Katsushi Yamada

Publications of Katsushi Yamada

• Reduction in the incidence of MRSA with use of alcohol-based hand rub solutions and gloves.

  Authors: Kazuaki Matsumoto, Akari Shigemi, Keiko Yaji, Yoshihiro Shimodozono, Yasuo Takeda, Kazuro Ikawa, Norifumi Morikawa, Hiroaki Miyanohara, Hideki Kawamura, Michiyo Orita, Koichi Tokuda, Junichiro Nishi, Katsushi Yamada

  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 09/2011;

  Methicillin-resistant Staphylococcus aureus (MRSA) is highly contagious. It is spread by direct contact with MRSA-infected people or objects. Healthcare workers' hands are the most common vehicle forMethicillin-resistant Staphylococcus aureus (MRSA) is highly contagious. It is spread by direct contact with MRSA-infected people or objects. Healthcare workers' hands are the most common vehicle for the transmission of healthcare-associated pathogens from patient to patient and within the healthcare environment. The present study aimed to investigate the correlation between the incidence of MRSA among Staphylococcus aureus recovered from clinical culture and the use of alcohol-based hand rub solutions or gloves and antimicrobial use density (AUD). All data were examined every 6 months between January 2005 and June 2008. The increasing use of alcohol-based hand rub solutions was correlated with a decreasing incidence of recovery of MRSA from clinical cultures (r (2) = 0.58). A statistically significant (P < 0.05) correlation (r (2) = 0.68) was observed between glove use and the incidence of MRSA. On the other hand, we did not find any correlation between the AUD of each antibiotic group and the incidence of MRSA. Thus, we suggest that it is important to use not only alcohol-based hand rubs, but also gloves, because MRSA is transmitted from patient to patient by the hands of healthcare workers.

• Safety analysis of liposomal amphotericin B in adult patients: anaemia, thrombocytopenia, nephrotoxicity, hepatotoxicity and hypokalaemia.

  Authors: Akari Shigemi, Kazuaki Matsumoto, Kazuro Ikawa, Keiko Yaji, Yoshihiro Shimodozono, Norifumi Morikawa, Yasuo Takeda, Katsushi Yamada

  International journal of antimicrobial agents. 08/2011; 38(5):417-20.

  Liposomal amphotericin B (L-AmB), which was developed to reduce side effects, has been shown to have a better safety profile than both the deoxycholate and lipid complex forms of amphotericin B;Liposomal amphotericin B (L-AmB), which was developed to reduce side effects, has been shown to have a better safety profile than both the deoxycholate and lipid complex forms of amphotericin B; however, the frequency of major side effects is still unclear. Thus, the aim of the present study was to assess retrospectively the frequency of L-AmB-induced anaemia, thrombocytopenia, nephrotoxicity, hepatotoxicity and hypokalaemia as well as the relationship between daily dose of L-AmB and these side effects. A low red blood cell (RBC) count (post-/pre-treatment) and anaemia were observed in 7 and 10 of 21 adult patients, respectively. Thrombocytopenia was observed in 11 of 19 adult patients. Doses of L-AmB that are estimated to cause side effects of a low RBC count, anaemia and thrombocytopenia with 50% probability are 4.0, 3.3 and 3.0mg/kg/day, respectively. Nephrotoxicity was observed in 6 of 22 patients. Variations of total bilirubin, γ-glutamyl transpeptidase, aspartate aminotransferase and alanine aminotransferase used as indices of hepatotoxicity were observed in 6, 7, 8 and 8 of 22 patients, respectively. Hypokalaemia was observed in 4 of 9 patients; however, nephrotoxicity, hepatotoxicity and hypokalaemia were not caused in a dose-dependent manner. In conclusion, the present analyses showed that L-AmB dose-dependently induced anaemia and thrombocytopenia in adult patients. It is important to pay attention to causing anaemia and thrombocytopenia when patients are receiving L-AmB at doses of >3.3mg/kg/day and >3.0mg/kg/day, respectively.

• An initial dosing method for teicoplanin based on the area under the serum concentration time curve required for MRSA eradication.

  Authors: Naoko Kanazawa, Kazuaki Matsumoto, Kazuro Ikawa, Tomohide Fukamizu, Akari Shigemi, Keiko Yaji, Yoshihiro Shimodozono, Norifumi Morikawa, Yasuo Takeda, Katsushi Yamada

  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 04/2011; 17(2):297-300.

  Teicoplanin is a glycopeptide antibacterial agent that has a long serum half-life and therefore takes time to achieve steady-state conditions. An appropriate initial dosing is needed for teicoplaninTeicoplanin is a glycopeptide antibacterial agent that has a long serum half-life and therefore takes time to achieve steady-state conditions. An appropriate initial dosing is needed for teicoplanin to promptly reach an effective serum trough concentration. However, little information is available on tailoring the initial dosing for patients with various characteristics. The objective of this study was to develop a nomogram for determining teicoplanin initial dose to promptly reach an effective trough concentration (≥ 13 μg/mL). A logistic regression analysis was performed to test whether the area under the concentration time curve (AUC) is a significant predictor of microbiological response (persistence 0; eradication 1). The study included 24 adult patients with methicillin-resistant Staphylococcus aureus infections [minimal inhibitory concentration (MIC) for the isolates was <2 μg/mL). Each AUC was estimated using individual dose, creatinine clearance (CL(cr)), and body weight data. The target value, which gives about a 0.9 microbiological eradication probability, was 750 μg h/mL for AUC from zero to 24 h (AUC(0-24 h)). Using published population pharmacokinetic parameters, the dose required to achieve the AUC(0-24 h) target was calculated as dose (mg) = 750 × (0.00498 × CL(cr) (mL/min) + 0.00426 × body weight (kg). For various combinations of CL(cr) and body weight, we checked the calculated doses using a therapeutic drug monitoring (TDM)-supporting software and developed a nomogram. The nomogram would be useful for initial dose adjustment to promptly reach an effective serum trough concentration and avoid adverse events of teicoplanin.

• Wnt-5a signaling is correlated with infiltrative activity in human glioma by inducing cellular migration and MMP-2.

  Authors: Masayuki Kamino, Michiko Kishida, Toshiro Kibe, Kyoko Ikoma, Mikio Iijima, Hirofumi Hirano, Mai Tokudome, Lin Chen, Chihaya Koriyama, Katsushi Yamada, Kazunori Arita, Shosei Kishida

  Cancer science. 03/2011; 102(3):540-8.

  Wnts are secreted ligands that consist of 19 members in humans, regulate cell proliferation, differentiation, motility and fate in many stages including the embryonic stage and tumorigenesis. WntsWnts are secreted ligands that consist of 19 members in humans, regulate cell proliferation, differentiation, motility and fate in many stages including the embryonic stage and tumorigenesis. Wnts bind to cell surface receptors named Frizzleds and LRPs, and transduce their signals through β-catenin-dependent and -independent intracellular pathways. Gliomas are one of the most common intracranial tumors. Gliomas exhibit a progression associated with widespread infiltration into surrounding neuronal tissues. However, the molecular mechanisms that stimulate the invasion of glioma cells are not fully understood. We established two cell lines from human glioma cases and analyzed the expression of all Wnt and Frizzled members in these cell lines and other well-known glioma cell lines by real-time PCR study. The mRNA of Wnt-5a and -7b and Frizzled-2, -6 and -7 were overexpressed in glioma cells. The elevation of Wnt-5a expression was most remarkable. Although Wnt-5a is reported to have oncogenic and antioncogenic activity in several cancers, the role of Wnt-5a signaling in human glioma cells remains unclear. Immunohistochemical study also revealed high expression of Wnt-5a in 26 (79%) of 33 human glioma cases. The positivity of Wnt-5a expression was correlated with the clinical grade. Knockdown of Wnt-5a expression suppressed migration, invasion and expression of matrix metalloproteinase-2 of glioma cells. Reciprocally, treatment with purified Wnt-5a ligand resulted in stimulation of cell migration and invasion. MMP-2 inhibitor suppressed the Wnt-5a-dependent invasion of U251 cells. These results suggested that Wnt-5a is not only a prognostic factor but also a therapeutic target molecule in gliomas for preventing tumor cell infiltration.

• Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells.

  Authors: Ryuji Ikeda, Lee C Vermeulen, Elim Lau, Zhisheng Jiang, Kamakshi Sachidanandam, Katsushi Yamada, Jill M Kolesar

  International journal of oncology. 02/2011; 38(2):513-9.

  Gemcitabine is an effective chemotherapy against non-small cell lung cancer (NSCLC). However, resistance to gemcitabine reduces its efficacy. We have isolated gemcitabine-resistant human non-smallGemcitabine is an effective chemotherapy against non-small cell lung cancer (NSCLC). However, resistance to gemcitabine reduces its efficacy. We have isolated gemcitabine-resistant human non-small cell lung cancer A549 cells, termed A549/GR cells. A549/GR cells were resistant to gemcitabine as well as paclitaxel and docetaxel but not carboplatin and irinotecan. The expression level of multidrug resistance protein 7 (MRP7) in A549/GR cells was higher than that in A549 cells, and the inhibitor of MRP7 by cepharanthine increased the sensitivity to gemcitabine in A549/GR cells. These findings indicate that cepharanthine reversed gemcitabine resistance. To determine predictive molecular markers of gemcitabine resistance for more effective treatment of these tumors, we performed PCR array. We identified that CDKN1A/p21, CYP3A5, microsomal epoxide hyrolase 1 (EPHX1) and ABCC6 (MRP6) were up-regulated >5-fold in A549/GR cells. Gemcitabine also induced the expression of p21 and CYP3A5 in A549 cells. A better understanding of the characterization and mechanism of the resistance to gemcitabine in A549/GR cells may help identify agents that reverse clinical gemcitabine resistance in NSCLC.

• Multidrug resistance protein 2 implicates anticancer drug-resistance to sorafenib.

  Authors: Yoshihiko Shibayama, Kou Nakano, Hiroshi Maeda, Miyuki Taguchi, Ryuji Ikeda, Mitsuru Sugawara, Ken Iseki, Yasuo Takeda, Katsushi Yamada

  Biological & pharmaceutical bulletin. 01/2011; 34(3):433-5.

  Sorafenib and sunitinib is a small molecule inhibitor of certain receptor tyrosine kinases, and have improved outcomes for patients with advanced renal cell carcinoma. Inhibitory concentration of 50%Sorafenib and sunitinib is a small molecule inhibitor of certain receptor tyrosine kinases, and have improved outcomes for patients with advanced renal cell carcinoma. Inhibitory concentration of 50% cell growth of sorafenib significantly rose to 6.4-fold in a multidrug resistance protein 2 (MRP2) transfected cell line versus control cell line. The concentration of sorafenib was significantly decreased to 74% of control cells after 3 h treatment. In contrast, a tyrosine kinase inhibitor sunitinib did not show alteration of inhibitory concentration of 50% cell growth and accumulation into the cells of MRP2 transfected cells. The present study suggest that sorafenib is a substrate for MRP2, suggesting that MRP2 may implicate drug resistance to sorafenib.

• Effect of 5-fluorouracil treatment on SN-38 absorption from intestine in rats.

  Authors: Yoshihiko Shibayama, Yoshitaka Iwashita, Yoshimi Yoshikawa, Tomoko Kondo, Ryuji Ikeda, Yasuo Takeda, Takayuki Osada, Mitsuru Sugawara, Katsushi Yamada, Ken Iseki

  Biological & pharmaceutical bulletin. 01/2011; 34(9):1418-25.

  5-Fluorouracil (5-FU)-based chemotherapies with irinotecan have been applied for the treatment of cancers, and a common dose-limiting toxicity is neutropenia and diarrhea. In this study, we5-Fluorouracil (5-FU)-based chemotherapies with irinotecan have been applied for the treatment of cancers, and a common dose-limiting toxicity is neutropenia and diarrhea. In this study, we investigated the effect of 5-FU treatment on expression levels of drug transporters for SN-38 transportation and SN-38 absorption from the intestine following 5-FU treatment. Expression levels of several drug transporters and nuclear receptors in rats after 5-FU treatment were evaluated. SN-38 absorption from the intestine was evaluated by SN-38 concentration levels in serum following SN-38 injection into the intestine of 5-FU treated rats. The levels of renal multidrug resistance protein 2 (Mrp2) on day 4 after treatment (400 mg/kg) showed significant upregulation, 359.2 ± 33.2% (mean ± S.E.) of control. Mrp2 levels in the intestine were downregulated to 26.2 ± 8.4% of control. 5-FU treatment (400 mg/kg) also significantly downregurated expression levels of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) to 41.2 ± 14.7%, 15.7 ± 4.3% of control, respectively. To evaluate SN-38 absorption from the intestine, SN-38 was loaded in to the intestine on day 4 after 5-FU treatment. Pretreatment with 5-FU significantly increased SN-38 concentration in the blood 30, 60 and 90 min after SN-38 administration. The area under the curve for SN-38 in the 5-FU group was significantly higher than in vehicle groups. 5-FU treatment decreased expression levels of P-glycoprotein and Bcrp in intestine. The present study suggests that combination chemotherapy of 5-FU with irinotecan (CPT-11) may elevate SN-38 absorption from intestine.

• Alternative splicing of the pituitary adenylate cyclase-activating polypetide (PACAP) receptor contributes to function of PACAP-27.

  Authors: Mina Ushiyama, Ryuji Ikeda, Morikatsu Yoshida, Kenji Mori, Kenji Kangawa, Hideki Sugawara, Kazuhiko Inoue, Katsushi Yamada, Atsuro Miyata

  Journal of molecular neuroscience : MN. 11/2010; 42(3):341-8.

  Pituitary adenylate cyclase-activating polypeptide (PACAP)-27 and PACAP-38 are neuropeptides performing a variety of physiological functions. The PACAP-specific receptor PAC1 has several variantsPituitary adenylate cyclase-activating polypeptide (PACAP)-27 and PACAP-38 are neuropeptides performing a variety of physiological functions. The PACAP-specific receptor PAC1 has several variants that result mainly from alternative splicing in the mRNA region encoding the first extracellular (EC1) domain and the third intracellular cytoplasmic (IC3) loop. To characterize the molecular forms of alternative splicing variants of PAC1, we examined the binding affinity and activation of two major second messenger pathways (cAMP production and changes in [Ca(2+)]( i )) by PACAP-27. Activation of cAMP was influenced by the variant in both of the EC1 domain and IC3 loops. In the N form in the EC1 domain, the suppressive effect of the HOP1 form in the IC3 loop was enhanced. Regarding the intracellular calcium mobilization assay, the rank order of the potency of PACAP-27 for the different PAC1 isoforms was S/HOP1>N/R~S/R>N/HOP1. In particular, PACAP-27 exhibited remarkable potency of calcium mobilization in the S/HOP1-expressing cells at sub-picomolar concentrations even though the affinities of PACAP-27 to the four PAC1 isoforms were not significantly different. This suggests the specific functions of PACAP-27 due to PACAP-27 preferring PAC1 activation, and leads in clarification of the pleiotoropic function of PACAP.

• The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells.

  Authors: Shigeto Matsushita, Ryuji Ikeda, Yukihiko Nishizawa, Xiao-Fang Che, Tatsuhiko Furukawa, Kazutaka Miyadera, Sho Tabata, Mina Ushiyama, Yusuke Tajitsu, Masatatsu Yamamoto, Yasuo Takeda, Kentaro Minami, Hironori Mataki, Tamotsu Kanzaki, Katsushi Yamada, Takuro Kanekura, Shin-Ichi Akiyama

  International journal of oncology. 05/2010; 36(5):1193-200.

  Thymidine phosphorylase (TP) is an enzyme involved in reversible conversion of thymidine to thymine. TP is identical to an angiogenic factor, pletelet-derived endothelial cell growth factor (PD-ECGF)Thymidine phosphorylase (TP) is an enzyme involved in reversible conversion of thymidine to thymine. TP is identical to an angiogenic factor, pletelet-derived endothelial cell growth factor (PD-ECGF) and the expression levels of TP in a variety of malignant tumors were higher than the adjacent non-neoplastic tissues. To investigate the molecular basis for the effect of TP on the metabolic process and the anticancer effect of 5-fluorouracil (5-FU), human gastric carcinoma AZ521 cells and epidermoid carcinoma KB cells were transfected with TP cDNA, and AZ521/TP and KB/TP were cloned. AZ521/TP and KB/TP cells overexpressed TP and were more sensitive to 5-FU than the counterpart parental cells. TPI, a newly synthesized inhibitor for TP (Ki=2.36 x 10(-9) M), decreased the sensitivity to 5-FU of the TP expressing cells but not of the parental cells. 5-Formyl-tetrahydrofolate (leucovorin; LV) stabilized the complex of thymidylate synthase (TS) and 5-fluoro-deoxyuridine-monophosphate (FdUMP), increased the sensitivity to 5-FU of TP expressing AZ521 cells, but not of the parental cells. The levels of FdUMP in TP expressing cells were significantly higher than in parental cells and TPI considerably decreased FdUMP to the level comparable to that in the parental cells. 5-FU increased the expression of early growth response protein-1 (Egr-1) and an angiogenesis inhibitor, thrombospondin-1 (TSP-1), in KB/TP cells but only slightly in KB/CV cells, if any. TPI attenuated the induction of Egr-1 and TSP-1 mRNA by 5-FU, while LV increased the expression of Egr-1 and TSP-1 mRNA in KB/TP cells. These findings demonstrate that the TP has a principal role in the production of FdUMP and the enhanced responses to 5-FU by leucovorin in TP-overexpressing KB and AZ521 cells, and FdUMP but not FUTP is implicated in the induction of Egr-1 and TSP-1 in KB cells.

• Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction.

  Authors: Kazuaki Matsumoto, Ayumi Takeshita, Kazuro Ikawa, Akari Shigemi, Keiko Yaji, Yoshihiro Shimodozono, Norifumi Morikawa, Yasuo Takeda, Katsushi Yamada

  International journal of antimicrobial agents. 04/2010; 36(2):179-81.

  The major adverse event associated with linezolid treatment is reversible myelosuppression, mostly thrombocytopenia. Recent studies have reported that the incidence of linezolid-inducedThe major adverse event associated with linezolid treatment is reversible myelosuppression, mostly thrombocytopenia. Recent studies have reported that the incidence of linezolid-induced thrombocytopenia was higher in patients with renal failure than in patients with normal renal function, although the underlying mechanisms of this toxicity are still unknown. The present study thus aimed to investigate the relationship between renal function and linezolid exposure as well as the effects of drug exposure on thrombocytopenia. A statistically significant (P<0.01) strong correlation (r=0.933) was observed between linezolid clearance and creatinine clearance. A negative correlation (r=-0.567) was also shown between linezolid clearance and blood urea nitrogen, although the correlation was not statistically significant. In thrombocytopenic patients, the trough concentration was 14.4-35.6 mg/L and the area under the plasma linezolid concentration-time curve for 24h (AUC(24h)) was 513.1-994.6 mg h/L; in non-thrombocytopenic patients, drug exposure was relatively low (6.9 mg/L and 7.2mg/L for trough concentration and 294.3 mg h/L and 323.6 mg h/L for AUC(24h)). These results provide a pharmacokinetic explanation for the mechanism of the adverse event that renal dysfunction increased linezolid trough concentration and AUC and that higher drug exposure induced thrombocytopenia.

• Determination of teicoplanin trough concentration target and appropriate total dose during the first 3 days: a retrospective study in patients with MRSA infections.

  Authors: Kazuaki Matsumoto, Naoko Kanazawa, Kazuro Ikawa, Tomohide Fukamizu, Akari Shigemi, Keiko Yaji, Yoshihiro Shimodozono, Norifumi Morikawa, Yasuo Takeda, Katsushi Yamada

  Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 03/2010; 16(3):193-9.

  An initial loading procedure has been recommended to enable teicoplanin to promptly reach an effective serum concentration for the treatment of methicillin-resistant Staphylococcus aureus (MRSA).An initial loading procedure has been recommended to enable teicoplanin to promptly reach an effective serum concentration for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to retrospectively evaluate the pharmacokinetics and pharmacodynamics of teicoplanin to determine the therapeutic target for the teicoplanin trough concentration and an appropriate dosing method during the first 3 days. The mean trough concentrations were 13.2 mg/L for patients with eradication of MRSA. Moreover, logistic regression analysis showed that the teicoplanin trough concentration was 13 mg/L to achieve MRSA eradication with a probability of 89.0%. The rates of achieving >or=13 mg/L in <or=24, 24-36 and >or=36 mg/kg (total dose during the first 3 days) groups were 9.1, 48.4 and 87.5%, respectively. These results suggest that the administration of >or=36 mg/kg during the first 3 days is appropriate to promptly obtain a trough concentration target of >or=13 mg/L for the initial treatment of MRSA infections.

• Major vault protein forms complexes with hypoxia-inducible factor (HIF)-1alpha and reduces HIF-1alpha level in ACHN human renal adenocarcinoma cells.

  Authors: Ken-ichi Iwashita, Ryuji Ikeda, Yasuo Takeda, Tomoyuki Sumizawa, Tatsuhiko Furukawa, Tatsuya Yamaguchi, Shin-ichi Akiyama, Katsushi Yamada

  Cancer science. 02/2010; 101(4):920-6.

  Vaults are evolutionarily highly conserved ribonucleoprotein (RNP) particles with a hollow barrel-like structure. Although roles in multidrug resistance and innate immunity have been suggested, theVaults are evolutionarily highly conserved ribonucleoprotein (RNP) particles with a hollow barrel-like structure. Although roles in multidrug resistance and innate immunity have been suggested, the physiological function of vaults remains unclear. Major vault protein (MVP), the main component of the vault particle, has been reported to be induced by hypoxia. However, there are no reports about the effect of vaults on cellular responses to hypoxia. We thus examined whether vaults are implicated in cellular responses to hypoxia. In this study, we focused on hypoxia-inducible factor-1alpha (HIF-1alpha), which is a master regulator of hypoxic responses, and found that: (i) MVP knockdown by RNA interference increases HIF-1alpha protein levels induced by hypoxia and hypoxia mimetics; (ii) MVP knockdown does not affect HIF-1alpha mRNA levels, but decreases the ubiquitination and degradation of HIF-1alpha protein; and (iii) vaults form complexes with HIF-1alpha, PHD2, and pVHL. Taken together, these results suggest that vaults function as scaffolds in HIF-1alpha degradation pathway and promote the ubiquitination and degradation of HIF-1alpha.

• Correlation between meropenem and doripenem use density and the incidence of carbapenem-resistant Pseudomonas aeruginosa.

  Authors: Akari Shigemi, Kazuaki Matsumoto, Keiko Yaji, Yoshihiro Shimodozono, Yasuo Takeda, Hiroaki Miyanohara, Hideki Kawamura, Michiyo Orita, Koichi Tokuda, Junichiro Nishi, Katsushi Yamada

  International journal of antimicrobial agents. 09/2009;

  Optimal use of carbapenems is an important issue in the prevention of resistance in Pseudomonas aeruginosa. In this study, we investigated the correlation between antimicrobial use density (AUD) ofOptimal use of carbapenems is an important issue in the prevention of resistance in Pseudomonas aeruginosa. In this study, we investigated the correlation between antimicrobial use density (AUD) of carbapenems and imipenem/cilastatin (IPM/CS) or meropenem (MEPM) susceptibility of P. aeruginosa strains. The AUD of five carbapenems [IPM/CS, panipenem/betamipron, biapenem, MEPM and doripenem (DRPM)] was examined every 6 months between 2006 and 2008. The AUD was calculated using the defined daily doses methodology developed by the World Health Organisation. A minimum inhibitory concentration of IPM/CS or MEPM of </=4mg/L was considered to be sensitive. There was a significant negative correlation between MEPM susceptibility and the total AUD of MEPM and DRPM [r=-0.823, 95% confidence interval (CI) -0.035 to -0.980; P=0.044]. Furthermore, there was a significant correlation between MEPM susceptibility and IPM/CS susceptibility (r=0.839, 95% CI 0.084 to 0.981; P=0.037). Cross-resistance was therefore investigated and only 5.6% of MEPM-insensitive strains were susceptible to IPM/CS, although 43.3% of IPM/CS-insensitive strains were susceptible to MEPM. These results suggest that curtailing the use of MEPM and DRPM may curb the emergence not only of MEPM-resistant strains but also IPM/CS-resistant strains.

• Enhanced platelet responsiveness due to chilling and its relation to CD40 ligand level and platelet-leukocyte aggregate formation.

  Authors: Osamu Ayukawa, Kazuo Nakamura, Hiroko Kariyazono, Ryuji Ikeda, Junko Arima, Terutoshi Shinkawa, Harunobu Iwase, Ryuzo Sakata, Katsushi Yamada

  Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. 05/2009; 20(3):176-184.

  To investigate platelet responsiveness during cold storage of whole blood, we examined platelet aggregation, expression of CD40 ligand (CD40L) on platelets, the plasma levels of soluble form of CD40LTo investigate platelet responsiveness during cold storage of whole blood, we examined platelet aggregation, expression of CD40 ligand (CD40L) on platelets, the plasma levels of soluble form of CD40L (sCD40L) as well as platelet-leukocyte aggregates. Flow cytometry analysis was performed to investigate platelet-leukocyte aggregate formation using antibodies against CD42b and CD45 and platelet activation using antibodies against P-selectin and PAC-1. Blood samples were collected from healthy volunteers, patients with cardiovascular diseases, or both. In the healthy volunteers' blood samples stored at 4 degrees C for 6 h, platelet aggregation in response to 1 mumol/l ADP was enhanced, and released levels of soluble form of P-selectin and thromboxane B2 in response to 1 mumol/l ADP markedly increased. In the samples stored at 4 degrees C for 6 h but not stimulated by any agonists, CD40L expression on the platelets was increased, and plasma levels of sCD40L were also elevated. Under the same condition, the increase in simultaneous expression of CD45 and CD42b was observed. In patients with cardiovascular diseases, the platelet aggregability, coexpression of P-selectin and PAC-1, expression of CD40L on platelets and both CD45-bound and CD42b-bound subsets were all comparable to those of healthy volunteers' samples stored at 4 degrees C for 6 h. Plasma levels of sCD40L in patients were higher than those in healthy volunteers' control. Taken together, storage of whole blood at 4 degrees C for 6 h caused platelet activation comparable to that of patients with cardiovascular diseases, and enhanced platelet activity in such patients may be involved in increased risk for thromboembolic events.

• Effect of methotrexate treatment on expression levels of organic anion transporter polypeptide 2, p-glycoprotein and bile salt export pump in rats.

  Authors: Yoshihiko Shibayama, Yasuo Takeda, Katsushi Yamada

  Biological & pharmaceutical bulletin. 04/2009; 32(3):493-6.

  High-dose methotrexate (HDMTX) chemotherapy with leucovorin (LV) rescue has been used as a therapeutic strategy in oncology since the 1970s. Adverse reactions following extension of methotrexateHigh-dose methotrexate (HDMTX) chemotherapy with leucovorin (LV) rescue has been used as a therapeutic strategy in oncology since the 1970s. Adverse reactions following extension of methotrexate (MTX) elimination are a crucial problem in HDMTX chemotherapy. MTX is a substrate for drug transporters, which are multidrug resistance protein 2 (Mrp2), organic anion transporter polypeptide 2 (Oatp2) and other transporters. We previously reported that MTX treatment downregulated the expression level of Mrp2 in rats. Here we examined the effect of MTX treatment on the expression of Oatp2, P-glycoprotein (P-gp) and bile salt export pump (Bsep) in rats. MTX was single-injected intraperitoneally at a dose of 150 mg/kg, and Western blot analysis was performed. The levels of Oatp2, P-gp and Bsep in the liver on day 4 after treatment were downregulated to 36.3+/-6.9%, 51.5+/-5.2% and 61.8+/-5.5% (mean+/-S.E.M.) of controls, respectively. Expression levels of P-gp in the kidney and ileum were also downregulated to 38.5+/-1.6% and 16.2+/-1.6% of controls, respectively. These effects of MTX were partially recovered by LV, which rescues normal cells from MTX toxicity. In conclusion, the result indicates that MTX treatment downregulates expression levels of Oatp2, P-gp and Bsep.

• Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes.

  Authors: Kazuaki Matsumoto, Kazuro Ikawa, Kazuko Abematsu, Naoko Fukunaga, Kentaro Nishida, Tomohide Fukamizu, Yoshihiro Shimodozono, Norifumi Morikawa, Yasuo Takeda, Katsushi Yamada

  International journal of antimicrobial agents. 03/2009;

  Voriconazole metabolism is mostly mediated via the cytochrome P450 (CYP) 2C19 isozyme. The non-wild (mutant) type of CYP2C19 is generally found in 60-70% of Asian populations. Because theVoriconazole metabolism is mostly mediated via the cytochrome P450 (CYP) 2C19 isozyme. The non-wild (mutant) type of CYP2C19 is generally found in 60-70% of Asian populations. Because the voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity, this study investigated the effect of CYP2C19 polymorphism on the relationship between voriconazole trough concentrations and liver function abnormalities in 29 Japanese patients with fungal infections (CYP2C19 wild-type, n=10; non-wild-type, n=19). Hepatotoxicity, defined as liver enzyme abnormality according to the National Cancer Institute criteria, was observed in 10 (34.5%) of 29 patients with a trough concentration >/=3.9mg/L. Logistic regression analysis suggested that the therapeutic range for the voriconazole trough concentration should be 2-4mg/L. Non-linear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2-8.9mg/kg/day for CYP2C19 wild-type and 4.4-6.5mg/kg/day for the non-wild-type in Japanese patients. These recommended initial dosages and subsequent dose adjustment for the target concentration range by therapeutic drug monitoring should avoid adverse events and thus enable continued effective voriconazole therapy for Japanese patients with mycoses.

• Contactin-associated protein (Caspr) 2 interacts with carboxypeptidase E in the central nervous system.

  Authors: Shigeru Oiso, Yasuo Takeda, Toshitaka Futagawa, Takehiko Miura, Satoshi Kuchiiwa, Kentaro Nishida, Ryuji Ikeda, Hiroko Kariyazono, Kazutada Watanabe, Katsushi Yamada

  Journal of neurochemistry. 02/2009;

  To identify proteins interacting with the intracellular domain of the neural cell adhesion molecule contactin-associated protein 2 (Caspr2), yeast two-hybrid screening was performed. We identifiedTo identify proteins interacting with the intracellular domain of the neural cell adhesion molecule contactin-associated protein 2 (Caspr2), yeast two-hybrid screening was performed. We identified carboxypeptidase E (CPE) as a Caspr2-interacting candidate protein. Glutatione S-transferase pull-down and immunoprecipitation analyses indicated that Caspr2 was associated with CPE in vitro and in vivo. Both Caspr2 and CPE were expressed predominantly in the central nervous system. Immunohistochemical analyses revealed that both Caspr2- and CPE-like immunoreactivities were found to co-localize in the apical dendrites and cell bodies of rat cortical neurons. In subcellular localization analysis, Caspr2- and CPE-like immunoreactivities were comigrated in the fractions of Golgi/ER. Additionally, in COS-7 cells cotransfected with CPE and Caspr2 cDNAs, Caspr2- and CPE-immunoreactivities were co-localized in both Golgi and membrane, whereas it was only observed in Golgi of either COS-7 cell transfected with CPE or Caspr2 cDNA alone. It is known that the membrane-bound form of CPE functions as a sorting receptor of prohormones in the trans-Golgi network. Taken together, our data suggest that CPE may be a key molecule to regulate Caspr2 trafficking to the cell membrane.

• Contactin-associated protein (Caspr) 2 interacts with carboxypeptidase E in the CNS

  Authors: Shigeru Oiso, Yasuo Takeda, Toshitaka Futagawa, Takehiko Miura, Satoshi Kuchiiwa, Kentaro Nishida, Ryuji Ikeda, Hiroko Kariyazono, Kazutada Watanabe, Katsushi Yamada

  J Neurochem. 01/2009; 109(1):158-67.

  To identify proteins interacting with the intracellular domain of the neural cell adhesion molecule contactin-associated protein 2 (Caspr2), yeast two-hybrid screening was performed. We identifiedTo identify proteins interacting with the intracellular domain of the neural cell adhesion molecule contactin-associated protein 2 (Caspr2), yeast two-hybrid screening was performed. We identified carboxypeptidase E (CPE) as a Caspr2-interacting candidate protein. Glutathione S-transferase pull-down and immunoprecipitation analyses indicated that Caspr2 was associated with CPE in vitro and in vivo. Both Caspr2 and CPE were expressed predominantly in the CNS. Immunohistochemical analyses revealed that both Caspr2- and CPE-like immunoreactivities were found to co-localize in the apical dendrites and cell bodies of rat cortical neurons. In subcellular localization analysis, Caspr2- and CPE-like immunoreactivities were co-migrated in the fractions of Golgi/ER. Additionally, in COS-7 cells co-transfected with CPE and Caspr2 cDNAs, Caspr2- and CPE-immunoreactivities were co-localized in both Golgi and membrane, whereas it was only observed in Golgi of either COS-7 cell transfected with CPE or Caspr2 cDNA alone. It is known that the membrane-bound form of CPE functions as a sorting receptor of prohormones in the trans-Golgi network. Taken together, our data suggest that CPE may be a key molecule to regulate Caspr2 trafficking to the cell membrane.

• Renal function as a predictor of linezolid-induced thrombocytopenia.

  Authors: Kazuaki Matsumoto, Yasuo Takeda, Ayumi Takeshita, Naoko Fukunaga, Akari Shigemi, Keiko Yaji, Yoshihiro Shimodozono, Katsushi Yamada, Kazuro Ikawa, Norifumi Morikawa

  International journal of antimicrobial agents. 10/2008;

• Up-regulation of matrix metalloproteinase-3 in the dorsal root ganglion of rats with paclitaxel-induced neuropathy.

  Authors: Kentaro Nishida, Satoshi Kuchiiwa, Shigeru Oiso, Toshitaka Futagawa, Shogo Masuda, Yasuo Takeda, Katsushi Yamada

  Cancer science. 09/2008; 99(8):1618-25.

  Paclitaxel-induced painful peripheral neuropathy is a major dose-limiting factor. Recently, it has been reported that macrophages accumulated in the dorsal root ganglion of paclitaxel-treated rats,Paclitaxel-induced painful peripheral neuropathy is a major dose-limiting factor. Recently, it has been reported that macrophages accumulated in the dorsal root ganglion of paclitaxel-treated rats, and their activation is suggested to contribute to generation and development of the neuropathy. However, the mechanism for macrophage activation is still unknown. In this study, to explore candidate genes involved in the mechanism for macrophage activation in the dorsal root ganglion of paclitaxel-treated rats, we developed model rats for paclitaxel-induced neuropathic pain and performed a microarray assay to analyze the changes of gene expressions in the dorsal root ganglion. Among the genes with changed expression levels, we focused on matrix metalloproteinase-3 (MMP-3, stromelysin-1) and CD163, a macrophage marker. By reverse transcription-polymerase chain reaction, the expression levels of MMP-3 and CD163 were markedly up-regulated in paclitaxel-treated dorsal root ganglion. As a result of immunohistochemical study, large ganglion neurons, but neither Schwann cells nor macrophages, predominantly expressed MMP-3. This MMP-3 up-regulation occurred prior to macrophage accumulation in the dorsal root ganglion. In addition, recombinant MMP-3 led to the activation of RAW264 macrophages in vitro. Taken together, the up-regulation of MMP-3 and following macrophage activation caused in the dorsal root ganglion might be a significant event to trigger a series of reactions developing paclitaxel-induced peripheral neuropathic pain.