KINDAI UNIVERSITY


*A space between the first name and last name, please enter

TAKADA Mitsutaka

Profile

FacultyDepartment of Pharmacy / Graduate School of Medicine
PositionProfessor
Degree
Commentator Guidehttps://www.kindai.ac.jp/meikan/794-takada-mitsutaka.html
URL
Mail
Last Updated :2020/09/30

Research Activities

Published Papers

  • Comparison of CYP3A5*3 genotyping assays for personalizing immunosuppressive therapy in heart transplant patients ., Uno T, Wada K, Matsuda S, Terada Y, Oita A, Takada M, Yanase M, Fukushima N, International journal of clinical pharmacology and therapeutics, International journal of clinical pharmacology and therapeutics, 57(6), 315 - 322, Jun. 2019 , Refereed
  • Gastrointestinal risk factors and prescribing pattern of antiulcer agents in patients taking low-dose aspirin in Japan., Iwasawa M, Wada K, Takada M, The International journal of pharmacy practice, The International journal of pharmacy practice, 26(4), 369 - 372, Aug. 2018 , Refereed
  • Impact of the CYP3A5*1 Allele on the Pharmacokinetics of Tacrolimus in Japanese Heart Transplant Patients., Uno T, Wada K, Matsuda S, Terada Y, Oita A, Kawase A, Takada M, European journal of drug metabolism and pharmacokinetics, European journal of drug metabolism and pharmacokinetics, 43(6), 665 - 673, Apr. 2018 , Refereed
  • An integrative approach using real-world data to identify alternative therapeutic uses of existing drugs., Hosomi K, Fujimoto M, Ushio K, Mao L, Kato J, Takada M, PloS one, PloS one, 13(10), e0204648, 2018 , Refereed
  • Limited sampling strategy for mycophenolic acid in Japanese heart transplant recipients: comparison of cyclosporin and tacrolimus treatment., Wada K, Takada M, Kotake T, Ochi H, Morishita H, Komamura K, Oda N, Mano A, Kato TS, Hanatani A, Nakatani T, Circulation journal : official journal of the Japanese Circulation Society, Circulation journal : official journal of the Japanese Circulation Society, 71(7), 1022 - 1028, Jul. 2007 , Refereed
  • Relationship between acute rejection and cyclosporine or mycophenolic acid levels in Japanese heart transplantation., Wada K, Takada M, Ueda T, Ochi H, Kotake T, Morishita H, Hanatani A, Nakatani T, Circulation journal : official journal of the Japanese Circulation Society, Circulation journal : official journal of the Japanese Circulation Society, 71(3), 289 - 293, Mar. 2007 , Refereed
  • Pharmacokinetic study and limited sampling strategy of cyclosporine in Japanese heart transplant recipients., Wada K, Takada M, Ueda T, Ochi H, Morishita H, Hanatani A, Nakatani T, Circulation journal : official journal of the Japanese Circulation Society, Circulation journal : official journal of the Japanese Circulation Society, 70(10), 1307 - 1311, Oct. 2006 , Refereed
  • Heart failure elevates serum levels of cibenzoline in arrhythmic patients., Kotake T, Takada M, Komamura K, Kamakura S, Miyatake K, Kitakaze M, Morishita H, Circulation journal : official journal of the Japanese Circulation Society, Circulation journal : official journal of the Japanese Circulation Society, 70(5), 588 - 592, May 2006 , Refereed
  • Clotrimazole troches can alter everolimus pharmacokinetics in post-transplant patients: A case report., Takaya Uno, Kyoichi Wada, Sachi Matsuda, Megumi Ikura, Hiromi Takenaka, Nobue Terakawa, Akira Oita, Satoshi Yokoyama, Atsushi Kawase, Kouichi Hosomi, Mitsutaka Takada, British journal of clinical pharmacology, British journal of clinical pharmacology, 85(9), 2176 - 2178, Sep. 2019 , Refereed
  • Adherence to guidelines for antiulcer drug prescription in patients receiving low-dose aspirin therapy in Japan., Makiko Iwasawa, Keiko Sagami, Satoshi Yokoyama, Kouichi Hosomi, Mitsutaka Takada, International journal of clinical pharmacology and therapeutics, International journal of clinical pharmacology and therapeutics, 57(4), 197 - 206, Apr. 2019 , Refereed
    Summary:OBJECTIVE: Prevalence of guideline adherence for antiulcer drug prescription in patients receiving low-dose aspirin (LDA) therapy was examined and the association of risk factors with the adherence was assessed. MATERIALS AND METHODS: A retrospective cohort study using a population-based longitudinal healthcare database was conducted. Claims data between January 2005 and April 2016 were analyzed. A total of 3,079 patients were included in the study. The selected patients taking LDA were divided into two categories: those taking and those not taking antiulcer drugs in an inpatient setting. Additionally, they were classified into four groups according to the time antiulcer therapy was initiated. The risk factors for ulcer, such as history of gastrointestinal injuries; age ≥ 65 years; and concomitant use of anticoagulants, antiplatelets, oral corticosteroids, and nonsteroidal anti-inflammatory drugs except aspirin, were assessed. RESULTS: A total of 3,079 patients were included in the study. The rate of LDA patients using antiulcer drugs was 65.2%, with the strongest single factor associated with the use of antiulcer drugs being the concomitant use of corticosteroids. Among the LDA patients not taking antiulcer drugs, 66.8% had more than one risk factor. Irrespective of the use of concomitant treatment with antiulcer drug prior to hospital admission, 78.3% of the LDA patients continued their home regimen after hospital admission. CONCLUSION: Our results showed that the requirement of antiulcer therapy is not routinely evaluated at hospital admission, and antiulcer drugs for patients with ulcer risks are under-prescribed. Developing strategies to screen gastrointestinal risk factors at hospital admission is required to improve the guideline adherence for LDA-induced ulcer.
  • Voriconazole trough concentration and hepatotoxicity in patients with low serum albumin ., Atsushi Hirata, Keisuke Noto, Ryosuke Ota, Satoshi Yokoyama, Kouichi Hosomi, Mitsutaka Takada, Hiroshi Matsuoka, International journal of clinical pharmacology and therapeutics, International journal of clinical pharmacology and therapeutics, 57(3), 135 - 143, Mar. 2019 , Refereed
    Summary:OBJECTIVE: We aimed to investigate the relationship between voriconazole (VRCZ) trough concentrations and hepatotoxicity and to evaluate whether the recommended trough concentration is adequate in our clinical setting. MATERIALS AND METHODS: A retrospective study was performed to investigate the relationship between serum VRCZ concentrations and the development of hepatotoxicity at the Kindai University Nara Hospital. Patients treated with VRCZ from March 2010 to January 2018 were identified from the medical records. A total of 42 patients (mean age of 61.9 ± 16.9 years; 33 males and 9 females) were enrolled in this study. RESULTS: Hepatotoxicity developed in 28.6% (12/42) of patients treated with VRCZ, and 91.7% (11/12) of these patients developed hepatotoxicity within 3 weeks after initiating the treatment. Significantly increased aspartate aminotransferase (AST; p < 0.001), alkaline phosphatase (ALP; p < 0.001), and alanine aminotransferase (p = 0.001) levels were observed after the initiation of VRCZ therapy. In addition, significant positive correlations between AST and VRCZ trough concentrations (p = 0.017) and between ALP and VRCZ trough concentrations (p = 0.012) were observed. VRCZ trough concentration was identified as a significant independent risk factor for hepatotoxicity (adjusted odds ratio: 1.611, 95% confidence interval: 1.131 - 2.579, p = 0.006), and the cutoff serum trough concentration was calculated to be 4.2 μg/mL. CONCLUSION: VRCZ-induced hepatotoxicity should be noted in the early stages of therapy. A sustained VRCZ trough concentration of ~ < 4.2 μg/mL is recommended to prevent hepatotoxicity in patients with low serum albumin levels.
  • Risk of malignant lymphoma in patients with rheumatoid arthritis treated with biological disease-modifying antirheumatic drugs and methotrexate ., Ryo Inose, Kouichi Hosomi, Katsuyuki Takahashi, Satoshi Yokoyama, Mitsutaka Takada, International journal of clinical pharmacology and therapeutics, International journal of clinical pharmacology and therapeutics, 57(2), 63 - 72, Feb. 2019 , Refereed
    Summary:OBJECTIVE: This study investigated whether using biological disease-modifying antirheumatic drugs (bDMARDs) further increases the risk of malignant lymphoma in patients with rheumatoid arthritis undergoing methotrexate therapy using spontaneous adverse reaction databases in different countries. MATERIALS AND METHODS: Patient data were acquired from the US Food and Drug Administration's Adverse Event Reporting System (FAERS), the Japanese Adverse Drug Event Report (JADER), and the Canada Vigilance Adverse Reaction Online Database (CVARD) from the first quarter of 2004 to the end of 2015. Data subset analysis was performed to investigate whether the use of bDMARDs further increased the risk of malignant lymphoma in patients receiving methotrexate therapy. RESULTS: The FAERS subset data indicated a significant association between Hodgkin lymphoma and methotrexate with infliximab (reporting odds ratio (ROR): 8.28. 95% CI: 5.70 - 12.02; information component (IC): 2.04, 95% CI: 1.59 - 2.49). In addition, signal scores suggested that methotrexate with infliximab (ROR: 3.26. 95% CI: 2.68 - 3.98; IC: 1.31, 95% CI: 1.04 - 1.58) was significantly associated with non-Hodgkin lymphoma (NHL). The CVARD subset data also indicated a significant association between NHL and methotrexate with infliximab (ROR: 22.82. 95% CI: 5.02 - 103.78; IC: 1.77, 95% CI: 0.13 - 3.41). However, the JADER subset data revealed no significant associations. CONCLUSION: The present study shows that using infliximab further increases the risk of malignant lymphoma in patients receiving methotrexate therapy.
.
  • Effects of clotrimazole on tacrolimus pharmacokinetics in patients with heart transplants with different CYP3A5 genotypes., Takaya Uno, Kyoichi Wada, Sachi Matsuda, Yuka Terada, Nobue Terakawa, Akira Oita, Satoshi Yokoyama, Atsushi Kawase, Kouichi Hosomi, Mitsutaka Takada, European journal of clinical pharmacology, European journal of clinical pharmacology, 75(1), 67 - 75, Jan. 2019 , Refereed
    Summary:PURPOSE: This study aimed to investigate the effects of clotrimazole on the pharmacokinetics of tacrolimus in Japanese patients with heart transplants with different CYP3A5 genotypes. METHODS: Twenty-six patients who underwent heart transplantation between June 2012 and July 2017 were enrolled in this retrospective study. The CYP3A5 (rs776746; CYP3A5*3) genotype was determined after monitoring and analysing tacrolimus blood concentrations. The pharmacokinetic profile of tacrolimus was examined before and after the discontinuation of clotrimazole and in patients with different CYP3A5 genotypes. RESULTS: The CYP3A5*1/*1, *1/*3 and *3/*3 genotypes were detected in 2, 8 and 16 patients, respectively. After clotrimazole was discontinued, the CYP3A5 expresser (CYP3A5*1/*1 or *1/*3) group had a 3.3-fold median increase in apparent oral clearance of tacrolimus (0.27 vs. 0.89 L/h/kg, P = 0.002) compared with the CYP3A5 non-expresser (CYP3A5*3/*3) group with a 2.2-fold median increase (0.18 vs. 0.39 L/h/kg, P < 0.0001). Significant correlations were observed between C0 and area under the concentration-time curve (AUC0-12) of tacrolimus after the discontinuation of clotrimazole in the CYP3A5 expresser and non-expresser groups, respectively (R2 = 0.49 and 0.42, all P < 0.05), but not before the discontinuation of clotrimazole. CONCLUSION: The effects of clotrimazole on tacrolimus pharmacokinetics in the CYP3A5 expresser patients were significantly greater than those in the CYP3A5 non-expresser patients. In addition, clotrimazole disturbed the correlation between C0 and AUC0-12 of tacrolimus. Careful dose adjustment of tacrolimus based on CYP3A5 genotypes may be beneficial for the patients with heart transplants who are concomitantly treated with clotrimazole.
  • Effects of vitamin K epoxide reductase complex 1 gene polymorphisms on warfarin control in Japanese patients with left ventricular assist devices (LVAD), Kazuki Nakagita, Kyoichi Wada, Yutaro Mukai, Takaya Uno, Ryoji Nishino, Sachi Matsuda, Hiromi Takenaka, Nobue Terakawa, Akira Oita, Mitsutaka Takada, European Journal of Clinical Pharmacology, European Journal of Clinical Pharmacology, 74(7), 885 - 894, Jul. 01 2018 , Refereed
    Summary:Purpose: This study aimed to investigate relationships between times in therapeutic range (TTR) or warfarin sensitivity indexes (WSI) and VKORC1-1639G> A and CYP2C9 polymorphisms in patients with left ventricular assist devices (LVAD). Methods: Severe heart failure patients who received LVAD from January 1, 2013 to October 31, 2017 were recruited. Relationships between TTR or WSI and VKORC1-1639G> A and CYP2C9 gene polymorphisms were investigated immediately after LVAD implantation (period 1) and immediately prior to hospital discharge (period 2). Results: Among 54 patients, 31 (72.1%) had VKORC1-1639AA and CYP2C9*1/*1 (AA group) polymorphisms and 12 (27.9%) had VKORC1-1639GA and CYP2C9*1/*1 (GA group) polymorphisms. During period 1, mean prothrombin time-international normalized ratio (PT-INR) values were significantly higher in the AA group than in the GA group (2.21 vs. 2.05, p < 0.0001). Mean WSI values were 1.68-fold greater in the AA group than in the GA group (1.14 vs. 0.68, p < 0.0001). In addition, times below the therapeutic range (TBTR) in the GA group were significantly greater than in the AA group during period 1 (39.8 vs. 28.3%, p = 0.032), and insufficient PT-INR was more frequent in the GA group than in the AA group. However, mean PT-INR values during period 2 did not differ and no significant differences in TTR, TATR, and TBTR values were identified. In subsequent multivariable logistic regression analyses, the VKORC1-1639GA allele was significantly associated with insufficient anticoagulation. Conclusion: Patients with the VKORC1-1639GA and CYP2C9*1/*1 alleles may receive insufficient anticoagulation therapy during the early stages after implantation of LVAD, and VKORC1-1639G> A and CYP2C9 genotyping may contribute to more appropriate anticoagulant therapy after implantation of LVAD.
  • Association between Serum Amiodarone and N-Desethylamiodarone Concentrations and Development of Thyroid Dysfunction, Mikie Yamato, Kyoichi Wada, Tomohiro Hayashi, Mai Fujimoto, Kouichi Hosomi, Akira Oita, Mitsutaka Takada, Clinical Drug Investigation, Clinical Drug Investigation, 38(1), 39 - 48, Jan. 01 2018 , Refereed
    Summary:Objective: This retrospective cohort study was performed to examine the association between serum amiodarone (AMD) and N-desethylamiodarone (DEA) concentrations and the development of thyroid dysfunction. Methods: Patients treated with AMD from January 2012 to April 2016 were identified from the computerized hospital information system database at the National Cerebral and Cardiovascular Center. Only patients whose serum AMD and DEA concentrations had been determined at least once were included in the study. Results: A total of 377 patients were enrolled. Consequently, 54 (14.3%) and 60 (15.9%) patients who developed AMD-induced thyrotoxicosis and hypothyroidism were included. The mean DEA/AMD ratio during the pre-index period in the thyrotoxicosis group (0.86 ± 0.24) was significantly higher than in the hypothyroidism (0.68 ± 0.27) and euthyroidism (0.78 ± 0.30 p <  0.0001) groups. In addition, the mean DEA/AMD ratio during the post-index period in the thyrotoxicosis group (1.05 ± 0.40) was significantly higher than in the hypothyroidism (0.81 ± 0.24) and euthyroidism (0.88 ± 0.22 p <  0.0001) groups. A persistently higher DEA/AMD ratio was observed throughout the study period in the thyrotoxicosis group. In addition, good correlations between the DEA/AMD ratio and the levels of free thyroxine, free triiodothyronine levels, and log (thyroid-stimulating hormone) were observed in the thyrotoxicosis and euthyroidism groups. Conclusion: Patients with AMD-induced thyrotoxicosis had an increased DEA/AMD ratio and patients with AMD-induced hypothyroidism had a decreased DEA/AMD ratio before the development of thyroid dysfunction. The DEA/AMD ratio may be a predictive marker for AMD-induced thyroid dysfunction.
  • Use of rifabutin to treat tuberculosis in a cardiac transplant recipient: A case report, Maya Takayoshi, Kyoichi Wada, Yuka Terada, Sachi Matsuda, Kazuki Nakagita, Akira Oita, Mitsutaka Takada, Aki Shionoiri, Haruki Sunami, Seiko Nakajima, Kensuke Kuroda, Takuma Sato, Osamu Seguchi, Masanobu Yanase, Norihide Fukushima, International Journal of Clinical Pharmacology and Therapeutics, International Journal of Clinical Pharmacology and Therapeutics, 56(4), 184 - 188, 2018 , Refereed
    Summary:Objective: Tuberculosis is an important concern following organ transplantation. Unfortunately, several antituberculosis drugs interact with immunosuppres-sants. This report describes our experience with rifabutin (RBT) in the treatment of acute tuberculosis in a cardiac transplant recipient. Case: A 61-year-old cardiac transplant recipient developed tuberculosis meningitis during treatment of miliary tuberculosis. RBT was given for 27 days concomitantly with cyclosporine (CsA). CsA concentrations at 0 hour (C0) decreased within 3 days of starting RBT. The serum concentration-curve from 0 to 12 hours (AUC0-12h)/dose 7 days after starting RBT therapy decreased by 28%, compared to the values before RBT therapy. The apparent clearance at both 7 and 21 days after starting RBT therapy was 1.4 times higher than before RBT therapy. Conclusion: RBT has fewer drug-drug interactions than rifampin and should be preferentially used for the treatment of tuberculosis in transplant patients treated with CsA. Close monitoring of CsA blood concentration during RBT therapy minimized the risk of under- or over-immunosuppression in a cardiac transplant patient.
  • Effect of fluconazole on the pharmacokinetics of everolimus and tacrolimus in a heart transplant recipient: Case report, Kazuki Nakagita, Kyoichi Wada, Yuka Terada, Sachi Matsuda, Nobue Terakawa, Akira Oita, Mitsutaka Takada, International Journal of Clinical Pharmacology and Therapeutics, International Journal of Clinical Pharmacology and Therapeutics, 56(6), 270 - 276, 2018 , Refereed
    Summary:Objective: Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been used in combination with calcineurin inhibitors (tacrolimus and cyclosporine) to prevent allograft rejection following organ transplantation. In heart transplant recipients, everolimus should be maintained at a target blood concentration of 3 - 8 ng/mL, in combination with reduceddose calcineurin inhibitors and therefore, requires strict monitoring. Fluconazole, an azole antifungal agent, affects blood concentration of tacrolimus by inhibiting the cytochromes P450 (CYP) 3A4 and 3A5. Therefore, to avoid overexposure during everolimus-azole cotreatment, the dose of everolimus should be reduced. However, the mechanism of interaction between everolimus and fluconazole remains unclear. Case report: We report the case of a heart transplant recipient who experienced a 2.8-fold increase in everolimus clearance and a 3.5- fold increase in everolimus dosage, following withdrawal of fluconazole therapy. The clearance and dosage of tacrolimus increased 4.7- and 3.0-fold, respectively. Conclusion: The concentrations of everolimus and tacrolimus should be carefully monitored when administered concomitantly with fluconazole to heart transplant recipients. The patient in this case had a CYP3A5∗1/∗3 genotype, and CYP3A5 constituted the metabolic pathway. Therefore, concomitant use of fluconazole might have a relatively small impact on everolimus and tacrolimus pharmacokinetics in this case.
  • Bleeding Risk of Warfarin and Direct Oral Anticoagulants in Younger Population: A Historical Cohort Study Using a Japanese Claims Database., Satoshi Yokoyama, Yuki Tanaka, Kazuki Nakagita, Kouichi Hosomi, Mitsutaka Takada, International journal of medical sciences, International journal of medical sciences, 15(14), 1686 - 1693, 2018 , Refereed
    Summary:A historical cohort analysis of the Japan medical data center (JMDC) claims databases was performed to compare the incidence rates of bleeding events with warfarin (WF) versus direct oral anticoagulant (DOAC) treatment in patients with non-valvular atrial fibrillation. The aim of this study is to clarify the risk factors for bleeding events in younger patients newly treated with WF or DOAC in clinical practice setting. Patients who newly initiated WF or DOAC treatment from April 2012 to March 2015 were selected from the JMDC claims database. A 1:1 propensity score matching analysis was used for new users of WF or DOAC. Kaplan-Meier curves were generated to depict the time to bleeding event (total bleeding events, gastrointestinal hemorrhage, and intracranial hemorrhage) during the follow-up period. Cox proportional regression models were used to estimate the hazard ratios for total bleeding events caused by oral anticoagulants. Overall, 2,046 patients (503 WF and 1,543 DOAC) were included. After applying propensity score matching, Kaplan-Meier analysis of the WF and DOAC groups displayed comparable incidences of total bleeding events, gastrointestinal hemorrhage, and intracranial hemorrhage. Cox proportional hazards modeling showed that the use of WF was not associated with total bleeding events compared with DOAC (hazard ratio: 1.21, 95% confidence interval: 0.93-1.54, p = 0.15). This historical cohort study using a claims database indicates that the bleeding risk of DOAC was comparable to that of WF in Japanese younger population.
  • The influence of residual apixaban on bleeding complications during and after catheter ablation of atrial fibrillation, Yutaro Mukai, Kyoichi Wada, Koji Miyamoto, Kazuki Nakagita, Mai Fujimoto, Kouichi Hosomi, Takeshi Kuwahara, Mitsutaka Takada, Kengo Kusano, Akira Oita, Journal of Arrhythmia, Journal of Arrhythmia, 33(5), 434 - 439, Oct. 01 2017 , Refereed
    Summary:Background The periprocedural protocol for atrial fibrillation (AF) ablation commonly includes anticoagulation therapy. Apixaban, a direct oral anticoagulant, is currently approved for clinical use however, little is known about the effects of residual apixaban concentration on bleeding complications during/after AF ablation. Therefore, we measured residual apixaban concentration by using mass spectrometry and examined the anticoagulant's residual effects on bleeding complications. Methods Fifty-eight patients (Mean age of 64.7±12.5 years 31 males, 27 females) were enrolled and administered apixaban twice daily. We analyzed trough apixaban concentration, activated clotting time (ACT), heparin dose, and bleeding complications during/after AF ablation. Apixaban concentrations were directly measured using mass spectrometry. Results Bleeding complications were observed in 19 patients (delayed hemostasis at the puncture site, 16 hematuria, 3 hemosputum, 1). No patient required blood transfusion. The mean trough apixaban concentration was significantly lower in patients with bleeding complications than without (152.4±73.1 vs. 206.8±98.8 ng/mL respectively, P=0.037), while the heparin dose to achieve ACT> 300 s was significantly higher in patients with bleeding complications (9368.4±2929.0 vs. 7987.2±2135.2 U/body respectively, P=0.046). Interestingly, a negative correlation was found between the trough apixaban concentration and the heparin dose to achieve ACT> 300 s (P=0.033, R=-0.281). Conclusions Low residual plasma apixaban is associated with a higher incidence of bleeding complications during/after AF ablation, potentially because of a greater heparin requirement during AF ablation.
  • Response: Amiodarone-induced thyroid dysfunction and a perturbed N-desethyl-amiodarone to amiodarone ratio; could a drug-induced toxicity be regulating exposure to the offending agent?, Mitsutaka Takada, Mikie Yamato, Kyoichi Wada, Mai Fujimoto, Kouichi Hosomi, Tomohiro Hayashi, Akira Oita, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 73(8), 1053 - 1054, Aug. 2017 , Refereed
  • Angiotensin receptor blockers and the risk of cancer: data mining of a spontaneous reporting database and a claims database, Mai Fujimoto, Migiwa Kanou, Kouichi Hosomi, Mitsutaka Takada, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, 55(4), 295 - 303, Apr. 2017 , Refereed
    Summary:Objective: The aim of this study was to examine the associations between angiotensin receptor blockers (ARBs) and the risk of 10 major cancers by employing different pharmacoepidemiological assessments. Materials & methods: Data from the first quarter of 2004 through 2012 were downloaded from the US Food and Drug Administration Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR) and information component (IC) were used to detect the signals. Furthermore, symmetry analysis was applied to the claims database to identify the risk of cancer after using ARBs from January 2005 to July 2013. Results: Significant inverse associations were found for all cancer types assessed as a whole (ROR: 0.78, 95% confidence interval (CI): 0.75 - 0.80; IC: -0.36, 95% CI: -0.40 to -0.31) in the analyses of FAERS database. Likewise, significant inverse association was found for all cancer types assessed as a whole (adjusted sequence ratio: 0.89, 95% CI: 0.82 - 0.96) in claims database. In addition, a significantly decreased risk for breast cancer and increased risks for pancreatic and prostate cancer were found in patients treated with ARBs in the analyses of individual cancers. Conclusions: Significant inverse association was found between ARB use and all cancer types assessed as a whole. However, in the analyses of individual cancers, the risks of ARB-induced cancer may differ according to cancer site. It may be reasonable to assume that the risks ofARB-induced cancer may differ according to cancer site.
  • Association between N-desethylamiodarone/amiodarone ratio and amiodarone-induced thyroid dysfunction, Mikie Yamato, Kyoichi Wada, Mai Fujimoto, Kouichi Hosomi, Tomohiro Hayashi, Akira Oita, Mitsutaka Takada, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 73(3), 289 - 296, Mar. 2017 , Refereed
    Summary:We used a retrospective data mining approach to explore the association between serum amiodarone (AMD) and N-desethylamiodarone (DEA) concentrations and thyroid-related hormone levels. Laboratory data sets from January 2012 to April 2016 were extracted from the computerized hospital information system database at the National Cerebral and Cardiovascular Center (NCVC). Data sets that contained serum AMD and DEA concentrations and thyroid function tests, including thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3), were analyzed. A total of 1831 clinical laboratory data sets from 330 patients were analyzed. Data sets were classified into five groups (euthyroidism, hyperthyroidism, subclinical hyperthyroidism, hypothyroidism, and subclinical hypothyroidism) based on the definition of thyroid function in our hospital. Most abnormal levels of thyroid hormones were observed within the therapeutic range of serum AMD and DEA concentrations. The mean DEA/AMD ratio in the hyperthyroidism group was significantly higher than that in the euthyroidism group (0.95 +/- 0.42 vs. 0.87 +/- 0.28, p = 0.0209), and the mean DEA/AMD ratio in the hypothyroidism group was significantly lower than that in the euthyroidism group (0.77 +/- 0.26 vs. 0.87 +/- 0.28, p = 0.0038). The suppressed TSH group (0.98 +/- 0.41 vs. 0.87 +/- 0.28, p < 0.001) and the elevated FT4 level group (0.90 +/- 0.33 vs. 0.84 +/- 0.27, p = 0.0037) showed significantly higher DEA/AMD ratios compared with normal level groups. The elevated TSH group showed a significantly lower DEA/AMD ratio compared with the normal group (0.81 +/- 0.25 vs. 0.87 +/- 0.28, p < 0.0001). High and low DEA/AMD ratios were associated with AMD-induced hyperthyroidism and hypothyroidism, respectively. The DEA/AMD ratio may be a predictive marker for AMD-induced thyroid dysfunction.
  • Circadian pharmacokinetics and limited sampling strategy of everolimus in heart transplant patients, Yuka Terada, Kyoichi Wada, Sachi Matsuda, Takeshi Kuwahara, Atsufumi Kawabata, Mitsutaka Takada, Takuya Watanabe, Seiko Nakajima, Takuma Sato, Osamu Seguchi, Masanobu Yanase, Norihide Fukushima, Takeshi Nakatani, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, 55(1), 1 - 8, Jan. 2017 , Refereed
    Summary:Objective: To evaluate circadian changes in everolimus (EVL) pharmacokinetics and to identify the time point of blood sampling with the strongest correlation with the area under the blood concentration time curve (AUC) of EVL in heart transplant patients. Methods: Heart transplant patients receiving the same dose of EVL twice a day were reviewed. In 28 patients enrolled, whole blood samples were collected before (C-0), and 1, 2, 4, 6, 8, and 12 hours after each administration of EVL. Blood concentrations of EVL were compared between active (9:00 AM to 9:00 PM) and resting periods (9:00 PM to 9:00 AM). Results: AUC(0-4h), peak concentration (C-max), C-max/minimum concentration, and peak-trough fluctuation in the resting period were significantly lower than those in the active period (p = 0.008, 0.017, 0.022, and 0.011, respectively). Halflife and mean residence time were significantly longer in the resting period than in the active period (p = 0.002 and 0.002, respectively). AUC(0-12h) in the active period was similar (p = 0.154) and correlated with that in the resting period (r(2) = 0.93). Two-point blood samplings, C-0 and C-2, correlated more strongly with AUC(0-12h) for EVL, compared with C-0 alone (0.92 vs. 0.79, respectively, for r(2) in the active period). Conclusions: EVL pharmacokinetics showed circadian changes, suggesting delayed absorption and decreased metabolic activity at rest. However, the circadian changes did not affect AUC(0-12h). A 2-time-point model that included C-0 and C-2 was more accurate for predicting the AUC(0-12h) of EVL than C-0 alone in heart transplant patients.
  • Tacrolimus Triggers Transient Receptor Potential Vanilloid-1-Dependent Relapse of Pancreatitis-Related Pain in Mice, Yuka Terada, Maho Tsubota, Hiiragi Sugo, Kohei Wakitani, Fumiko Sekiguchi, Kyoichi Wada, Mitsutaka Takada, Akira Oita, Atsufumi Kawabata, PHARMACOLOGY, PHARMACOLOGY, 99(5-6), 281 - 285, 2017 , Refereed
    Summary:Transient receptor potential vanilloid-1 (TRPV1) expressed in nociceptors is directly phosphorylated and activated by protein kinase C, and involved in the signaling of pancreatic pain. On the other hand, Ca(v)3.2 T-type Ca2+ channels expressed in nociceptors are functionally upregulated by phosphorylation with protein kinase A and also play a role in pancreatitis-related pain. Calcineurin, a phosphatase, negatively regulates various channel functions including TRPV1, and calcineurin inhibitor-induced pain syndrome by tacrolimus, a calcineurin inhibitor, used as an immunosuppressant, has been a clinical problem. We thus examined the effect of tacrolimus on pancreatitis-related pain in mice. Repeated treatment with cerulein caused referred hyperalgesia accompanying acute pancreatitis, which was unaffected by tacrolimus. Pancreatitis-related symptoms disappeared in 24 h, whereas the referred hyperalgesia recurred following the administration of tacrolimus, which was abolished by the blockers of TRPV1 but not T-type Ca2+ channels. Thus, tacrolimus appears to cause the TRPV1-dependent relapse of pancreatitis-related pain, suggesting the involvement of calcineurin in the termination of pancreatic pain. (C) 2017 S. Karger AG, Basel
  • Risk factors for amiodarone-induced thyroid dysfunction in Japan, Sayoko Kinoshita, Tomohiro Hayashi, Kyoichi Wada, Mikie Yamato, Takeshi Kuwahara, Toshihisa Anzai, Mai Fujimoto, Kouichi Hosomi, Mitsutaka Takada, Journal of Arrhythmia, Journal of Arrhythmia, 32(6), 474 - 480, Dec. 01 2016 , Refereed
    Summary:Background Amiodarone is associated with a number of significant adverse effects, including elevated transaminase levels, pulmonary fibrosis, arrhythmia, and thyroid dysfunction. Although thyroid dysfunction is considered to be a common and potentially serious adverse effect of amiodarone therapy, the exact pathogenesis remains unknown because of its complex manifestations. Therefore, the prevalence of, and risk factors for, amiodarone-induced thyroid dysfunction in Japanese patients were investigated in the present study. Methods A retrospective analysis of patients treated with amiodarone between January 2012 and December 2013 was performed. A total of 317 patients with euthyroidism, or subclinical hyperthyroidism or hypothyroidism, were enrolled in this study. Results After being treated with amiodarone, 30 (9.5%) and 60 patients (18.9%) developed amiodarone-induced hyperthyroidism and amiodarone-induced hypothyroidism, respectively. Ten (33.3%) patients with amiodarone-induced hyperthyroidism and 40 (66.6%) with amiodarone-induced hypothyroidism were diagnosed within two years of the initiation of amiodarone therapy. Dilated cardiomyopathy (DCM) [Adjusted odds ratio (OR) 3.30 (95% confidence interval (CI): 1.26–8.90)], and cardiac sarcoidosis [Adjusted OR 6.47 (95% CI: 1.60–25.77)] were identified as predictors of amiodarone-induced hyperthyroidism. The baseline free thyroxine (T4) level [Adjusted OR 0.13 (95% CI: 0.03–0.68)], and thyroid-stimulating hormone (TSH) level [Adjusted OR1.47 (95% CI: 1.26–1.74)] were identified as predictors of amiodarone-induced hypothyroidism. Conclusion DCM and cardiac sarcoidosis were identified as risk factors for amiodarone-induced hyperthyroidism. Risk factors for amiodarone-induced hypothyroidism included higher baseline TSH level and lower baseline free T4 level, suggesting that subclinical hypothyroidism may be a potential risk factor for the development of amiodarone-induced hypothyroidism.
  • Long-term impact of therapeutic drug monitoring on the risk of hypoglycemia in HOCM patients on cibenzoline therapy, Yutaro Mukai, Kyoichi Wada, Mai Fujimoto, Kouichi Hosomi, Takeshi Kuwahara, Mitsutaka Takada, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, 54(10), 795 - 803, Oct. 2016 , Refereed
    Summary:Objective: The purpose of this study was to evaluate the long-term impact of therapeutic drug monitoring (TDM) services on the risk of hypoglycemia in cibenzoline therapy. In addition, we evaluated the impact of changes in clinical setting or patient background on the risk of hypoglycemia in patients receiving cibenzoline. Methods: TDM services for cibenzoline have been performed at the Japan National Cerebral and Cardiovascular Center since March 1998. A case-control study was performed from September 2012 to February 2013, and the calculated risk of hypoglycemia associated with cibenzoline use was compared with data from our previous studies, which were performed similar to 15 years ago. Results: A significantly increased risk for hypoglycemia was observed for users of cibenzoline (adjusted OR: 2.6; 95% CI: 1.5 -4.7). In an additional analysis, the calculated risk was slightly reduced (adjusted OR; 2.1, 95% CI; 1.1 -3.8) and hypertrophic obstructive cardiomyopathy (HOCM) was identified as a possible risk factor for hypoglycemia (adjusted OR: 4.7, 95% CI: 1.8 -12.3). There was a significant difference in the mean level of cibenzoline between outpatients with and without HOCM (360.5 +/- 166.9 ng/mL vs. 276.4 +/- 136.3 ng/ mL). An inverse relationship was observed between the percentage of outpatients whose cibenzoline serum level had been measured and their risk of hypoglycemia. Conclusions: Consistent TDM services for cibenzoline have contributed to a reduced risk of hypoglycemia associated with cibenzoline therapy. Patients with HOCM have a higher risk of developing hypoglycemia. Clinicians should therefore carefully monitor serum glucose levels in patients with HOCM taking cibenzoline.
  • Association between Benzodiazepine Use and Dementia: Data Mining of Different Medical Databases, Mitsutaka Takada, Mai Fujimoto, Kouichi Hosomi, INTERNATIONAL JOURNAL OF MEDICAL SCIENCES, INTERNATIONAL JOURNAL OF MEDICAL SCIENCES, 13(11), 825 - 834, 2016 , Refereed
    Summary:Purpose: Some studies have suggested that the use of benzodiazepines in the elderly is associated with an increased risk of dementia. However, this association might be due to confounding by indication and reverse causation. To examine the association between benzodiazepine anxiolytic drug use and the risk of dementia, we conducted data mining of a spontaneous reporting database and a large organized database of prescriptions. Methods: Data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) from the first quarter of 2004 through the end of 2013 and data from the Canada Vigilance Adverse Reaction Online Database from the first quarter of 1965 through the end of 2013 were used for the analyses. The reporting odds ratio (ROR) and information component (IC) were calculated. In addition, prescription sequence symmetry analysis (PSSA) was performed to identify the risk of dementia after using benzodiazepine anxiolytic drugs over the period of January 2006 to May 2014. Results: Benzodiazepine use was found to be associated with dementia in analyses using the FAERS database (ROR: 1.63, 95% CI: 1.61-1.64; IC: 0.66, 95% CI: 0.65-0.67) and the Canada Vigilance Adverse Reaction Online Database (ROR: 1.88, 95% CI: 1.83-1.94; IC: 0.85, 95% CI: 0.80-0.89). ROR and IC values increased with the duration of action of benzodiazepines. In the PSSA, a significant association was found, with adjusted sequence ratios of 1.24 (1.05-1.45), 1.20 (1.06-1.37), 1.23 (1.11-1.37), 1.34 (1.23-1.47), 1.41 (1.29-1.53), and 1.44 (1.33-1.56) at intervals of 3, 6, 12, 24, 36, and 48 months, respectively. Furthermore, the additional PSSA, in which patients who initiated a new treatment with benzodiazepines and anti-dementia drugs within 12- and 24-month periods were excluded from the analysis, demonstrated significant associations of benzodiazepine use with dementia risk. Conclusion: Multi-methodological approaches using different methods, algorithms, and databases suggest that long-term use of benzodiazepines and long-acting benzodiazepines are strongly associated with an increased risk of dementia.
  • Inverse Association between Sodium Channel-Blocking Antiepileptic Drug Use and Cancer: Data Mining of Spontaneous Reporting and Claims Databases, Mitsutaka Takada, Mai Fujimoto, Haruka Motomura, Kouichi Hosomi, INTERNATIONAL JOURNAL OF MEDICAL SCIENCES, INTERNATIONAL JOURNAL OF MEDICAL SCIENCES, 13(1), 48 - 59, 2016 , Refereed
    Summary:Purpose: Voltage-gated sodium channels (VGSCs) are drug targets for the treatment of epilepsy. Recently, a decreased risk of cancer associated with sodium channel-blocking antiepileptic drugs (AEDs) has become a research focus of interest. The purpose of this study was to test the hypothesis that the use of sodium channel-blocking AEDs are inversely associated with cancer, using different methodologies, algorithms, and databases. Methods: A total of 65,146,507 drug-reaction pairs from the first quarter of 2004 through the end of 2013 were downloaded from the US Food and Drug Administration Adverse Event Reporting System. The reporting odds ratio (ROR) and information component (IC) were used to detect an inverse association between AEDs and cancer. Upper limits of the 95% confidence interval (CI) of < 1 and < 0 for the ROR and IC, respectively, signified inverse associations. Furthermore, using a claims database, which contains 3 million insured persons, an event sequence symmetry analysis (ESSA) was performed to identify an inverse association between AEDs and cancer over the period of January 2005 to May 2014. The upper limit of the 95% CI of adjusted sequence ratio (ASR) < 1 signified an inverse association. Results: In the FAERS database analyses, significant inverse associations were found between sodium channel-blocking AEDs and individual cancers. In the claims database analyses, sodium channel-blocking AED use was inversely associated with diagnoses of colorectal cancer, lung cancer, gastric cancer, and hematological malignancies, with ASRs of 0.72 (95% CI: 0.60 - 0.86), 0.65 (0.51 - 0.81), 0.80 (0.65 - 0.98), and 0.50 (0.37 - 0.66), respectively. Positive associations between sodium channel-blocking AEDs and cancer were not found in the study. Conclusion: Multi-methodological approaches using different methodologies, algorithms, and databases suggest that sodium channel-blocking AED use is inversely associated with colorectal cancer, lung cancer, gastric cancer, and hematological malignancies.
  • Interaction between Warfarin and Linezolid in Patients with Left Ventricular Assist System in Japan, Sayoko Kinoshita, Kyoichi Wada, Sachi Matsuda, Takeshi Kuwahara, Haruki Sunami, Takuma Sato, Osamu Seguchi, Masanobu Yanase, Takeshi Nakatani, Mitsutaka Takada, INTERNAL MEDICINE, INTERNAL MEDICINE, 55(7), 719 - 724, 2016 , Refereed
    Summary:Objective The purpose of this study was to investigate the possible interaction between warfarin and linezolid in patients with a left ventricular assist system (LVAS) for the treatment of severe heart failure. Methods Patients with LVAS who were treated with linezolid for the treatment of infections from January 2003 to March 2013 were identified from medical records. The impact of linezolid on the clotting function, as well as the dose of warfarin during the first 10 days of linezolid therapy, was investigated. The mean prothrombin time-international normalized ratio (PT-INR) and mean doses of warfarin during 7 days before and 10 days after the initiation of linezolid therapy were calculated for individual patients. The PT-INR per mg of WF dose on the previous day (X) was calculated. The warfarin dose, PT-INR, and warfarin sensitivity index (WSI) value before and after the initiation of linezolid were compared to evaluate the impact of linezolid on the effect of warfarin. Results Sixteen patients were enrolled in the study. Although the mean PT-INR increased from 3.74 to 4.06, no significant difference was observed (p=0.05). A significant difference was observed in the mean dose of warfarin before and after the initiation of linezolid administration, with a decrease from 3.23 to 2.69 mg/day (p=0.001). In contrast, the mean WSI value significantly increased from 1.37 to 1.82 (p=0.014). After 10 days of linezolid administration, the mean X values increased over the baseline value by 31.7%. Conclusion These findings suggest that co-administration of linezolid results in increased PT-INR in patients with LVAS treated with warfarin.
  • Association between Statin Use and Cancer: Data Mining of a Spontaneous Reporting Database and a Claims Database, Mai Fujimoto, Tomoya Higuchi, Kouichi Hosomi, Mitsutaka Takada, INTERNATIONAL JOURNAL OF MEDICAL SCIENCES, INTERNATIONAL JOURNAL OF MEDICAL SCIENCES, 12(3), 223 - 233, 2015 , Refereed
    Summary:Purpose: In recent years, the potential risk of cancer associated with statin use has been a focus of much interest. However, it remains uncertain whether statin therapy is associated with cancer risk. To examine the association between statin use and the risk of cancer, we conducted data mining using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and a large organized database of claims constructed by a database vendor (The Japan Medical Data Center Co., Ltd, Tokyo, Japan [JMDC]). Methods: Relevant reports in the FAERS, which included data from the first quarter of 2004 through the end of 2012, were identified and analyzed. The reporting odds ratio (ROR) was used to detect spontaneous report signals and was calculated using the case/non-case method. Additionally, signals were detected via the information component (IC) using the IC025 metric. Furthermore, event sequence symmetry analysis (ESSA) was applied to identify the risk of cancer following treatment with statins over the period January 2005 to July 2013. Results: In the FAERS database analyses, significant signals for colorectal cancer and pancreatic cancer were found for statins as a class. In the ESSA, significant associations between statin use and colorectal cancer and pancreatic cancer were found, with adjusted sequence ratios (95% confidence intervals) of 1.20 (1.08-1.34) and 1.31 (1.13-1.53), respectively, at an interval of 48 months. Conclusions: Multi-methodological approaches using different algorithms and databases suggest that statin use is associated with an increased risk for colorectal cancer and pancreatic cancer.
  • Association of statin use with storage lower urinary tract symptoms (LUTS): data mining of prescription database, Mai Fujimoto, Tomoya Higuchi, Kouichi Hosomi, Mitsutaka Takada, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, 52(9), 762 - 769, Sep. 2014 , Refereed
    Summary:Objective: The efficacy and safety of statins have been studied in a number of clinical trials and epidemiological studies. In recent years, the Medicine and Healthcare Products Regulatory Agency (MHRA) has assessed the evidence available on the following adverse reactions associated with the use of statins: sleep disturbances, memory loss, micturition disorders (problems with urination), sexual disturbances, depression, and interstitial pneumopathy. However, the association between statin use and the risk of these adverse reactions remains unclear. To examine the association between statin use and the risk of lower urinary tract symptoms (LUTS) or the disorder causing LUTS, we carried out data mining using a prescription database. Methods: A large organized database of prescriptions constructed by a database vendor was used in the study. Symmetry analysis was used to identify the risk of LUTS after using statins over the period January 2006 to August 2013. Statin use in combination with drugs administered for storage LUTS was examined by prescription sequence symmetry analysis (PSSA). Results: A significant association between statins and drugs for storage LUTS was found, with adjusted sequence ratios (ASRs) of 1.21 (95% CI, 1.00-1.46), 1.19(95% CI, 1.04-1.38), and 1.17 (95% CI, 1.05-1.30) for intervals of 91, 182, and 365 days, respectively. In the analyses of individual statins, significant associations were found only for pravastatin. Significant associations with individual drugs for storage LUTS were found for solifenacin succinate with ASRs of 1.36 (95% CI, 1.02-1.81), 1.48 (95% CI, 1.19-1.84), and 1.47 (95% CI, 1.25-1.73) for intervals of 91, 182, and 365 days, for fiavoxate hydrochloride with an ASR of 1.56 (95% CI, 1.13-2.17) at an interval of 182 days, and for oxybutynin hydrochloride with ASRs of 2.06(95% CI, 1.11-3.94) and 1.71 (95% CI, 1.09-2.72) at intervals of 182 and 365 days. Significant associations with gender were found only in females with ASRs of 1.25(95% CI, 1.04-1.51) and 1.23(95% CI, 1.07-1.41) at intervals of 182 and 365days, respectively. Conclusions: Analysis of the prescription database showed significant association for storage LUTS in statin users.
  • Association of Statin Use with Sleep Disturbances: Data Mining of a Spontaneous Reporting Database and a Prescription Database, Mitsutaka Takada, Mai Fujimoto, Kohei Yamazaki, Masashi Takamoto, Kouichi Hosomi, DRUG SAFETY, DRUG SAFETY, 37(6), 421 - 431, Jun. 2014 , Refereed
    Summary:Particular interest has been generated regarding the possible influence of statin use on sleep quality. However, no conclusive evidence exists that a particular statin is more likely to be associated with sleep disturbances versus others. It remains uncertain whether different statins produce different risks for sleep disturbance. To examine the association between statin use and the risk of sleep disturbances, we conducted data mining using the US Food and Drug Administration Adverse Event Reporting System (FAERS) and a large organized database of prescriptions constructed by a database vendor (Japan Medical Information Research Institute, Inc. Japan). Relevant reports in the FAERS were identified and analyzed. Data from the first quarter of 2004 through the end of 2013 were included in this study. The reporting odds ratio (ROR) was used to detect spontaneous report signals, calculated using the case/non-case method. For the ROR, a signal was detected if the lower limit of 95 % two-sided confidence interval (95 % CI) was > 1. Additionally, signal detection using the IC was conducted using the IC025 metric, a lower limit of the 95 % CI of the IC, where a signal is detected if the IC025 value exceeds 0. In addition, symmetry analysis was used to identify the risk of insomnia after using statins over the period of January 2006 to August 2013. In the analyses of the FAERS database, significant signals for sleep disturbances including disturbances in initiating and maintaining sleep, sleep disorders NEC, sleeping disorders due to a general medical condition, and parasomnias were found. In the prescription sequence symmetry analysis, a significant association between statin use and hypnotic drug use was found, with adjusted sequence ratios of 1.14 (1.03-1.26), 1.20 (1.11-1.29), and 1.18 (1.11-1.25) at intervals of 91, 182, and 365 days, respectively. Multi-methodological approaches using different algorithms and databases strongly suggest that statin use is associated with an increased risk for sleep disturbances including insomnia.
  • Statin-associated lower urinary tract symptoms: data mining of the public version of the FDA adverse event reporting system, FAERS, Mai Fujimoto, Kouichi Hosomi, Mitsutaka Takada, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, 52(4), 259 - 266, Apr. 2014 , Refereed
    Summary:Objective: To examine the association between statin use and the risk of lower urinary tract symptoms (LUTS) in reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) between 2004 and 2011. Methods: Relevant reports in the FAERS were identified and analyzed. The reporting odds ratio (ROR) was used to detect spontaneous report signals, calculated using the case/non-case method. Cases were identified by the presence of reports of an adverse drug reaction (ADR) in which statins were the suspected drug. Non-cases were all the reports of the same reactions induced by drugs other than statins. The reporting odds ratio (ROR) and 95% confidential interval (CI) was calculated as a measure of disproportionality. Results: A total of 44,959,104 drug-reaction pairs was found in 2,681,739 reports. Significant RORs were found for both voiding (ROR; 1.16,95% CI; 1.10 - 1.23) and storage symptoms (ROR; 1.25, 95% CI; 1.20 - 1.30). Analysis of individual statins showed that rosuvastatin, atorvastatin, and lovastatin had significant disproportionality for voiding symptoms, while simvastatin, rosuvastatin, pravastatin, atorvastatin, pitavastatin, and lovastatin had significant disproportionality for storage symptoms. Of the four voiding symptoms, significant RORs were found for urine flow decrease and dysuria. Of the four storage symptoms, significant RORs were found for pollakiuria and nocturia. No fundamental differences in disproportionality were observed between genders. Conclusions: Analysis of the FAERS database showed small but reliable signals for LUTS in statin users. The mechanism responsible for these reactions is unknown. However, these adverse events should be monitored closely.
  • Difference in risk of gastrointestinal complications between users of enteric-coated and buffered low-dose aspirin, Mitsutaka Takada, Mai Fujimoto, Kouichi Hosomi, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, 52(3), 181 - 191, Mar. 2014 , Refereed
    Summary:Objective: Difference in the risk of gastrointestinal (GI) complications between users of enteric-coated and buffered low-dose aspirin (LDA) is unclear. The purpose of the study is to examine the difference in risk of GI damage between enteric-coated and buffered LDA products. Methods: A large and chronologically organized receipt database constructed by a database vendor was utilized. Prescription and event sequence symmetry analysis was used to identify the risk of LDA-induced GI complications over the period from January 2005 to July 2011. LDA use in combination with H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) was examined by prescription sequence symmetry analysis. Likewise, symmetry analysis was undertaken to evaluate the association between the diagnosis of GI disease and the prescription of LDA products. Results: In July 2011, enteric-coated LDA users were more frequently co-administered PPIs than buffered LDA users (25.4% vs. 14.4%). Prescription sequence symmetry analysis of acid inhibitor use found no significant associations with enteric-coated LDA use and buffered LDA use. The event sequence symmetry analysis of ulcer, gastritis and duodenitis, and melena found significant associations with enteric-coated LDA use, with adjusted sequence ratios (ASRs) of 1.58 (1.23 - 2.06), 1.30 (1.03 - 1.65), and 14.38 (2.19 - 607.95), respectively, at the 6-month interval. At the 12-month interval, analysis of ulcers and melena found significant associations for enteric-coated LDA users, with ASRs of 1.39 (1.13 - 1.73) and 20.83 (3.33 - 863.25), respectively. Conclusions: Our findings do not support that there is no difference in the risk of GI complications between enteric-coated LDA and buffered LDA, but rather may imply that the risk of GI complications associated with enteric-coated LDA is higher than that with buffered LDA.
  • Difference between the frequencies of antisecretory drug prescriptions in users of buffered vs. enteric-coated low-dose aspirin therapies, Hiroko Hachiken, Ai Murai, Kyoichi Wada, Takeshi Kuwahara, Kouichi Hosomi, Mitsutaka Takada, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, 51(10), 807 - 815, Oct. 2013 , Refereed
    Summary:Objective: To provide further insights on the risks of gastrointestinal (GI) complications in individuals using low-dose aspirin (LDA), we investigated the concomitant use of LDA and antisecretory drugs. Additionally, we examined the frequency distributions of prescribing sequences for LDA and antisecretory drugs. Methods: Data from a computerized prescription order entry system was analyzed at the National Cerebral and Cardiovascular Center of Japan. LDA use in combination with H2-receptor antagonists (H2RAs) and proton pomp inhibitors (PPIs) was examined over the period from January 2001 to December 2010. Prescription sequence symmetry analyses were used to identify LDA-induced H2RAs or PPIs users. Results: In December 2010, PPIs accounted for 9.9% of the prescriptions for buffered LDA users and 16.1% of those for enteric-coated LDA users. Incident use of PPIs occurred more frequently among enteric-coated LDA users than buffered LDA users (17.6% vs. 11.0%, respectively). Prescription sequence symmetry analyses of PPI use revealed significant associations with enteric-coated LDA use, resulting in adjusted sequence ratios of 1.82 (95%CI, 1.11 - 3.03) and 1.87 (95% CI, 1.26 - 2.83) at intervals of 182 and 365 days, respectively. Enteric-coated LDA users tended to initiate PPI therapy on the same date more frequently than buffered LDA users (35.1% vs. 10.8%, respectively). Conclusions: Our findings do not support the notion that enteric-coated LDA products confer a lower risk for GI complications than buffered formulations, but may conversely imply that the risk of GI complications associated with buffered LDA is lower than that of enteric-coated LDA.
  • Evaluation of Brilliance and Visibility of Fluorescence and Chemiluminescence Solution for Training of Preparing Injections, Shunji Ishiwata, Atsushi Taga, Hiroyuki Sano, Masataka Kobayashi, Jun Nomiyama, Shiro Harada, Ayako Kita, Mitsutaka Takada, Reiko Sugiura, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 131(9), 1361 - 1367, Sep. 2011 , Refereed
    Summary:Personnel who prepare and administer chemotherapeutic agents have been reported to develop untoward effects. The use of appropriate techniques for preparing these agents is encouraged, and educational training systems that involve the use of a fluorescent or chemiluminescence reagent as placebos have been established to minimize potential exposure to these agents. However, the optimum conditions for the use and visibility of these placebos remain obscure. In this study, our results indicated that the fluorescence intensity of fluorescent reagent decreased when it was used at a concentration greater than 0.01%. Because drops created due to splashes and leaks are extremely small and easily evaporate, it is possible that the fluorescence resulting from such drops readily disappears despite using an anti-evaporation reagent. We also developed a method to evaluate the visibility of the small drop; using this method, we determined the distance at which the drop present on the pin could be seen by the observer. The distance at which the drop was clearly recognized as a pinpoint by using the fluorescence method was almost comparable to that for the chemiluminescence method. In the chemiluminescence method, the drop on the pin was faintly visible as a slightly bright area because of low background when observed at a certain distance that was much greater than that at which the drop was clearly visible; however, such an area was not observed in the fluorescence method. The results of our study will help in the selection of a training method depending on the situation.
  • Drug Interaction Between Tacrolimus and Carbamazepine in a Japanese Heart Transplant Recipient: A Case Report, Kyoichi Wada, Mitsutaka Takada, Mika Sakai, Hiroyuki Ochi, Takeshi Kotake, Hiroshi Okada, Hideki Morishita, Noboru Oda, Akiko Mano, Tomoko S. Kato, Kazuo Komamura, Takeshi Nakatani, JOURNAL OF HEART AND LUNG TRANSPLANTATION, JOURNAL OF HEART AND LUNG TRANSPLANTATION, 28(4), 409 - 411, Apr. 2009 , Refereed
    Summary:This article reports changes in tacrolimus (FK506) blood levels connected with carbamazepine (CBZ). A drug interaction between FK506 and CBZ was investigated in a woman, who was in her 40s, who underwent heart transplantation. Pharmacokinetic parameters were measured, including dose and trough blood levels (C(0)), area under the serum concentration-time curve from 0 to 12 hours (AUC(0-12)h, and apparent clearance of oral FK506 (CL/F) for FK506 alone (about 3 months before starting CBZ) and combined with CBZ (11 days and about 3 months after starting CBZ) FK506 C(0) levels were decreased within 7 days of CBZ treatment. FK506 dosing required a 1.3- to 1.4-fold increase to maintain adequate blood levels while taking 200 mg CBZ daily. The AUC(0-12h)/dose 11 days after CBZ treatment was about 50% of the value before CBZ, and was about 70% at 3 months after CBZ treatment. The CL/F at 11 days and about 3 months after starting CBZ treatment was about 2 times higher than before CBZ therapy. FK506 C(0) levels are decreased by CBZ treatment, and blood levels should be closely monitored. J Heart Lung Transplant 2009;28:409-11. Copyright (C) 2009 by the international Society for Heart and Lung Transplantation.

Misc

  • Applied Data Mining of the FDA Adverse Event Reporting System, FAERS, and the Japanese Adverse Drug Event Report Database, JADER: Signal Detection of Adverse Events by New Quinolones, Hosomi Kouichi, Arai Mari, Fujimoto Mai, Takada Mitsutaka, Jpn.J.Drug Inform., 17, 1, 15, 20,   2015 , 10.11256/jjdi.17.15, http://ci.nii.ac.jp/naid/130005084058
    Summary:Objective: Signal detection by analyzing adverse event spontaneous report databases is used to monitor drug safety.  One of the major spontaneous report databases is the FDA Adverse Event Reporting System (FAERS).  Recently, the Japanese Adverse Drug Event Report database (JADER) was released.  To compare FAERS and JADER, we calculated the signals of adverse events by new quinolones (NQs).Methods: We extracted reports of adverse events by NQs from FAERS and JADER, and analyzed them using the ROR data mining algorithm.  Thirteen kinds of NQs were extracted, and the terms of adverse events extracted were defined by MedDRA.Results: There were 35,990,645 reports in FAERS and 1,643,404 reports in JADER.  Significant RORs were found for hypersensitivity (FAERS: 1.78, JADER: 1.47), arrhythmia (1.07, 0.68), hypoglycemia (1.80, 2.03), hyperglycemia (0.72, 0.78), rhabdomyolysis (1.01, 0.78), tendon disorders (15.18, 6.59), psychiatric symptoms (1.12, 0.45) and convulsion (0.99, 1.31).  We identified 4 types of adverse events by comparing FAERS and JADER: 1) Signal detection in both, 2) No signal detection in either, 3) Signal detection only in FAERS, 4) Signal detection only in JADER.Conclusion: Analyzing spontaneous report databases has several limitations, but is still a valuable tool for identifying potential associations between drugs and adverse events.  Spontaneous report databases may also be useful for detecting differences in adverse events between different races, countries and regions.
  • Signal Detection of hepatitis B and hepatitis C by molecularly-targeted drugs for cancer::Data Mining of FDA Adverse Event Reporting System and Japanese Adverse Drug Event Report database, Inose Ryo, Hosomi Kouichi, Park Binawool, Fujimoto Mai, Takada Mitsutaka, Japanese Journal of Hospital Pharmacy, 40, 5, 268, 277,   2014 , 10.5649/jjphcs.40.268, http://ci.nii.ac.jp/naid/130005068222
    Summary:Several case reports of hepatitis B virus reactivation after rituximab administration have been documented. We investigated the association between hepatitis B and C and 15 kinds of molecular-targeted drugs for cancer. We compared two databases, the Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER) of the Pharmaceuticals and Medical Devices Agency (PMDA). Quantitative analysis involved calculating the reporting odds ratio (ROR) and 95% confidence interval (95% CI) as a measure of disproportionality. ROR is a tool that detects signals of adverse events for individual drugs, with signals detected when the lower limit of the 95% CI of ROR is > 1. We also investigated the timing of the adverse events and the age of the patients. There were 29,017,485 reports in FAERS and 2,079,653 reports in JADER. Signals were detected for rituximab-associated hepatitis B and hepatitis C, trastuzumab-associated hepatitis B, and imatinib-associated hepatitis B. In FAERS, hepatitis B often occurred within 1 month, whereas rituximab-associated hepatitis B often occurred 2-6 months after administration. In JADER, hepatitis B and rituximab-associated hepatitis B often occurred 1-3 months after administration. We conclude that signals of rituximab-associated hepatitis B and hepatitis C, trastuzumab-associated hepatitis B, and imatinib-associated hepatitis B are marked. Analyzing the timing and age of the patient at the occurrence of adverse events may suggest a relationship between drugs and these events.
  • Gastrointestinal tract injury Associated with Aspirin and Other Drugs: Data Mining of the FDA Adverse Event Reporting System, FAERS, Hosomi Kouichi, Fujimoto Mai, Hachiken Hiroko, Sumitoko Keita, Takada Mitsutaka, Jpn.J.Drug Inform., 15, 4, 147, 154,   2014 , 10.11256/jjdi.15.147, http://ci.nii.ac.jp/naid/130004941473
    Summary:Objective: To examine the signal of gastrointestinal tract injury induced by aspirin and other drugs, we analyzed the US FDA Adverse Event Reporting System (FAERS).Methods: After deleting duplicate submissions, we analyzed the reports involving gastrointestinal tract injury associated with aspirin, H2-receptor antagonists (H2RAs), proton pump inhibitors (PPIs), ACE inhibitors, angiotensin II receptor blockers (ARBs), and antiplatelet and antithrombotic drugs.  The reporting odds ratio (ROR), a recognized pharmacovigilance tool, was used for the quantitative detection of signals.Results: Based on 29,017,485 co-occurrences, i.e., drug-adverse event pairs, found in 1,645,605 reports from 2004 to 2009, the ROR-associated gastrointestinal tract injury for aspirin alone, aspirin with H2RAs, aspirin with PPIs, aspirin with ACE inhibitors, aspirin with ARBs, and aspirin with antiplatelet and antithrombotic drugs were 2.88, 1.42, 1.46, 1.00, 1.05, and 2.98-8.26, respectively.  The following summarizes the types of listed reports: 86 reports described the daily aspirin doses, and 36/86 were between 75 and 100 mg; 343 reports described the periods between the start-date for aspirin and the date when gastrointestinal tract injury occurred, of which 128/343 were within one month while 215/343 were over one month; additionally, 78 reports described the total cumulative doses of aspirin, and 17/78 were between 1 and 5 g.Conclusion: The data suggest that H2RAs, PPIs, ACE inhibitors, and ARBs may reduce gastrointestinal tract injury associated with aspirin in possibility.
  • The Association between Statin Use and the Risk of Sleep Disturbances: Data Mining of Claims Database, Fujimoto Mai, Takamoto Masashi, Hosomi Kouichi, Takada Mitsutaka, Jpn.J.Drug Inform., 16, 2, 53, 62,   2014 , http://ci.nii.ac.jp/naid/130004688313
    Summary:Objective: To examine the association between statin use and the risk of sleep disturbances, data mining was performed on a claims database. Methods: Symmetry analysis was carried out to identify the risk of sleep disturbances after statin use during the period from January 2005 to December 2011.  Statin use in combination with hypnotic drugs was examined by prescription sequence symmetry analysis.  In this study, hypnotic drugs that are commonly prescribed for the treatment of insomnia were used as markers of sleep disturbances produced by statins. Likewise, event sequence symmetry analysis was undertaken to evaluate the association between statin use and the diagnosis of sleep disturbances.Results: Significant associations of statin use with short-acting hypnotic drugs were found, with an adjusted SR (sequence ratio) of 1.23 (95%CI: 1.04-1.45) at an interval of 12 months.  Otherwise, significant associations between individual statin use and hypnotic drug use were not found.  Significant associations between use of statins and the diagnosis of sleep disturbances were not also found in this study.Conclusions: Analysis of the claim database demonstrated that statin therapy might be associated with an emergence of sleep disturbances.  Therefore, individuals prescribed statins should be considered as having an increased risk of sleep disturbances.
  • Study on Risk of Gastrointestinal Complications in Low-dose Aspirin Therapy Using the National Receipt Database, Takada Mitsutaka, Japanese Journal of Hospital Pharmacy, 39, 8, 471, 481,   2013 , 10.5649/jjphcs.39.471, http://ci.nii.ac.jp/naid/130004678964
    Summary:To garner additional insights into the risk of gastrointestinal (GI) complications among users of low-dose aspirin (LDA) products, concomitant use of LDA products and anti-secretory drugs was investigated using the national database. The frequencies of gastrointestinal diseases among users of LDA products were also investigated. The main purpose of this study was to assess the differences in gastrointestinal damage risk between enteric-coated and buffered LDA product use.LDA use in combination with histamine H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) was examined for the period January 2010 to December 2010. In addition, the frequencies of claim codes for gastrointestinal diseases among users of enteric-coated LDA and buffered LDA products were investigated for December 2010.In 2010, 24.0% of enteric-coated LDA users and 17.2% of buffered LDA users concomitantly used PPIs. There were substantial differences between enteric-coated LDA and buffered LDA users with regard to the frequency of PPI use. H2RAs were concomitantly used by 21.5% of enteric-coated LDA users and 20.8% of buffered LDA users. During December 2010, the frequencies of hemorrhagic gastric ulcer and lower gastrointestinal hemorrhage among entericcoated LDA users were higher than among buffered LDA users (0.31% vs 0.26%, and 0.085% vs 0.062%, respectively).These findings may imply that the risk of GI complications associated with buffered LDA use is lower than that with enteric-coated LDA use.
  • 6. An Example of Utilization of the National Database from an Academic Standpoint, TAKADA Mitsutaka, Japanese Journal of Pharmacoepidemiology/Yakuzai ekigaku, 17, 2, 155, 162,   2013 , 10.3820/jjpe.17.155, http://ci.nii.ac.jp/naid/130003372616
    Summary:Over the last several years, a number of health insurance claims have been electronically submitted and entered into the national database(NDB) by the Ministry of Health, Labor & Welfare(MHLW). A trial was initiated where the NDB would be evaluated for its utility in quality improvement of healthcare services. I had the opportunity to perform the drug utilization study using the NDB, and in this article, I review the procedures by which MHLW make the NDB available and report on issues in analyzing the NDB and in using the NDB for pharmacoepidemiological studies. The NDB is much larger and more encompassing than other medical databases and its findings are expected to havea great influence on a pharmacoepidemiological studies in Japan in providing valuable information on the rational use of drugs. (Jpn J Pharmacoepidemiol 2012; 17(2): 155-162)
  • Change in lipid hydroperoxide product in fat emulsion for intravenous injection, 北小路 学, 髙田 充隆, 医学と生物学, 156, 4, 168, 171,   2012 04 , http://ci.nii.ac.jp/naid/40019296766
  • An Investigation on Attitudes toward the Promotion of Generic Products for Pharmacists in Chain Community Pharmacies in Japan, Nagai Noriaki, Ono Hikaru, Yamato Mikie, Horino Tomomi, Kitakouji Manabu, Ito Yoshimasa, Takada Mitsutaka, Japanese Journal of Hospital Pharmacy, 38, 2, 111, 117,   2012 , 10.5649/jjphcs.38.111, http://ci.nii.ac.jp/naid/130004502722
    Summary:The penetration of low-priced generic drugs of good quality leads to not only a lower financial burden on patients, but also financial improvement of Japans medical insurance system. In this study, we investigated the relationship between the usage conditions of generic products (GE) and attitudes toward the reduction of national medical expense for pharmacists in chain community pharmacies in Japan using a questionnaire survey. The 20 - 25% usage conditions of GE were the highest in this study. The majority (89.2%) of pharmacists in the community pharmacy (positive group) have a positive attitude toward the reduction of national medical expense using GE, and the usage conditions of GE in the positive group are higher than that in the pharmacists that have a negative attitude toward the reduction of national medical expense using GE (negative group). In addition, the results of the questionnaire survey show that the pharmacists in the negative group still have doubts about the quality, effect and supply of GE in comparison with the positive group, and the pharmacists in the positive group were more interested in the generic drug dispensing fee in comparison with the negative group. In conclusion, the present study demonstrates that most pharmacists in this study have a positive attitude toward the reduction of national medical expense using GE, and the attitude toward GE in pharmacies relates to the usage conditions of GE. These findings provide significant information on the need for a reduction of national medical expense using GE.
  • Quantitative Analyses by Text Mining of Journal Articles on Medical Pharmacy:– A comparison between the Japanese Journal of Pharmaceutical Health Care and Sciences and the Journal of Japanese Society of Hospital Pharmacists –, Hachiken Hiroko, Matsuoka Arisa, Murai Ai, Kinoshita Sayoko, Takada Mitsutaka, Jpn.J.Drug Inform., 13, 4, 152, 159,   2012 , 10.11256/jjdi.13.152, http://ci.nii.ac.jp/naid/130004551365
    Summary:Objective: To quantitatively investigate the history of medical pharmacy research by pharmacists in Japan, original article titles from the Japanese Journal of Pharmaceutical Health Care and Sciences (Jpn J Pharm Health Care Sci) and the Journal of Japanese Society of Hospital Pharmacists (JJSHP) were analyzed by text-mining.Method: The titles of all original articles (2,611 and 2,260 articles) published in Jpn J Pharm Health Care Sci and JJSHP between 1975 and 2009 were collected from article databases and analyzed using KH Coder, the free software for quantitative text analysis of the Japanese language.  KH Coder extracts basic text information data by counting the occurrence rate of certain words.  Article titles were assigned to nine research categories according to coding rules, and the categorization results were analyzed quantitatively.Results: Between 1975 and 1989, "pharmaceutical investigation" was the major area of research in the Jpn J Pharm Health Care Sci.  Articles assigned to the category "drug therapy" gradually increased through the 1990s and, since 2000, "drug therapy" has dominated medical pharmacy research.  In the JJSHP between 1975 and 2004, no characteristic research area was found, and mainly research articles directly related to pharmacist practice were published.  However, from 2005 to 2009, articles assigned to the "drug therapy" category accounted for 34% of all published articles making "drug therapy" the major research area in the JJSHP.  Thus, in recent years, there is no obvious difference in research areas between the two journals.Conclusion: Our analyses suggest that drug therapy research is now at the center of medical pharmacy research by pharmacists in Japan.
  • Prediction of the Possibility a Right-Turn Driving Behavior at Intersection Leads to an Accident by Detecting Deviation of the Situation from Usual when the Behavior is Observed, HAYASHI Toshinori, YAMADA Keiichi, SANO Hiroyuki, KOBAYASHI Masataka, NOMIYAMA Jun, HARADA Shiro, KITA Ayako, TAKADA Mitsutaka, SUGIURA Reiko, YAKUGAKU ZASSHI, 131, 7, 1361, 1367,   2011 07 01 , 10.1541/ieejeiss.131.1361, http://ci.nii.ac.jp/naid/10030526954
    Summary:Personnel who prepare and administer chemotherapeutic agents have been reported to develop untoward effects. The use of appropriate techniques for preparing these agents is encouraged, and educational training systems that involve the use of a fluorescent or chemiluminescence reagent as placebos have been established to minimize potential exposure to these agents. However, the optimum conditions for the use and visibility of these placebos remain obscure. In this study, our results indicated that the fluorescence intensity of fluorescent reagent decreased when it was used at a concentration greater than 0.01%. Because drops created due to splashes and leaks are extremely small and easily evaporate, it is possible that the fluorescence resulting from such drops readily disappears despite using an anti-evaporation reagent. We also developed a method to evaluate the visibility of the small drop; using this method, we determined the distance at which the drop present on the pin could be seen by the observer. The distance at which the drop was clearly recognized as a pinpoint by using the fluorescence method was almost comparable to that for the chemiluminescence method. In the chemiluminescence method, the drop on the pin was faintly visible as a slightly bright area because of low background when observed at a certain distance that was much greater than that at which the drop was clearly visible; however, such an area was not observed in the fluorescence method. The results of our study will help in the selection of a training method depending on the situation.
  • Quantitative Analysis of Japanese Journal Articles on Medical Pharmacy, Goto Sayoko, Hachiken Hiroko, Takada Mitsutaka, Japanese Journal of Hospital Pharmacy, 37, 1, 21, 30,   2011 , 10.5649/jjphcs.37.21, http://ci.nii.ac.jp/naid/130004502649
    Summary:To quantitatively investigate the history of medical pharmacy research in Japan,we analyzed the titles of articles in theJapanese Journal of Pharmaceutical Health Care and Sciences and the Japanese Journal of Hospital Pharmacy,the principalmedical pharmacy journals in Japan,by text-mining.All article titles (2884 articles) between 1975 and 2009 were collectedfrom article databases,and the text of titles was analyzed using the KH Coder,free software for quantitative textanalysis of the Japanese language.This software produces basic information on text data such as the rate of occurrence ofcertain words.Nine research categories were identified through multivariate analysis of frequently appearing words.Also,coding rules were created to assign article titles to these research categories,and the categorization results were analyzed quantitatively.Pharmaceutical investigation was the principal category in the 1970 s and 80 s,with the quality evaluation of drugs asthe major area of research.Articles assigned to this category accounted for 41.4% of all articles published during the period1980-1984.Articles assigned to the drug therapy category began to gradually increase in the 1990 s,and since 2000,drugtherapy has been the major area of medical pharmacy research in Japan.In addition,there has been an increase in investigationsassociated with the education of pharmacists and pharmacy students in recent yearsOur findings suggest that there has been a shift in the dominant research area of medical pharmacy in Japan from qualityevaluation of drugs to patient care.
  • Study on the Dosing Regimen of Epoprostenol in Japanese Children with Primary Pulmonary Hypertension, Okada Hiroshi, Takada Mitsutaka, Morishita Hideki, Yamada Osamu, Japanese journal of pharmaceutical health care and sciences, 32, 8, 805, 812,   2006 08 10 , 10.5649/jjphcs.32.805, http://ci.nii.ac.jp/naid/110004781846
    Summary:The guideline on the dosing of Epoprostenol sodium (PGI_2) was established based on data for adults. In order to study the dosing regimen in children in Japan, we followed-up 7 patients under 16 years old with primary pulmonary hypertension (PPH) who received PGI_2 and analyzed their doses, hemodynamic parameters and brain natriuretic peptide (BNP) levels. The mean initial dose of PGI_2 was 2.0±0.7ng/kg/min and increases in the PGI_2 dosage occurred mostly within 2 weeks of the start of administration. Up to 28 days after starting administration, the mean interval between dose increases was 2.9±3.3 days and the mean dosage increase increment was 0.8±0.4ng/kg/min. Up to 3 months after starting administration, there was no statistically significant difference in doses between adults and children. Among severe adverse effects reported in acute dose-ranging in Japan, 7 of 18 cases were in children and the initial doses in 4 of them were over 2ng/kg/min. Based on these findings, appropriate dosing of PGI_2 in children is considered to be as follows: 1) The initial dose should be 0.5ng/kg/min, 2) The dosage increase interval should be over 2 days and the dosage increase increment between 0.5 and 1ng/kg/min, 3) Up to 3 months, the dose in children may be increased to the same extent as in adults.
  • Research on Drugs Prescribed for Treatment of Myocardial Infarction at the National Cardiovascular Center (NCVC) : Comparison of Prescribing Trends between March 1996 and March 2004, Kawato Nobuyuki, Takada Mitutaka, Inoue Tomomi, Hashizume Hiromi, Nonogi Hiroshi, Morishita Hideki, Japanese journal of pharmaceutical health care and sciences, 32, 3, 242, 249,   2006 03 10 , 10.5649/jjphcs.32.242, http://ci.nii.ac.jp/naid/110004656732
    Summary:In 1996, research was conducted at the National Cardiovascular Center to determine prescribing trends for drugs used in the treatment of myocardial infarction (MI). Since much evidence was collected and clinical guidelines for the treatment of MI were established, we thought that the prescribing trends might have changed in the following years so in 2004, we conducted research to determine what changes had occurred in the period from 1996 to 2004. The frequency of prescribing platelet aggregation inhibitors, β-adrenergic antagonists, angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) was higher in 2004, when platelet aggregation inhibitors were prescribed for 91.6% of the patients with MI, and aspirin was prescribed for 86.4% of the patients. The frequencies of prescribing multiple drugs for ischemic heart disease was high in both 1996 and 2004, and β-adrenergic antagonists had become the predominant drugs in multiple drug therapy in 2004. β_1-selective adrenergic antagonists without intrinsic sympathetic activity and αβ-adrenergic antagonists were major drugs among the β-adrenergic antagonists. Among calcium antagonists, the frequency of amlodipine use showed an upward trend in this eight-year period. In conclusion, our findings indicate that standard pharmacotherapy for MI based on the evidence and clinical guidelines has been introduced at NCVC.
  • Research on Drugs Prescribed for Treatment of Myocardial Infarction at the National Cardiovascular Center (NCVC)-Comparison of Prescribing Trends between March 1996 and March 2004-:—Comparison of Prescribing Trends between March 1996 and March 2004—, Kawato Nobuyuki, Takada Mitutaka, Inoue Tomomi, Hashizume Hiromi, Nonogi Hiroshi, Morishita Hideki, Japanese Journal of Hospital Pharmacy, 32, 3, 242, 249,   2006 , 10.5649/jjphcs.32.242, http://ci.nii.ac.jp/naid/130004502215
    Summary:In 1996, research was conducted at the National Cardiovascular Center to determine prescribing trends for drugs used in the treatment of myocardial infarction (MI). Since much evidence was collected and clinical guidelines for the treatment of MI were established, we thought that the prescribing trends might have changed in the following years so in 2004, we conducted research to determine what changes had occurred in the period from 1996 to 2004. The frequency of prescribing platelet aggregation inhibitors, β-adrenergic antagonists, angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) was higher in 2004, when platelet aggregation inhibitors were prescribed for 91.6% of the patients with MI, and aspirin was prescribed for 86.4% of the patients. The frequencies of prescribing multiple drugs for ischemic heart disease was high in both 1996 and 2004, and β-adrenergic antagonists had become the predominant drugs in multiple drug therapy in 2004. β1-selective adrenergic antagonists without intrinsic sympathetic activity and αβ-adrenergic antagonists were major drugs among the β-adrenergic antagonists. Among calcium antagonists, the frequency of amlodipine use showed an upward trend in this eight-year period. In conclusion, our findings indicate that standard pharmacotherapy for MI based on the evidence and clinical guidelines has been introduced at NCVC.
  • Pharmacoepidemiological Studies on Evaluation and Promotion of the Rational Use of Antiarrhythmic Drugs, TAKADA Mitsutaka, Japanese Journal of Pharmacoepidemiology/Yakuzai ekigaku, 10, 1, 29, 39,   2005 , 10.3820/jjpe1996.10.29, http://ci.nii.ac.jp/naid/130004345331
    Summary:To evaluate and promote the rational use of antiarrhythmic drugs, a series of pharmacoepidemiological studies were performed. First, studies on hypoglycemia induced by cibenzoline were performed. The mechanism of the hypoglycemic effect of cibenzoline is related to an increase in insulin secretion. A significantly increased risk of hypoglycemia was observed in patients treated with cibenzoline in a case-controlled study. In particular, close attention should be paid to the occurrence of cibenzoline-induced hypoglycemia in elderly patients, those receiving high doses and in those with reduced renal function. After the introduction of TDM, the risk of hypoglycemia associated with cibenzoline use decreased together with an increase of the percentage of patients whose serum concentrations of cibenzoline had been measured. Dose adjustment based on TDM was beneficial for patients treated with cibenzoline in order to prevent hypoglycemia. In general, drugs are used in accordance with an approved dosage regimen in the expectation of an appropriate balance between efficacy and toxicity. However, a difference was seen between the approved dosage and the actual dose in cibenzoline therapy. Secondly, prescription research of several antiarrhythmic drugs was performed at five national hospitals. Antiarrhythmic drugs were used in lower doses than the approved dosage in clinical practice in Japan. Differences were seen between the approved dosage and the actual dose, and remarkable variations were seen in the dose distribution among the hospitals. The discrepancy between the approved dosage and practical dosage suggests that there is doubt as to whether the approved dosing regimens for antiarrhythmic drugs are appropriate.
  • Study on Awareness of Adverse Drug Reactions in Hospitals : ADR Awareness Investigated through Questionnaire Sent to National Hospitals, and Situation at National Cardiovascular Center, Kotake Takeshi, Takada Mitsutaka, Hashimoto Hiroshi, Wada Kyouiti, Shibakawa Masahiko, Japanese journal of pharmaceutical health care and sciences, 30, 10, 642, 650,   2004 10 10 , 10.5649/jjphcs.30.642, http://ci.nii.ac.jp/naid/110001166776
    Summary:Up till now, the major drug information-related activity of hospital pharmacists has been to disseminate drug safety information issued by the Ministry of Health, Labour and Welfare. However, another important activity of pharmacists is noting adverse drug reactions (ADR) occurring in their own hospital and informing other medical staff about them. This information should also be reported to the Ministry of Health, Labour and Welfare so that the adverse reactions may be widely known among the medical community. In order to investigate the extent that pharmacists actually conduct such activities, a questionnaire survey was sent to 62 national hospitals and the number of ADR reports to the Ministry of Health, Labour and Welfare from 189 national hospitals in fiscal 2003 was investigated. The results indicated that most hospitals were insufficiently aware of the ADRs that occurred. A major reason for this was considered to be the lack of systems for collecting and reporting adverse reactions. Pharmacists were found to be involved in 78% of ADR reports. For the National Cardiovascular Center, the survey showed that the introduction of an ADR collecting system in which pharmacists played a leading role had significantly increased the number of ADR reports to the Ministry of Health, Labour and Welfare. Moreover, 37% of the reported ADRs were related to safety information from the Ministry of Health, Labour and Welfare. The survey results also suggested that providing safety information to physicians is effective in improving safety in the use of drugs. Although medical staff were only aware of about 3% of the ADRs, the crucial role of pharmacists in collecting and reporting ADRs was recognized.
  • Pilot Study on Evaluation of Clinical Pharmacy Practice at National Cardiovascular Center, Kotake Takeshi, Shimeda Yuka, Tanaka Kazuhiko, Takada Michitaka, Shibakawa Masahiko, Japanese journal of pharmaceutical health care and sciences, 30, 3, 185, 190,   2004 03 10 , 10.5649/jjphcs.30.185, http://ci.nii.ac.jp/naid/110001166798
    Summary:Conducting clinical pharmacy practice in consideration of inpatient needs is one of the most important activities of pharmacists. In view of this, we conducted a pilot study at the National Cardiovascular Center to evaluate the effectiveness of our practice of clinical pharmacy. During the study period, 892 drug compliance instructions were given to 312 patients and there were 1,785 events that had to be managed. In order to manage these events, we provided information in 2,007 instances to patients (65%) or medical staff (35%). Among the events, the frequency of adverse reactions was 6.3%, with a rate per drug compliance instruction of one in eight. Medical errors accounted for 1.9% of the events, giving a rate of one error per 24 drug compliance instructions. Twenty percent of all prescription changes arose from information provided by pharmacists and 6.0% of changes in prescriptions were attributable to the medication errors detected by pharmacists. Thus, pharmacists were involved in about 25% of prescription changes. As our conclusion, clinical pharmacy practice which helps to avoid adverse reactions and provides useful information to patients and medical staff is a prerequisite for effective pharmacotherapy.
  • Promoting Proper use of Ticlopidine Hydrochloride through Prescription Order Entry System, Wada Kyoichi, Hattori Yuji, Takada Mitsutaka, Shibakawa Masahiko, Japanese journal of pharmaceutical health care and sciences, 30, 3, 211, 216,   2004 03 10 , 10.5649/jjphcs.30.211, http://ci.nii.ac.jp/naid/110001166802
    Summary:Ticlopidine has been reported to cause critical adverse reactions, among them thrombotic thrombocytopenic purpura, granulocytopenia and liver failure. In view of this, emergency safety information has been issued on two occasions and after it was issued for the second time in July 2002, a warning function was incorporated into the computerized order entry system. Under this function, a warning message is displayed on the screen when this drug is to be prescribed for a patient for the first time and physicians can only enter a prescription order for ticlopidine when they have acknowledged the message. We compared the frequencies of prescribing ticlopidine and of conducting blood tests, and the rate of adverse reactions before and after the issue of the emergency safety information and introduction of the warning function. Patients treated with ticlopidine were selected from the prescription database file created from the prescription order entry system, which contains details of all the prescriptions filled for outpatients between January 1998 and December 2002. Following the issue of emergency safety information for the second time, the prescription frequency of ticlopidine started to decrease and there was a significant increase in the frequency of blood tests, though there had been no difference in the amount of blood testing between before and after the issue of emergency safety information for the first time. This showed that the timely provision of safety information to physicians through the computerized order entry system has been effective in promoting the proper use of ticlopidine.
  • Pilot Study on Evaluation of Clinical Pharmacy Practice at National Cardiovascular Center, Kotake Takeshi, Shimeda Yuka, Tanaka Kazuhiko, Takada Michitaka, Shibakawa Masahiko, Japanese Journal of Hospital Pharmacy, 30, 3, 185, 190,   2004 , 10.5649/jjphcs.30.185, http://ci.nii.ac.jp/naid/130004346602
    Summary:Conducting clinical pharmacy practice in consideration of inpatient needs is one of the most important activities of pharmacists. In view of this, we conducted a pilot study at the National Cardiovascular Center to evaluate the effectiveness of our practice of clinical pharmacy. During the study period, 892 drug compliance instructions were given to 312 patients and there were 1, 785 events that had to be managed. In order to manage these events, we provided information in 2, 007 instances to patients (65 %) or medical staff (35%). Among the events, the frequency of adverse reactions was 6.3 %, with a rate per drug compliance instruction of one in eight. Medical errors accounted for 1.9% of the events, giving a rate of one error per 24 drug compliance instructions. Twenty percent of all prescription changes arose from information provided by pharmacists and 6.0 % of changes in prescriptions were attributable to the medication errors detected by pharmacists. Thus, pharmacists were involved in about 25 % of prescription changes. As our conclusion, clinical pharmacy practice which helps to avoid adverse reactions and provides useful information to patients and medical staff is a prerequisite for effective pharmacotherapy.
  • Promoting Proper use of Ticlopidine Hydrochloride through Prescription Order Entry System, Wada Kyoichi, Hattori Yuji, Takada Mitsutaka, Shibakawa Masahiko, Japanese Journal of Hospital Pharmacy, 30, 3, 211, 216,   2004 , 10.5649/jjphcs.30.211, http://ci.nii.ac.jp/naid/130004346606
    Summary:Ticlopidine has been reported to cause critical adverse reactions, among them thrombotic thrombocytopenic purpura, granulocytopenia and liver failure. In view of this, emergency safety information has been issued on two occasions and after it was issued for the second time in July 2002, a warning function was incorporated into the computerized order entry system. Under this function, a warning message is displayed on the screen when this drug is to be prescribed for a patient for the first time and physicians can only enter a prescription order for ticlopidine when they have acknowledged the message.<BR>We compared the frequencies of prescribing ticlopidine and of conducting blood tests, and the rate of adverse reactions before and after the issue of the emergency safety information and introduction of the warning function. Patients treated with ticlopidine were selected from the prescription database file created from the prescription order entry system, which contains details of all the prescriptions filled for outpatients between January 1998 and December 2002.<BR>Following the issue of emergency safety information for the second time, the prescription frequency of ticlopidine started to decrease and there was a significant increase in the frequency of blood tests, though there had been no difference in the amount of blood testing between before and after the issue of emergency safety information for the first time. This showed that the timely provision of safety information to physicians through the computerized order entry system has been effective in promoting the proper use of ticlopidine.
  • Interaction of Warfarin and Fluvoxamine on Medical Report, Wada Kyoichi, Yasuda Chieko, Hanafusa Sayuri, Takada Mitsutaka, Shibakawa Masahiko, Japanese journal of pharmaceutical health care and sciences, 28, 5, 468, 472,   2002 10 10 , 10.5649/jjphcs.28.468, http://ci.nii.ac.jp/naid/110001166633
    Summary:Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is widely used in the treatment of. patients with depression. It is known that fluvoxamine inhibits the activity of human cytochrome P450 enzymes (CYP) responsible for the oxidative metabolism of many drugs. Inhibition of CYP results in a number of clinically important pharmacokinetic drug interactions. Therefore, the interaction between warfarin and fluvoxamine was evaluated. The patients treated with fluvoxamine were selected from the prescription database file made for the prescriptions order entry system, which contains all the prescriptions filled for the inpatients and outpatients. There were 106 patients treated with fluvoxamine between July 2000 and June 2001. Of 106 patients, 20 used warfarin concomitantly during the study period. Increased INR/Dose values were observed in all patients after the initiation of fluvoxamine therapy. Subsequently, the high INR/Dose values were observed during the concomitant use of warfarin and fluvoxamme (P<0.01). It is suggested that the increase in the anticoagulant activity of warfarin occurred when fluvoxamine is used concomitantly. Therefore, frequent coagulation tests are required in patients treated with warfarin after the initiation or discontinuation of fluvoxamine therapy. In conclusion, warfarin should be used with worry when fluvoxamine is used concomitantly.
  • Evaluation of the Optimal Dosage of Alopurinol in Japanese Patients, Okada Hiroshi, Oita Akira, Ueno Kazuyuki, Takada Mitsutaka, Shibakawa Masahiko, Japanese journal of pharmaceutical health care and sciences, 28, 6, 564, 570,   2002 10 10 , 10.5649/jjphcs.28.564, http://ci.nii.ac.jp/naid/110001166645
    Summary:Allopurinol is often used for the treatment of patients suffering from gout and hyperuricemia. However, adverse effects due to the accumulation of oxipunnol, the main active metabolite of allopurinol, have been reported in patients with renal insufficiency. Therefore, in order to prevent such adverse effects, some guidelines for the optimal dosage of allopurinol have been advocated. To evaluate these guidelines, the serum oxipurinol concentration in 101 patients with hyperuricemia treated with allopurinol was measured by HPLC. The serum oxipurinol concentration/dosage increased (p<0.01) as the creatinine clearance level decreased. In addition, to evaluate the optimum dosage based on the renal function, Ccr was classified into three groups (Ccr≦30mL/min 30mL/min<Ccr≦50mL/min, Ccr<50mL/min). A positive correlation was observed between the dosage of allopurinol and the serum oxipurinol concentration in each group (Ccr≦30mL/min, Ccr<50mL/min : p<0.01 30mL/min<Ccr : ≦50mL/min : p<0.05). Regarding the serum oxipurinol concentration/dosage in each group, it increased as the creatinine clearance level decreased (p<0.05). Based on our findings, the optimal dosages of allopurinol in each group in Japanese are considered to be as follows 1) Ccr≦30mL/min : 50mg/day 2) 30mL/min<Ccr≦50mL/mm : 100mg/day 3) Ccr<50mL/min : 200mg/day
  • A Simple Assay for Serum Carvedilol Concentration by HPLC and its Clinical Application, Kato Ryuji, Ueno Kazuyuki, Tsuchishita Yoshimasa, Yoshimura Hironori, Takada Mitsutaka, Komamura Kazuo, Kamakura Shiro, Miyatake Kunio, Shibakawa Masahiko, Japanese journal of pharmaceutical health care and sciences, 28, 1, 9, 15,   2002 02 10 , 10.5649/jjphcs.28.9, http://ci.nii.ac.jp/naid/110001166570
    Summary:Carvedilol demonstrates α_1-, β_1-, β_2-receptor blocking activity and has recently been used for the treatment of heart failure. The serum concentrations of carvedilol were measured by high performance liquid chromatography (HPLC) using the method of Hokama et al. and Louis et al. with slight modifications. To extract carvedilol from the serum, we employed solid-phase extraction. The retention times of carvedilol and the internal standard were 7.1 and 5.8 minute, respectively. The detection limit was 0.25ng/mL. These results suggest that this assay is a rapid, simple and sensitive method. On the other hand, the mean±SD clearance of carvedilol was 1.10±0.541L/hr/kg and 0.611±0.320L/hr/kg in 4 male volunteers who received 10mg carvedilol orally and in 21 inpatients who received carvedilol b.i.d. for at least a week, respectively. Our findings indicated that even though the carvedilol concentrations increased depending on the dose, the individual variations among individuals were large.
  • Interaction of Warfarin and Rifampicin on Medical Report, Wada Kyoichi, Kojima Etsuko, Takada Mitsutaka, Shibakawa Masahiko, Japanese journal of pharmaceutical health care and sciences, 28, 1, 85, 90,   2002 02 10 , 10.5649/jjphcs.28.85, http://ci.nii.ac.jp/naid/110001166582
    Summary:Rifampicin's ability to induce hepatic-microsomal enzymes is well known. As a result, rifampicin has often been implicated in drug interactions by reducing the effectiveness of many drugs that are metabolized by the hepatic-microsomal enzyme system. One such well known interaction is that of rifampicin and warfarin. The concomitant administration of rifampicin and warfarin results in the need for an unusually high maintenance dose of warfarin in order to obtain the desired therapeutic effect. The interaction between warfarin and rifampicin was investigated. The patients treated with rifampicin were selected from the prescription database file made for the prescriptions order entry system, and which contains all the prescriptions filled for the inpatients and outpatients. Thirty patients were treated with rifampicin between July 2000 and June 2001. Four of them used warfarin concomitantly during the study period. Decreased INR values were observed in all patients between 5 and 10 days after the initiation of rifampicin therapy. To maintain proper INR, rifampicin therapy resulted in the need for a two-to three-fold increase in the warfarin dosage. Subsequently, low INR/Dose values were observed during the concomitant use of warfarin and rifampicin (30%〜50%). A decrease in the anticoagulant activity of warfarin frequently occurs when rifampicin is used concomitantly. After the initiation and discontinuation of rifampicin therapy, frequent coagulation tests are required in patients treated with warfarmn. In conclusion, warfarin should be used with caution when rifampicin is used concomitantly.
  • Interaction of Warfarin and Fluvoxamine on Medical Report., Wada Kyoichi, Yasuda Chieko, Hanafusa Sayuri, Takada Mitsutaka, Shibakawa Masahiko, Japanese Journal of Hospital Pharmacy, 28, 5, 468, 472,   2002 , 10.5649/jjphcs.28.468, http://ci.nii.ac.jp/naid/130004346456
    Summary:Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is widely used in the treatment of patients with depression. It is known that fluvoxamine inhibits the activity of human cytochrome P450 enzymes (CYP) responsible for the oxidative metabolism of many drugs. Inhibition of CYP results in a number of clinically important pharmacokinetic drug interactions.<BR>Therefore, the interaction between warfarin and fluvoxamine was evaluated. The patients treated with fluvoxamine were selected from the prescription database file made for the prescriptions order entry system, which contains all the prescriptions filled for the inpatients and outpatients. There were 106 patients treated with fluvoxamine between July 2000 and June 2001. Of 106 patients, 20 used warfarin concomitantly during the study period. Increased INR/Dose values were observed in all patients after the initiation of fluvoxamine therapy. Subsequently, the high INR/Dose values were observed during the concomitant use of warfarin and fluvoxamine (P<0.01). It is suggested that the increase in the anticoagulant activity of warfarin occurred when fluvoxamine is used concomitantly. Therefore, frequent coagulation tests are required in patients treated with warfarin after the initiation or discontinuation of fluvoxamine therapy. In conclusion, warfarin should be used with worry when fluvoxamine is used concomitantly.
  • A Simple Assay for Serum Carvedilol Concentration by HPLC and its Clinical Application., Kato Ryuji, Ueno Kazuyuki, Tsuchishita Yoshimasa, Yoshimura Hironori, Takada Mitsutaka, Komamura Kazuo, Kamakura Shiro, Miyatake Kunio, Shibakawa Masahiko, Japanese Journal of Hospital Pharmacy, 28, 1, 9, 15,   2002 , 10.5649/jjphcs.28.9, http://ci.nii.ac.jp/naid/130004346421
    Summary:Carvedilol demonstrates α<SUB>1-</SUB>, β<SUB>1-</SUB>, β<SUB>2-</SUB> receptor blocking activity and has recently been used for the treatment of heart failure. The serum concentrations of carvedilol were measured by high performance liquid chromatography (HPLC) using the method of Hokama et al. and Louis et al. with slight modifications. To extract carvedilol from the serum, we employed solid-phase extraction. The retention times of carvedilol and the internal standard were 7.1 and 5.8 minute, respectively. The detection limit was 0.25ng/mL. These results suggest that this assay is a rapid, simple and sensitive method. On the other hand, the mean±SD clearance of carvedilol was 1.10 ±0.541L/hr/kg and 0.611±0.320L/hr/kg in 4 male volunteers who received 10mg carvedilol orally and in 21 inpatients who received carvedilol b.i.d. for at least a week, respectively. Our findings indicated that even though the carvedilol concentrations increased depending on the dose, the individual variations among individuals were large.
  • Interaction of Warfarin and Rifampicin on Medical Report., Wada Kyoichi, Kojima Etsuko, Takada Mitsutaka, Shibakawa Masahiko, Japanese Journal of Hospital Pharmacy, 28, 1, 85, 90,   2002 , 10.5649/jjphcs.28.85, http://ci.nii.ac.jp/naid/130004346432
    Summary:Rifampicin's ability to induce hepatic-microsomal enzymes is well known. As a result, rifampicin has often been implicated in drug interactions by reducing the effectiveness of many drugs that are metabolized by the hepatic-microsomal enzyme system. One such well known interaction is that of rifampicin and warfarin. The concomitant administration of rifampicin and warfarin results in the need for an unusually high maintenance dose of warfarin in order to obtain the desired therapeutic effect.<BR>The interaction between warfarin and rifampicin was investigated. The patients treated with rifampicin were selected from the prescription database file made for the prescriptions order entry system, and which contains all the prescriptions filled for the inpatients and outpatients. Thirty patients were treated with rifampicin between July 2000 and June 2001. Four of them used warfarin concomitantly during the study period. Decreased INR values were observed in all patients between 5 and 10 days after the initiation of rifampicin therapy. To maintain proper INR, rifampicin therapy resulted in the need for a two-to three-fold increase in the warfarin dosage. Subsequently, low INR/Dose values were observed during the concomitant use of warfarin and rifampicin (30%-50%). A decrease in the anticoagulant activity of warfarin frequently occurs when rifampicin is used concomitantly. After the initiation and discontinuation of rifampicin therapy, frequent coagulation tests are required in patients treated with warfarin. In conclusion, warfarin should be used with caution when rifampicin is used concomitantly.
  • Generic prescribing and generic drugs from the standpoint of pharmacists, Mitsutaka Takada, Masahiko Shibakawa, IRYO - Japanese Journal of National Medical Services, 56, 8, 465, 468,   2002 , 10.11261/iryo1946.56.465, http://ci.nii.ac.jp/naid/130004316126
    Summary:Introduction of generic prescribing and effective utilization of generic drugs are useful measures for suppression of health care cost. However, medical doctors, pharmacists and patients should have correct understandings of meaning of generic prescribing and advantages and defects of generic drugs. Furthermore, generic drug companies should make efforts in the securement of stable supply, development of system for drug information collecting and service, and thoroughness of manufacturing and quality controls. With respect to the quality control, pharmacists have concerns about the bioequivalence between original drug and generic drug. The drugs with narrow therapeutic range should be used with attention, which are required to monitor the drug levels as they have a tendency to produce some side effects or decrease the efficacy along with the slight change of drug level. Pharmacists are held accountable for the logical choice of drugs when the generic names are used to prescribe the drugs, because the rational drug should be selected from viewpoints of patient's economic strain and pharmaceutical rationality. © 2002, Japanese Society of National Medical Services. All rights reserved.
  • Generic prescribing and generic drugs from the standpoint of pharmacists, Mitsutaka Takada, Masahiko Shibakawa, IRYO - Japanese Journal of National Medical Services, 56, 8, 465, 468,   2002 , 10.11261/iryo1946.56.465, http://ci.nii.ac.jp/naid/40019864098
    Summary:Introduction of generic prescribing and effective utilization of generic drugs are useful measures for suppression of health care cost. However, medical doctors, pharmacists and patients should have correct understandings of meaning of generic prescribing and advantages and defects of generic drugs. Furthermore, generic drug companies should make efforts in the securement of stable supply, development of system for drug information collecting and service, and thoroughness of manufacturing and quality controls. With respect to the quality control, pharmacists have concerns about the bioequivalence between original drug and generic drug. The drugs with narrow therapeutic range should be used with attention, which are required to monitor the drug levels as they have a tendency to produce some side effects or decrease the efficacy along with the slight change of drug level. Pharmacists are held accountable for the logical choice of drugs when the generic names are used to prescribe the drugs, because the rational drug should be selected from viewpoints of patient's economic strain and pharmaceutical rationality. © 2002, Japanese Society of National Medical Services. All rights reserved.
  • Assessment and revision of network computer-assisted management system for blood transfusion, TAKADA Masahiro, IWATANI Yasuyuki, KAWAI Takeshi, YAMAMOTO Suguru, MIYATA Shigeki, CHIBA Yoshihide, NAKAZAWA Kazuo, TAKADA Mitsutaka, SHIBAKAWA Masahiko, 医療情報学連合大会論文集, 20, 176, 177,   2000 11 23 , http://ci.nii.ac.jp/naid/10010610646
  • A Case Report of Hemodialysis Patient with Successful Determination of Pilsicainide and Digoxin Dosage by Therapeutic Drug Monitoring, MORII MEGUMI, UENO KAZUYUKI, MATSUMOTO KANA, TAKADA MITSUTAKA, NOJIMA YUHEI, SAKAMAKI FUMIO, NAKANISHI NORIFUMI, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 26, 4, 398, 402,   2000 08 10 , 10.5649/jjphcs1975.26.398, http://ci.nii.ac.jp/naid/110001166995
    Summary:A 67-year-old man who had been receiving hemodialysis (HD) was administered pilsicainide and digoxin for the treatment of paroxysmal atrial fibrillation. Thereafter, when undergoing HD, ventricular fibrillation and flutter frequently appeared, and he was therefore admitted to National Cardiovascular Center. After being admitted, the administration of pilsicainide and digoxin was immediately stopped due to a widening QRS on ECG. After that the terminal half-time (t_<1/2>) of pilsicainide and digoxin were calculated and these drugs were restarted base on his calculated t_<1/2>. Subsequently a good control of arrhythmia without any side effects was obtained at this dosage. The above findings suggested that although the dose of digoxin in this case ranged from one-sixth to one-third of the normal dose when the renal function was normal, the dose of pilsicainide was only about one-tenth that of a normal dose, and a remarkable difference was observed between the dose of digoxin and pilsicainide. This case suggests that drugs, which are mainly eliminated in the kidney, especially pilsicainide, should thus be carefully monitored regarding their influence on the renal function in HD patients, since such therapy could lead to renal function failure.
  • Studies on Factor Affecting Pharmacokinetics of Cilostazol and Pharmacokinetics : Pharmacodynamics Analysis Based Platelet Aggregation, ISHIDA SHIGENOBU, MORII MEGUMI, UENO KAZUYUKI, TAKADA MITSUTAKA, SAKATA TOSIYUKI, OKAMOTO AKIRA, KOBAYASHI JUNJIRO, MONTA OSAMU, KOIZUMI NOBUTATU, SASAKO YOSHIKADO, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 26, 3, 264, 272,   2000 06 10 , 10.5649/jjphcs1975.26.264, http://ci.nii.ac.jp/naid/110001166977
    Summary:Cilostazol is being developed for the treatment of intermittent claudication due to peripheral arterial disease (PAD). In this study, we measured the serum cilostazol concentrations and plate-let aggregations induced by adenosine diphosphate (ADP) and collagen, and also investigated the pharmacokinetics and pharmacodynamics of cilostazol in inpatients receiving cilostazol therapy. No significant difference was observed in C/D (serum trough concentration/dose) between males and females. A trend toward increasing the serum cilostazol concentration by increasing the dose (mg/kg) was observed (P<0.05). The interindividual variation of the C/D for cilostazol was found to be very large. No significant difference was observed between the C/D for cilostazol and the age. GPT or Ccr. A statistical correlation was observed between the serum cilostazol concentration and the maximum extent of aggregation (%) induced by ADP and collagen (P<0.05).
  • Relationship between Serum Trough Concentrations of Cibenzoline and Fasting Blood Glucose Levels in Inpatiens Received Cibenzoline Therapy, UENO KAZUYUKI, MORII MEGUMI, ISHIDA SHIGENOBU, TAMAMURA AKIRA, MATSUMOTO KANA, ODA AYUMI, TAKADA MITSUTAKA, KAMAKURA SHIRO, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 26, 3, 304, 308,   2000 06 10 , 10.5649/jjphcs1975.26.304, http://ci.nii.ac.jp/naid/110001166982
    Summary:The relationship between the serum trough concentrations of cibenzoline and the fasting blood glucose (FBG) levels were evaluated in 78 inpatients received cibenzoline therapy. As a result, as the serum trough concentrations of cibenzoline increased, the FBG levels decreased in inverse proportion. The FBG levels after the administration of cibenzoline decreased significantly (P<0.01) more than before administration. In addition, when the serum cibenzoline concentrations were higher the FBG levels also decreased significantly (P<0.01) more than when the serum concentrations were lower. The mean serum concentration when the FBG levels were less than 80 mg/dL was higher than that when the FBG levels were lover 90 mg/dL (383±273 vs 284±189 ng/mL, P<0.071). These results suggest that more careful monitoring of the side effects of cibenzoline caused by a decrease in the FBG is thus needed in patients receiving cibenzoline therapy.
  • Variation of Constitution Ratio of Six Major Components in Teicoplanin Preparations, MATSUMOTO KANA, UENO KAZUYUKI, TAKADA MITSUTAKA, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 26, 3, 345, 348,   2000 06 10 , 10.5649/jjphcs1975.26.345, http://ci.nii.ac.jp/naid/110001166989
    Summary:Objectives : Teicoplanin is an antibiotic complex consisting of five closely related components of similar polarity designated A2-1, 2, 3, 4 and 5 and a more polar factor A 3. The variations in the constitution ratio of the six major components were measured to evaluate the validation of teicoplanin preparations. Methods : The concentrations of each component of teicoplanin were measured in 14 lots by high performance liquid chromatography. Results : No significant differences were observed regarding the variation in the constitution ratio between the A 2 and A 3 groups. However, significant differences were found in the A 2-1 component . Conclusions : Variations of the constitution ratio in Teicoplanin preparations may possibly affect the pharmacokinetics of teicoplanin. More care is thus called for during the manufacturing process.
  • A Case Report and Evaluation of Pirmenol Toxicity Appeared with Liver Injury, MORII MEGUMI, UENO KAZUYUKI, TAKADA MITSUTAKA, HINO YUTAKA, SASAKO YOSHIKADO, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 26, 2, 183, 187,   2000 04 10 , 10.5649/jjphcs1975.26.183, http://ci.nii.ac.jp/naid/110001166966
    Summary:A 56-year-old woman inpatient that had been administrated warfarin, digoxin, verapamil and disopyramide after undergoing surgery for a mitral and aortic valve replacement associated with artrial fibrillation received a 300 mg daily dose of disopyramide therapy before and after the operation. Although the serum disopyramide concentration was within the normal therapeutic range, dry mouth appeared as a side effect. Disopyramide was thus changed to pirmenol. The trough level of pirmenol was 2.1 μg/mL at seven days after starting pirmenol therapy at the dose of 300 mg/day, and the dose was there after decreased to 200 mg/day. About two weeks after pirmenol therapy was started. liver injury was observed. At approximately 30 days after pirmenol aciministration was stopped, the liver function returned to a normal level. On the other hand. according to recent reports pirmenol was suggested to show a high level in the liver. The reported levels of pirmenol were also similar to for amiodarone and aprindine. which are both well known to induce side effect in the liver. Therefore, one of the reasons that pimenol induced liver injury may be due to its high levels in the liver.
  • Studies on Factor Affecting Pharmacokinetics of Cilostazol and Pharmacokinetics-Pharmacodynamics Analysis Based Platelet Aggregation., ISHIDA SHIGENOBU, MORII MEGUMI, UENO KAZUYUKI, TAKADA MITSUTAKA, SAKATA TOSIYUKI, OKAMOTO AKIRA, KOBAYASHI JUNJIRO, MONTA OSAMU, KOIZUMI NOBUTATU, SASAKO YOSHIKADO, SHIBAKAWA MASAHIKO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 26, 3, 264, 272,   2000 , 10.5649/jjphcs1975.26.264, http://ci.nii.ac.jp/naid/130004299771
    Summary:Cilostazol is being developed for the treatment of intermittent claudication due to peripheral arterial disease (PAD). In this study, we measured the serum cilostazol concentrations and platelet aggregations induced by adenosine diphosphate (ADP) and collagen, and also investigated the pharmacokinetics and pharmacodynamics of cilostazol in inpatients receiving cilostazol therapy. No significant difference was observed in C/D (serum trough concentration/dose) between males and females. A trend toward increasing the serum cilostazol concentration by increasing the dose (mg/kg) was observed (P<0.05). The interindividual variation of the C/D for cilostazol was found to be very large. No significant difference was observed between the C/D for cilostazol and the age, GPT or Ccr. A statistical correlation was observed between the serum cilostazol concentration and the maximum extent of aggregation (%) induced by ADP and collagen (P<0.05).
  • Relationship between Serum Trough Concentrations of Cibenzoline and Fasting Blood Glucose Levels in Inpatiens Received Cibenzoline Therapy., UENO KAZUYUKI, MORII MEGUMI, ISHIDA SHIGENOBU, TAMAMURA AKIRA, MATSUMOTO KANA, ODA AYUMI, TAKADA MITSUTAKA, KAMAKURA SHIRO, SHIBAKAWA MASAHIKO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 26, 3, 304, 308,   2000 , 10.5649/jjphcs1975.26.304, http://ci.nii.ac.jp/naid/130004299776
    Summary:The relationship between the serum trough concentrations of cibenzoline and the fasting blood glucose (FBG) levels were evaluated in 78 inpatients received cibenzoline therapy. As a result, as the serum trough concentrations of cibenzoline increased, the FBG levels decreased in inverse proportion. The FBG levels after the administration of cibenzoline decreased significantly (P<0.01) more than before administration. In addition, when the serum cibenzoline concentrations were higher the FBG levels also decreased significantly (P<0.01) more than when the serum concentrations were lower. The mean serum concentration when the FBG levels were less than 80mg/dL was higher than that when the FBG levels were lover 90mg/dL (383±273 vs 284±189ng/mL, P<0.071). These results suggest that more careful monitoring of the side effects of cibenzoline caused by a decrease in the FBG is thus needed in patients receiving cibenzoline therapy.
  • Variation of Constitution Ratio of Six Major Components in Teicoplanin Preparations., MATSUMOTO KANA, UENO KAZUYUKI, TAKADA MITSUTAKA, SHIBAKAWA MASAHIKO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 26, 3, 345, 348,   2000 , 10.5649/jjphcs1975.26.345, http://ci.nii.ac.jp/naid/130004299783
    Summary:Objectives: Teicoplanin is an antibiotic complex consisting of five closely related components of similar polarity designated A2-1, 2, 3, 4 and 5 and a more polar factor A 3. The variations in the constitution ratio of the six major components were measured to evaluate the validation of teicoplanin preparations.<BR>Methods: The concentrations of each component of teicoplanin were measured in 14 lots by high performance liquid chromatography.<BR>Results: No significant differences were observed regarding the variation in the constitution ratio between the A 2 and A 3 groups. However, significant differences were found in the A 2-1 component.<BR>Conclusions: Variations of the constitution ratio in Teicoplanin preparations may possibly affect the pharmacokinetics of teicoplanin. More care is thus called for during the manufacturing process.
  • A Case Report and Evaluation of Pirmenol Toxicity Appeared with Liver Injury., MORII MEGUMI, UENO KAZUYUKI, TAKADA MITSUTAKA, HINO YUTAKA, SASAKO YOSHIKADO, SHIBAKAWA MASAHIKO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 26, 2, 183, 187,   2000 , 10.5649/jjphcs1975.26.183, http://ci.nii.ac.jp/naid/130004299760
    Summary:A 56-year-old woman inpatient that had been administrated warfarin, digoxin, verapamil and disopyramide after undergoing surgery for a mitral and aortic valve replacement associated with artrial fibrillation received a 300mg daily dose of disopyramide therapy before and after the operation. Although the serum disopyramide concentration was within the normal therapeutic range, dry mouth appeared as a side effect. Disopyramide was thus changed to pirmenol. The trough level of pirmenol was 2.1μg/mL at seven days after starting pirmenol therapy at the dose of 300 mg/day, and the dose was there after decreased to 200mg/day. About two weeks after pirmenol therapy was started, liver injury was observed. At approximately 30 days after pirmenol administration was stopped, the liver function returned to a normal level.<BR>On the other hand, according to recent reports pirmenol was suggested to show a high level in the liver. The reported levels of pirmenol were also similar to for amiodarone and aprindine, which are both well known to induce side effect in the liver. Therefore, one of the reasons that pimenol induced liver injury may be due to its high levels in the liver.
  • A Case Report of Hemodialysis Patient with Successful Determination of Pilsicainide and Digoxin Dosage by Therapeutic Drug Monitoring., MORII MEGUMI, UENO KAZUYUKI, MATSUMOTO KANA, TAKADA MITSUTAKA, NOJIMA YUHEI, SAKAMAKI FUMIO, NAKANISHI NORIFUMI, SHIBAKAWA MASAHIKO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 26, 4, 398, 402,   2000 , 10.5649/jjphcs1975.26.398, http://ci.nii.ac.jp/naid/130004103223
    Summary:A 67-year-old man who had been receiving hemodialysis (HD) was administered pilsicainide and digoxin for the treatment of paroxysmal atrial fibrillation. Thereafter, when undergoing HD, ventricular fibrillation and flutter frequently appeared, and he was therefore admitted to National Cardiovascular Center. After being admitted, the administration of pilsicainide and digoxin was immediately stopped due to a widening QRS on ECG. After that the terminal half-time (t<SUB>1/2</SUB>) of pilsicainide and digoxin were calculated and these drugs were restarted base on his calculated t<SUB>1/2</SUB>. Subsequently a good control of arrhythmia without any side effects was obtained at this dosage.<BR>The above findings suggested that although the dose of digoxin in this case ranged from onesixth to one-third of the normal dose when the renal function was normal, the dose of pilsicainide was only about one-tenth that of a normal dose, and a remarkable difference was observed between the dose of digoxin and pilsicainide.<BR>This case suggests that drugs, which are mainly eliminated in the kidney, especially pilsicainide, should thus be carefully monitored regarding their influence on the renal function in HD patients, since such therapy could lead to renal function failure.
  • Effect of Albumin and α_1 Acid Glycoprotein on Binding of Cibenzoline, UENO KAZUYUKI, MORII MEGUMI, NISHIOKA JYUNKO, YOSHIMURA HIRONORI, TSUJI MIRI, HIRAKI KIYOKAZU, TAKADA MITSUTAKA, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 25, 6, 643, 648,   1999 12 10 , 10.5649/jjphcs1975.25.643, http://ci.nii.ac.jp/naid/110001166931
    Summary:The effect of albumin and α_1 acid-glycoprotein (AAG) on the binding of cibenzoline was studied using the pH 7.4 phosphate buffer (PBs) and human plasma. The binding in 40 inpatients who received cibenzoline therapy was measured. The cibenzoline concentrations of samples were measured by high performance liquid chromatography. As a result, not only the PBS but also human plasma samples the binding increased in propotion as the concentrations of albumin and AAG increased. On the other hard the binding decreased in inverse proportion as the total cibenzoline concentration increased. However, in the patient samples the effect of the total concentration of cibenzoline and the concentrations of albumin and AAG on the binding was slight and the mean binding ratio was about 80%. These results suggest that when clinically monitoring the cibenzoline blood concentration in clinical monitoring the total concentrations of cibenzoline alone appears to be sufficient.
  • Clinical and Basic Evaluation of Side Effect for Skin Irritation among Three Nitrate Patch Preparations for Ischemic Heart Disease, MORII MEGUMI, UENO KAZUYUKI, AKAI HIROKO, TSUJI MIRI, TAKADA MASAHIRO, TAKADA MITSUTAKA, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 25, 5, 495, 501,   1999 10 10 , 10.5649/jjphcs1975.25.495, http://ci.nii.ac.jp/naid/110001166911
    Summary:The side effects of nitrate patch preparations for ischemic heart disease were evaluated in both inpatients and volunteers. Therefore, a removal test of hony cells. adhesion test and down rolling ball (tack) test were all studied to clarify the pharmaceutical characteristics of these preparations. As a result. the score of the skin irritation of the NitrodermTTS^<[O!R]> preparation was significantly higher than that for the other two preparations (Antup^<[O!R]> and Frandol tape S^<[O!R]> preparation). No correlations were observed between skin irritation and the amount of homy cells removed by the NitrodermTTS^<[O!R]>. The Antupn^<[O!R]> preparation was the strongest for the adhesion test. How-ever. the NitrodermTTS^<[O!R]>) preparation was the strongest for the tack test. These findings suggest that one reason for the increased skin irritation of NitrodermTTS^<[O!R]> may be due to its high degree tack influence.
  • A Simple Assay for Amiodarone and Desethylamiodarone and its Clinical Application, MASAKI KOICHI, UENO KAZUYUKI, TSUJI MIRI, HIRAKI KIYOKAZU, TAKADA MITSUTAKA, KAMAKURA SHIRO, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 25, 1, 28, 33,   1999 02 10 , 10.5649/jjphcs1975.25.28, http://ci.nii.ac.jp/naid/110001166852
    Summary:A simple reverse-phase high-performance liquid chromatographic (HPLC) assay for the measurement of amiodarone and its metabolite, desethylamiodarone in the serum was established. The ODS-2 column was used and the absorbance of the effluent from the column at 254 nm was measured. The standard curves for amiodarone and desethylamiodarone were linear up to 5μg/ml. The coefficent of variation (CV) was within 10% at a concentration of 100 ng/ml, and the CV of the intra-and interday variation was within 10% at concentrations of 0.25. 0.5 and I μg/ ml, respectively. These results suggest that the limit of detection is 100 ng/ml for amiodarone and desethylamiodarone, and this assay is thus considered to be a reliable method in clinical practice. On the other hand, the serum amiodarone and desethylamiodarone concentrations were measured in 10 inpatients who received amiodarone for at least 1 month. No significant correlation was observed between the doses and serum drug concentrations. There findings therefore suggest that TDM(Therapeutic Drug Monitoring) should be performed on anyone taking amiodarone.
  • A Case of Hepatic Failure Due to the Administration of Warfarin, HASHIMOTO HIROSHI, UENO KAZUYUKI, HIRAKI KIYOKAZU, TAKADA MITSUTAKA, MATSUO HIROSHI, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 25, 1, 60, 64,   1999 02 10 , 10.5649/jjphcs1975.25.60, http://ci.nii.ac.jp/naid/110001166857
    Summary:A 61-year-old woman weighting 57.9 kg was hospitalized with deep vein thrombosis. She received warfarin therapy. At first 2 mg/day of warfarin was administered for five days while from the 6 th day the dose was increased to 3 mg/day. From the 8 th day the dose was increased to 4 mg/day. Although the GOT and GPT value was within the normal range before the warfarin therapy was started, on the 5 th day after the therapy was started the GOT and GPT Ievels were 68 and 61 Iu/1, respectively, while on the 12 th day the GOT and GPT had increased even more (99 and 212). We consider such hepatic evidence to be due to the administration of warfarin and its administration was thus stopped. On the 4 th day after warfarin was stopped the GOT and GPT Ievels decreased to 55 and 128, respectively, and after that it decreased even more. Both the GOT and GPT decreased to the normal range wlthin one month. On the other hand, in order to evaluate an allergy to warfarin, a patch test of warfarin was examined, however, the results of the test was negative. No reports of hepatic failure due to the administration of warfarin could be found on Midline from 1966 to February 1998. These results suggest this case to be a very rare one, however, further study is called for in the future.
  • Effect of Albumin and .ALPHA.1 Acid-Glycoprotein on Binding of Cibenzoline., UENO KAZUYUKI, MORII MEGUMI, NISHIOKA JYUNKO, YOSHIMURA HIRONORI, TSUJI MIRI, HIRAKI KIYOKAZU, TAKADA MITSUTAKA, SHIBAKAWA MASAHIKO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 25, 6, 643, 648,   1999 , 10.5649/jjphcs1975.25.643, http://ci.nii.ac.jp/naid/130004299742
    Summary:The effect of albumin and α<SUB>1</SUB> acid-glycoprotein (AAG) on the binding of cibenzoline was studied using the pH 7.4 phosphate buffer (PBs) and human plasma. The binding in 40 inpatients who received cibenzoline therapy was measured. The cibenzoline concentrations of samples were measured by high performance liquid chromatography. As a result, not only the PBs but also human plasma samples the binding increased in propotion as the concentrations of albumin and AAG increased. On the other hard the binding decreased in inverse proportion as the total cibenzoline concentration increased. However, in the patient samples the effect of the total concentration of cibenzoline and the concentrations of albumin and AAG on the binding was slight and the mean binding ratio was about 80%. These results suggest that when clinically monitoring the cibenzoline blood concentration in clinical monitoring the total concentrations of cibenzoline alone appears to be sufficient.
  • Clinical and Basic Evaluation of Side Effect for Skin Irritation among Three Nitrate Patch Preparations for Ischemic Heart Disease., MORII MEGUMI, UENO KAZUYUKI, AKAI HIROKO, TSUJI MIRI, TAKADA MASAHIRO, TAKADA MITSUTAKA, SHIBAKAWA MASAHIKO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 25, 5, 495, 501,   1999 , 10.5649/jjphcs1975.25.495, http://ci.nii.ac.jp/naid/130004299722
    Summary:The side effects of nitrate patch preparations for ischemic heart disease were evaluated in both inpatients and volunteers. Therefore, a removal test of horny cells, adhesion test and down rolling ball (tack) test were all studied to clarify the pharmaceutical characteristics of these preparations. As a result, the score of the skin irritation of the NitrodermTTS<SUP>®</SUP> preparation was significantly higher than that for the other two preparations (Antup<SUP>®</SUP> and Frandol tape S<SUP>®</SUP> preparation).<BR>No correlations were observed between skin irritation and the amount of horny cells removed by the NitrodermTTS<SUP>®</SUP>. The Antup<SUP>®</SUP> preparation was the strongest for the adhesion test. However, the NitrodermTTS<SUP>®</SUP> preparation was the strongest for the tack test. These findings suggest that one reason for the increased skin irritation of NitrodermTTS<SUP>®</SUP> may be due to its high degree tack influence.
  • A Simple Assay for Amiodarone and Desethylamiodarone and its Clinical Application., MASAKI KOICHI, UENO KAZUYUKI, TSUJI MIRI, HIRAKI KIYOKAZU, TAKADA MITSUTAKA, KAMAKURA SHIRO, SHIBAKAWA MASAHIKO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 25, 1, 28, 33,   1999 , 10.5649/jjphcs1975.25.28, http://ci.nii.ac.jp/naid/130004299679
    Summary:A simple reverse-phase high-performance liquid chromatographic (HPLC) assay for the measurement of amiodarone and its metabolite, desethylamiodarone in the serum was established. The ODS-2 column was used and the absorbance of the effluent from the column at 254 nm was measured. The standard curves for amiodarone and desethylamiodarone were linear up to 5μg/ml. The coefficent of variation (CV) was within 10% at a concentration of 100 ng/ml, and the CV of the intra-and interday variation was within 10% at concentrations of 0.25, 0.5 and 1μg/ml, respectively. These results suggest that the limit of detection is 100 ng/ml for amiodarone and desethylamiodarone, and this assay is thus considered to be a reliable method in clinical practice. On the other hand, the serum amiodarone and desethylamiodarone concentrations were measured in 10 inpatients who received amiodarone for at least 1 month. No significant correlation was observed between the doses and serum drug concentrations. There findings therefore suggest that TDM (Therapeutic Drug Monitoring) should be performed on anyone taking amiodarone.
  • A Case of Hepatic Failure Due to the Administration of Warfarin., HASHIMOTO HIROSHI, UENO KAZUYUKI, HIRAKI KIYOKAZU, TAKADA MITSUTAKA, MATSUO HIROSHI, SHIBAKAWA MASAHIKO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 25, 1, 60, 64,   1999 , 10.5649/jjphcs1975.25.60, http://ci.nii.ac.jp/naid/130004299684
    Summary:A 61-year-old woman weighting 57.9 kg was hospitalized with deep vein thrombosis. She received warfarin therapy. At first 2 mg/day of warfarin was administered for five days while from the 6 th day the dose was increased to 3 mg/day. From the 8 th day the dose was increased to 4 mg/day. Although the GOT and GPT value was within the normal range before the warfarin therapy was started, on the 5 th day after the therapy was started the GOT and GPT levels were 68 and 61 Iu/l, respectively, while on the 12 th day the GOT and GPT had increased even more (99 and 212). We consider such hepatic evidence to be due to the administration of warfarin and its administration was thus stopped. On the 4 th day after warfarin was stopped the GOT and GPT levels decreased to 55 and 128, respectively, and after that it decreased even more. Both the GOT and GPT decreased to the normal range within one month. On the other hand, in order to evaluate an allergy to warfarin, a patch test of warfarin was examined, however, the results of the test was negative. No reports of hepatic failure due to the administration of warfarin could be found on Medline from 1966 to February 1998. These results suggest this case to be a very rare one, however, further study is called for in the future.
  • Reports of Patients Consultation, Part 1 : A Case Report of Digoxin Toxicity Presented with Visual Disturbance, MORII MEGUMI, UENO KAZUYUKI, TAKADA MITSUTAKA, TAKARADA SHIGEHO, KAMAKURA SHIRO, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 24, 6, 683, 686,   1998 12 10 , 10.5649/jjphcs1975.24.683, http://ci.nii.ac.jp/naid/110001799805
    Summary:A 65-year-old woman inpatient had been administered methyldigoxin, verapamil and warfarin for the treatment of artrial fibrillation and mitral stenosis disease. About six day after the start of treatment the dose of methyldigoxin was increased from 0.1 to 0.2 mg/day and, as a result, a visual disturbance occurred. However, no other side effects of digoxin were not presented and the serum digoxin concentration was found to be within the normal therapeutic range. The dose was decreased and about five days later, her side effects disappeared. This case suggested that such side effects of digoxin as visual disturbance therefore need to be carfully monitored when ever digoxin and verapamil, which is one of the inhibitors of P-glycoprotein, are coadministered.
  • Effect of Age on the Kinds of Drugs Prescribed to Outpatients at the National Cardiovascular Center, UENO KAZUYUKI, ISEKI JYUNJI, KAWAZOE ATSUKO, NISHIOKA JYUNKO, HASHIMOTO HIROSHI, TAKADA MITSUTAKA, SHIBAKAWA MASAHIKO, Journal of the Nippon Hospital Pharmacists Association, 24, 6, 745, 749,   1998 12 10 , 10.5649/jjphcs1975.24.745, http://ci.nii.ac.jp/naid/110001799814
    Summary:The relationship between the kinds of drugs prescribed and age was investigated in 20990 outpatients (males ; 11,716, females ; 9,274) over the age of twenty at our hospital. No medicines for external application except for patch preparations for ischemic heart disease and injection preparations were caluculated in this studies. The following results were obtained : both preparation for the male and female outpatients increased with age. Although the mean kinds of drugs for patients in their twenties was 2.6, the mean kinds in patients in their eighties was 5.7. In addition, the number of outpatients with diabetes was increased significantly with age than in those without diabetes.
  • The Effect of either Cibenzoline or Disopyramide Administration on Fasting Blood Sugar, TAKADA MITSUTAKA, ASADA YOKO, NAGAI SATOKO, SHIBAKAWA MASAHIKO, KANAZAWA AKIO, HARANO YUTAKA, Journal of the Nippon Hospital Pharmacists Association, 24, 5, 541, 547,   1998 10 10 , 10.5649/jjphcs1975.24.541, http://ci.nii.ac.jp/naid/110001799774
    Summary:Hypoglycemia has been reported to occur in some patients undergoing treatment with such class la antiarrhythmic drugs as cibenzoline and disopyramide. The changes in the fasting blood sugar (FBS) levels were surveyed in 251 outpatients before and after treatment with cibenzoline and in 416 outpatients before and after treatment with disopyramide at the National Cardiovascular Center from October to November 1996. The FBS before and after treatment with cibenzoline in 43 patients and with disopyramide in 42 patients were thus retrospectively analyzed. Cibenzoline treatment significantly reduced the FBS level (from 98.6±14.2 to 92.1±17.0 mg/dl, p< 0.05), whereas disopyramide treatment did not significantly change the FBS level. Furthermore, in patients receiving cibenzoline treatment, a significant reduction of the FBS was also observed in elderly patients (>65 years), in patients receiving high doses (>300 mg/day), and in patients with a reduced renal function (BUN : >20 mg/dl or Scr : M>1.3, F>1.0 mg/dl). These results suggest that close attention should thus be paid to the occurrence of cibenzoline-induced hypoglycemia in eiderly patients, those receiving high doses and those with a reduced renal function.
  • Reports of Patients Consultation, Part 1 A Case Report of Digoxin Toxicity Presented with Visual Disturbance., MORII MEGUMI, UENO KAZUYUKI, TAKADA MITSUTAKA, TAKARADA SHIGEHO, KAMAKURA SHIRO, SHIBAKAWA MASAHIKO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 24, 6, 683, 686,   1998 , 10.5649/jjphcs1975.24.683, http://ci.nii.ac.jp/naid/130004299659
    Summary:A 65-year-old woman inpatient had been administered methyldigoxin, verapamil and warfarin for the treatment of artrial fibrillation and mitral stenosis disease. About six day after the start of treatment the dose of methyldigoxin was increased from 0.1 to 0.2 mg/day and, as a result, a visual disturbance occurred. However, no other side effects of digoxin were not presented and the serum digoxin concentration was found to be within the normal therapeutic range. The dose was decreased and about five days later, her side effects disappeared. This case suggested that such side effects of digoxin as visual disturbance therefore need to be carfully monitored when ever digoxin and verapamil, which is one of the inhibitors of P-glycoprotein, are coadministered.
  • Survey on Job Functions of Hospital Pharmacists in Kansai Area, Murakami Etsuko, Kawabata Atsufumi, Iwaki Masahiro, Ogiso Taro, Suzuki Shigeo, Oda Yasuo, Kuroda Ryotaro, Kakehi Kazuaki, Mishima Masahiko, Takada Mitsutaka, Bulletin of Pharmaceutical Research and Technology Institute, 6, 93, 103,   1997 , http://ci.nii.ac.jp/naid/110000560682
  • Evaluation of fluorescent polarization immunoassay in determination of blood level of aprindine., 高田 充隆, 福井 啓祐, 小林 雅典, 大石 輝樹, 川本 忠正, 山本 雅彦, 河南 昌樹, 松山 榮一, Jpn. J. Clin. Pharmacol. Ther., 20, 1, 195, 196,   1989 , 10.3999/jscpt.20.195, http://ci.nii.ac.jp/naid/130002046497
  • Evaluation of the fluorescence polarization immunoassay method for determination of serum aprindine concentration, M. Takada, K. Fukui, M. Kobayashi, Y. Watanabe, T. Kawamoto, M. Yamamoto, Japanese Journal of Hospital Pharmacy, 14, 4, 256, 261,   1988 , 10.5649/jjphcs1975.14.256, http://ci.nii.ac.jp/naid/130004894596
    Summary:The fluorescence polarization immunoassay (FPIA) method for the determination of serum aprindine (AP) concentrations was evaluated by comparison with HPLC method.The withinrun precision of FPIA method was 4.6-6.8% as the coefficient of variation (C. V.).The C.V. value of between-run precision was 4.1-8.7%.The values of serum AP concentrations determined by FPIA method correlated well with those determined by HPLC method.The correlation coefficient was 0.987.FPIA method, reliable, simple and rapid, seems to be a useful method for routine clinical use.
  • Evaluation of the fluorescence polarization immunoassay method for determination of serum aprindine concentration, M. Takada, K. Fukui, M. Kobayashi, Y. Watanabe, T. Kawamoto, M. Yamamoto, Japanese Journal of Hospital Pharmacy, 14, 4, 256, 261,   1988 , 10.5649/jjphcs1975.14.256, http://ci.nii.ac.jp/naid/110001798547
    Summary:The fluorescence polarization immunoassay (FPIA) method for the determination of serum aprindine (AP) concentrations was evaluated by comparison with HPLC method. The within-run precision of FPIA method was 4.6-6.8% as the coefficient of variation (C.V.). The C.V. value of between-run precision was 4.1-8.7%. The values of serum AP concentrations determined by FPIA method correlated well with those determined by HPLC method. The correlation coefficient was 0.987. FPIA method, reliable, simple and rapid, seems to be a useful method for routine clinical use.
  • Effects of bile acid preparations on lipase activity, M. Takada, H. Murakami, T. Akano, Japanese Journal of Hospital Pharmacy, 11, 5, 387, 391,   1985 , 10.5649/jjphcs1975.11.387, http://ci.nii.ac.jp/naid/110001798127
    Summary:The effects of chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) on enzymic activity of lipase, as well as the relationship between the lipase activity and the concentration of bile acids in bile, were studied. In the presence of bile administered CDCA, the lipase activity was enhanced significantly. A correlation between the lipase activity and the common logarithm of the concentration of total bile acid and CDCA in bile was observed, correlation coefficients being 0.723 (n=30) and 0.732 (n=30), respectively. In addition, it was observed from the result of multiple regression that CDCA and UDCA increased the lipase activity.
  • Effect of Food on the Prolonged Activity of L-Keflex, UENO KAZUYUKI, MORITA TOSHIHIKO, TAKADA MITSUTAKA, NAKATA IZUMI, FUKUI SUMIO, OZAKI TERUYOSHI, Journal of the Nippon Hospital Pharmacists Association, 9, 1, 53, 56,   1983 02 20 , http://ci.nii.ac.jp/naid/110001797138
    Summary:L-Keflex is a sustained-release preparation of cephalexin (CEX). It is composed of non-enteric coated granules and enteric coated ones at the potency ratio of 3 to 7. The effect of food on the prolonged activity of L-Keflex was investigated in six volunteers by a cross-over method. 1000 mg of L-Keflex was orally administered to the volunteers after usual meal or light meal. The followings are the results of the study : In both groups of usual and light meals, L-Keflex level of more than 3.13 μg/ml in serum lasted for about 8 hours. However, the serum level pattern in the light meal group was apparently different from that in the usual meal group. The former group showed 2 peaks of serum levels, whereas the latter one gave only a single peak.
  • Effect of Food on the Prolonged Activity of L-Keflex, UENO KAZUYUKI, MORITA TOSHIHIKO, TAKADA MITSUTAKA, NAKATA IZUMI, FUKUI SUMIO, OZAKI TERUYOSHI, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 9, 1, 53, 56,   1983 , http://ci.nii.ac.jp/naid/130004299953
    Summary:L-Keflex is a sustained-release preparation of cephalexin (CEX). It is composed of non-enteric coated granules and enteric coated ones at the potency ratio of 3 to 7. The effect of food on the prolonged activity of L-Keflex was investigated in six volunteers by a cross-over method. 1000 mg of L-Keflex was orally administered to the volunteers after usual meal or light meal. The followings are the results of the study: In both groups of usual and light meals, L-Keflex level of more than 3.13μg/ml in serum lasted for about 8 hours. However, the serum level pattern in the light meal group was apparently different from that in the usual meal group. The former group showed 2 peaks of serum levels, whereas the latter one gave only a single peak.
  • Comparative Study of Commercial FAD Injections by High-Performance Liquid Chromatograhy, HIRANO YOSHINOBU, TANAKA GIICHI, HASEGAWA KENZI, HASHIZUME AKIHITO, TAKATA MITUTAKA, NAKATA IZUMI, SAYO MASAHIRO, NIO NAGATOMO, Journal of the Nippon Hospital Pharmacists Association, 8, 2, 133, 137,   1982 06 20 , http://ci.nii.ac.jp/naid/110001796922
    Summary:Eight types of the commercial FAD injection were studied from the pharmaceutical viewpoint with high-performance liquid chromatography (HPLC). It was found that most of the commercial FAD injections had lower content of FAD than their labeled amount. FAD was detected from the HPLC peaks whether it is manufactured by synthetic method or fermentation method.
  • Comparative Study of Commercial FAD Injections by High-Performance Liquid Chromatography, HIRANO YOSHINOBU, TANAKA GIICHI, HASEGAWA KENZI, HASHIZUME AKIHITO, TAKATA MITUTAKA, NAKATA IZUMI, SAYO MASAHIRO, NIO NAGATOMO, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 8, 2, 133, 137,   1982 , http://ci.nii.ac.jp/naid/130004103315
    Summary:Eight types of the commercial FAD injection were studied from the pharmaceutical viewpoint with high-performance liquid chromatography (HPLC). lt was found that most of the commercial FAD injections had lower content of FAD than their labelled amount. FAD was detected from the HPLC peaks whether it is manufactured by synthetic method or fermentation method.
  • Effects of Bile Acid on Lipase Activity of Digestive Enzyme Preparations, TAKADA MITUTAKA, SATOU MAKOTO, HASHIZUME AKITO, HIRANO YOSHINOBU, OZAKI TERUYOSHI, Journal of the Nippon Hospital Pharmacists Association, 7, 5, 265, 268,   1981 12 20 , http://ci.nii.ac.jp/naid/110001796878
    Summary:It has been widely known that bile acids increase lipase activity, and the lipase activity of various digestive enzyme preparations has been reported. Clinically, bile acids have often been administered in combination with digestive enzyme preparations. In this study, effects of three bile salts (sodium ursodesoxycholate, sodium chenodesoxycholate and sodium dehydrocholate) on the lipase activity of digestive enzyme preparations were examined. When soybean oil emulsified by polyvinyl alcohol was used as a substrate, these bile salts increased their lipase activity. In the presence of sodium chenodesoxycholate, sodium ursodesoxycholate and sodium dehydrocholate, digestive enzyme preparations increased their lipase activity by 2.2, 1.5 and 1.3 times, respectively, stronger than that in the absence of these bile salts. When soybean oil was used as a substrate, only sodium chenodesoxycholate increased the lipase activity.
  • Effects of Bile Acids on Lipase Activity of Digestive Enzyme Preparations, TAKADA MITUTAKA, SATOU MAKOTO, HASHIZUME AKITO, HIRANO YOSHINOBU, OZAKI TERUYOSHI, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 7, 5, 265, 268,   1981 , http://ci.nii.ac.jp/naid/130004299914
    Summary:It has been widely known that bile acids increase lipase activity, and the lipase activity of various digestive enzyme preparations has been reported. Clinically, bile acids have often been administered in combination with digestive enzyme preparations. In this study, effects of three bile salts (sodium ursodesoxycholate, sodium chenodesoxycholate and sodium dehydrocholate) on the lipase activity of digestive enzyme preparations were examined. When soybean oil emulsified by polyvinyl alcohol was used as a substrate, these bile salts increased their lipase activity. In the presence of sodium chenodesoxycholate, sodium ursodesoxycholate and sodium dehydrocholate, digestive enzyme preparations increased their lipase activity by 2.2, 1.5 and 1.3 times, respectively, stronger than that in the absence of these bile salts. When soybean oil was used as a substrate, only sodium chenodesoxycholate increased the lipase activity.