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Biomedical subjects

H Kamimura

Publications and source records attributed to H Kamimura.

At least 19 recordsLinked to original sources
PubMed2006

Genetic polymorphism of cytochrome P450s in beagles: possible influence of CYP1A2 deficiency on toxicological evaluations.

A number of human cytochrome P450 (CYP) isozymes have been shown to be genetically polymorphic, and extensive pharmaceutical studies have been conducted to characterize the clinical relevance of the polymorphism. Although the beagle is extensively used in the safety assessment studies of new drug candidates and agricultural chemicals, only a limited number of studies have been reported on the significance of the CYP isozyme polymorphism in dogs. Recently, a single nucleotide polymorphism that results in a deficiency of canine CYP1A2 was discovered. This deficiency was shown to significantly alter the pharmacokinetic behavior of two drugs, and can be associated with a large inter-individual difference in the kinetic behavior of a third. In this article, the five genetically polymorphic canine CYP isozymes that have been reported so far are reviewed, and the altered pharmacokinetics of the drugs concerned are described. Although little information on toxicological relevance has been reported, it is possible that the modified pharmacokinetics may also cause altered toxic responses as well. This phenomenon may occur only with the types of chemicals that are eliminated mainly through polymorphic-enzyme mediated metabolism. However, it is recommended that genetically pure beagles are used for the toxicity studies and safety assessment of new chemical entities in order to reduce the potential inter-individual differences.

Animals↗
PubMed2006

Effects of tetrabromobisphenol A, brominated flame retardant, in ICR mice after prenatal and postnatal exposure.

Tetrabromobisphenol A (TBBPA), brominated flame retardant, is produced in the largest amounts globally for use in plastics or building materials. TBBPA has been detected in sediment, air at the dismantling plant or human serum samples. In the present study, we examined the effects of prenatal and postnatal exposure to TBBPA in mice. TBBPA (99.1% pure) in diet was administered to pregnant ICR mice at doses of 0% (control), 0.01%, 0.1% or 1.0% from gestational day 0 to weaning at postnatal day 27. The average daily food intake and body weight of dams showed no significant differences between the control and treated groups. There were no dose-related effects on reproductive data. Serum concentrations of total-cholesterol and liver weights of treated dams and offspring were higher than those of the control mice. Histological findings in treated dams or offspring showed the increase of focal necrosis of hepatocytes and inflammatory cell infiltration in the liver, and increase of dilation or atrophy of renal tubules and cyst in the kidney. TBBPA was developed as a new, safe class of flame retardant and was not highly toxic. However, the present data suggested that TBBPA caused a lipid metabolic disorder and hepatic or kidney lesion, under these conditions.

Alanine Transaminase↗
PubMed2005

Identification of metabolites of [14C]zonampanel, an a-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist, following intravenous infusion in healthy volunteers.

This study determined the pharmacokinetics, metabolism and excretion of an a-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist zonampanel monohydrate (YM872) after intravenous infusion of [14C]YM872 at 1 mg kg-1 h-1 for 2 h to four healthy male volunteers. Mean pharmacokinetic parameters of unchanged YM872 were 0.78 h for terminal half-life, 25.9 l h-1 for total clearance, 22.9 l h-1 for renal clearance, and 15.6 l for volume of distribution at steady-state. Urinary excretion of radioactivity accounted for 94.9% of the dose, and faecal excretion for only 0.5% of the dose. Measurement of YM872 concentrations by a high-performance liquid chromatography (HPLC)-ultraviolet method and radiometric HPLC metabolite profiling revealed that almost all of [14C]YM872 was excreted unchanged in the urine and that unchanged [14C]YM872 was the major circulating [14C] component in the plasma. Two minor metabolites, H1 and H2, detected in the urine and identified as the same chemical structures as those of the rat urinary metabolites, have a hydroxyamino group and an amino group, respectively, which were probably formed by reduction of the nitro group of YM872. These results show that virtually all of the administered YM872 remains unchanged, with urinary excretion representing the major elimination pathway. The high renal clearance implies tubular secretion of this drug.

Adolescent↗
PubMed2004

Identification of the novel canine CYP1A2 1117 C > T SNP causing protein deletion.

The pharmacokinetics of YM-64227 (4-cyclohexyl-1-ethyl-7-methylpyrido[2,3-d]-pyrimidine-2-(1H)-one), a novel and selective phosphodiesterase type 4 inhibitor, was characterized in beagle dogs. Based on the plasma parent drug to major hydroxylated metabolite ratio, 21 dogs were phenotyped as 16 extensive metabolizers (EM) and five poor metabolizers (PM). Nucleotide sequences of CYPs 1A2, 2B11, 2C21, 2D15, 2E1 and 3A12 were investigated in the EM and PM dogs. A CYP1A2 1117 C>T single nucleotide polymorphism was found, which resulted in an amino acid change from an Arg codon to a stop codon at position 373. All dogs phenotyped as PM were T/T homozygous, whereas EMs were C/C homozygous and C/T heterozygous. In Western blotting of liver microsomes, CYP1A protein expression was detected in the C/C and C/T types, but not in the T/T type. Of 65 dogs genotyped using genome DNA, the frequencies of the C and T alleles were 0.61 and 0.39, respectively, suggesting approximately 15% of the dogs would not express the CYP1A2 protein. The findings provide a coherent explanation for the inter-individual variability in the pharmacokinetics of CYP1A2 substrate drugs in dogs.

Alleles↗
PubMed2002

Effects of the concomitant administration of tamsulosin (0.8 mg) on the pharmacokinetic and safety profile of intravenous digoxin (Lanoxin) in normal healthy subjects: a placebo-controlled evaluation.

A 20-day, nonrandomized, open-label, placebo-controlled study was performed to investigate whether concomitant administration of tamsulosin (0.8 mg) affects the pharmacokinetic and safety profile of intravenous digoxin (0.5 mg) in healthy subjects. Ten healthy subjects aged 21-39 years received a single oral dose of placebo on study days 1-8 and tamsulosin on days 9-18. Tamsulosin was initiated at 0.4 mg/day and the dose was increased to 0.8 mg/day from day 11. On days 2 and 15, subjects received a single intravenous dose of digoxin (0.5 mg). Safety monitoring was carried out throughout the study. Following digoxin administration, blood was drawn and urine collected over a 96-h period for pharmacokinetic determinations. Plasma tamsulosin concentrations were measured at regular intervals after dosing on day 15. The digoxin pharmacokinetic parameters with and without concomitant tamsulosin were compared. No significant difference was observed, and no irregularity was found in the plasma tamsulosin concentration data. Six subjects experienced adverse events while receiving placebo and seven while on tamsulosin. The most frequent adverse event was mild dizziness reported by four subjects. Moderate chest pain was reported in two subjects, but this was not considered to be related to the administration of the study medications. Some significant changes in vital signs were observed; however, none was accompanied by symptoms of medical concern. These changes were not temporally related to the administration of study drugs. Thus, concurrent administration of digoxin with tamsulosin did not produce any change in the pharmacokinetics of digoxin and the safety profile was acceptable. As reflected in the prescribing information for tamsulosin, no adjustment in tamsulosin dosing is required when it is administered concomitantly with digoxin.

Administration, Oral↗
PubMed2001

The technique of laparoscopically assisted total gastrectomy with jejunal interposition for early gastric cancer.

BACKGROUND: In recent years, laparoscopic gastrectomy has been applied to the treatment of gastric cancer in Japan. However, there are few reports of laparoscopic or laparoscopically assisted total gastrectomy in the treatment of gastric cancer because of the difficulty of the surgical technique. Laparoscopically assisted total gastrectomies with jejunal interpositions were performed on four patients with early gastric cancer located in the upper portion of the stomach. METHODS: Four surgical ports were inserted into the abdomen. The stomach was lifted to the abdominal wall using newly developed retraction tubes. Gastric arteries were divided using ultrasonically activated coagulating shears and ligated with ligation forceps. Following these steps, a total gastrectomy reconstruction was performed by jejunal interposition through a small transverse laparotomy. An esophagojejunostomy and a jejunoduodenostomy were made with circular staplers. RESULTS: The mean operating time and blood loss were 246 min and 236 ml, respectively. The operations were performed without serious complications. All patients were pain free and ambulatory after the laparoscopically assisted total gastrectomy, and the mean postoperative hospital stay was 16 days. CONCLUSION: We successfully performed laparoscopically assisted total gastrectomies in a relatively short period of time. When patients are carefully selected, the laparoscopic procedure can be curative and minimally invasive as a treatment for early gastric cancer.

Adenocarcinoma↗
PubMed2001

Pharmacokinetic properties of a novel tissue-type plasminogen activator pamiteplase after single intravenous administration to rats, dogs, and monkeys.

The pharmacokinetics of pamiteplase and recombinant tissue-type plasminogen activator (rt-PA) in rats, dogs, and monkeys were examined using a newly developed enzyme-linked immunosorbent assay (ELISA). Plasma concentrations after intravenous administration of pamiteplase to rats declined in a triphasic manner. Plasma concentrations after intravenous administration of pamiteplase to dogs or monkeys declined in a biphasic manner. The area under the plasma concentration-time curve from zero to infinity (AUC(0-->infinity)) in rats and dogs increased with increasing dose. The half-life and mean residence time of pamiteplase in rats, dogs, and monkeys were shown to be longer than those of rt-PA. Total clearance (CL(total)) of pamiteplase was only 7-16% that of rt-PAs, suggesting that concentrations of pamiteplase in plasma were higher and more continuous than those of rt-PA in these experimental animals. The data suggest that a bolus administration of pamiteplase shows the same thrombolytic activity as continuous infusion of rt-PA in experimentally induced thrombosis in rats and dogs. The pharmacokinetic parameters distribution volume at the steady state and CL(total) calculated by immunoreactive concentration after administration of pamiteplase to rats, dogs, and monkeys show high correlation with body weights (r(2)=.7728 and .9039).

Animals↗
PubMed2001

[Identification system for Sildenafil in health foods].

A substantially available identification system for Sildenafil in health foods was established using 3 different analytical methods; i.e. TLC, preparative TLC/MS and HPLC/photo-diode array. Sildenafil in health foods was extracted with ethyl acetate under alkaline conditions as sample solutions for TLC and preparative TLC, and also extracted with 50% methanol and then diluted with solution of HPLC mobile phase for HPLC. The sample solution for TLC was applied to Silica gel 60 F254 plates with chloroform/methanol/28% ammonia (90:1:5, under layer) as mobile phase. Spots were located under UV radiation at 254 nm and 366 nm, and spraying dragendorff reagent. The conditions for preparative TLC were the same as these of TLC method, and samples abtained from preparative TLC were determined by MS with APCI interface, under both positive and negative modes. The HPLC analysis was carried out on a column of Cosmosil 5C18-AR (4.6 mm x 150 mm, 5 microns) with 0.05 mol/l phosphate buffer pH 3.0/acetonitrile(73:27) as mobile phase and the eluate was monitored by a photo-diode array detector. The quantitative analysis was available, when the peak of this sample on HPLC was detected at 290 nm. When this system was applied to commercial health foods, Sildenafil was identified and their contents were 25 mg-45 mg/tablet or bottle. These contents nearly correspond to that in Viagra, 25 mg, 50 mg/tablet. Therefore, there is a fear of side effects for Sildenafil, when it is taken as health foods.

Chromatography, High Pressure Liquid↗
PubMed2001

[Formation of ethyl carbamate in umeshu (plum liqueur)].

Samples of umeshu, a Japanese plum liqueur made from unripe plums, shochu and crystal sugar, were stored under fluorescent light, in the dark and in the refrigerator. The amount of ethyl carbamate formed in umeshu exposed to light or room temperature was larger than that in the dark or at low temperature. The amount of ethyl carbamate formed in umeshu to which cyanide had been added was larger than that in the absence of added cyanide. Thus, the amount of ethyl carbamate formed in the umeshu was increased by not only light and higher temperature, but also cyanide. Samples of model alcoholic beverages were stored under various conditions using red, yellow and blue cellophanes. The amount of ethyl carbamate formed in the model alcoholic beverage with blue cellophane was larger than in the cases of red and yellow cellophanes. It was found that the amount of ethyl carbamate formed in the model alcoholic beverage was increased by light in the wavelength range of 375-475 nm.

Alcoholic Beverages↗
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

Kex2 family endoprotease furin is expressed specifically in pit-region parietal cells of the rat gastric mucosa.

The proprotein-processing endoprotease furin is localized in the gastric epithelial cells of the pit region in the rat gastric gland. The gastric pit is composed of several cell types, including gastric surface mucosal (GSM) cells and parietal cells. Furin converts many growth- or differentiation-related proproteins to their active forms. We examined identification of furin-positive cells by immunostaining of rat gastric mucosa and regulators of the furin expression by measuring the furin promoter activity by luciferase assay. Furin-positive cells were stained for H(+)-K(+)-ATPase, indicating that they are parietal cells. Furin-positive parietal cells were not stained for transforming growth factor-alpha (TGF-alpha) but were surrounded by TGF-alpha-positive GSM cells. In contrast, parietal cells below the proliferative zone were positive for TGF-alpha but not for furin. Furin-positive parietal cells expressed a high level of epidermal growth factor receptor (EGFR). TGF-alpha stimulated the furin promoter activity highly in a mouse GSM cell line GSM06. Thus we suggest that the parietal cells of the pit region have furin-mediated functions that can be stimulated by EGFR signaling.

Animals↗
PubMed1999

Gastrin stimulates the growth of gastric pit with less-differentiated features.

Gastrin stimulates the growth of gastric mucosa by increasing mostly its glandular region but is not known to induce the growth of a pit region where its major constituent cells, gastric surface mucous (GSM) cells, turn over rapidly. To investigate the effect of gastrin on GSM cells, we generated hypergastrinemic mice by expressing a human gastrin transgene. We obtained a hypergastrinemic mouse line whose average serum gastrin level is 671 +/- 252 pg/ml (normal level <150 pg/ml). Gastrin-positive cells were found in the fundic mucosa. The gastric mucosa exhibited hypertrophic growth, which was characterized by an elongated pit with an active proliferative zone, but the glandular region containing parietal cells was normal or reduced in size. The GSM cells contained fewer mucous granules than those of control littermates and lost reactivity to the GSM cell-specific cholera toxin beta-subunit lectin. GSM cells along the foveolar region and many mucous neck cells became Alcian blue positive, suggesting the appearance of sialomucin in these cells. We suggest that gastrin stimulates the growth of the proliferative zone of gastric glands, which results in the elongation of the pit region whose GSM cells exhibit less-differentiated features.

Animals↗
PubMed1998

Identification of cytochrome P450 isozymes involved in metabolism of the alpha1-adrenoceptor blocker tamsulosin in human liver microsomes.

1. The in vitro human liver metabolism of the alpha1-adrenoceptor blocker tamsulosin was investigated. When 14C-tamsulosin was incubated with human liver microsomes, it was converted to five known urinary metabolites and at least three unknown metabolites. Of the former group, the predominant metabolite was the O-deethylated metabolite (M-1), followed by the o-ethoxyphenoxy acetic acid (AM-1) and the m-hydroxylated metabolite (M-3). 2. There was a good linear relationship between AM-1 formation and testosterone 6beta-hydroxylase activity in microsomes from each of 10 individual donors. The rate of M-1 formation also correlated with the same activity, albeit the correlation curve did not pass through the origin. By contrast, the rates of M-3 and the O-demethylated metabolite (M-4) formation correlated with dextromethorphan O-demethylase activity. 3. Ketoconazole strongly inhibited AM-1 formation and reduced that of M-1 by c. 60%. Immunoinhibition studies using anti-rat antibodies supported these results. The formation of M-3 and M-4 was inhibited by quinidine and sparteine. 4. It is concluded that formation of tamsulosin metabolites, AM-1 and M-1, is catalysed by CYP3A4 whereas that of M-3 and M-4 is catalysed by CYP2D6. However, minor contributions from other CYPs cannot be excluded.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1998

Pharmacokinetics and plasma protein binding of tamsulosin hydrochloride in rats, dogs, and humans.

The pharmacokinetics of tamsulosin hydrochloride, a selective alpha1-adrenoceptor antagonist, was investigated after single iv and oral dosing to rats and dogs, and oral dosing to healthy male volunteers. After iv dosing, plasma tamsulosin concentrations declined in an apparent biexponential manner with terminal half-lives of 0.32 hr in rats and 1.13 hr in dogs. Values for total blood clearance (CLB) were 6.57 l/hr/kg in rats and 1.61 l/hr/kg in dogs, suggesting "hepatic blood flow-limited" and "intermediate flow-dependent" clearance, respectively. After oral dosing, tamsulosin was rapidly absorbed and reached maximum levels within 1 hr in rats and dogs, and at 1.0-1.8 hr in humans. Values for oral clearance (CLoral) in rats, dogs, and humans were 34.5-113.6, 3.01-3. 99, and 0.031-0.041 l/hr/kg, respectively, showing wide variation among these species. The absolute bioavailability (F) increased with dose in rats (from 6.9% at 1 mg/kg to 22.8% at 10 mg/kg), but was almost constant in dogs (29.7-42.0% over the 0.3-3 mg/kg dose range). The plasma protein binding of 14C-tamsulosin in humans was much higher (98.9-99.1%) than that in rats and dogs (79.0-80.6% and 90. 2-90.3%, respectively). The ratio of blood to plasma concentrations (RB) value in rats, dogs, and humans decreased in this order (1.2, 0. 72, and 0.53, respectively), corresponding to the decrease in plasma unbound fraction (fu) in these species. These results imply that the large interspecies difference in CLoral is attributable to a difference not only in hepatic metabolism but also in protein binding among these species.

Administration, Oral↗
PubMed1997

Highly sensitive method for the determination of tamsulosin hydrochloride in human plasma dialysate, plasma and urine by high-performance liquid chromatography-electrospray tandem mass spectrometry.

A highly sensitive method for the determination of tamsulosin hydrochloride, a structurally new type of sulphamoile derivative, in human plasma dialysate, plasma and urine has been developed by using liquid chromatography-electrospray tandem mass spectrometry (LC-MS-MS). Plasma dialysate, plasma and urine samples were extracted by brief liquid-phase extraction and analyzed using an HPLC system coupled to a mass spectrometer via an electrospray ionization interface. Selected reaction monitoring was used for the detection of tamsulosin and its internal standard. This method was validated in the concentration range 10-1000 pg/ml in plasma dialysate, 0.5-50 ng/ml in plasma, and 1-100 ng/ml in urine with sufficient specificity, accuracy and precision. The in vivo protein binding study demonstrated that the unbound tamsulosin in human plasma obtained by the equilibrium dialysis after 0.4-mg oral dosing was measurable. In addition, the percentage of unbound tamsulosin in an in vitro study (0.71-0.91%) obtained by using spiked 14C-labelled tamsulosin was slightly larger than that of the in vivo study (0.68-0.86%), indicating that the unbound concentration calculated by the product of the plasma concentration and the in vitro unbound fraction (fu) was unfavorably overestimated. These results suggest that the combination of LC-MS-MS and equilibrium dialysis method has enough sensitivity to determine the unbound concentration in clinical use and gives the concentration more exactly than the in vitro fu.

Adrenergic alpha-Antagonists↗