution of acetate cannot be explained using a linear kinetic model. We studied the pharmacokinetics of acetate during ethanol oxidation in the rabbit. METHODS: An ethanol saline solution (0.5, 1.5, and 2.5 g/kg) was injected bolus intravenously. We measured blood ethanol, acetaldehyde, and acetate concentrations by using head-space gas chromatography. RESULTS: Blood acetate concentration changed in three phases: an ascending, a plateau, and a declining phase. The first-order rate constant of the declining phase was smaller than that of the ascending phase and decreased dose dependently. Statistical moment analysis of the blood acetate profiles showed that the normalized area under the curve (AUC/Dose) and the mean residence time (MRT) increased with increasing dose amount. These increases suggest a capacity-limited elimination of acetate. We attempted simultaneous multiline fitting, using the three blood acetate disappearance curves, to determine the pharmacokinetic model. Consequently, the blood acetate profile was best described by a Michaelis-Menten elimination kinetic model. The Vmax and Km values of acetate elimination were 40.80 +/- 14.10 mM/hr and 0.47 +/- 0.19 mM, respectively. The fraction of a dose of ethanol converted to acetate (f(AcA)) was calculated to be 0.54. The estimated values are average parameter values of three different doses. Fitted curves suggest smaller f(AcA) at a low dose and larger f(AcA) at a higher dose, which indicate increases of accumulation and redistribution of acetate at higher doses. CONCLUSIONS: Acetate elimination during ethanol oxidation obeys capacity-limited kinetics.

Acetaldehyde↗
PubMed1999

Michaelis-Menten elimination kinetics of acetate in rabbit.

BACKGROUND: Acetate redistribution from hepatic to peripheral tissues was reported during ethanol metabolism when saturating conditions were reached for acetate metabolism. Because this redistribution cannot be clarified by linear kinetics, elimination kinetics of acetate was studied in the rabbit. METHODS: A sodium-acetate solution in physiological saline (0.5 and 1.0 g/kg of body weight) was injected as an intravenous bolus. The blood acetate profile was measured by headspace gas chromatography. RESULTS: Blood acetate disappeared rapidly. Statistical moment analysis of the blood acetate profiles showed that the normalized area under the curve and the mean residence time increased with an increasing dose amount. These increases suggested a capacity-limited elimination of acetate. Simultaneous multilines fitting after two acetate doses was used to estimate the pharmacokinetic model by the application of minimum Akaike's information criterion estimation. As a result, the blood acetate concentration-time curve was best described by a two-compartment open model with Michaelis-Menten elimination kinetics. The Vmax value was approximately two times larger than that of ethanol obtained by using the same compartment model. The Km value (1.5 mM) was almost the same as that of ethanol and corresponded to blood acetate levels during ethanol oxidation that had been reported to be approximately 2 mM. CONCLUSION: The elimination of acetate obeys nonlinear kinetics, which can clarify the saturation of acetate metabolism.

Animals↗
PubMed1998

Effects of repeated cocaine administration on alcohol consumption.

OBJECTIVE: Alcohol consumption (alcohol preference or alcohol intake) in animals is an index of human drinking behavior. Cocaine is the most frequently abused drug at present. Therefore, an increasing number of cases demonstrating concurrent use of alcohol and cocaine is being noted. We examined whether cocaine affects alcohol consumption and studied the mechanism of change in alcohol consumption following cocaine administration. METHOD: We measured alcohol consumption in inbred mice, C57BL/6J and C3H/HeJ, when 10 or 50 mg/kg cocaine was administered intraperitoneally once a day for 1 week. Then the rate of blood ethanol disappearance from C57BL/6J mice in vivo was measured. Also, liver alcohol dehydrogenase(ADH) and aldehyde dehydrogenase(ALDH) activity in vitro were measured in the C57BL/6J mice. RESULTS: Following 50 mg/kg cocaine administration, alcohol consumption was reduced in C57BL/6J mice, but there was no clear change in C3H/HeJ mice. The rate of blood ethanol disappearance was not changed by pretreatment with cocaine. Neither liver ADH nor ALDH activity was changed by repeated cocaine administration. CONCLUSIONS: The present study showed that repeated cocaine administration decreased alcohol consumption in C57BL/6J mice without altering the metabolism of ethanol.

Alcohol Dehydrogenase↗
PubMed1996

Problems in pharmacokinetic analysis of alcohol disposition: a trial of the Bayesian least-squares method.

The technical problems of the pharmacokinetic analysis of alcohol disposition were studied using the Michaelis-Menten elimination kinetic model. This model was defined by two forms of equations: differential and integrated, with the latter being derived by integration of the differential equation. We compared the parameter values, estimated by one-line curve-fitting, using these two equation forms. We concluded that, for the kinetic analysis of alcohol disposition, curve-fitting with the differential equation was superior to that with the integrated equation. We also studied the methodological problems involved in one-line fitting. The ordinary least-squares (OLS) method was compared with the Bayesian least-squares (BLS) method. Correlation between the Vmax and beta (ethanol elimination rate) values, and between the Vmax and K(m) values was seen when the parameter values were estimated by the OLS method. These results suggested that one-line fitting by the OLS method was not adequate for Michaelis-Menten-type elimination kinetic analysis. BLS analysis resulted in no correlation between the estimated parameter values that did not change with the level of the dose. The BLS method seemed to be more useful than the OLS method for the estimation of individual pharmacokinetic parameter values.

Animals↗
PubMed1996

Noncompetitive-like inhibition of ethanol elimination by cyanamide treatment: pharmacokinetic study.

The effect of acetaldehyde accumulation of ethanol elimination is of interest in medico-legal practice in Japan. We examined the pharmacokinetic mechanism of the inhibition of ethanol metabolism by cyanamide, an inhibitor of mitochondrial aldehyde dehydrogenase. An ethanol solution (0.25-2.0 g/kg body weight) was injected intravenously into male rabbits with or without administration of cyanamide. Cyanamide was injected intraperitoneally (25 mg/kg body weight) to the cyanamide-treated group 2 hr before ethanol injection. Blood ethanol and acetaldehyde concentrations were measured periodically by head-space gas chromatography. The MULTI(RUNGE) computer program was applied for the pharmacokinetic analysis. One- or two-compartment open models with Michaelis-Menten elimination kinetics were used for simultaneous multi-line fitting. The ethanol elimination rate decreased by cyanamide treatment. The border-point concentration between pseudolinear and curvilinear phases was not affected by cyanamide treatment. The estimated Vmax value decreased by cyanamide treatment, whereas the K(m) value did not change. Our results correspond to a noncompetitive-like inhibition of ethanol metabolism. K(m) is related to the border point between pseudolinear and curvilinear phases. Thus, our findings in the blood ethanol concentration-time curve suggest adequate curve-fitting. The product, or competitive, inhibition of alcohol dehydrogenase by acetaldehyde had been reported in enzymological study. The pharmacokinetic manner of inhibition in vivo was different from the enzymologic mechanism in vitro. Other metabolic factors related to ethanol metabolism are thought to be more important than acetaldehyde accumulation itself.

Acetaldehyde↗
PubMed1989

Buthionine sulfoximine inhibition of glutathione biosynthesis enhances hepatic lipid peroxidation in rats during acute ethanol intoxication.

A single intraperitoneal injection of DL-buthionine-S,R-sulfoximine (BSO) (4 mmol/kg) to overnight-starved rats caused a 70% inhibition of hepatic gamma-glutamylcysteine synthetase and induced a decrease in liver-reduced glutathione (GSH) for several hours. There was, however, no difference in hepatic lipid peroxidation, as assessed by malondialdehyde accumulation, between the control and BSO groups. During acute ethanol intoxication (5 g/kg), hepatic lipid peroxidation was increased by approx. 40% within 6 hr. Hepatic [GSH] was also significantly decreased by ethanol. The effect of ethanol on GSH level was not observed in rats pretreated with BSO, though the ethanol-induced enhancement of hepatic lipid peroxidation was potentiated by the BSO pretreatment. Under these conditions there were no apparent effects on blood concentrations of ethanol and acetaldehyde nor on activities of hepatic alcohol dehydrogenase, aldehyde dehydrogenase, glutathione-dependent detoxifying enzymes, superoxide dismutase or catalase. These results suggest that, although a decrease (by BSO) in GSH by itself does not alter the degree of endogenous lipid peroxidation, it is associated with a potentiation of the enhancement of hepatic lipid peroxidation caused by acute ethanol intoxication.

Alcoholic Intoxication↗
PubMed1988

The metabolism of acetaldehyde and not acetaldehyde itself is responsible for in vivo ethanol-induced lipid peroxidation in rats.

A single oral administration of ethanol (5 g/kg) to rats induced a marked increase in lipid peroxidation, in the liver and kidney within 9 hr, as assessed by malondialdehyde accumulation. The pretreatment with alcohol dehydrogenase (ADH) inhibitor, 4-methylpyrazole (1 mmol/kg) caused approximately 50% inhibition of the hepatic ADH activity and abolished this ethanol-induced lipid peroxidation. The disulfiram treatment (100 mg/kg) significantly inhibited 63% of the hepatic low Km aldehyde dehydrogenase (ALDH) but not the high Km ALDH. The cyanamide treatment (15 mg/kg) effectively decreased 83% of the low Km and 70% of the high Km ALDH in the liver. Although there was more than a 20-fold elevation of acetaldehyde levels by the inhibition of acetaldehyde metabolism with disulfiram or cyanamide, the ethanol-induced lipid peroxidation was significantly suppressed by pretreatment with these drugs. More than 90% inhibition of xanthine oxidase and dehydrogenase by the pretreatment with allopurinol (100 mg/kg), with no effect on the hepatic ADH and ALDH activities, did not alter the enhancement of lipid peroxidation following ethanol administration. We propose that the metabolism of acetaldehyde (probably via the low Km ALDH) and not acetaldehyde itself is responsible for the ethanol-induced lipid peroxidation in vivo and that the contribution of xanthine oxidase, as an initiator of lipid peroxidation through acetaldehyde oxidation is minute during acute intoxication.

Acetaldehyde↗
PubMed1985

Ethanol induced changes in lipid peroxidation and nonprotein sulfhydryl content. Different sensitivities in rat liver and kidney.

Acute ethanol ingestion (5 g/Kg) led to an acceleration of lipid peroxidation and reduction in non-proteinic free sulfhydryl (NPFSH) levels in the rat liver and kidney. In the liver, progressive changes of these phenomena were inversely related, and maximal effects were observed 6 hr after ethanol ingestion. Unlike the liver, in the kidney, there was a rapid fall in NPFSH content followed by constantly reduced levels during ethanol intoxication, whereas acceleration of lipid peroxidation was detected only after 6-8 hr of ethanol. In addition, a lower dose (2 g/Kg) which caused no significant change in the liver, was effective in reducing renal NPFSH, but not in enhancing lipid peroxidation. These results suggest that acceleration of lipid peroxidation may not be required for the NPFSH decrease, at least in case of kidney.

Animals↗
PubMed1983

Polycystic kidney disease and intracranial aneurysms. Early angiographic diagnosis and early operation for the unruptured aneurysm.

From August, 1981, to August, 1982, the authors performed four-vessel angiography in 17 patients with polycystic kidney disease (PKD) who had no neurological deficit and no history of subarachnoid hemorrhage. Seven cases of unruptured aneurysms were found among these 17 patients (an incidence of 41.2%). Five of the unruptured aneurysms were operated on prophylactically, with no mortality or morbidity. Nine of the 17 patients had hypertension and, of these, two (22.2%) had aneurysms. Of the eight patients without hypertension, five (62.5%) had aneurysms. This study suggests that the coexistence of PKD and intracranial aneurysms might not be due to the hypertension that occurs concomitant with PKD, but instead may be attributable to congenital factors. The authors stress the necessity of early diagnosis and early operation for unruptured aneurysms in patients with PKD.

Adult↗
PubMed1976

[Diencephalic cyst--in relation to other midline dysraphism (author's transl)].

The abnormal midline cyst of diencephalic origin was termed "diencephalic cyst" by Brocklehurst in 1973. Since then, several case reports of so-called "diencephalic cyst" have appeared, but its clinical picture, especially its relation to other midline dysraphisms, does not seem to be well understood. Our experience with four cases of so-called "diencephalic cyst" were reported and their relation to holoprosencephaly as well as simple agenesis of corpus callosum was discussed. (1) In all of these cases, there was an abnormal space in the midline which freely communicated with the lateral ventricle. In the first two cases, their clinical pictures as well as the features of contrast studies were typical of alobar holoprosencephaly. In the third case, the absence of the olfactory tract, the incompletely separated cerebrum, and the monoventricle were confirmed at autopsy. In the last case, the ventricle was also incompletely separated. From these observations, such a malformation should better be considered as a variant of holoprosencephaly, and it would not be appropriate to classify this malformation, as Brocklehurst claimed, as "a maldevelopment lying between the group associated with anterior neuropore closure and prosencephalization (anterior encephaloceles and holoprosencephaly) and the group associated with maldevelopment of the hind brain (cerebellar and fourth ventricle encephaloceles and Dandy-Walker cyst of the rhombencephalon)." (2) This malformation is apparently formed before the 40 mm stage of the embryo, since by this time the diencephalic roof has already sunk to the level of the adult form. This maldevelopment should be clearly differenciated from simple agenesis of the corpus callosum which is formed after the 60 mm stage of the embryo. In simple agenesis of the corpus callosum, the deep venous system might take an abnormal course, but is well formed, whereas in holoprosencephaly or so-called "diencephalic cyst", the internal cerebral vein as well as the straight sinus and the inferior sagittal sinus is absent. (3) In all of our cases, there was an abnormal space posterior and inferior to the elevated lateral sinus. Autopsy done in two cases revealed that this abnormal space was a Dandy-Walker cyst in one case, the the dorsal sack of diencephalic origin in the other case. The latter case tells that in the cases of holoprosencephaly the lateral sinus does not necessarily mark the boundary between the cerebrum and the cerebellum. (4) "Diencephalic cyst" often accompanies severe hydrocephalus. However, even with successful surgical treatment of hydrocephalus, the outcome of intelligence in these cases would be grave.

Agenesis of Corpus Callosum↗