The effects of polyamines on the melting of polyriboadenylic acid plus polyribouridylic acid complexes in a solution.
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Amines↗
Biomedical subjects
S Higuchi
Publications and source records attributed to S Higuchi.
A simple method for the determination of YM060 in plasma and urine by high performance liquid chromatography.
We developed a simple method for the determination of YM060, a new 5-HT3 receptor antagonist, in plasma and urine. The method has good accuracy and precision, and sufficient sensitivity to allow use in pharmacokinetic studies of YM060 in humans and laboratory animals.
Animals↗
Pharmacokinetics of [125I]-recombinant human interleukin-11: 1. Absorption, distribution and excretion after subcutaneous administration to male rats.
Absorption, distribution, metabolism and excretion of [125I]-rhIL-11 (recombinant human interleukin-11) after subcutaneous administration in rats were investigated. After a single administration, the concentration of radioactivity in the tissues was 2-6-fold higher in the liver and kidneys, and slightly higher in the gastrointestinal tract as compared to the plasma concentration. However, since the concentration in the other tissues was lower than the plasma concentration, the transport of rhIL-11 into tissues appeared to be low. Tissue radioactivity rapidly diminished, thus accumulation of rhIL-11 in tissues was thought to be low. Excretion of radioactivity into urine and feces was almost complete 72 h after administration, with 88.5% of the dosed radioactivity being found in urine and 7.9% in feces. When [125I]-rhIL-11 was administered to bile-duct cannulated rats, 44.4% of the dosed radioactivity was excreted into bile up to 48 h after administration. Most radioactivity in bile and urine was found in the TCA supernatant and low molecular weight fraction by HPLC analysis, indicating that rhIL-11 was eliminated from the body by metabolism.
Animals↗
Pharmacokinetics of [125I]-recombinant human interleukin-11: 2. Placental transfer and excretion into milk after subcutaneous administration to rats.
Placental transfer and excretion into milk of [125I]-rhIL-11 (recombinant human interleukin-11) after subcutaneous administration in female rats were investigated. After administration of [125I]-rhIL-11 to rats on the 14th day of gestation, radioactivity in the kidney was the highest among excised tissues, being 3 times higher than that in the plasma at 1.5 h. Radioactivity in other tissues, including the mammary gland, ovary, uterus, placenta and amniotic fluid, was lower than that in the plasma. Although radioactivity in fetuses was detected 6 h after administration, the level was only 2% of the plasma concentration in dams, and the radioactivity was not found in fetal-derived TCA precipitates. These results indicate that rhIL-11 does not readily pass through the placenta into the fetus. After subcutaneous administration of [125I]-rhIL-11 to lactating rats 14 days after delivery, radioactivity in milk was 1.1-1.6 times that in the plasma of dams. Radioactivity in clotted milk in the stomachs of suckling infants was almost equal to that in the dam's milk; however, only a small amount of radioactivity was detected in infant kidneys.
Animals↗
CYP2C19 polymorphism effect on phenobarbitone. Pharmacokinetics in Japanese patients with epilepsy: analysis by population pharmacokinetics.
OBJECTIVE: The aim of this study was to clarify the effect of genetic polymorphisms of CYP2C19 on the pharmacokinetics of phenobarbitone (PB) using a nonlinear mixed-effects model (NONMEM) analysis in Japanese adults with epilepsy. METHODS: A total of 144 serum PB concentrations were obtained from 74 subjects treated with both PB and phenytoin but without valproic acid. All patients were classified into three groups by CYP2C19 genotyping: G1, G2 and G3 were homozygous for the wild type of CYP2C19 (*1/*1), heterozygous extensive metabolizers (EMs), (*1/*2 or *1/*3), and poor metabolizers (PMs), (*2/*2, *2/*3), respectively. All data were analyzed using NONMEM to estimate pharmacokinetic parameters of PB with respect to the CYP2C19 genotype. RESULTS: Thirty-three patients belonged to G1 (44.6%), 35 to G2 (47.3%), and 6 to G3 (8.1%). The total clearance (CL) of PB significantly decreased by 18.8% in PMs (G3) relative to EMs (G1 and G2). The CL tended to be lower in G2 than in G1. CONCLUSION: In this study, we first demonstrated the effect of the CYP2C19 polymorphism on pharmacokinetics of PB by genotyping. The contribution of other metabolic enzymes in the metabolism of PB in humans remains to be elucidated; however, it appears that the disposition of PB is mediated in part by this enzyme. The estimated population clearance values in the three genotype groups can be used to predict the PB dose required to achieve an appropriate serum concentration in an individual patient.
Adolescent↗
Changes in cerebrospinal fluid biotinidase activity in Staphylococcus aureus meningitis.
An early increase in activity of biotinidase in the cerebrospinal fluid (CSF) during the course of acute Staphylococcus aureus meningitis in a subject with subacute sclerosing panencephalitis (SSPE) is reported. A possible role of CSF biotinidase in the hydrolysis of specific opioid neuropeptides during acute inflammatory processes involving the CSF-central nervous system compartment is suggested.
Amidohydrolases↗
Drug interactions of zonisamide with phenytoin and sodium valproate: serum concentrations and protein binding.
The influence of co-medication with zonisamide (ZNS) on the serum concentration and protein binding of phenytoin (PHT) and sodium valproate (VPA) was studied in 21 pediatric patients. No significant correlation between the daily ZNS dose, and total serum concentrations, free concentrations or free fractions (FF) of PHT or VPA was observed. The patient study showed that changes in the FF of PHT and VPA were correlated more closely with the serum protein and bilirubin levels than changes in the ZNS dosage. An in vitro study revealed that the addition of ZNS caused decreases in the FF of PHT and VPA. However, these decreases were within the range of measurement error and were negligible. In conclusion, no significant effect of ZNS on the serum concentration or protein binding of PHT or VPA was demonstrated.
Adolescent↗
No association between DLST gene and Alzheimer's disease or Wernicke-Korsakoff syndrome.
Among many candidate genes for the genetically heterogeneous Alzheimer's disease (AD), only apolipoprotein E (ApoE) has been confirmed. Another candidate is the dihydrolipoyl succinyltransferase (DLST) gene, one of three components of thiamine-dependent mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC), because KGDHC activity is reported reduced in AD patients. Also characterized by reduced KGDHC activity is another neuropsychiatric disease, Wernicke-Korsakoff syndrome (WKS), which results from thiamine deficiency. Examination of specific DLST gene polymorphism in 247 Japanese AD patients, 53 alcoholic WKS patients, and 368 nondemented Japanese control subjects revealed no significant differences in DLST genotypes and failed to replicate the findings of earlier studies indicating an association between DLST gene polymorphism and AD.
Acyltransferases↗
Cerebrospinal fluid tau protein as a potential diagnostic marker in Alzheimer's disease.
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Alzheimer Disease↗
Physical performance tests after stroke: reliability and validity.
OBJECTIVE: To evaluate the reliability and validity of the modified physical performance tests for stroke survivors who live in a community. DESIGN: The subjects included 40 stroke survivors and 40 apparently healthy independent elderly persons. The physical performance tests for the stroke survivors comprised two physical capacity evaluation tasks that represented physical abilities necessary to perform the main activities of daily living, e.g., standing-up ability (time needed to stand up from bed rest) and walking ability (time needed to walk 10 m). RESULTS: Regarding the reliability of tests, significant correlations were confirmed between test and retest of physical performance tests with both short and long intervals in individuals after stroke. Regarding the validity of tests, the authors studied the significant correlations between the maximum isometric strength of the quardriceps muscle and the time needed to walk 10 m, centimeters reached while sitting and reaching, and the time needed to stand up from bed rest. CONCLUSIONS: The authors confirmed that there were significant correlations between the instrumental activity of daily living and the time needed to stand up from bed rest, along with the time needed to walk 10 m for the stroke survivors. These physical performance tests are useful guides for evaluating a level of activity of daily living and physical frailty of stroke survivors living in a community.
Activities of Daily Living↗
Nutritional copper deficiency in severely handicapped patients on a low copper enteral diet for a prolonged period: estimation of the required dose of dietary copper.
Six cases of nutritional copper deficiency were identified in a nursery institute for severely handicapped patients. All had been on prolonged enteral feeding of a copper-deficient diet and all had abnormalities related to the copper deficiency. Two of them had leukopenia, with or without macrocytic and normochromic anemia. After the oral administration of copper, the clinical and laboratory observations including neutrophil counts and serum copper and ceruloplasmin levels showed a complete recovery. The dietary copper requirement was estimated to be approximately 20 micrograms/kg/day for these patients, based on the correlation between the dietary copper intake and the levels of copper in the serum.
Adolescent↗
Influence of additional therapy with zonisamide (Excegran) on protein binding and metabolism of carbamazepine.
The influence of comedication with zonisamide (ZNS) on protein binding and carbamazepine (CBZ) metabolism was studied in 16 pediatric epileptic patients. Correlations were evaluated between ZNS daily dose and individual change of level per dose ratio (L/D ratio), free fraction, and carbamazepine-10,11-epoxide/CBZ level ratio (CBZE/CBZ). Statistical significant negative correlation was observed between L/D ratio and ZNS daily dose. Despite alteration in the L/D ratio, the free fraction of CBZ was unaltered in combination with ZNS. To assess the effect of addition of ZNS on CBZ metabolism, the CBZE/CBZ level ratio was compared; this ratio showed a tendency to increase with increase in ZNS dose. Consequently, ZNS is considered to have a significant effect on CBZ metabolism but not on protein binding.
Adolescent↗
A new test for evaluating nonsteroidal anti-inflammatory drugs in vitro: inhibition of prostaglandin E2 production in minced intestinal tissue.
A new method for evaluating the inhibitory effect of nonsteroidal anti-inflammatory drugs on prostaglandin E2 production is presented. Minced rat intestinal tissue was incubated with a nonsteroidal anti-inflammatory drug and homogenized. After centrifugation, prostaglandin E2 in the supernatant was measured by radioimmunoassay. The production of prostaglandin E2 was decreased by nonsteroidal anti-inflammatory drugs, in a concentration-dependent manner, the order of potency being diclofenac greater than loxoprofen greater than indomethacin greater than ibuprofen greater than TA-847 (imidazole derivative). Loxoprofen, a prodrug, inhibited the prostaglandin E2 production. In a classical enzyme assay with sheep seminal vesicle microsomal prostaglandin endoperoxide synthase, the order of inhibitory potency was TA-847 greater than diclofenac greater than indomethacin greater than ibuprofen. The inhibitory effect of loxoprofen was very weak. On the other hand, the potency order of these nonsteroidal anti-inflammatory drugs, with regard to their anti-inflammatory effect as determined in the rat carrageenin-induced paw edema model, was loxoprofen greater than indomethacin greater than diclofenac greater than ibuprofen greater than TA-847. The results of the new method with intestinal tissue showed thus a good correlation with the anti-inflammatory activity in vivo.
Animals↗
Metabolic N-demethylation of 1,3-bis[[1-cycloheptyl-3-(p- dimethylaminophenyl)ureido]methyl]benzene dihydrochloride, a novel acyl-coenzyme A:cholesterol acyltransferase inhibitor.
The metabolism of 1,3-bis[[1-cycloheptyl-3-(p-dimethylamino- phenyl)ureido]methyl]benzene dihydrochloride (YM17E) in rat liver microsomes was investigated. After incubation of YM17E with rat liver microsomes in the presence of NADPH, a significant amount of YM17E was consumed and several products appeared. The structures of these products were identified by thermospray-linked LC/MS. By comparison of fragmentation patterns between these products and authentic compounds, five metabolites were eventually identified. All five metabolites--termed M1, M2-a, M2-b, M3, and M4--were sequentially formed through N-demethylation. The formation of these metabolites was NADPH-dependent, and was inhibited by SKF-525A, metyrapone, and carbon monoxide, which are inhibitors of cytochrome P-450. These results suggest that N-demethylation of YM17E is one of the main pathways of its biotransformation, and that this metabolism is catalyzed by cytochrome P-450-mediated monooxygenase.
Animals↗
Hepatoprotective effect of SY-640, a novel acetamide derivative, on Propionibacterium acnes and lipopolysaccharide-induced liver injury in mice.
The hepatoprotective effect of SY-640 on Propionibacterium acnes and lipopolysaccharide-induced liver injury in mice and its protective mechanism were examined. Oral administration of SY-640, 150 mg/kg once daily for 7 days, significantly inhibited Propionibacterium acnes and lipopolysaccharide-induced liver injury, but a single administration was without effect. Liver-infiltrating cells (T-lymphocytes and macrophages) play an important role in Propionibacterium and lipopolysaccharide-induced liver injury and express a higher level of leukocyte function-associated antigen-1. SY-640 inhibited the number of liver-infiltrating cells and attenuated the increased expression of leukocyte function-associated antigen-1 on these cells. Tumor necrosis factor-alpha mediated Propionibacterium acnes and lipopolysaccharide-induced liver injury, and SY-640 inhibited the elevation of the serum tumor necrosis factor-alpha concentration after injection of lipopolysaccharide in Propionibacterium acnes-primed mice. The putative effects of SY-640 are inhibitory effects on infiltration into the liver and on activation of T-lymphocytes and macrophages after Propionibacterium acnes-priming, and attenuation of expression of cell adhesion molecules such as leukocyte function-associated antigen-1. The immunological effect of SY-640 is likely to be closely related to the inhibition of Propionibacterium and lipopolysaccharide-induced liver injury.
Acetamides↗
Expression of prostaglandin H synthase-2 in endotoxic shock induced in rats.
We investigated the expression of prostaglandin H synthase-2 in rats subjected to endotoxic shock. The prostaglandin H synthase activities were assessed by measuring the plasma prostaglandins (PGE2 and 6-keto-PGF1 alpha) after arachidonic acid administration (3 mg/kg, i.v.). The plasma prostaglandin concentrations increased immediately after administration of arachidonic acid, reached a peak at 30-60 seconds, and then rapidly decreased. Lipopolysaccharide (1 mg/kg, i.v.) also increased the plasma prostaglandin concentrations, reached a peak 1 hour after administration, and then gradually decreased to normal levels. The production of plasma prostaglandin, induced by administration of arachidonic acid, was markedly enhanced in the lipopolysaccharide-treated rats. A low dose of acetylsalicylic acid (3 mg/kg, i.v.) blocked the prostaglandin production in the nontreated rats but not in the lipopolysaccharide-treated rats. In the latter group of rats, a high dose of acetylsalicylic acid (30 mg/kg, i.v.), given 10 to 30 minutes before administration of arachidonic acid, completely blocked the prostaglandin production, but recovery of this production was seen with acetylsalicylic acid (30 mg/kg) treatment at 1 to 2 hours before administration of arachidonic acid. These data suggest that pretreatment with lipopolysaccharide enhances the prostaglandin production by forming newly synthesized prostaglandin H synthase. Immunoblots of the levels of enzyme protein from rat aorta endothelial cells were analyzed. The enzyme protein cross-reacting with antibody against prostaglandin H synthase-2 was increased by lipopolysaccharide treatment in endothelial cells, and was constitutively expressed in the stomach, kidney and liver, but not in the lung and the intestine. The induction of prostaglandin H synthase-2 by lipopolysaccharide treatment was observed only in endothelial cells. The enhancement of the prostaglandin production in lipopolysaccharide-treated rats was blocked by pretreatment with dexamethasone, prior to administration of lipopolysaccharide, this suppression is apparently the result of a decrease of the prostaglandin H synthase-2 protein in endothelial cells, as determined by Western blotting. The enhanced production of prostaglandin, induced by lipopolysaccharide, seems to be due to the in vivo expression of prostaglandin H synthase-2.
Animals↗
Effects of methylglyoxal bis (cyclopentylamidinohydrazone) (MGBCP) on cell cycle progression in three human osteosarcoma cell lines.
Our previous experiments have indicated that the antitumor effects of a polyamine biosynthetic inhibitor, methylglyoxal bis(cyclopentylamidinohydrazone) (MGBCP), on human osteosarcoma cell lines such as MG-63, G-292 and HOS cells are obtained by its action depleting the cellular polyamine contents. In the present study, the effects of polyamine depletion by MGBCP on the cell cycle progression in these osteosarcoma cell lines were investigated by flow cytofluormetric analysis. MGBCP arrested the tumor cells at the G1 phase by preventing the G/S phase transition. Mitotic indexes (MIs) in these MGBCP-inhibited tumor cells were also decreased. These findings suggest that MGBCP suppresses the cell cycle progression in osteosarcoma MG-63, G-292 and HOS cells by inhibiting intracellular polyamine biosynthesis.
Antineoplastic Agents↗
5-Hydroxytryptamine3 receptor and regulation of gastric emptying in rats.
We investigated the role of the 5-hydroxytryptamine3 (5-HT3) receptor in the regulation of gastric emptying in rats using various 5-HT3 receptor antagonists, including GK128, a novel and selective 5-HT3 receptor antagonist. GK128 dose-dependently accelerated gastric emptying in rats. The accelerating effect of GK128 on gastric emptying was more potent than that of the other 5-HT3 receptor antagonists used in this study. However, the rank order of potency of the selective 5-HT3 receptor antagonists, except for the benzamide derivatives, on the accelerating effect of gastric emptying, was not consistent with that of their 5-HT3 receptor-binding affinity in the rat cortex. GK128 improved the gastric emptying delayed by m-chlorophenylbiguanide, a 5-HT3 receptor agonist, and by cisplatin, which is known to cause damage to the small intestine and to release 5-HT from enterochromaffin cells. Furthermore, 5,7-dihydroxytryptamine, an indoleamine neurotoxin known to destroy 5-HT-containing neurons, significantly accelerated gastric emptying, and no further acceleration was observed after administration of GK128. These results may suggest that 5-HT3 receptor antagonists induce, at least in part, the acceleration of gastric emptying in rats via a peripheral mechanism, and that endogenous serotonin has an inhibitory regulatory effect on gastric emptying in rats. Furthermore, the difference in rank order between the accelerating effect of gastric emptying and the 5-HT3 receptor antagonistic potencies in the cortex suggests that the 5-HT3-like receptor, modulating gastric emptying, is not identical to the classically defined 5-HT3 receptor.
Animals↗