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Biomedical subjects

Michiko Yamamoto

Publications and source records attributed to Michiko Yamamoto.

13 recordsLinked to original sources
PubMed2006

Phase I and pharmacologic study of irinotecan and amrubicin in advanced non-small cell lung cancer.

PURPOSE: We conducted a Phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 as well as the dose-limiting toxicities (DLT) of this combination in patients with advanced non-small cell lung cancer. PATIENTS AND METHODS: Eleven patients with stage IIIB or IV disease were treated at 3-week intervals with amrubicin (5-min intravenous injection on days 1-3) plus 60 mg/m2 of CPT-11 (90-min intravenous infusion on days 1 and 8). The starting dose of amrubicin was 25 mg/m2, and it was escalated in 5 mg/m2 increments until the maximum tolerated dose was reached. RESULTS: The 30 mg/m2 of amrubicin dose was one dose level above the MTD, since three of the five patients experienced DLT during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the DLT, while thrombocytopenia was only a moderate problem. Amrubicin did not affect the pharmacokinetics of CPT-11, SN-38 or SN-38 glucuronide. Except for one patient, the biliary index on day-1 correlated well with the percentage decrease of neutrophils in a sigmoid Emax model. There were five partial responses among 11 patients for an overall response rate of 45%. CONCLUSION: The combination of amrubicin and CPT-11 seems to be active against non-small cell lung cancer with acceptable toxicity. The recommended dose for Phase II studies is 60 mg/m2 of CPT-11 (days 1 and 8) and 25 mg/m2 of amrubicin (days 1-3) administered every 21 days.

Anthracyclines↗
PubMed2005

Drug interaction between gefitinib and warfarin.

Gefitinib is a synthetic, oral anilinoquinazoline specifically designed to inhibit the epidermal growth factor receptor tyrosine kinase, and is the first targeted drug to demonstrate reproducible activity in non-small cell lung cancer patients who do not respond to platinum-based chemotherapy. In this report, we present two cases of an interaction between gefitinib and warfarin which has not been reported previously. Because of the potentially serious consequences of this interaction, close monitoring of the International Normalized Ratio and warfarin dosage adjustment are recommended for patients receiving warfarin together with gefitinib.

Aged↗
PubMed2005

Infusion of the beta-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats.

OBJECTIVE: Since beta-blocker therapy is known to be effective in patients with an injured heart, such as infarction, we designed the present study to examine the protective effects of infusion of the beta1-selective blocker esmolol on myocardial function in peritonitis-induced septic rats using an isolated working heart preparation. DESIGN: Randomized animal study. SETTING: University research laboratory. SUBJECTS: Thirty-one rats treated with cecal ligation and perforation to evoke peritonitis. INTERVENTIONS: After cecal ligation and perforation, rats were randomly allocated to the control group (normal saline 2 mL/hr, n = 11), low-dose esmolol group (10 mg/kg/hr, n = 10), or high-dose esmolol group (20 mg/kg/hr, n = 10). After obtaining blood samples for measurement of arterial lactate and tumor necrosis factor-alpha at 24 hrs, we assessed cardiac output, myocardial oxygen consumption, and cardiac efficiency (cardiac output x peak systolic pressure/myocardial oxygen consumption) at various preloads in an isolated perfused heart preparation. MEASUREMENTS AND MAIN RESULTS: Esmolol infusion did not cause an elevation of arterial lactate levels but reduced tumor necrosis factor-alpha concentrations vs. the control group (p < .05). Both cardiac output and cardiac efficiency in the esmolol-treated rats were significantly higher throughout the study periods vs. the control group (p < .05). CONCLUSIONS: Esmolol infusion in sepsis improved oxygen utilization of myocardium and preserved myocardial function.

Adrenergic beta-1 Receptor Antagonists↗
PubMed2005

Sivelestat, a neutrophil elastase inhibitor, attenuates neutrophil priming after hepatoenteric ischemia in rabbits.

Neutrophils play an important role in ischemia-reperfusion injury. The neutrophil elastase not only causes tissue damage, but also mediates neutrophil priming. In the present study, we use a rabbit model of hepatoenteric ischemia-reperfusion to test the hypothesis that neutrophil elastase inhibition ameliorates an ischemia-reperfusion injury by attenuating neutrophil priming and suppressing enzymatic activity. Twenty-four Japanese white rabbits underwent 30 min of supraceliac aortic cross-clamping and 180 min of reperfusion under isoflurane anesthesia. The rabbits randomly received the neutrophil elastase inhibitor, sivelestat (n = 10), or saline (n = 14). Neutrophil priming was then assayed with luminol-dependent neutrophil chemiluminescence. Hepatic, intestinal, renal, and pulmonary damages were assessed with serum transaminase, lactate dehydrogenase concentrations, urinary N-acetyl glucosaminidase activity, and protein concentration in post mortem bronchoalveolar lavage fluid. We discovered that neutrophil elastase inhibition suppressed plasma neutrophil elastase, and that lipid peroxide concentrations increased after reperfusion. It improved ischemia-reperfusion injuries in the liver, intestine, kidney, and lung. Furthermore, inhibition of neutrophil elastase with sivelestat significantly attenuated post-reperfusion neutrophil priming. The results of this study demonstrate that neutrophil elastase inhibition could effectively attenuate an ischemia-reperfusion injury caused by supraceliac aortic cross-clamping, most likely from the attenuation of neutrophil priming.

Acetylglucosaminidase↗
PubMed2005

Epidural analgesia prevents endotoxin-induced gut mucosal injury in rabbits.

In the present study, we evaluated the effect of epidural analgesia on the alterations of gut barrier function elicited by endotoxin in rabbits. After the placement of an epidural catheter, 28 male rabbits were randomized into either 0.5% lidocaine (group E) or saline (group C) group. The solutions (0.4 mL/kg) were epidurally injected, followed by continuous infusion (0.1 mL . kg(-1) . h(-1)) throughout the study period. Under a continuous infusion of lipopolysaccharide (15 microg . kg(-1) . h(-1)), mean arterial blood pressure, intramucosal pH, and plasma thrombomodulin concentrations were measured. At 4 h, mean arterial blood pressure was lower (P < 0.05), intramucosal pH was higher (P < 0.01), and the progression of hemodilution more profound (P < 0.05) in group E versus group C, whereas plasma thrombomodulin levels were increased to a similar extent between the groups. With less wet-to-dry weight ratio of ileum, histopathological injury scores of gut mucosa were significantly less in group E versus group C (P < 0.01). In a separate series of experiments (n = 10 each group), mucosal permeability in group E was significantly less compared with group C (P < 0.05). Collectively, these studies showed that despite a significant decrease of perfusion pressure and arterial oxygen content, epidural analgesia minimized endotoxin-induced functional and structural injury of gut mucosa possibly through endothelium-independent mechanisms.

Algorithms↗
PubMed2003

Olprinone, a phosphodiesterase III inhibitor, reduces gut mucosal injury and portal endotoxin level during acute hypoxia in rabbits.

BACKGROUND: Preservation of gut integrity has become a therapeutic goal to obviate bacterial translocation in the critically ill. The authors examined whether olprinone, a phosphodiesterase III inhibitor, protected functional and structural integrity of gut mucosa against acute progressive hypoxia. METHODS: Thirty-two animals were randomly allocated to a control group (n = 12), a low-dose group (0.2 microg x kg-1 x min-1 olprinone; n = 10), or a high-dose group (0.6 microg x kg-1 x min-1 olprinone; n = 10) after preparatory surgery. Ascending aortic and portal blood flow, intramural pH of the ileum, and portal endotoxin levels were measured at normoxia and through three stages of progressive hypoxia (fraction of inspired oxygen = 0.17, 0.13, and 0.10). RESULTS: At normoxia, ascending aortic flow in the high-dose group was approximately 20% higher than in the control and low-dose groups. During progressive hypoxia, both ascending aortic and portal flow in the control group were depressed, whereas olprinone infusion attenuated such alterations and redistributed blood to the splanchnic area in a dose-dependent manner. On the contrary, the reduction of intramural pH of the ileum and the elevation of portal endotoxin levels observed in the control group were significantly minimized in both the low- and high-dose groups to a similar extent during acute hypoxia. Histopathologic alterations of gut mucosa observed in the control group were minimized by olprinone infusion dose-independently, accompanied by reduction of mortality rate of the animals. CONCLUSIONS: Olprinone slows progression of intestinal mucosal acidosis and gut barrier dysfunction, concurrently with preservation of microscopic structures, through both flow-dependent and -independent mechanisms under acute hypoxia. Such properties of olprinone may serve to protect the host under insult.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19.

The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. In the present study, the frequencies of mutant alleles and PMs in each race were analyzed based on information from published studies, considering the genetic polymorphisms of CYP2D6 and CYP2C19 as the causal factors of racial and inter-individual differences in pharmacokinetics. As a result, it was shown that there were racial differences in the frequencies of each mutant allele and PMs. The frequencies of PMs on CYP2D6 are 1.9% of Asians and 7.7% of Caucasians, and those of PMs on CYP2C19 are 15.8% of Asians and 2.2% of Caucasians. Based on the results, it was suggested that there would be racial differences in the frequencies of PM subjects whose blood concentrations might be higher for drugs metabolized by these enzymes. Additionally, it was suggested that enzyme activities would vary according to the number of functional alleles even in subjects judged to be extensive metabolizers (EMs). In the bridging study, genetic information regarding CYP2D6 and CYP2C19 of the subjects will help extrapolate foreign clinical data to a domestic population.

Journal Article↗
PubMed2003

[Safety information project on drug, food and chemicals. Division of Safety Information on Drug, Food and Chemicals. National Institute of Health Sciences].

Recent issues on BSE(Bovine Spongiform Encephalopathy) and health hazards caused by adverse reactions of medical drugs, have strongly emphasized the necessity for safety measures to secure public health. These issues have been attributed to the delay to obtain overseas information on safety and regulation, and the lack of an adequate system for acquirement and assessment of such information. In order to develop a system where domestic and international safety information is collected, analyzed, assessed and presented both scientifically and systematically, the Division of Chem-Bio Informatics of the National Institute of Health Sciences was reorganized to the Division of Safety Information on Drug, Food and Chemicals in April, 2003. Collection and evaluation of safety information on medical drugs, food and chemical substances is now centralized at the Division, which consists of 5 sections, the first, second and third sections being newly established. The first section assesses information on medical drugs, the second section deals with food microorganisms, and the third section focuses on chemicals in food. The fourth and fifth sections retain their previous functions, namely, chemical safety information research and information network infrastructure support within the institute, respectively. The purpose of this paper is to describe how we will manage safety information on drug, food and chemicals, focusing on the role of the three new sections.

Consumer Product Safety↗
PubMed2002

A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: identification of a novel gain of function mutation (Ser(820)Phe) in the calcium-sensing receptor.

To date about 20 activating mutations in the calcium-sensing receptor (CaR) gene have been identified to cause autosomal dominant hypocalcemia (ADH) or sporadic hypoparathyroidism. We report a novel activating mutation in the CaR gene in a Japanese family with ADH. The proband, a 15-yr-old boy, and 5 other patients in 3 generations were asymptomatic, except for the proband's grandmother who had a history of seizures. They showed mild hypocalcemia (1.68-1.98 mmol/liter) with normal urinary calcium excretion and low normal serum PTH levels. Their serum magnesium concentrations were below normal in 3 adults and within the normal range in 3 teenagers. There was a significant positive correlation (r = 0.90; P < 0.05) between the serum calcium and magnesium concentrations of 6 affected members. Nucleotide sequencing revealed that the proband had a known polymorphism (Gly(990)Arg) and a novel heterozygous mutation substituting phenylalanine for serine at codon 820 (Ser(820)Phe) in the sixth transmembrane helix of the CaR. In other family members, the Ser(820)Phe mutation cosegregated with hypocalcemia. The mutation was not detected in 50 control subjects. The Gly(990)Arg polymorphism was observed in 8 of 9 family members with or without hypocalcemia and in 36 of 50 controls. The sensitivity of the Ser(820)Phe mutant CaR to calcium was assessed using transiently transfected HEK293 cells and measuring the increases in intracellular Ca(2+) concentrations in response to the changes in extracellular Ca(2+). The concentration-response curve of the mutant receptor was left-shifted, and its EC(50) (2.5 mM) was significantly (P < 0.05) lower than that of the wild-type CaR (3.3 mM). We conclude that the Ser(820)Phe mutation in the CaR caused ADH in this family. The positive correlation between serum calcium and magnesium levels observed in this family may support the concept that renal CaR acts as a magnesium sensor as well as a calcium sensor.

Adolescent↗
PubMed2002

Involvement of cyclo-oxygenase-2 in osteoclast formation and bone destruction in bone metastasis of mammary carcinoma cell lines.

We previously reported that mouse mammary carcinoma cell lines (MMT060562 and BALB/c-MC) induced osteoclast formation through production of prostaglandin E2 (PGE2) in cocultures with mouse bone marrow cells, but the mechanism(s) of PG production remained unclear. In the present in vitro and in vivo studies, we tested the involvement of cyclo-oxygenase-2 (COX-2), an inducible rate-limiting enzyme in PG biosynthesis, in the stimulation of osteoclast formation by mouse mammary carcinoma cell lines. Addition of a selective COX-2 inhibitor, JTE-522, to cocultures of mammary carcinoma cell lines and bone marrow cells lowered PGE2 concentration in the culture media and inhibited osteoclast formation in a dose-dependent manner. Northern blotting showed a very high level of COX-2 messenger RNA (mRNA) expression in MMT060562. The mRNA expression was low in BALB/c-MC, but it increased when BALB/c-MC and bone marrow cells were cocultured. The results of immunocytochemistry for COX-2 protein in respective cultures were compatible with the results of COX-2 mRNA. In vivo, BALB/c-MC injected into the heart of Balb/c mice metastasized to bone and formed osteolytic lesions in their hindlimbs. Histological examination revealed that tumor cells had metastasized to the bone marrow cavity and destroyed the bone trabeculae. Immunohistochemistry demonstrated that bone marrow stromal cells adjacent to tumor cells expressed COX-2 protein. These findings suggest that COX-2 plays an important role in the osteolysis of bone metastasis in vivo as well as in osteoclast formation in cocultures used as an in vitro model of metastatic bone disease.

Animals↗
PubMed2002

[PTH/PTHrP receptor and pseudohypoparathyroidism].

The PTH/PTHrP receptor, a G protein coupled receptor, mediates the actions of PTH and PTHrP. Homozygous inactivating mutations in this receptor cause a rare disorder called Blomstrand chondrodystrophy. Since this disease is lethal in utero or perinatal period, the existence of PTH resistance has not been verified. Inactivating mutations in PTH/PTHrP receptor have not been found in the patients with pseudohypoparathyroidism (PsH), a group of disorders characterized by biochemical hypoparathyroidism and unresponsiveness to PTH. In patients with PsH type Ia, numerous heterozygous inactivating mutations have been identified in the gene (GNAS1) encoding the alpha-subunit of Gs protein (Gs alpha) which couples multiple receptors to the stimulation of adenylate cyclase. It is suggested that some abnormality in GNAS1 outside the coding exons may lead to PsH type Ib. To explain the heredity and phenotypic variation of PsH, tissue- or cell-specific imprinting of Gs alpha has been implicated.

Humans↗