PubMed Health⌕ Search

Biomedical subjects

S Higuchi

Publications and source records attributed to S Higuchi.

At least 73 records · Page 4Linked to original sources
PubMed2000

Comparison of drug disposition between wild-type and novel tissue-type plasminogen activator pamiteplase in rats.

The pharmacokinetics of pamiteplase in rats was compared with the pharmacokinetics of recombinant wild-type tissue-type plasminogen activator (rwt-PA). The half-life in the beta-phase and total clearance after administration of (125)I-labeled pamiteplase ((125)I-pamiteplase) to rats were 480 and 22% of those of (125)I-labeled rwt-PA ((125)I-rwt-PA), respectively. The amount of radioactivity distributed in the liver after administration of (125)I-pamiteplase was lower than that of (125)I-rwt-PA; consequently, a possible difference in metabolism between the drugs was assessed by an integration plot and a tissue-sampling single-injection technique. Use of these two methods revealed that the hepatic clearances of both compounds accounted for almost all of the total clearance and also revealed that the hepatic clearance of (125)I-pamiteplase was markedly lower than that of (125)I-rwt-PA. Therefore, the lower distribution of pamiteplase in the liver compared with rwt-PA is thought to contribute greatly to the higher plasma concentration of pamiteplase. Additionally, the uptake of (125)I-pamiteplase in the liver was inhibited by rwt-PA, suggesting that there is a common uptake mechanism for both compounds.

Animals↗
PubMed2000

CYP3A4 is a major isoform responsible for oxidation of 7-hydroxy-Delta(8)-tetrahydrocannabinol to 7-oxo-delta(8)-tetrahydrocannabinol in human liver microsomes.

The human liver enzyme microsomal alcohol oxygenase was able to oxidize both 7alpha- and 7beta-hydroxy-Delta(8)-tetrahydrocannabinol (7alpha- and 7beta-hydroxy-Delta(8)-THC) to 7-oxo-Delta(8)-THC. The oxidative activity was determined by using a panel of 12 individual cDNA-expressed human cytochrome P450s (CYPs) (1A1, 1A2, 2A6, 2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Met, 2D6-Val, 2E1 and 3A4). Among the CYP isoforms examined, CYP3A4 showed the highest activity for both of substrates. The metabolism of 7alpha- and 7beta-hydroxy-Delta(8)-THC to 7-oxo-Delta(8)-THC was also detected for CYPs 1A1 (4.8% of CYP3A4), 1A2 (4.7%), 2A6 (2.3%), 2C8 (16.6%), and 2C9-Cys (5.4%), and CYPs 1A1 (0.4%), 2C8 (1.3%), 2C9-Arg (4.3%), and 2C9-Cys (0.9%), respectively. The 7alpha- and 7beta-hydroxy-Delta(8)-THC microsomal alcohol oxygenase activities in human liver were significantly inhibited by addition of 100 microM troleandomycin, 1 microM ketoconazole, and anti-CYP3A antibody, although these activities were not inhibited by 1 microM 7, 8-benzoflavone and 50 microM sulfaphenazole. When the substrates were incubated with the CYP3A4-expressed microsomes under oxygen-18 gas phase, atmospheric oxygen was incorporated into 35% of 7-oxo-Delta(8)-THC formed from 7alpha-OH-Delta(8)-THC, but only 12% of 7-oxo-Delta(8)-THC formed from 7beta-OH-Delta(8)-THC. These results indicate that CYP3A4 is a major isoform responsible for the oxidation of 7alpha- and 7beta-hydroxy-Delta(8)-THC to 7-oxo-Delta(8)-THC in liver microsomes of humans, although the oxidation mechanisms for 7alpha- and 7beta-hydroxy-Delta(8)-THC might be different.

Adolescent↗
PubMed1999

Mutational analysis of the anion exchanger 3 gene in familial paroxysmal dystonic choreoathetosis linked to chromosome 2q.

Familial paroxysmal dystonic choreoathetosis (PDC) is an autosomal dominant neurological disorder characterized by episodes of involuntary movement precipitated by caffeine, alcohol, or emotional stress. The locus for PDC has recently been mapped to chromosome 2q32-36, but its causative gene has not yet been identified. PDC is most likely a kind of channelopathy, as suggested by the fact that other paroxysmal neurological disorders are caused by various ion channel mutations. Although no ion channel is located in this candidate region, anion exchanger 3 (AE3) has been mapped to 2q36 and has also been reported to be the most promising candidate gene of PDC. In this study we performed sequencing of the coding region of the AE3 gene in patients with familial PDC linked to chromosome 2q and excluded the AE3 gene as the causative gene for PDC. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:733-737, 1999.

Amino Acid Sequence↗
PubMed1999

Utility of postcolumn addition of 2-(2-methoxyethoxy)ethanol, a signal-enhancing modifier, for metabolite screening with liquid chromatography and negative ion electrospray ionization mass spectrometry.

A strategy for highly sensitive metabolite screening by liquid chromatography-electrospray ionization (ESI) mass spectrometry with the negative-ion mode that involves the use of a reversed-phase column in gradient-elution mode and postcolumn addition of 2-(2-methoxyethoxy)ethanol (2-MEE), a novel signal-enhancing modifier, has been described. When a mobile phase of 50 mM ammonium acetate/acetic acid buffer (pH 4.4) at a flow rate of 100 microL/min was employed, poor ESI response of ibuprofen as a model drug, probably due to both the high surface tension of the mobile phase and the ion-suppression effect of acetate anion in the mobile phase, was observed. On the other hand, the postcolumn addition of 2-MEE (50 microL/min) into the mobile phase counteracted the ion suppression as well as the surface tension problem, resulting in approximately 100-fold signal enhancement of the analyte. The metabolite screening of ibuprofen in human urine was subsequently carried out comparing the results with and without postcolumn addition of 2-MEE. The results indicated that the postcolumn addition of 2-MEE dramatically improved the ESI responses of all urinary metabolites detected without affecting the chromatographic separation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Molecular cloning and sequence analysis of cDNAs coding for 3-methylcholanthrene-inducible cytochromes P450 in Xenopus laevis liver.

Liver microsomes of Xenopus laevis were investigated for specific cytochrome P450s (CYPs) that would be inducible in response to the administration of either 3-methylcholanthrene (3MC) or beta-naphthoflavone (BNF), potent inducers for mammalian CYP1A. When probed with antibodies raised against rat CYP1A1, a 54-kDa protein was detected after administration of polycyclic aromatic hydrocarbons. However, there was no immunoreactive protein in microsomes from untreated frogs. In order to obtain structural information about this CYP1A-like protein, a liver cDNA library of 3MC-treated frog was constructed and screened using a fragment of rat CYP1A2 cDNA under low stringency conditions. We have isolated two cDNA clones (MC1 and MC2) with inherent features of the CYP1A subfamily. The sequence determination revealed that both of them coded for polypeptides composed of 526 amino acid residues, which differed from each other by 30 amino acids. A comparison with other mammalian CYP enzymes demonstrated that both of the sequences share 55 to 63% identity with the sequences of CYP1A family members. Northern blot analysis and RT-PCR results further demonstrated that two discrete transcripts corresponding to clones MC1 and MC2 are indeed inducible in the frog liver by treatment with 3MC or BNF. The names CYP1A6 and CYP1A7 were given to clones MC1 and MC2, respectively.

Animals↗
PubMed1999

Bradykinin-potentiating peptides and C-type natriuretic peptides from snake venom.

Cloning of cDNAs encoding bradykinin-potentiating peptides (BPPs)-C-type natriuretic peptide (CNP) precursor or its homologue was performed for cDNA libraries of Bothrops jararaca (South American snake), Trimeresurus flavoviridis, Trimeresurus gramineus and Agkistrodon halys blomhoffi (Asian snakes), all belonging to Crotalinae subfamily. Each cDNA library was constructed from the venom glands of a single snake to preclude ambiguity by intraspecies variation in venom components. Thirteen positive clones derived from B. jararaca were divided into two types depending on restriction sites. Differences in the nucleotide sequence arise at three locations and two of them accompanied amino acid conversions. Despite the differences, both types of cDNA clones encode the BPP-CNP precursor of 256 amino acid residues. Sequence analysis demonstrated that cDNA clones from three Asian snakes encode homologues of the BPP-CNP precursor from B. jararaca. In a precursor polypeptide, a signal sequence (approximately 25 aa) at the N-terminus is followed by sequences of BPP or the analogue (5-13 aa) with flanking spacer sequences (indefinite number of aa), an intervening linker sequence (approximately 144 aa) with unidentified function, and a CNP sequence (22 aa) with a preceding processing signal sequence (10 aa). cDNA clones from A. halys blomhoffi encode two distinct peptides in place of BPP, and T. flavoviridis and T. gramineus were shown to have considerably different sequences in the BPP domain from those known as BPP sequences. The present results provide evidence for a wide distribution of the orthologous gene expressing a series of bioactive peptides among Crotalinae subfamily.

3' Untranslated Regions↗
PubMed1999

Suppression of FRP-1/CD98-mediated multinucleated giant cell and osteoclast formation by an anti-FRP-1/CD98 mAb, HBJ 127, that inhibits c-src expression.

When anti-CD98 mAb 6-1-13, 4-5-1, or 38-2-2 was added to the culture fluids of monocytes, extensive cell aggregation and polykaryocyte formation were induced. These multinucleated giant cells were tartrate-resistant acid phosphatase (TRAP) positive. On the other hand, when monocytes were incubated with another anti-CD98 mAb, HBJ 127, polykaryocyte formation was not detected, although extensive cell aggregation was induced. When HBJ 127 and 6-1-13 were simultaneously added to the culture fluids, anti-CD98 mAb-induced cell fusion was inhibited almost completely. HBJ 127 suppressed formation of 6-1-13-induced cell fusion in a dose-dependent manner. If, however, HBJ 127 was added after incubation of monocytes with mAb 6-1-13 for 6 h, an appreciable degree of TRAP-positive polykaryocyte formation was found. The bindings of 6-1-13 and HBJ 127 were not mutually competed. When monocytes were incubated with 6-1-13 or HBJ 127, 6-1-13 induced c-src mRNA, while HBJ 127 did not. Furthermore, when monocytes were incubated with both 6-1-13 and HBJ 127, c-src mRNA could not be detected, showing that HBJ 127 suppresses c-src expression. Therefore, CD98-mediated osteoclast formation can be regulated by modification of CD98 system.

Antibodies, Monoclonal↗
PubMed1999

Rapid characterization of urinary metabolites of pibutidine hydrochloride in humans by liquid chromatography/electrospray ionization tandem mass spectrometry.

The metabolic products of pibutidine hydrochloride, a new H(2)-receptor antagonist, in human urine after oral administration of 40 mg/man were characterized by high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) with electrospray ionization (ESI). Two-stage collision-induced dissociation (CID) experiments, with in-source CID by increasing the octapole offset voltage and collision-cell CID, were performed in order to develop a very rapid screening procedure that enhanced selectivity toward pibutidine-related compounds. It was possible to detect metabolites of pibutidine directly from a crude biological matrix without prior extraction, enabling confirmation of the identity of eight metabolites in urine. In addition, the linear range in ESI for pibutidine-related compounds was studied to determine the urinary excretion of pibutidine and its metabolites in humans.

Chromatography, Liquid↗
PubMed1999

Plasma protein binding of tamsulosin hydrochloride in renal disease: role of alpha1-acid glycoprotein and possibility of binding interactions.

OBJECTIVE: To investigate the factors that affect the plasma protein binding of tamsulosin in patients with lowered renal function compared with that in healthy subjects and to evaluate the possibility of binding interactions. METHODS: Blood was donated from patients with renal dysfunction and from healthy subjects. The binding of 14C-tamsulosin to plasma proteins was determined by the ultrafiltration method. In addition, plasma protein binding interactions were investigated between tamsulosin and other drugs used concomitantly. RESULTS: The mean percentage of unbound 14C-tamsulosin was 0.90% in the healthy subjects (control) and was 0.71% in the patients. The unbound fraction in the patients with alpha1-acid glycoprotein (alpha1-AGP) levels over 0.9 mg/ml was significantly lower than that in the healthy subjects. In contrast, the unbound fraction in the patients with alpha1-AGP levels less than 0.7 mg/ml, which is the mean normal level, was almost equal to the control levels. A significant correlation existed between the Cb/Cu of tamsulosin and plasma alpha1-AGP level (r2 = 0.580, P < 0.001), while no correlation existed between the Cb/Cu and plasma albumin level (r2 = 0.021, P = 0.381) in both groups. No apparent binding interactions were observed between tamsulosin and the other drugs examined. CONCLUSIONS: Tamsulosin is highly bound to alpha1-AGP. The extent of plasma protein binding of tamsulosin correlated with the alpha1-AGP level but not with the albumin level. Furthermore, there appears to be no or little possibility of binding interactions between tamsulosin and other drugs in clinically concomitant use, despite its strong binding to alpha1-AGP.

Adrenergic alpha-Antagonists↗
PubMed1999

Inhibitory effect of TS-962 on the formation of early atherosclerotic lesions in high fat-fed hyperlipidemic hamsters.

The hypocholesterolemic and anti-atherosclerotic effect of TS-962, a specific ACAT inhibitor, was investigated in a hamster model fed a high fat diet containing 10% coconut oil and 0.05% cholesterol. Lipid accumulated atherosclerotic lesions were detected by using oil red O staining in the lesion-prone aortic arch. A high dose, estimated to be 15 mg/kg, of TS-962 decreased serum cholesterol to normal levels with reduction of liver cholesterol contents below normal levels, and as a consequence, entirely inhibited the lipid accumulation in the aortic arch. Furthermore, a low dose, estimated to be 1.5 mg/kg, of TS-962 remarkably inhibited aortic lipid accumulation by 73% compared with the control group, without changing either serum cholesterol level or liver cholesterol content. These findings suggest that TS-962 is effective in the primary prevention of atherosclerosis by directly suppressing the formation of foam cells in arteries.

Acetamides↗
PubMed1999

Gene expression during osteoclast-like cell formation induced by antifusion regulatory protein-1/CD98/4F2 monoclonal antibodies (MAbs): c-src is selectively induced by anti-FRP-1 MAb.

Human blood monocytes can differentiate into osteoclast-like cells when they are cultured in the presence of anti-FRP-1. Messenger (mRNA) expression of markers related to osteoclasts was analyzed during differentiation of osteoclasts from monocytes. As markers related to osteoclasts, we selected cathepsin-K, carbonic anhydrase (CA) II, vacuolar H(+)-ATPase (v-ATPase), vitronectin receptor (VNR), tartrate-resistant acid phosphatase (TRAP), osteopontin (OPN), galectin-3, c-src, c-fos, and c-fms. The mRNAs other than c-src mRNA were expressed in freshly isolated monocytes or monocytes incubated with control antibody or anti-FRP-1 monoclonal antibody (MAb) for 14 days. Of these mRNAs, cathepsin-K, CA II, v-ATPase, VNR, TRAP, OPN, and c-fms mRNAs were expressed at higher levels in the osteoclast-like cells than those in monocytes cultured with control antibody. On the other hand, galectin-3 mRNA was expressed at lower levels in the osteoclast-like cells, and there was no significant difference in c-fos mRNA expression between the monocytes cultured with control antibody and anti-FRP-1 MAb. c-src mRNA could not be detected in monocytes freshly isolated or incubated with control antibody. Surprisingly, expression of c-src mRNA was induced in monocytes by anti-FRP-1 MAb and was detectable as early as 3 h after anti-FRP-1 MAb treatment, indicating that c-src is selectively induced by anti-FRP-1 MAb treatment. Furthermore, the osteoclast-like cells expressed calcitonin receptor. Receptor activator of NF-kappaB (RANK) mRNA was detectable in freshly isolated monocytes or monocytes cultured with control antibody or anti-FRP-1 MAbs. Maximal expression of RANK was observed in osteoclast-like cells. On the other hand, no receptor activator of NF-KB ligand (RANKL) mRNA was detectable in any of the samples, suggesting that anti-FRP-1 mAb can induce osteoclast-like cells from blood monocytes without RANKL.

Antibodies, Monoclonal↗
PubMed1999

Association of a polymorphism of the 5HT2A receptor gene promoter region with alcohol dependence.

Approximately 10% of Japanese alcoholics develop their disease despite having an inactive form of aldehyde dehydrogenase-2 (ALDH2), known as a genetic deterrent of heavy drinking due to adverse reactions after drinking. Such alcoholics are considered to be advantageous in genetic research because they should show reduced heterogeneity and possess genetic factors conferring susceptibility to alcohol dependence. Examination of the -1438 A/G polymorphism of the serotonin 2A (5HT2A) receptor gene in 225 Japanese alcoholics with inactive ALDH2 revealed the presence of significantly more of the G allele than was found in 361 control subjects. The frequency of the G allele in 282 alcoholics with active ALDH2 fell between the G allele frequencies of controls and subjects with inactive ALDH2. These data suggest that although the effect is relatively small, genetic variability in the 5HT2A receptor is involved in the development of alcohol dependence.

Alcoholism↗
PubMed1999

Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping: possible effect of age, liver disease and length of therapy.

AIMS: To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of healthy young subjects (n = 78) and patients with peptic ulcer (n = 72). METHODS: Healthy subjects were administered a single dose of omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio of the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdose was determined and used as a measure of CYP2C19 activity. The CYP2C19 wild type (wt) gene and four mutant alleles associated with the poor metaboliser phenotype of (S)-mephenytoin, CYP2C19*2 in exon 5, CYP2C19*3 in exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were analysed. RESULTS: In the healthy volunteer study there was complete concordance between genotype and phenotype. However, eight of the patients who had the EM genotype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in the eight mismatched patients. They were all genotypic heterozygous EMs, elderly (> or = 65 years) and/or had hepatic disease. Therefore, impaired CYP2C19 activity combined with partial saturation of omeprazole metabolism during multiple dosing may have contributed to the discrepancy between CYP2C19 genotyping and phenotyping. CONCLUSION: Although omeprazole has been used instead of mephenytoin as a probe for polymorphic CYP2C19, it does not appear to be reliable enough for clinical application in Japanese patients.

Adult↗
PubMed1999

Population analysis for the optimization of digoxin treatment in Japanese paediatric patients.

BACKGROUND AND OBJECTIVES: Information about the pharmacokinetics of digoxin in paediatric patients is limited. We therefore aimed to investigate the effects of physiological factors on the digoxin clearance in Japanese paediatric patients. METHOD: We used routinely collected therapeutic drug monitoring data (n=544), derived from the steady-state serum concentrations of digoxin in 181 hospitalized paediatric patients. RESULTS: Of those physiological factors which have been examined in this study, age and total body weight were most closely correlated with digoxin clearance. Data on neonates within the first postnatal month indicated a tendency towards lower clearance for premature neonates than full-term neonates (P<0.01). Digoxin clearance was reduced by spironolactone in patients younger than 4 months (P<0.05). Patients with congestive heart failure showed a lower digoxin clearance than the others (P<0.001). Serum creatinine and gender did not have a statistically significant effect on digoxin clearance. CONCLUSION: Age and total body weight are important factors influencing digoxin clearance in children. Spironolactone affected digoxin clearance and needs to be considered when dosing paediatric subjects.

Age Factors↗
PubMed1999

Interaction of the new histamine H2-receptor antagonist pibutidine hydrochloride with canine cloned H2-receptor expressed cells.

The effect of a new histamine H2-receptor antagonist, pibutidine hydrochloride ((Z)-3-amino-4-{4-{4-[(piperidinomethyl)pyrid-2-yl]oxy} but-2-enylamino}cyclobut-3-ene-1,2-dione monohydrochloride, CAS 126463-66-9, IT-066 displaced the binding of [3H]tiotidine to cells transfected with the wild-type H2-receptor in a concentration-dependent manner. Compared with the 50% inhibitory concentration values (IC50) among five H2-receptor antagonists tested, the value of IT-066 was lowest. The inhibitory effect of IT-066 was enhanced by preincubation of IT-066 with the cells, and preincubation for 60 min increased potency about 2-fold. Famotidine also has such effects. When H2-receptor transfected cells were treated with IT-066 for 30 min, the inhibitory effect of IT-066 on the [3H]tiotidine binding still remained even after the cells were extensively washed. Scatchard plot analysis supported the non-competitive and irreversible action of IT-066. When the canine mutated H2-receptor-expressed cells were used, which have substituted amino acid of 190Alanine (Ala; position: 190th amino acid) for 190Threonine (Thr) in the fifth transmembrane domain, IT-066 also inhibited [3H]tiotidine binding to the cells concentration-dependently. However, in the case of the 190Ala mutated cells, the inhibitory effect of IT-066 attenuated with a decrease in maximal response after washing of the cells. These results show that IT-066 could tightly bind H2-receptor in a time-dependent manner and suggest the possibility that the irreversible inhibition of IT-066 is important in the interaction with 190Thr in the fifth transmembrane domain of H2-receptor.

Alanine↗
PubMed1999

Alcohol consumption as a major risk factor for the rise in liver cancer mortality rates in Japanese men.

BACKGROUND: Age-adjusted liver cancer mortality rates have been increasing for both men and women in Japan since 1970; however, increases in mortality rates in men are much greater than those in women. Hepatitis C virus infections and heavy alcohol consumption are considered to be the major risk factors of liver cancer deaths in Japanese. The purpose of this study is (1) to examine the pattern of liver cancer mortality by gender and birth year to compare those with the pattern of other alcohol-related mortality and (2) to estimate the attributable risk per cent of heavy alcohol consumption for liver cancer deaths in Japanese men. METHODS: Age-specific liver cancer mortality rates by gender were compared with those of cirrhosis mortality rates. Then male-to-female mortality rate ratios were calculated by birth cohort and compared with cirrhosis mortality rate ratios and oesophageal cancer mortality rate ratios. The attributable risk per cent of alcohol consumption for liver cancer death was calculated, using female liver cancer mortality rates as standard rates. RESULTS: Examination of both gender and birth cohort mortality rates revealed that male-to-female liver cancer mortality rate ratios by birth cohort correspond well with those rate ratios for liver cirrhosis and oesophageal cancer mortality. The attributable risk per cent of alcohol consumption for liver cancer deaths in Japanese men was 70%. CONCLUSION: Alcohol consumption is more important than hepatitis C virus infections as a major cause of liver cancer deaths in Japanese men.

Adult↗
PubMed1999

Predictive performance of equations to estimate creatinine clearance from serum creatinine in Japanese patients with congestive heart failure.

Seven methods using patient's age, weight, gender, and serum creatinine concentration were evaluated for mathematical and clinical predictive performance in estimating the creatinine clearance of Japanese patients. We compared the measured and estimated creatinine clearance in 179 hospitalized heart failure patients. The Gates equation was the most biased (mean prediction error, 17.9 mL/min), and the Yukawa equation was the most precise (mean absolute prediction error, 10.4 mL/min), followed by the Jelliffe, Bjornsson, Cockcroft and Gault, and Mawer equations. For all methods, precision was less when serum creatinine concentrations of <0.6 mg/dL were rounded than when serum creatinine concentrations of >/=0.6 mg/dL were rounded. We conclude that in clinical practice where the renal function can vary widely, any of the published formulas can give satisfactory results. The Yukawa formula is concise and gives better results in Japanese patients.

Adolescent↗