Measurement of alpha s from energy-energy correlations at the Z0 resonance.
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Journal Article↗
Biomedical subjects
K Furuno
Publications and source records attributed to K Furuno.
Precise measurement of the left-right cross section asymmetry in Z boson production by e+e- collisions.
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Journal Article↗
Simple and sensitive assay of zonisamide in human serum by high-performance liquid chromatography using a solid-phase extraction technique.
A rapid and sensitive method for the assay of zonisamide in serum was developed using a solid-phase extraction technique followed by high-performance liquid chromatography. A 20-microliter volume of human serum was first purified with a Bond-Elut cartridge column. Then, the methanol eluate was injected onto a reversed-phase HPLC column with a UV detector. The mobile phase was acetonitrile-methanol-distilled water (17:20:63, v/v) and the detection wavelength was 246 nm. The detection limit was 0.1 micrograms/ml in serum. The coefficients of variation were 4.2-5.6% and 5.1-9.1% for the within-day and between-day assays, respectively. This method can be used for clinical pharmacokinetic studies of zonisamide in serum even in infant patients with epilepsy.
Anticonvulsants↗
First-pass metabolism of omeprazole in rats.
To clarify the in vivo first-pass metabolism of omeprazole, the pharmacokinetics were examined after oral, intraduodenal (i.d.), intraportal venous (i.p.v), and intravenous (i.v.) administration at various doses to rats. Extraction ratios in the liver and intestinal tract were determined from the areas under the concentration-time curve (AUC) for i.p.v. and i.v. administration and from those for id and ipv administration, respectively. Assuming that the drug was absorbed from the gastrointestinal tract completely, the hepatic and intestinal extraction ratios were 0.80, 0.63, and 0.59 at doses of 2.5, 5, and 10 mg/kg and 0.70 and 0.73 at doses of 5 and 10 mg/kg, respectively. The bioavailability of orally administered omeprazole was 6.4, 9.6, and 12.6% at the doses of 10, 20, and 40 mg/kg, respectively. There were no differences in the distribution volume of steady state, total clearance, or elimination half-life at any doses. In addition, the AUC value after oral administration (20 mg/kg) in rats acutely intoxicated with CCl4 was 2.4 times larger than that in the control. These findings suggest that omeprazole undergoes a first-pass metabolism in the intestinal mucosa and/or lumen, as well as in the liver, and that the major contribution to the dose-dependent increase in bioavailability is a saturation of the first-pass metabolism in the liver.
Administration, Oral↗
Simultaneous determination of primidone and its active metabolites in rat plasma by high-performance liquid chromatography using a solid-phase extraction technique.
Primidone (PRM) and its active metabolites, phenylethylmalonamide (PEMA) and phenobarbital (PB), in rat plasma were simultaneously determined using a solid-phase extraction technique followed by high-performance liquid chromatography (HPLC). Twenty microliters of plasma was applied to a Bond-Elut C-18 cartridge column with 0.1 microgram of acetanilide (internal standard, IS). After the column was washed, PRM, PEMA, PB, and IS were eluted with methanol and injected into the HPLC system. Calibrations for these substances were linear in the range of 0-20 micrograms/mL. The coefficients of variation were 1.5-7.9% and 3.4-9.1% in the within-day and between-day assays, respectively. The recovery rates were 96.8-101.8%. The pharmacokinetics of these substances were examined after oral administration of PRM (50 mg/kg) to rats. The Tmax values for PRM, PEMA, and PB were 1.4, 5.7, and 6.6 h, respectively, and the Cmax values were 18.2, 8.1, and 9.6 micrograms/mL, respectively. This method is useful for pharmacokinetic studies of PRM and its active metabolites.
Administration, Oral↗
High peroxidative susceptibility of fish oil polyunsaturated fatty acid in cultured rat hepatocytes.
The peroxidative susceptibility in cultured rat hepatocytes of eicosapentaenoic acid (EPA) and other polyunsaturated fatty acids (PUFA) with different numbers of double bonds was examined. Lipid peroxidation was evaluated using a newly developed HPLC procedure which includes the determination of malondialdehyde (MDA). Following exposure to 0.25-1.0 mM EPA adsorbed to BSA (EPA-BSA), cultured hepatocytes produced MDA in the fatty acid concentration- and incubation time-dependent manner. The rate of MDA production by hepatocytes varied greatly with the degree of PUFA unsaturation, and ranked as follows: docosahexaenoic acid > EPA > arachidonic acid > alpha-linolenic acid = gamma-linolenic acid > linoleic acid > oleic acid. Prolonged exposure of cultured hepatocytes to 1.0 mM EPA-BSA resulted in substantial leakage of LDH into the medium. The cell injury was associated with the loss of cellular GSH and protein thiol groups. Cotreatment of the EPA-supplemented hepatocytes with a GSH-depleting agent, diethylmaleate, promoted the cellular protein thiol loss and LDH leakage. An iron chelator, deferoxamine, and other antioxidants such as N,N-diphenyl-p-phenylenediamine and gamma-tocopherol efficiently prevented MDA production and consequently LDH leakage in the EPA-supplemented hepatocytes. These results show that peroxidative deterioration in excess of GSH-dependent defense mechanisms may occur in hepatocytes loaded with highly peroxidizable fish oil PUFA.
Animals↗
Effect of cumene hydroperoxide on lipid peroxidation in cultured rat hepatocytes supplemented with eicosapentaenoic acid.
The present study was undertaken to examine whether the oxidative effect of organic hydroperoxide on cultured rat hepatocytes is enhanced by eicosapentaenoic acid (EPA). The cells were pretreated with 0.8 mM EPA which was complexed to bovine serum albumin (EPA-BSA) for 4 h, and then challenged to cumene hydroperoxide (CMHP). By the addition of CMHP to the cell culture, lipid peroxidation estimated as production of malondialdehyde (MDA) was provoked to a much greater extent in the EPA-loaded hepatocytes than in the non-loaded cells. The CMHP treatment also resulted in more severe cell injury in association with the decrease in intracellular levels of glutathione and protein thiols in the EPA-loaded cells as compared with results in the non-loaded cells. The addition of antioxidants such as N,N'-diphenyl-p-phenylenediamine (DPPD), promethazine and gamma-tocopherol to the culture medium prevented the CMHP-induced oxidative injury effectively for the EPA-loaded cells but had little effect for the non-loaded cells. The potency of other unsaturated fatty acids with different numbers of double bonds in enhancing the CMHP-induced lipid peroxidation and injury was also examined. The deleterious effects of CMHP were little affected by unsaturated fatty acids with one or two double bonds but were markedly intensified by those with more than 4 double bonds. These data showed that the supplementation with highly unsaturated fatty acids makes the cells susceptible to the drug-induced oxidative stress.
Albumins↗
[ICG-disappearance rate during sevoflurane- or neurolept anesthesia].
We evaluated the effect of sevoflurane or neuroleptanesthesia on ICG-disappearance rate in 22 patients undergoing elective extra-abdominal surgery. We divided the patients into three groups, i.e., SN-group (n = 8), SH-group (n = 8) and NLA-group (n = 6). Systolic arterial pressure (SAP) in the patients of SN-group or SH-group was maintained with sevoflurane at about 100% or 70% of the preoperative value respectively. There was no significant difference in SAP between SN-group and NLA-group. In SN-group and NLA-group, there was no significant difference in the ICG-disappearance rate between the values during anesthesia and those during preoperative period. In SH-group, however, it was significantly lower than the preoperative value. We conclude that, when normal systolic arterial pressure can be maintained, sevoflurane or neuroleptanesthesia has little effect on the liver function and hepatic blood flow. Sevoflurane anesthesia with 70% of preoperative SAP, however, may depress the liver function and hepatic blood flow.
Aged↗
Possible explanations for the antagonism by nicotine against reserpine-induced depletion of monoamines in mouse brain.
The inhibitory effect of nicotine pretreatment on reserpine-induced depletion of monoamines in mouse brain was investigated. The depletion of brain monoamines by 24 h after intraperitoneal injection of reserpine (2 mg/kg) was dose-dependently inhibited by nicotine (0.3-10 mg/kg, s.c.) pretreatment 20 min before reserpine injection. This effect of nicotine was more marked on dopamine depletion than on noradrenaline or 5-hydroxytryptamine depletion. The nicotine pretreatment also inhibited the reserpine-induced hypothermia and decrease in the locomotor activity. When reserpine (2 mg/kg) was injected intraperitoneally, the inhibitory effect of nicotine (3 mg/kg, s.c.) on the reserpine-induced depletion of brain monoamines and heart noradrenaline was not antagonized by hexamethonium (8 mg/kg, s.c.) but rather potentiated by mecamylamine (2 mg/kg, s.c.). However, when reserpine (0.5 mg/kg) was injected intravenously, pretreatment with nicotine (3 mg/kg, s.c.) inhibited the reserpine-induced dopamine depletion only, and this effect of nicotine was completely blocked by mecamylamine but not by hexamethonium. These results suggest that inhibitory effect of nicotine on the intraperitoneal reserpine-induced depletion of brain monoamines is due to an inhibition of absorption of reserpine, and that central nicotinic action is also involved in the antagonism by nicotine of reserpine-induced dopamine depletion.
Animals↗
Effect of beta-adrenergic receptor antagonists on nicotine-induced tail-tremor in rats.
The effects of various beta-adrenergic receptor antagonists on nicotine-induced tail-tremor were investigated in rats. Atenolol (5 and 10 mg/kg, IP), arotinolol (5 and 10 mg/kg, IP), and carteolol (5 and 10 mg/kg, IP), hydrophilic beta-adrenergic receptor antagonists, did not affect the tail-tremor induced by nicotine given at a dose of 0.5 mg/kg SC. However, propranolol (5-20 mg/kg, IP) and pindolol (5-20 mg/kg, IP), nonselective and lipophilic beta-adrenergic receptor antagonists, did suppress the tail-tremor dose dependently. In contrast, metoprolol (5-20 mg/kg, IP), lipophilic and beta 1-selective adrenergic receptor antagonists, did not show such an effect. These results suggest that nicotine-induced tail-tremors may be mediated through central beta 2-adrenergic receptors as an appearance and developmental mechanism.
Adrenergic beta-1 Receptor Antagonists↗
Chronic nicotine treatment potentiates behavioral responses to dopaminergic drugs in rats.
In the present study, the behavioral effects of apomorphine, methamphetamine, and haloperidol were examined in nicotine-treated rats. All animals were SC administered nicotine at a dose of 0.5 mg/kg or saline once daily for 14 days. Hyperlocomotion induced by apomorphine (0.2 mg/kg, IP) and methamphetamine (1.0 mg/kg, IP) was greater in nicotine-treated rats than in control rats. Stereotyped behaviors induced by apomorphine (1.0 mg/kg, IP) and methamphetamine (5.0 mg/kg, IP) were also potentiated in nicotine-treated rats. However, the incidence of catalepsy induced by haloperidol (0.25-1.5 mg/kg, IP) was slightly lower in nicotine-treated rats. These results suggest that chronic nicotine treatment may increase the susceptibility of the dopaminergic system to dopaminergic drugs.
Animals↗
Cycling of two endogenous lysosomal membrane proteins, lamp-2 and acid phosphatase, between the cell surface and lysosomes in cultured rat hepatocytes.
Our previous studies provided evidence that a 107-kDa major lysosomal membrane glycoprotein termed lamp-1 shuttles between lysosomes and the plasma membrane along the endocytic pathway in rat hepatic cells [Furuno et al. (1989) J. Biochem. 106, 708-716; Furuno et al. (1989) J. Biochem. 106, 717-722]. In the present study, we investigated the movement of a 96-kDa major lysosomal membrane glycoprotein, referred to as lamp-2, and lysosomal acid phosphatase (LAP) in the endocytic membrane transport system of cultured rat hepatocytes. Fab' fragments of anti-lamp-2 and anti-LAP antibodies conjugated with horseradish peroxidase (HRP) were used as probes to analyze quantitatively the transport of these two membrane proteins from the cell surface to lysosomes. After the addition of HRP-anti-lamp-2 and anti-LAP Fab' fragments to the culture medium, the delivery of the antibody conjugates to lysosomes was examined by cell fractionation on a Percoll density gradient. The amount of these HRP tracers in the lysosomal fraction became larger as the period of cell incubation was increased. Km values for uptake of HRP-anti-lamp-2, and LAP Fab' fragments were 0.74 and 0.62 microM, respectively, which were comparable to that of HRP-anti-lamp-1 Fab' (0.57 microM). The endocytic process of the two HRP-antibodies continued for an extended period in the cells exposed to the protein synthesis inhibitor, cycloheximide. Furthermore, we measured the transit times of HRP-anti-lamp-1, anti-lamp-2, and anti-LAP Fab' fragments from the cell surface to lysosomes.(ABSTRACT TRUNCATED AT 250 WORDS)
Acid Phosphatase↗
The influence of increased plasma protein binding on the disposition of quinidine in turpentine-treated rats.
The effect of the increased plasma protein binding of quinidine on its disposition was investigated in turpentine-treated rats, since turpentine treatment is known to increase the plasma concentration of alpha 1-acid glycoprotein which preferentially binds basic drugs. The plasma free fraction of quinidine 16 and 48 h after turpentine treatment was decreased by 30 and 76%, respectively, compared to the control value. The treatment did not cause liver injury nor alter the hepatic blood flow. The disappearance of quinidine in plasma after an intravenous injection (3.0, 7.0, 12.5 mg/kg) was analyzed by a two-compartment open model in both control and turpentine-treated rats. The blood total body clearance (CLb) of quinidine at 48 h after the treatment was decreased by 30 to 65% in a dose-dependent manner, compared to that in control rats. The distribution volume (Vdss) of quinidine (12.5 mg/kg) at 16 and 48 h after turpentine treatment was decreased by 30 and 79%, respectively. Hepatic extraction ratio (HER) of quinidine, which was determined at steady state blood concentrations from 0.5 to 2.3 micrograms/ml, was decreased from 0.8 to 0.35 with an increase in the quinidine concentration in control rats. The HER value 48 h after turpentine treatment was consistently reduced by 15 to 40% in a concentration-dependent manner compared to the corresponding control value. These findings indicate that the increased plasma binding of quinidine caused a reduction of HER of the drug, and the reduced HER resulted in the decrease in CLb in turpentine-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Synthesis of thiazolo[3,2-a]pyridine derivatives and their reactions].
By the reaction of 2-benzoylmethyl-4-methylthiazole (6) with polarized olefins (3, 4) in the presence of base (K2CO3 or NaH), the corresponding thiazolo[3,2-a]pyridine derivatives (7, 8) were obtained. Methylsulfinylthiazolopyridine derivative (11) obtained by the reaction of 8b with m-chloroperbenzoic acid (MCPBA), easily underwent nucleophilic substitution to give the corresponding substituted compounds (10, 12).
Pyridines↗
Influences of exposure to cigarette smoke on concentration of nicorandil in plasma of rats.
Influences of acute exposure to cigarette smoke on plasma concentrations of nicorandil administered orally and parenterally were investigated in rats by HPLC. The animals were exposed to tobacco smoke of two kinds of cigarettes using a smoking machine (i.e., the cigarette smoke contained either low or high nicotine and tar). The plasma concentration of nicorandil administered orally at a dose of 10 mg/kg had a lower absorption phase in two cigarette smoke-exposed groups, particularly in the high nicotine and tar-containing cigarette smoke-exposed group, compared with the nonsmoking control group. The AUC and MRT values in a high nicotine and tar-containing cigarette smoke-exposed group were lower and higher, respectively, than in the nonsmoking control group. However, there was no marked difference in nicorandil plasma concentrations between the cigarette smoke-exposed group and the nonsmoking control group when nicorandil was administered ip or iv at a dose of 5 mg/kg. These results suggest that cigarette smoke exposure causes the suppression or delay of absorption of nicorandil from the gastrointestinal tract.
Administration, Oral↗
Effects of exposure to standard- and nicotine-reduced-cigarette smoke on pharmacokinetics of theophylline and cimetidine in rats.
Influences of exposure to standard- (containing nicotine and tar) and nicotine-reduced-cigarette smoke on the pharmacokinetics of theophylline (20 mg/kg, per os) and cimetidine (50 mg/kg, per os) were investigated in rats. Animals were exposed to standard- or nicotine-reduced-cigarette smoke for 8 min with a "smoking machine". In control rats, theophylline concentrations in plasma increased rapidly, peaked 2 h later, and then decreased gradually. Concentrations of theophylline in plasma of rats exposed to standard- and nicotine-reduced-cigarette smoke were suppressed in comparison with that of control rats, and the suppressive effect of nicotine-reduced-cigarette smoke was weaker than that of standard-cigarette smoke. The suppression of theophylline concentrations in plasma induced by exposure to cigarette smoke may be due to nicotine and other constituents of the cigarette smoke, even if the effects are slight. For cimetidine, no difference was found between drug concentration in plasma of rats exposed to nicotine-reduced-cigarette smoke and that of control rats; however, the drug concentration in plasma of rats exposed to standard-cigarette smoke was markedly suppressed. These results suggest that the suppression of cimetidine concentrations in plasma may be due solely to nicotine in cigarette smoke.
Animals↗
Distribution of quinidine in rats with carbon tetrachloride-intoxicated hepatic disease.
The disposition of quinidine was investigated in rats with experimental hepatic disease caused by an intraperitoneal injection of CCl4. The plasma disappearance of quinidine after a 12.5 mg/kg i.v. bolus injection was analyzed by a two-compartment open model in both control and CCl4-intoxicated rats. In the CCl4-intoxicated rats, plasma total body clearance (CLtot), elimination rate constant of the central compartment (kel) and the volume of distribution (Vdss) of quinidine were decreased by 73, 51 and 36%, respectively, compared to those in the control rats. At a steady state of quinidine plasma concentration of 1 micrograms/ml, tissue-to-plasma partition coefficient (Kp,vivo) of the drug in the lung, spleen, heart, kidney and liver in the CCl4-intoxicated rats were decreased ranging from 32 to 42% compared to those in the control rats. The plasma free fraction of quinidine in the intoxicated rats was decreased by 34% of that in the control rats. Neither tissue binding of quinidien in vitro, nor plasma pH was altered in the intoxicated rats. Thus, the decrease in Vdss and Kp,vivo for quinidine in the intoxicated rats seems likely to be due to an increase in plasma protein binding of the drug. Metabolic activity in the liver, the hepatic extraction ratio for quinidine, and the hepatic blood flow in the CCl4-intoxicated rats were decreased by 84, 57 and 47%, respectively, compared to those in the control rats. The decrease in CLtot and kel in the intoxicated rats is considered to be attributed to both the reduction of liver functions and the increase in the plasma protein binding of the drug.
Animals↗
Accumulation of propranolol in cultured rat fibroblasts.
In order to clarify the involvement of phosphatidylserine (PhS) in the cellular accumulation of propranolol, we have characterized the binding of 3H-propranolol to cultured rat fibroblasts and to liposomes containing PhS. The properties of propranolol binding to the cells and liposomes were analyzed by means of a Scatchard plot. The cells contained at least two classes of propranolol binding sites, one site of high affinity/low capacity and the second site of lower affinity/higher capacity, while the liposomes contained only one class of binding site. The values of the association constant (K) and number of binding sites (n), given on a PhS basis for the propranolol binding site in the liposomes, were both very close to those of corresponding binding parameters for the high affinity/low capacity binding site in the cells. Cell death, caused by various toxic reagents, resulted in a marked decrease in propranolol accumulation in the cells. Kinetic analysis of the drug binding to dead cells showed one binding site with binding parameters comparable to those of the low affinity/high capacity binding site in the intact cells. Polar cations, methylamine and NH4Cl, completely inhibited propranolol binding to the liposomes. On the other hand, these cations partially inhibited propranolol accumulation in intact cells and failed to inhibit the drug binding to dead cells. These results suggest that PhS in cytomembranes represents the high affinity/low capacity propranolol binding site in cultured rat fibroblasts.
Ammonium Chloride↗