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Biomedical subjects

K Uchino

Publications and source records attributed to K Uchino.

At least 37 records · Page 2Linked to original sources
PubMed1998

Amelioration by cyclosporin A of brain damage in transient forebrain ischemia in the rat.

The immunosuppressant drug cyclosporin A (CsA) is considered to be inherently protective in conditions of ischemia, e.g. in hepatic and cardiac tissue. However, investigations of effects of CsA on neuronal tissue have been contradictory, probably because the blood-brain barrier (BBB) is virtually impermeable to CsA. In the present study, we exploited the finding that the insertion of a syringe needle into brain parenchyma obviously disrupts the BBB and allows influx of CsA, and explored whether CsA, given as intraperitoneal injections daily for 1 week before and 1 week after forebrain ischemia of 7 or 10 min duration, ameliorates the damage incurred to the hippocampal CA 1 sector. In other experiments, the needle insertion and the first i.p. injection of CsA were made 30 min after the start of recirculation, with continued daily administration of CsA during the postinsult week. In animals which were injected with CsA in daily doses of 10 mg kg-1, but in which no needle was inserted, the drug failed to ameliorate CA1 damage, whether the ischemia had a duration of 7 or 10 min. Likewise, needle insertion had no effect on CA1 damage if CsA was not administered. In contrast, when CsA was given to animals with a needle insertion, CA1 damage was dramatically ameliorated, whether treatment was initiated 1 week before ischemia, or 30 min after the start of recirculation. The effect of CsA seemed larger than that of any other drug proposed to have an anti-ischemic effect in forebrain/global ischemia. Injection of tritiated CsA in one animal with BBB disruption lead to detectable radioactivity throughout the ventricular system, suggesting a generalised increase of the entry of CsA across the BBB. The results demonstrate that immunosuppressants of the type represented by CsA markedly ameliorate delayed neuronal damage after transient forebrain ischemia, provided that they can pass the BBB. It is discussed whether the effect of the drug is one involving calcineurin, a protein phosphatase, or if CsA counteracts a permeability transition of the inner mitochondrial membrane, assumed to occur in response to adverse conditions, e.g. gradual accumulation of Ca2+ in the mitochondria in the postischemic period.

Analysis of Variance↗
PubMed1997

Mastoparan-stimulated prolactin secretion in rat pituitary GH3 cells involves activation of Gq/11 proteins.

Mastoparan has been reported to induce a wide variety of cellular actions by activating GTP-binding proteins (G proteins) in various cells. Here, we demonstrate that mastoparan is able to stimulate the secretion of PRL from rat anterior pituitary tumor GH3 cells in dose- and time-dependent manners. Mastoparan had no effect on the accumulation of intracellular cAMP; however, it induced a rapid increase in the intracellular Ca2+ concentration in GH3 cells. Extracellular Ca2+ was required for mastoparan-induced PRL secretion, which was inhibited by nifedipine, an L-type Ca2+ channel blocker. Incubation of mastoparan with myo-[3H]inositol-labeled GH3 cells also resulted in the increased formation of inositol phosphates (InsPs) compared with control cells. Neomycin sulfate and U73122, both phospholipase C inhibitors, suppressed mastoparan-induced PRL secretion. Guanosine 5'-1beta-thioldiphosphate (GDPbetaS) encapsulated in GH3 cells by reversible electropermeabilization suppressed the response to mastoparan. However, pretreatment with pertussis toxin had no effect on the stimulation of PRL secretion by mastoparan, and both Mas7 (a highly active analogue of mastoparan) and Mas17 (an inactive analogue) enhanced the secretion of PRL to a similar level to that of mastoparan-induced GH3 cells. In contrast, the substance P-related peptide GPant-2A, a Gq antagonist, inhibited mastoparan-induced PRL release, whereas GPant-2, a G(i/o) antagonist, did not in electropermeabilized GH3 cells. Moreover, a specific G(q/11) antibody against the carboxyl terminus of the G(q/11) alpha-subunit blocked the stimulatory effect of mastoparan on secretion and mastoparan-stimulated InsPs production in digitonin-permeabilized GH3 cells. These results indicate that mastoparan induces the Ca2+-regulated secretion of PRL from GH3 cells by activating G(q/11) and the phospholipase C pathway.

Animals↗
PubMed1997

Hesperidin as an inhibitor of lipases from porcine pancreas and Pseudomonas.

In the course of our screening work for new types of lipase inhibitors, hesperidin was identified as a simple and small molecular weight inhibitor in the peels of Citrus unshiu. Hesperidin inhibited lipase activity from porcine pancreas and that from Pseudomonas, and their IC50 was 32 and 132 micrograms/ml, respectively. Hesperidin, neohesperidin, narirutin, and naringin are known as the main flavonoids in Citrus unshiu. Neohesperidin also inhibited the lipase from procine pancreas, but did not have any effect on Pseudomonas. Narirutin and naringin did not show this effect on lipases from porcine pancreas and Pseudomonas. In animal experiments, the concentration of plasma triglyceride in rats fed a diet containing 10% hesperidin were significantly lower than that fed the control diet.

Animal Feed↗
PubMed1996

Sulfated pentagalloyl glucose (Y-ART-3) inhibits HIV replication and cytopathic effects in vitro, and reduces HIV infection in hu-PBL-SCID mice.

To evaluate the efficacy of Y-ART-3 as an antiviral drug for HIV infections, its anti-HIV activity was assessed in vitro in cell culture systems and in vivo in hu-PBL-SCID mice. The results indicated that Y-ART-3 invariably inhibited not only HIV-1, but also HIV-2 and SIV strains. Its mechanism of action is ascribed to inhibition of viral adsorption to CD4-positive cells. In an in vivo study, human Ig- and CD4-positive cells were detected at similar levels in Y-ART-3-treated hu-PBL-SCID mice that were infected with HIV, and in PBS-treated control hu-PBL SCID mice that were not infected with HIV. If HIV positivity was calculated using the number of tests in which HIV was detected (i.e. PCR, and p24 from co-cultures of spleen and peritoneal wash cells), a significant effect of Y-ART-3 at a dose of 4 mg/kg was noted. Therefore, Y-ART-3 may be considered to be a potent and effective anti-HIV compound.

Animals↗
PubMed1996

Adenosine A1 receptor and its gene expression in ventricles from spontaneously hypertensive rats.

We characterized the adenosine A1 receptor and the levels of its mRNA expression in the ventricles of 6- and 13-wk-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The binding of 2-chloro-[3H]cyclopentyladenosine ([3H]CCPA), an A1 agonist ligand, to ventricular membranes was saturable and reversible. The receptor density was significantly lower in SHR than in WKY at 13 wk. The dissociation constant values were not different among these groups. In Northern blot analysis using rat A1 receptor cDNA, levels of mRNA did not differ significantly in the two groups at 13 wk, but the level in SHR significantly exceeded that in WKY at 6 wk. Because plasma adenosine levels were reported to be increased at 13 wk in SHR and we found mRNA levels were similar at this age, the discrepancy between A1 receptor density and its mRNA levels might be related to the desensitization of A1 receptors. Although the implication of this decreased density of A1 receptors is not known, it may involve an increased susceptibility to ischemia.

Animals↗
PubMed1996

Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes.

The oxidative metabolism of cinnarizine [(E)-1-(diphenylmethyl)-4-(3-phenyl-2-propyl)piperazine, CZ] and flunarizine [(E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propyl)piperazine, FZ] was examined in microsomes from lymphoblastoid cells that expressed human cytochrome P450 (CYP) enzymes. Among 10 kinds of CYP enzymes examined, only CYP2D6 catalyzed p-hydroxylation of the cinnamyl phenyl ring of CZ (C-2 formation) and FZ (F-2 formation), and only CYP2B6 exhibited activity for p-hydroxylation (C-4 formation) of the diphenylmethyl group of CZ at a substrate concentration of 50 microM. On the other hand, CYP2C9 together with CYP1A1, -1A2 and/or -2A6 mediated N-desalkylation at the 1- and 4-positions of the piperazine ring of the two drugs that formed C-1 and C-3 from CZ and F-1 and F-3 from FZ, respectively, whereas CYP2C8, -2C19, -2E1 or -3A4 did not show detectable activity for these reactions under the conditions used. We then examined kinetics for the oxidative metabolism of CZ and FZ using CYP2B6 and -2D6 that have considerable activities. CYP2D6 with Km values of 2 to 4 microM had intrinsic clearance values (Vmax/Km) of 0.31 and 0.14 ml/min/nmol CYP for C-2 and F-2 formation, respectively, while CYP2B6 with a Km value of 17 microM exhibited the clearance value of 0.10 ml/min/nmol CYP for C-4 formation. These results suggest that CYP2D6 mainly mediates p-hydroxylation of the cinnamyl phenyl rings of CZ and FZ, and CYP2B6 mediates that of the diphenylmethyl group of CZ.

B-Lymphocytes↗
PubMed1996

[Reye syndrome evaluated by 99mTc-ECD SPECT: a case report].

We report a three-year-old boy with Reye syndrome evaluated by 99mTc-ECD SPECT. On acute stage, 99mTc-ECD brain SPECT disclosed diffuse high uptake in the cerebral cortex in spite of normal findings on brain X-ray CT. These lesions changed to general low uptake on the chronic state and multiple high intensity areas were shown on T2 weighted MRI image. Such a change of cerebral tracer uptake was considered to reflect the neuropathological change of Reye syndrome. 99mTc-ECD SPECT was a useful modality to diagnose Reye syndrome complementary.

Brain↗
PubMed1995

The relationship between pharmacokinetic behaviour of glycyrrhizin and hepatic function in patients with acute hepatitis and liver cirrhosis.

The pharmacokinetic behavior of glycyrrhizin in four patients with acute hepatitis (hepatitis group) and six patients with liver cirrhosis (cirrhosis group) receiving chronically an IV administration of a 120 mg dose once a day or once every other day of glycyrrhizin was investigated. The plasma concentration of glycyrrhizin declined monoexponentially in both groups. The elimination half-life (t1/2) for glycyrrhizin in the hepatitis and cirrhosis groups varied significantly in the range of 2.7-7.6 h and 6.2-40.1 h, and the total body clearance (CLtot) in the range of 2.8-23.2 mL h-1 kg-1 and 1.4-12.9 mL h-1 kg-1, respectively. The t1/2 for glycyrrhizin in the hepatitis and the cirrhosis groups was about twice and eight times that in normal subjects, respectively, as reported previously, and CLtot values were about 0.7 and 0.23 times that in normal subjects, respectively. There was significant correlation between the CLtot and hepatic function (aspartate aminotransferase and alanine aminotransferase in serum) in both patient groups. With improvement of the liver function, the CLtot for glycyrrhizin increased from 2.8 ml h-1 kg-1 to 11.4 mL h-1 kg-1, and the t1/2 shortened from 7.6 h to 3.4 h. These findings indicated that the variation of pharmacokinetic behaviour of glycyrrhizin in both groups was closely related to the extent of the liver function.

Adult↗
PubMed1995

Angiotensin I converting enzyme (ACE) gene polymorphism and essential hypertension in Japan. Ethnic difference of ACE genotype.

A polymorphism of the angiotensin I converting enzyme (ACE) gene has recently been reported and analysis of this polymorphism has indicated that it is associated with several cardiovascular diseases. However, the results are still controversial and such association has not yet been established conclusively. To determine whether the ACE gene may be responsible for essential hypertension in a Japanese population, we also compared the distribution of genotypes and the allele frequency of this polymorphism in our findings of a Japanese population with these features in other countries. Eighty-seven hypertensive patients with a family history of essential hypertension and 95 normotensive patients whose parents had no such history were enrolled in the study. Polymorphism of the ACE gene was determined by using the polymerase chain reaction. Homozygotes for this polymorphism had either a 490-bp band (II) or a 190-bp band (DD) and heterozygotes had both bands (ID). In hypertensive subjects, the numbers and frequency of the ACE genotypes were: II, 44 (0.51); ID, 26 (0.30); DD, 17 (0.19). In normotensive subjects these were: II, 35 (0.37); ID, 43 (0.45); DD, 17 (0.18). There were no significant differences between the two groups in derived allele frequencies (chi 2 = 1.41). The difference between the overall allelic frequency in Japan and that reported in several other countries was significant. We did not find any association between ACE gene polymorphism and essential hypertension in Japan. However, there were significant differences in derived allele frequencies between our findings in a Japanese population and those reported from Europe and Australia.

Alleles↗
PubMed1995

Administration-route dependency of absorption of glycyrrhizin in rats: intraperitoneal administration dramatically enhanced bioavailability.

The pharmacokinetic behavior of glycyrrhizin after intravenous (i.v.), oral and intraperitoneal (i.p.) administration was compared in rats. The elimination half-life, total body clearance and volume of distribution at steady-state of glycyrrhizin were not significantly different among doses (2, 10 and 50 mg/kg i.v.). Glycyrrhizin was only detected in the plasma (maximum level: 1.3 micrograms/ml) after oral administration of 50 mg/kg. From comparison of the area under the plasma concentration-time curves after i.v. and oral administration of 50 mg/kg, the bioavailability of glycyrrhizin was estimated to be approximately 1%. Glycyrrhizin was stable for at least 3 h in gastric juice. The plasma concentration of glycyrrhizin after oral administration to neomycin-treated rats was not significantly different from that after administration to untreated rats. Furthermore, in in situ absorption study the cumulative ratio of glycyrrhizin in the mesenteric venous plasma after injection was only 1-2% of the dose. From these results, it appeared that the extremely low bioavailability by the oral route may be due to poor absorption of glycyrrhizin from the intestinal tract. On the other hand, the plasma concentration of glycyrrhizin rapidly increased after i.p. administration of doses of 2, 10 and 50 mg/kg, and reached a maximum level (4.7, 33.0 and 238.9 micrograms/ml, respectively) within 30 min. The bioavailability (65-90%) of glycyrrhizin after i.p. administration was enhanced dramatically. The i.p. route of administration may thus improve the bioavailability of glycyrrhizin.

Animals↗
PubMed1995

Altered platelet alpha 2-adrenoceptors in patients with ischemic heart disease.

We evaluated the characteristics of platelet alpha 2-adrenoceptors in 12 patients with effort angina pectoris, 11 patients with variant angina pectoris and 11 normal control subjects. alpha 2-Adrenoceptors were quantified using a radioligand binding assay with radiolabelled rauwolscine, an alpha 2-selective antagonist. In addition, plasma norepinephrine concentrations were measured by high performance liquid chromatography. The mean value of the maximal number of binding sites (Bmax) in patients with effort angina (205.1 +/- 11.3 fmol/mg protein) was significantly lower than that in control subjects (293.0 +/- 10.2 fmol/mg protein). Bmax did not differ between patients with variant angina (322.9 +/- 45.4 fmol/mg protein) and control subjects. There was no significant difference in the dissociation constant (Kd) among the 3 groups. The plasma norepinephrine concentration tended to be higher in patients with effort angina or variant angina than in normal controls, but this difference was not statistically significant. In addition, studies in another group of young volunteers (n = 20) revealed a negative correlation (r = -0.50, p < 0.05) between the Bmax of 3H-rauwolscine binding to platelets and the percent change in the plasma norepinephrine concentration when subjects moved from the supine to the standing position. This suggests a functional correlation between platelet alpha 2-adrenoceptors and those located at presynaptic sites. If platelet alpha 2-adrenoceptors correlate with presynaptic alpha 2-adrenoceptors, the current findings of decreased alpha 2-adrenoceptor density in platelets from patients with effort angina could represent attenuated negative feedback of norepinephrine by presynaptic alpha 2-adrenoceptors.

Adult↗
PubMed1994

Construction of an overproduction vector containing the novel srp (sterically repressed) promoter.

We report the design, synthesis, and evaluation of a novel Escherichia coli promoter intended for use in overproduction of proteins that are deleterious to the host. In this sterically repressed promoter (srp), the lac operator site is positioned between the -10 and -35 elements, where it can interfere sterically with RNA polymerase and thereby prevent assembly of a poised transcriptional complex. An srp-containing phagemid, pKEN1, and a tac-containing phagemid, pHN1, which has been widely used in protein overproduction but is often unstable, are compared with respect to levels of uninduced and induced protein expression. The level of uninduced protein synthesis by the srp promoter in vivo is approximately 50% of that observed with tac, whereas the levels of induced protein synthesis with the 2 vectors are approximately equal. A remarkable increase in stability of overproduction and growth was observed when the toxic Ada protein was overproduced in pKEN1, demonstrating the potential utility of this vector in overproducing toxic proteins.

Bacterial Proteins↗
PubMed1993

Pharmacokinetic profiles of glycyrrhizin in patients with chronic hepatitis.

The pharmacokinetics of glycyrrhizin (G) in eight patients with chronic hepatitis receiving chronically i.v. administration of 120 mg dose of G was investigated. The plasma concentration of G in the patients after dosing declined in a monophasic manner. However, the pharmacokinetic profiles varied among patients. The mean elimination half-life (t1/2) and the total body clearance (CLtot) were 6.0 h (range 4.3-10.7 h) and 7.9 ml h-1 kg-1 (4.5-12.7 ml h-1 kg-1), respectively. The variation of the CLtot for G was closely related to that of aspartate aminotransferase (r = -0.739, p < 0.05) and alanine aminotransferase (r = -0.783, p < 0.05) activities in the plasma.

Adult↗
PubMed1993

Kinetic analysis of glycyrrhetic acid, an active metabolite of glycyrrhizin, in rats: role of enterohepatic circulation.

The role of enterohepatic circulation of glycyrrhetic acid (GA) in rats was determined by kinetic analysis of GA. The concentrations of GA in the plasma of the control rat (without bile duct cannulation) during the first 5 h after intravenous (iv) administration of GA (2, 5, 10, and 20 mg/kg) were similar to those in the bile duct-cannulated rat at each dose. No significant difference was observed in the values of the terminal half-life, the total body clearance, the distribution volume at steady state, the area under the curve of concentration in plasma versus time, and the mean residence time in each dose between both groups. When GA (2, 5, 10, and 20 mg/kg) was administered i.v. to the bile duct-cannulated rat, excretion of unchanged GA in bile was < 1% of each dose, that of the acid-hydrolyzed products was 14-16%, and that of GA-3-O-glucuronide was only 1-2%. In the control rat, a secondary peak of GA concentration was observed 12 h after i.v. administration of GA (20 mg/kg). The enterohepatic circulation of GA was confirmed by the linked-rat method in which bile of the donor rat after i.v. administration of GA (20 mg/kg) was allowed to flow directly into the duodenum of the recipient rat. GA was found in the plasma of the recipient rat after 6 h, and its concentration reached the maximum (approximately 0.5 microgram/mL) 8-12 h after dosing the donor rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Prediction of dystocia by entanglement (impaction) in vertex-vertex type twin delivery.

We studied the fetal position in vertex-vertex type twins in 6 impaction cases and in 23 cases of vaginal deliveries without impaction. The results obtained were as follows: (1) In 6 impaction cases, the presenting head of the first fetus was shown to be at the maternal pubic side and the head of the second fetus at the maternal sacral side. (2) In 23 cases without impaction, the presenting head of the first fetus was shown to be at the maternal sacral side and the head of the second fetus at the maternal pubic side. (3) There was a statistical significant difference between the 6 impaction cases and the 23 non impaction cases as determined by the Chi-square test (p < 0.001). Our study suggests that it is possible to predict the occurrence of impaction in vertex-vertex type twin deliveries by examining the positional relationship of the presenting heads of the first and second fetuses. There was a higher possibility of impaction when the head and body of twin 1 was located in the maternal-pubic position, while the head of twin 2 was in the sacral position. In contrast, impaction never occurred when the head and body of twin 1 was in the maternal-sacral position and the head of twin 2 was in the pubic position.

Adult↗
PubMed1992

Pharmacokinetic profile of glycyrrhizin in healthy volunteers by a new high-performance liquid chromatographic method.

An improved high-performance liquid chromatographic method was developed for the quantification of glycyrrhizin and its metabolites in human plasma. The improved method was selective and made it possible to determine precisely glycyrrhizin at levels as low as 500 ng/mL. The pharmacokinetic behavior of glycyrrhizin and its metabolites after oral and intravenous administration of glycyrrhizin to normal subjects was investigated. After oral administration of glycyrrhizin (100 mg) to three normal subjects, the major metabolite of glycyrrhizin (glycyrrhetic acid) appeared in plasma (less than 200 ng/mL), but glycyrrhizin was not found. On the other hand, glycyrrhizin was found in urine, and the amount excreted was 1.1-2.5% of the dose. This finding suggests that glycyrrhizin is partly absorbed in the intact form from the gastrointestinal tract. The concentration of glycyrrhizin in plasma after intravenous administration of glycyrrhizin (40, 80, and 120 mg) showed biexponential profiles during the 24-h period after administration of each dose. The glycyrrhizin metabolites, glycyrrhetic acid and glycyrrhetic acid-3-O-glucuronide, were not detected in either plasma or urine. The terminal half-life of glycyrrhizin, the apparent volume of the central compartment, the steady-state distribution volume, and the total body clearance in three dosing experiments were 2.7-4.8 h, 37-64 mL/kg, 59-98 mL/kg, and 16-25 mL/kg/h, respectively. Glycyrrhizin was not detected in plasma after oral administration of the usual therapeutic dose of glycyrrhizin, and no dose dependency of the drug was observed in the dose range of 40-120 mg.

Administration, Oral↗