24 results on '"Shunsaku Nakagawa"'
Search Results
2. Therapeutic Outcome of Inhalation-support Team Collaboration with Hospital and Community Pharmacists
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Susumu Sato, Kanae Hokoyama, Sachio Fukatsu, Kazuo Matsubara, Toyohiro Hirai, Makoto Terao, Hisako Matsumoto, Yuko Yoshida, Mitsuhiro Sugimoto, Hiroki Yamamoto, Atsushi Yonezawa, Noriaki Kitada, Kazuya Tanimura, Kayoko Asakura, and Shunsaku Nakagawa
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medicine.medical_specialty ,Inhalation ,business.industry ,medicine ,Pharmacology (medical) ,Intensive care medicine ,business ,Outcome (game theory) - Published
- 2020
3. Potential application of measuring serum infliximab levels in rheumatoid arthritis management: A retrospective study based on KURAMA cohort data
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Motomu Hashimoto, Miyuki Nakamura, Kosaku Murakami, Masaya Denda, Kotaro Itohara, Atsushi Yonezawa, Takayuki Nakagawa, Koichi Murata, Ryu Watanabe, Masao Tanaka, Sho Masui, Kazuo Matsubara, Hiromu Ito, Noriko Iwamoto, Satoshi Imai, Takashi Shimada, Kazuto Nakae, Shunsaku Nakagawa, Makoto Hayakari, Kotoko Yokoyama, and Yasuaki Ikemi
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Male ,Physiology ,Biochemistry ,Steroid Therapy ,Arthritis, Rheumatoid ,Japan ,Animal Cells ,Materials Physics ,Tandem Mass Spectrometry ,Red Blood Cells ,Dose escalation ,Medicine and Health Sciences ,Multidisciplinary ,medicine.diagnostic_test ,Pharmaceutics ,Physics ,Therapeutic Drug Monitoring ,Middle Aged ,C-Reactive Proteins ,Glucocorticoid Therapy ,Body Fluids ,Blood ,Treatment Outcome ,Rheumatoid arthritis ,Antirheumatic Agents ,Cohort ,Physical Sciences ,Medicine ,Female ,Cellular Types ,Anatomy ,Sedimentation ,medicine.drug ,Research Article ,Adult ,medicine.medical_specialty ,Science ,Immunology ,Materials Science ,Rheumatoid Arthritis ,Autoimmune Diseases ,Pharmacokinetics ,Rheumatology ,Drug Therapy ,Internal medicine ,medicine ,Oral diseases ,Humans ,Aged ,Retrospective Studies ,Pharmacology ,Blood Cells ,Receiver operating characteristic ,business.industry ,Arthritis ,Biology and Life Sciences ,Proteins ,Retrospective cohort study ,Cell Biology ,medicine.disease ,Infliximab ,Therapeutic drug monitoring ,Clinical Immunology ,Clinical Medicine ,business ,Chromatography, Liquid - Abstract
Background Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). On the other hand, in some patients, the efficacy of IFX therapy is not adequate, or gradually diminishes with the lapse of the treatment. Although previous studies have reported a positive relationship between serum IFX levels and therapeutic efficacy, the potential application of IFX therapeutic drug monitoring (TDM) in clinical practice remains unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Methods Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance, KURAMA,cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. Results Out of the 311 RA patients who received IFX therapy, 41 were eligible for analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.4 µg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the High-IFX group (n = 31) than in the Low-IFX group (n = 10). Conversely, at the maximum effect point, when DAS28-ESR (the 28 joint disease activity score incorporating erythrocyte sedimentation rate) was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the Low- and High-IFX groups. Conclusions In clinical practice, IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement. However, IFX TDM could facilitate the identification of secondary non-responders, and in turn, proper IFX use.
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- 2021
4. Antibiotic-induced microbiome depletion alters renal glucose metabolism and exacerbates renal injury after ischemia-reperfusion injury in mice
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Yuika Osada, Shunsaku Nakagawa, Atsushi Yonezawa, Satoshi Imai, Aimi Shimazaki, Kanako Ishibe, Kazuo Matsubara, Kotaro Itohara, Shota Takao, and Takayuki Nakagawa
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Blood Glucose ,Male ,Physiology ,medicine.drug_class ,Antibiotics ,Ischemia ,Levofloxacin ,Pharmacology ,Carbohydrate metabolism ,Kidney ,Mice ,Renal injury ,Vancomycin ,Pyruvic Acid ,medicine ,Animals ,Microbiome ,Mice, Inbred BALB C ,business.industry ,Acute Kidney Injury ,medicine.disease ,Anti-Bacterial Agents ,Gastrointestinal Microbiome ,Glucose ,Gluconeogenesis ,Gene Expression Regulation ,Reperfusion Injury ,Glucose-6-Phosphatase ,business ,Reperfusion injury ,Phosphoenolpyruvate Carboxykinase (ATP) - Abstract
Recent studies have revealed the impact of antibiotic-induced microbiome depletion (AIMD) on host glucose homeostasis. The kidney has a critical role in systemic glucose homeostasis; however, information regarding the association between AIMD and renal glucose metabolism remains limited. Hence, we aimed to determine the effects of AIMD on renal glucose metabolism by inducing gut microbiome depletion using an antibiotic cocktail (ABX) composed of ampicillin, vancomycin, and levofloxacin in mice. The results showed that bacterial 16s rRNA expression, luminal concentrations of short-chain fatty acids and bile acids, and plasma glucose levels were significantly lower in ABX-treated mice than in vehicle-treated mice. In addition, ABX treatment significantly reduced renal glucose and pyruvate levels. mRNA expression levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the renal cortex were significantly higher in ABX-treated mice than in vehicle-treated mice. We further examined the impact of AIMD on the altered metabolic status in mice after ischemia-induced kidney injury. After exposure to ischemia for 60 min, renal pyruvate concentrations were significantly lower in ABX-treated mice than in vehicle-treated mice. ABX treatment caused a more severe tubular injury after ischemia-reperfusion. Our findings confirm that AIMD is associated with decreased pyruvate levels in the kidney, which may have been caused by the activation of renal gluconeogenesis. Thus, we hypothesized that AIMD would increase the vulnerability of the kidney to ischemia-reperfusion injury.
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- 2021
5. First-in-Human Evaluation of Positron Emission Tomography/Computed Tomography With [18F]FB(ePEG12)12-Exendin-4: A Phase 1 Clinical Study Targeting GLP-1 Receptor Expression Cells in Pancreas
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Naotaka Fujita, Norio Harada, Masahiro Ono, Hideo Saji, Hiroyuki Watanabe, Kohei Sano, Keita Hamamatsu, Nobuya Inagaki, Tsuneo Saga, Atsushi Murakami, Mitsuharu Hirai, Yoichi Shimizu, Kaori Togashi, Takaaki Murakami, Takayoshi Ishimori, Hiroyuki Kimura, Shunsaku Nakagawa, Hiroshi Nakamura, Hiroyuki Fujimoto, Yuji Nakamoto, and Kentaro Toyoda
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Adult ,Blood Glucose ,Male ,Fluorine Radioisotopes ,Endocrinology, Diabetes and Metabolism ,Standardized uptake value ,Hypoglycemia ,Diseases of the endocrine glands. Clinical endocrinology ,β-cell imaging ,Glucagon-Like Peptide-1 Receptor ,Young Adult ,Endocrinology ,Diabetes mellitus ,Positron Emission Tomography Computed Tomography ,exendin-4 ,medicine ,Dosimetry ,Humans ,Tissue Distribution ,first-in-human study ,Pancreas ,Glucagon-like peptide 1 receptor ,Original Research ,medicine.diagnostic_test ,business.industry ,RC648-665 ,medicine.disease ,Healthy Volunteers ,medicine.anatomical_structure ,PET ,Positron emission tomography ,Cohort ,Exenatide ,glucagon-like peptide-1 receptor (GLP-1R) ,Radiopharmaceuticals ,business ,Nuclear medicine - Abstract
Pancreatic β-cell mass (BCM) has a central importance in the pathophysiology of diabetes mellitus. Recently, pancreatic β-cell-specific imaging, especially positron emission tomography (PET) with exendin-based probes, has emerged for non-invasive evaluation of BCM. We developed a novel exendin-based probe labeled with fluorine-18, [18F]FB(ePEG12)12-exendin-4 (18F-Ex4) for PET imaging. We subsequently conducted a first-in-human phase 1 study of 18F-Ex4 PET/computed tomography (CT) and investigated the safety and utility for visualizing the pancreas. Six healthy male subjects were enrolled in this study. A low dose (37.0 MBq) of 18F-Ex4 PET/CT was administered (first cohort: n = 2), and subsequently a higher dose (74.0 MBq) was administered (second cohort: n = 4). In the first and second cohorts, 38.6 ± 4.8 and 71.1 ± 4.8 MBq of 18F-Ex4 were administered, respectively. No serious adverse events were observed in both groups. Only one participant in the first cohort showed transient hypoglycemia during the PET scans. 18F-Ex4 PET/CT successfully visualized the pancreas in all participants. The mean standardized uptake value of the pancreas was found to be higher than that in the surrounding organs, except for the bladder and kidney, during the observation. Dosimetry analyses revealed the effective systemic doses of 18F-Ex4 as 0.0164 ± 0.0019 mSv/MBq (first cohort) and 0.0173 ± 0.0020 mSv/MBq (second cohort). 18F-Ex4 PET/CT demonstrated the safety and utility for non-invasive visualization of the pancreas in healthy male subjects. 18F-Ex4 is promising for clinical PET imaging targeting pancreatic β cells.
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- 2021
6. Risk factors of breakthrough aspergillosis in lung transplant recipients receiving itraconazole prophylaxis
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Kotaro Itohara, Shunsaku Nakagawa, Takayuki Nakagawa, Yuya Matsuda, Hiroshi Date, Atsushi Yonezawa, Yuko Yoshida, Daisuke Nakajima, Tomohiro Terada, Yuki Yamamoto, Satona Tanaka, Yoshiki Katada, Kazuo Matsubara, Satoshi Imai, and Miki Nagao
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Microbiology (medical) ,medicine.medical_specialty ,Itraconazole ,medicine.medical_treatment ,Patient demographics ,Aspergillosis ,Antiviral Agents ,Risk Factors ,Internal medicine ,Epidemiology ,medicine ,Lung transplantation ,Humans ,Pharmacology (medical) ,Risk factor ,Ganciclovir ,Lung ,Cause of death ,Aged ,Retrospective Studies ,business.industry ,medicine.disease ,Transplant Recipients ,Infectious Diseases ,medicine.anatomical_structure ,Case-Control Studies ,business ,medicine.drug - Abstract
Invasive Aspergillus infection (IA) in lung transplantation can result in poor outcomes. Itraconazole has been shown to be effective for fungal prophylaxis in lung transplant recipients. However, IA remains a major cause of death after lung transplantation. Therefore, we aimed to clarify the risk factors for IA on itraconazole prophylaxis.We examined 120 recipients to uncover their IA epidemiology, clinical characteristics, and outcomes. In addition, a case-control study was performed to identify risk factors of IA.Of the 120 patients, 12 developed IA under itraconazole prophylaxis. The patient demographics and clinical characteristics were compared among the following two groups: IA group, 12 patients, and control group, 108 patients. Significant differences were observed in age (p = 0.004), history of interstitial pneumonia (p = 0.032), and CMV infection (p 0.001) between the groups. Before the onset of IA, 92% (11/12) of the patients received itraconazole with trough concentrations above the therapeutic range. IA developed at 272.9 ± 114.1 days after lung transplantation. Of the 12 patients who developed IA, 66.7% (8/12) had early cessation of cytomegalovirus (CMV) prophylaxis due to toxicity of valganciclovir, as follows: leukocytopenia in 4 patients, and renal dysfunction in 4 patients. Of the 8 patients who stopped valganciclovir, 75% (6/8) developed CMV infection subsequently.This study suggests that older age, history of interstitial pneumonia, and CMV infection may be important risk factors for IA on itraconazole prophylaxis. These results may help clinicians optimize prophylactic strategies for IA.
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- 2021
7. Extrapolation of physiologically based pharmacokinetic model for tacrolimus from renal to liver transplant patients
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Osamu Ogawa, Tomohiro Omura, Kaoru Sakai, Shunsaku Nakagawa, Atsuro Sawada, Kotaro Itohara, Kazuo Matsubara, Kojiro Taura, Akira Tochio, Ikuko Yano, Satoshi Imai, Atsushi Yonezawa, Takayuki Nakagawa, and Takashi Kobayashi
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Physiologically based pharmacokinetic modelling ,medicine.medical_specialty ,Special populations ,Population ,Urology ,Pharmaceutical Science ,Kidney ,Models, Biological ,Tacrolimus ,Pharmacokinetics ,Medicine ,Humans ,Pharmacology (medical) ,education ,Sensitivity analyses ,Pharmacology ,education.field_of_study ,business.industry ,Kidney Transplantation ,Liver Transplantation ,surgical procedures, operative ,Renal transplant ,Transplant patient ,business ,Immunosuppressive Agents - Abstract
Physiologically based pharmacokinetic (PBPK) modeling is useful for evaluating differences in drug exposure among special populations, but it has not yet been employed to evaluate the absorption process of tacrolimus. In this study, we developed a minimal PBPK model with a compartmental absorption and transit model for renal transplant patients using available data in the literature and clinical data from our hospital. The effective permeability value of tacrolimus absorption and parameters for the single adjusting compartment were optimized via sensitivity analyses, generating a PBPK model of tacrolimus for renal transplant patients with good predictability. Next, we extrapolated the pharmacokinetics of tacrolimus for liver transplant patients by changing the population demographic parameters of the model. When the physiological parameters of a population with normal liver function were changed to those of a population with impaired hepatic function (Child-Pugh class A) in the constructed renal transplant PBPK model, the predicted tacrolimus concentrations were consistent with the observed concentrations in liver transplant patients. In conclusion, the constructed tacrolimus PBPK model for renal transplant patients could predict the pharmacokinetics in liver transplant patients by slightly reducing the hepatic function, even at three weeks post-transplantation.
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- 2021
8. A Minimal Physiologically-Based Pharmacokinetic Model for Tacrolimus in Living-Donor Liver Transplantation: Perspectives Related to Liver Regeneration and the cytochrome P450 3A5 (CYP3A5) Genotype
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Toshimi Kaido, Atsushi Yonezawa, Shunsaku Nakagawa, Shinji Uemoto, Kazuo Matsubara, Kotaro Itohara, Ikuko Yano, Hideaki Okajima, Miwa Uesugi, and Tetsunori Tsuzuki
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Male ,Genotype ,Metabolic Clearance Rate ,medicine.medical_treatment ,Pharmacology ,Liver transplantation ,Models, Biological ,Tacrolimus ,Article ,Pharmacokinetics ,Living Donors ,medicine ,Cytochrome P-450 CYP3A ,Humans ,Pharmacology (medical) ,Postoperative Period ,CYP3A5 ,business.industry ,Research ,lcsh:RM1-950 ,Articles ,Liver regeneration ,Liver Regeneration ,Liver Transplantation ,Bioavailability ,Intestines ,surgical procedures, operative ,lcsh:Therapeutics. Pharmacology ,Liver ,Modeling and Simulation ,Female ,Liver function ,business ,Immunosuppressive Agents - Abstract
In adult patients after living‐donor liver transplantation, postoperative days and the cytochrome P450 3A5 (CYP3A5) genotype are known to affect tacrolimus pharmacokinetics. In this study, we constructed a physiologically‐based pharmacokinetic model adapted to the clinical data and evaluated the contribution of liver regeneration as well as hepatic and intestine CYP3A5 genotypes on tacrolimus pharmacokinetics. As a result, liver function recovered immediately and affected the total body clearance of tacrolimus only during a limited period after living‐donor liver transplantation. The clearance was about 1.35‐fold higher in the recipients who had a liver with the CYP3A5*1 allele than in those with the CYP3A5*3/*3 genotype, whereas bioavailability was ~0.7‐fold higher in the recipients who had intestines with the CYP3A5*1 allele than those with CYP3A5*3/*3. In conclusion, the constructed physiologically‐based pharmacokinetic model clarified that the oral clearance of tacrolimus was affected by the CYP3A5 genotypes in both the liver and intestine to the same extent.
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- 2019
9. Pharmacokinetics and Pharmacodynamics of Once-Daily Tacrolimus Compared With Twice-Daily Tacrolimus in the Early Stage After Living Donor Liver Transplantation
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Satohiro Masuda, Sachiyo Hashi, Shinji Uemoto, Mitsuhiro Sugimoto, Sachio Fukatsu, Masahide Fukudo, Toshimi Kaido, Atsushi Yonezawa, Shunsaku Nakagawa, Mami Iwasaki, Yuki Yamamoto, Ikuko Yano, and Kazuo Matsubara
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Urology ,living donor liver transplantation(LDLT) ,once-daily formulation(OD) ,030230 surgery ,Peripheral blood mononuclear cell ,Drug Administration Schedule ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Living Donors ,Medicine ,Humans ,Pharmacology (medical) ,Stage (cooking) ,tacrolimus ,calcineurin(CN)activity ,Pharmacology ,business.industry ,Immunosuppression ,Middle Aged ,Tacrolimus ,Phosphoric Monoester Hydrolases ,Liver Transplantation ,Calcineurin ,surgical procedures, operative ,Pharmacodynamics ,Area Under Curve ,Leukocytes, Mononuclear ,030211 gastroenterology & hepatology ,Female ,Living donor liver transplantation ,business ,pharmacokinetics ,Immunosuppressive Agents - Abstract
Background: This study investigates the pharmacokinetics and pharmacodynamics of tacrolimus using the once-daily (OD) formulation in the early stage after living donor liver transplantation (LDLT) in comparison with those using the twice-daily (TD) formulation. Methods: Nine patients undergoing primary LDLT and treated with the OD tacrolimus formulation were included. The trough blood concentration (C0) of tacrolimus was monitored every day for 3 weeks after LDLT. A time course study of the blood tacrolimus concentrations and calcineurin (CN) phosphatase activity in peripheral blood mononuclear cells was performed 3 weeks after LDLT. Pharmacokinetic and pharmacodynamic parameters were compared with previously reported data using the TD formulation. Results: The interindividual variability in the daily dose of tacrolimus was significantly larger in the OD formulation than in the TD formulation (P < 0.001). In the time course study, the tacrolimus blood concentrations at 4, 8, and 12 hours after administration and the area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) in the OD group were significantly higher than in the TD group, although the C0 was equivalent. In addition, the C0 was not significantly correlated with the AUC(0-24) in the OD formulation. The apparent clearance and the pharmacodynamic parameters examined were not significantly different between the OD and TD groups. Conclusions: The C0 monitoring of the OD formulation may not be optimal in patients at the early stage after LDLT because the C0 was not correlated with the AUC(0-24). If clinicians target the same C0 using the OD and TD formulations, the exposure of tacrolimus can be higher in the OD formulation, and excessive immunosuppression should be noted. Particular attention should be paid to the patients in the early stage after LDLT in the use of the OD oral formulation of tacrolimus.
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- 2018
10. Pharmacist-physician collaborative care for outpatients with left ventricular assist devices using a cloud-based home medical management information-sharing system: a case report
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Shinichi Nomoto, Asami Sukeishi, Hideo Kanemitsu, Kazuo Matsubara, Yoshiki Katada, Yuki Sato, Kenji Minakata, Momoe Utsumi, Atsushi Yonezawa, Takayuki Nakagawa, Shunsaku Nakagawa, Satoshi Imai, Noriaki Kitada, Katsuyuki Matsumura, and Kenji Minatoya
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medicine.medical_specialty ,Pharmacist ,lcsh:RS1-441 ,Collaborative Care ,Case Report ,Self-testing ,Left ventricular assist device ,Pharmacology (nursing) ,Pharmacy ,030204 cardiovascular system & hematology ,lcsh:Pharmacy and materia medica ,Anticoagulation ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Prothrombin time-international normalized ratio ,CoaguCheck® XS ,medicine ,Pharmacology (medical) ,030212 general & internal medicine ,business.industry ,lcsh:RM1-950 ,Warfarin ,Dilated cardiomyopathy ,medicine.disease ,Cloud-based home management system ,Management information systems ,lcsh:Therapeutics. Pharmacology ,Heart failure ,Emergency medicine ,business ,medicine.drug - Abstract
Background The standard anticoagulation therapy for patients implanted with left ventricular assist devices (LVADs) includes warfarin therapy. We developed a cloud-based home medical management information-sharing system named as LVAD@home. The LVAD@home system is an application designed to be used on iPad tablet computers. This system enables the sharing of daily information between a patient and care providers in real time. In this study, we reported cases of outpatients with LVADs using this system to manage anticoagulation therapy. Case presentation The patient, a man in his 40s with end-stage heart failure owing to non-ischemic dilated cardiomyopathy, underwent LVAD implantation and warfarin was started on postoperative day 1. He started to use LVAD@home to manage warfarin therapy after discharge (postoperative day 47). He sent his data to care providers daily. By using this system, the pharmacist observed his signs of reduced dietary intake 179 days after discharge, and after consulting the physician, told the patient to change the timing of the next measurement earlier than usual. On the next day, the prothrombin time-international normalized ratio increased from 2.0 to 3.0, and thus the dose was decreased by 0.5 mg. Four patients used this system to monitor warfarin therapy from October 2015 to March 2018. In these patients, the time in therapeutic range was 90.1 ± 1.3, which was higher than that observed in previous studies. Additionally, there were no thromboembolic events or bleeding events. Conclusions The cloud-based home management system can be applied to share real-time patient information of factors, including dietary intake that interact with warfarin. It can help to improve long-term anticoagulation outcomes in patients implanted with LVAD.
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- 2021
11. Association of proton pump inhibitors and concomitant drugs with risk of acute kidney injury: a nested case–control study
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Satoshi Imai, Atsushi Yonezawa, Shunsaku Nakagawa, Kotaro Itohara, Yuki Sato, Takayuki Nakagawa, Kazuo Matsubara, Keiko Ikuta, and Kenji Momo
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Male ,medicine.medical_specialty ,medicine.drug_class ,Epidemiology ,Antibiotics ,030232 urology & nephrology ,acute renal failure ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Japan ,law ,Risk Factors ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Clinical pharmacology ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,Acute kidney injury ,Absolute risk reduction ,toxicity ,Proton Pump Inhibitors ,General Medicine ,Acute Kidney Injury ,medicine.disease ,Pharmaceutical Preparations ,Concomitant ,Case-Control Studies ,Cohort ,Nested case-control study ,Medicine ,Female ,clinical pharmacology ,business - Abstract
ObjectivesThis study aimed to assess whether the combined use of proton pump inhibitors (PPIs) with non-steroidal anti-inflammatory drugs (NSAIDs) or antibiotics (penicillins, macrolides, cephalosporins or fluoroquinolones) was associated with an increased risk of acute kidney injury (AKI).DesignA nested case–control study.SettingA health insurance claims database constructed by the Japan Medical Data Center.ParticipantsPatients were eligible if they were prescribed a PPI, NSAID and antibiotic at least once between January 2005 and June 2017. The patients who were new PPI users and did not have any history of renal diseases before cohort entry were included (n=219 082). The mean age was 45 and 44% were women.InterventionsCurrent use of PPIs, NSAIDs, or antibiotics.Primary outcome measuresAcute kidney injury.ResultsDuring a mean follow-up of 2.4 (SD, 1.7) years, 317 cases of AKI were identified (incidence rate of 6.1/10 000 person-years). The current use of PPIs was associated with a higher risk of AKI compared with past PPI use (unadjusted OR, 4.09; 95% CI, 3.09 to 5.44). The unadjusted ORs of AKI for the current use of PPIs with NSAIDs, cephalosporins and fluoroquinolones, compared with the current use of PPIs alone, were 3.92 (95% CI, 2.40 to 6.52), 2.57 (1.43 to 4.62) and 3.08 (1.50 to 6.38), respectively. The effects of concurrent use of PPIs with NSAIDs, cephalosporins or fluoroquinolones remain significant in the adjusted model. The analyses on absolute risk of AKI confirmed the results from the nested case–control study.ConclusionsConcomitant use of NSAIDs with PPIs significantly increased the risk for AKI. Moreover, the results suggested that concomitant use of cephalosporins or fluoroquinolones with PPIs was associated with increased risk of incident AKI.
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- 2021
12. Cilostazol is an effective causal therapy for preventing paclitaxel-induced peripheral neuropathy by suppression of Schwann cell dedifferentiation
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Atsushi Yonezawa, Madoka Koyanagi, Takashi Ogihara, Takayuki Nakagawa, Shunsaku Nakagawa, Mamiko Saigo, Akari Moriya, Yui Nakazato, Mayuna Matsumoto, Yuki Iwamitsu, Kazuo Matsubara, and Satoshi Imai
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0301 basic medicine ,Male ,Paclitaxel ,Galectins ,Phosphodiesterase 3 ,Schwann cell ,Breast Neoplasms ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Myelin ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Ganglia, Spinal ,medicine ,Animals ,Humans ,Cyclic adenosine monophosphate ,Rats, Wistar ,Pharmacology ,business.industry ,Phosphodiesterase ,Peripheral Nervous System Diseases ,Blood Proteins ,Cell Dedifferentiation ,Sciatic Nerve ,Cilostazol ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Chemotherapy-induced peripheral neuropathy ,chemistry ,Hyperalgesia ,Cancer research ,Female ,Schwann cell differentiation ,Schwann Cells ,business ,030217 neurology & neurosurgery ,medicine.drug ,Demyelinating Diseases - Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) can lead to discontinuation of chemotherapy and is consequently a serious impediment to effective cancer treatment. Due to our limited understanding of mechanisms underlying the pathogenesis of CIPN, no causal therapy has been approved for relief of this condition. We previously demonstrated that taxanes (paclitaxel and docetaxel) induce Schwann cell dedifferentiation, characterized by increased expression of p75 and galectin-3, ultimately leading to demyelination. These changes appear to be responsible for CIPN pathogenesis. This study was designed to identify a novel candidate therapeutic for CIPN with the ability to suppress paclitaxel-induced Schwann cell dedifferentiation. Given that elevation of cyclic adenosine monophosphate (cAMP) signaling participates in Schwann cell differentiation, we performed immunocytochemical screening of phosphodiesterase (PDE) inhibitors. We found that the PDE3 inhibitor cilostazol strongly promoted differentiation of primary cultures of rat Schwann cells via a mechanism involving cAMP/exchange protein directly activated by cAMP (Epac) signaling. Co-treatment with cilostazol prevented paclitaxel-induced dedifferentiation of Schwann cell cultures and demyelination in a mixed culture of Schwann cells and dorsal root ganglia neurons. Notably, continuous oral administration of cilostazol suppressed Schwann cell dedifferentiation within the sciatic nerve and the development of mechanical hypersensitivity in a mouse model of paclitaxel-related CIPN. Importantly, cilostazol potentiated, rather than inhibited, the anti-cancer effect of paclitaxel on the human breast cancer cell line MDA-MB-231. These findings highlight the potential utility of cilostazol as a causal therapeutic that avoids the development of paclitaxel-related CIPN without compromising anti-cancer properties.
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- 2020
13. Prevalence of and risk factors for adverse events in Alzheimer’s patients receiving anti-dementia drugs in at-home care
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Hiroyuki Nakao, Atsushi Yonezawa, Hirohisa Imai, Ryosuke Kumazawa, Kazuo Matsubara, Takuya Hirai, and Shunsaku Nakagawa
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Male ,Medical Doctors ,Health Care Providers ,Inappropriate Prescribing ,Pharmacists ,0302 clinical medicine ,Japan ,Risk Factors ,Surveys and Questionnaires ,Medicine and Health Sciences ,Prevalence ,030212 general & internal medicine ,Medical Personnel ,Nootropic Agents ,media_common ,Aged, 80 and over ,Multidisciplinary ,Pharmaceutics ,Questionnaire ,Drugs ,Home Care Services ,Professions ,Neurology ,Research Design ,Anxiety ,Medicine ,Female ,medicine.symptom ,Research Article ,Drug ,medicine.medical_specialty ,Drug Research and Development ,Drug Adherence ,Clinical Research Design ,media_common.quotation_subject ,Science ,Pharmacy ,Research and Analysis Methods ,03 medical and health sciences ,Pharmacotherapy ,Drug Therapy ,Alzheimer Disease ,Physicians ,Mental Health and Psychiatry ,medicine ,Dementia ,Humans ,Adverse effect ,Aged ,Retrospective Studies ,Polypharmacy ,Pharmacology ,business.industry ,medicine.disease ,Health Care ,Emergency medicine ,People and Places ,Population Groupings ,Adverse Events ,business ,030217 neurology & neurosurgery - Abstract
Objective The objective of this study was to clarify the types and prevalence of, and the risk factors for, the adverse events that occur in patients receiving anti-dementia drugs. Methods A questionnaire survey was conducted. The respondents were pharmacists who were dispensing anti-dementia drugs. The pharmacists responded to questions about patients who were receiving anti-dementia drugs delivered to them at home by the pharmacists. The survey questions included questions about whether or not the patients experienced adverse reactions to the drugs, about the patients’ background characteristics, about the numbers of drugs the patients were taking when the pharmacists first visited the patients at home, and about the pharmacists’ assessments of the appropriateness of the use of the anti-dementia drugs. Results Data were collected on 3712 patients from 1673 pharmacies in a nationwide survey. Anti-dementia drugs had been prescribed to 863 of these patients; and 801 (92.8%) of these 863 patients were 75 years of age or older, and. confirmed adverse events occurred in 170 (21%) of these 863 patients. The most common adverse event was excitation/anxiety, at 45.1%. A multivariate analysis found that polypharmacy (10 or more types of drugs per day) (P = 0.030), inappropriate use (P = 0.002), and irregular medication use (P = 0.034) were risk factors. Interpretation In order to avoid adverse events when using anti-dementia drugs, doctors and pharmacists should carefully examine the prescribing of multiple medications, assess the applicability of the use of anti-dementia drugs, and investigate how to best manage patients’ drug use.
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- 2020
14. Identification of Biomarkers for Tubular Injury and Interstitial Fibrosis in Chronic Kidney Disease
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Shunsaku Nakagawa
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0301 basic medicine ,Inflammasomes ,Interleukin-1beta ,030232 urology & nephrology ,Gene Expression ,Pharmaceutical Science ,Nephron ,Kidney ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Renal Insufficiency, Chronic ,Myofibroblasts ,Pharmacology ,urogenital system ,business.industry ,Interleukin-18 ,medicine.disease ,IRAK4 ,Fibrosis ,Toll-Like Receptor 2 ,Up-Regulation ,Toll-Like Receptor 4 ,Interleukin-1 Receptor-Associated Kinases ,Kidney Tubules ,030104 developmental biology ,medicine.anatomical_structure ,Myeloid Differentiation Factor 88 ,Cancer research ,Tubulointerstitial fibrosis ,Pericyte ,Pericytes ,business ,Myofibroblast ,Biomarkers ,Signal Transduction ,Kidney disease - Abstract
In chronic kidney disease (CKD), progressive nephron loss causes tubulointerstitial fibrosis and progressive tubular injury. Recent identification of the major cell populations of myofibroblast precursors in the kidney has enabled us to dissect the fibrogenic process after tubular injury. Kidney pericytes are a possible precursor of myofibroblasts, and may be promising targets for treating fibrogenesis. Our recent studies have shown that pericytes activate Toll-like receptor (TLR) 2/4- and myeloid differentiation primary response 88 (MyD88)-dependent proinflammatory signaling in response to renal tubular injury. We also found active roles of inflammasomes in kidney pericytes, leading to interleukin (IL)-1β and IL-18 secretion. Genetic ablation of MyD88 in pericytes, or pharmacological inhibition of MyD88 signaling by an IL-1 receptor-associated kinase 4 (IRAK4) inhibitor, halted interstitial fibrosis after renal tubular injury. Our data indicate that pericytes not only contribute to interstitial fibrosis by aberrant wound-healing responses, but also serve as innate immune surveillance cells that regulate the inflammatory process, exacerbating tubular injury by the release of cytokines and chemokines. On the other hand, our recent study using a microarray analysis aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage in patients with CKD. The results indicated that 5 genes were up-regulated in the kidney of CKD patients, and that their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury. These findings provide important information for the development of diagnostic tools and therapeutic agents for predicting and preventing progressive renal disease.
- Published
- 2017
15. Concentration and Glycoform of Rituximab in Plasma of Patients with B Cell Non-Hodgkin’s Lymphoma
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Kazuo Matsubara, Sho Masui, Yuki Otani, Masaya Denda, Masahiro Tsuda, Tomohiro Omura, Toshiyuki Kitano, Atushi Yonezawa, Mayuko Mori, Ikuko Yano, Shunsaku Nakagawa, Yuki Sato, Takayuki Nakagawa, Makoto Hayakari, Yasuaki Ikemi, Akifumi Takaori-Kondo, Yui Isomoto, and Satoshi Imai
- Subjects
Adult ,Male ,Protein Conformation ,Pharmaceutical Science ,Antineoplastic Agents ,02 engineering and technology ,Pharmacology ,030226 pharmacology & pharmacy ,Plasma ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,immune system diseases ,hemic and lymphatic diseases ,Humans ,Medicine ,Pharmacology (medical) ,B cell ,Aged ,Glycoproteins ,B-Lymphocytes ,biology ,business.industry ,Lymphoma, Non-Hodgkin ,Organic Chemistry ,Middle Aged ,021001 nanoscience & nanotechnology ,medicine.disease ,Lymphoma ,Non-Hodgkin's lymphoma ,medicine.anatomical_structure ,Pharmacodynamics ,Plasma concentration ,biology.protein ,Molecular Medicine ,Female ,Rituximab ,Antibody ,0210 nano-technology ,business ,Biotechnology ,medicine.drug - Abstract
Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. Twenty B cell non-Hodgkin’s lymphoma patients who were treated with rituximab for the first time or after more than one year’s abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.
- Published
- 2019
16. Effect of medication adherence on disease activity among Japanese patients with rheumatoid arthritis
- Author
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Tsuneyo Mimori, Takao Fujii, Kazuo Matsubara, Mayumi Nakaishi, Hirohisa Imai, Atsushi Yonezawa, Takayuki Nakagawa, Satoshi Imai, Shunsaku Nakagawa, Masao Tanaka, Tomohiro Omura, Hiromu Ito, Wataru Yamamoto, Ran Nakashima, and Motomu Hashimoto
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Male ,Questionnaires ,Physical disability ,Arthritis ,lcsh:Medicine ,Aminotransferases ,Disease ,Severity of Illness Index ,Biochemistry ,Arthritis, Rheumatoid ,Cohort Studies ,Disability Evaluation ,0302 clinical medicine ,Medicine and Health Sciences ,030212 general & internal medicine ,lcsh:Science ,skin and connective tissue diseases ,Multidisciplinary ,Pharmaceutics ,Middle Aged ,Hospitals ,Enzymes ,Treatment Outcome ,Research Design ,Rheumatoid arthritis ,Antirheumatic Agents ,Cohort ,Disease Progression ,Female ,Cohort study ,Research Article ,musculoskeletal diseases ,Adult ,medicine.medical_specialty ,Patients ,Immunology ,Rheumatoid Arthritis ,Research and Analysis Methods ,Medication Adherence ,Autoimmune Diseases ,03 medical and health sciences ,Rheumatology ,Adverse Reactions ,Drug Therapy ,Transferases ,Internal medicine ,Severity of illness ,medicine ,Humans ,Aged ,030203 arthritis & rheumatology ,Pharmacology ,Survey Research ,business.industry ,lcsh:R ,Biology and Life Sciences ,Proteins ,medicine.disease ,Health Care ,Health Care Facilities ,Enzymology ,lcsh:Q ,Clinical Immunology ,Clinical Medicine ,business - Abstract
For the optimum efficacy of disease-modifying anti-rheumatic drugs (DMARDs), patients need to be adherent to their medication regimen. To clarify the effects of medication adherence on disease activity in Japanese patients with rheumatoid arthritis (RA), we conducted a cohort study in patients with various stages of RA. Patients were enrolled from the Kyoto University RA Management Alliance cohort, and followed up prospectively for 12 months. In this study, a total of 475 patients were analyzed and divided into 9 groups according to their medication adherence and the RA disease duration. The primary outcomes were based on the rate of a disease flare. The secondary outcomes were the changes in disease activity score using 28 joints (DAS28-ESR), simplified disease activity index (SDAI) and physical disability by health assessment questionnaire-disability index (HAQ). The changes in DAS28-ESR, HAQ, and the risk of disease flare in the highly adherent patients were significantly lower than those of the less adherent patients among the groups with RA ≤ 4.6 years but not those among the other groups. Taken together, this study identified a significant association between medication adherence and the disease flare during early-stage RA or short disease duration. These results emphasize the need to pay more attention to medication adherence in preventing the disease progression of RA.
- Published
- 2018
17. Effects of fasting on warfarin sensitivity index in patients undergoing cardiovascular surgery
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Akiko Nishimura, Kenji Minatoya, Hiromi Taue, Shunsaku Nakagawa, Kazuo Matsubara, Atsushi Yonezawa, Kenji Minakata, Satoshi Imai, Tomohiro Omura, Ikuko Yano, Takayuki Nakagawa, Kazuhiro Yamazaki, Yuki Sato, Yoshiki Katada, and Katsuyuki Matsumura
- Subjects
medicine.drug_class ,Drug Resistance ,Hemorrhage ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,medicine ,Humans ,heterocyclic compounds ,Pharmacology (medical) ,In patient ,cardiovascular diseases ,030212 general & internal medicine ,International Normalized Ratio ,Adverse effect ,Blood Coagulation ,Aged ,Retrospective Studies ,Pharmacology ,Prothrombin time ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Dietary intake ,Anticoagulant ,Warfarin ,Anticoagulants ,Retrospective cohort study ,General Medicine ,Fasting ,Middle Aged ,Anesthesia ,Prothrombin Time ,Blood Coagulation Tests ,business ,Metabolism, Inborn Errors ,medicine.drug - Abstract
Warfarin shows large inter- and intra-individual variabilities in its pharmacokinetics and pharmacodynamics. Sufficient understanding of factors affecting the response to warfarin is necessary to achieve improved outcomes for warfarin therapy. In this study, we evaluated effects of fasting on the anticoagulant properties of warfarin. We conducted a retrospective observational study involving a total of 58 patients, who received cardiovascular surgeries and subsequent warfarin therapy. The effect of dietary intake on the anticoagulant properties with warfarin was assessed by measurement of the international normalized ratio of prothrombin time (PT-INR): the anticoagulant activities of warfarin were expressed as the warfarin sensitivity index (WSI). Additionally, fluctuations in WSI during the study period were obtained as differences between the maximum and minimum WSI. The maximum PT-INR and WSI values were significantly higher for patients who were fasting for different reasons during the postoperative period than those in the group without reduced dietary intake. The differences between maximum and minimum WSI in the fasting group significantly increased compared with those in the groups with moderate or no reduced dietary intake. Meanwhile, effects of other markers of clinical conditions including the baseline Child-Pugh score and Charlson Comorbidity Index on WSI were not significant. Our results indicate that postoperative fasting was significantly associated with the anticoagulation activity of warfarin. In patients fasting for different reasons during the postoperative period, closer control of PT-INR values and warfarin adjustments may be required to avoid adverse effects such as bleeding in warfarin treatment.
- Published
- 2018
18. FRI0331 Trough concentration of mycophenolic acid correlates with renal function and serum albumin level in japanese patients with sle
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Shuji Akizuki, Ryosuke Hiwa, Ran Nakashima, Motomu Hashimoto, Masato Mori, Tsuneyo Mimori, Koichiro Ohmura, Kosaku Murakami, Masaaki Tanaka, Shunsaku Nakagawa, Nobuo Kuramoto, and Hajime Yoshifuji
- Subjects
medicine.medical_specialty ,biology ,medicine.diagnostic_test ,business.industry ,Serum albumin ,Renal function ,Mycophenolate ,Trough (economics) ,Gastroenterology ,Mycophenolic acid ,Therapeutic drug monitoring ,Internal medicine ,medicine ,biology.protein ,Prednisolone ,Trough Concentration ,business ,medicine.drug - Abstract
Background Mycophenolate mofetil (MMF) is an immunosuppressant used for treatment of lupus nephritis. MMF is converted to mycophenolic acid (MPA) by esterases, which is the active metabolite with pharmacological activities. A fixed dose of 2–3 g/day is administered as remission induction therapy.1 The usefulness of therapeutic drug monitoring (TDM) of MMF has not been elucidated. Moreover, little is known about the factor that affects the concentration of MPA in Asian patients. Objectives The aim of this study is to investigate the factor that affects the trough concentration of MPA in Japanese patients with SLE. Methods We recruited the SLE cases whose trough concentrations of MPA were measured from 2014 to 2017 at Kyoto University Hospital. When trough concentrations were measured multiple times in each patient with the same dose of MMF, median concentration was used for the analyses. Linear regression analysis was performed to identify the factor that affects the trough concentration of MPA. The association of trough concentration of MPA and adverse effects of MMF was investigated as well. Results Total of 20 cases were recruited and 43 trough concentrations were included for the analyses. The median daily dose of MMF (g) was 1.5 (range; 0.25–3.0) and the median trough concentration of MPA (μg/ml) was 2.0 (range; 0.4–15.0). Linear regression analysis (table 1) revealed that trough concentration of MPA was correlated with daily dose of MMF (p=0.0081, r=0.40, figure 1A), serum albumin level (p=3.3x10–4, r=0.52, figure 1B) and creatinine clearance (p=1.8x10–5, r=−0.60, figure 1C). Daily dose of prednisolone and serum C4 level were correlated with trough concentration of MPA as well, though multicollinearity was found in these two variables and serum albumin or creatinine clearance. Multivariate analysis (table 2) revealed that serum albumin and creatinine clearance were independently associated with trough concentration of MPA (p=6.2x10–4 and 1.6 × 10–5, respectively). Adverse effects of MMF, such as diarrhoea and cytopenia, were not associated with trough concentration of MPA. Conclusions Trough concentration of MPA was correlated with daily dose of MMF, serum albumin level and creatinine clearance. Reference [1] Ann Rheum Dis2012;71:1771–82. Disclosure of Interest None declared
- Published
- 2018
19. Chemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis: a case report
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Haruki Hirakawa, Shinya Kimura, Kazuo Matsubara, Naoko Sueoka-Aragane, Tomomi Nakamura, Chiho Nakashima, Taro Funakoshi, Takahiro Horimatsu, Shunsaku Nakagawa, Manabu Muto, and Masanori Masuda
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Urology ,Case Report ,Antineoplastic Agents ,Mediastinal yolk sac tumor ,Mediastinal Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Renal Dialysis ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Renal insufficiency ,Etoposide ,Medicine(all) ,Chemotherapy ,business.industry ,Endodermal Sinus Tumor ,Mediastinum ,Area under the curve ,General Medicine ,Surgery ,Regimen ,030104 developmental biology ,Hemodialysis ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Concomitant ,Cisplatin ,Tomography, X-Ray Computed ,business ,medicine.drug - Abstract
Background: The safety and efficacy of chemotherapy for patients undergoing concomitant hemodialysis have not been fully established and optimal doses of anti-cancer drugs and best timing of hemodialysis remains unclear. Although chemosensitive cancers, such as germ cell tumors, treated with chemotherapy should have sufficient dose intensity maintained to achieve the desired effect, many patients with cancer undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remains unknown. Case presentation: We describe a 31-year-old Japanese man with a mediastinal yolk sac tumor treated with surgery followed by five cycles of chemotherapy containing cisplatin and etoposide while concomitantly undergoing hemodialysis. The doses of these agents used in the first cycle were 50% of the standard dose of cisplatin (10 mg/m2) and 60% of the standard dose of etoposide (60 mg/m2) on days 1 through to 5; the doses were subsequently escalated to 75% with both agents. Hemodialysis was started 1 hour after infusions of these agents. Severe hematological toxicities were observed despite successful treatment. During treatment with concurrent hemodialysis, pharmacokinetic analysis of cisplatin was performed and its relationship with adverse effects was assessed. Compared with patients with normal renal function, the maximum drug concentration was higher, and concentration increased in the interval between hemodialysis and the subsequent cisplatin infusion, resulting in a higher area under the curve despite a reduction in the dose to 75% of the standard regimen. Conclusions: Because of the altered pharmacokinetics pharmacodynamics status of patients with renal dysfunction undergoing hemodialysis, pharmacokinetics pharmacodynamics analysis is deemed to be helpful for effective and safe management of chemotherapy in patients undergoing hemodialysis.
- Published
- 2017
20. Efficacy of protocol-based pharmacotherapy management on anticoagulation with warfarin for patients with cardiovascular surgery
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Yoshiki Katada, Kazuhisa Sakamoto, Taro Nakatsu, Yuki Sato, Hiromi Taue, Mizuho Odaka, Kazuhiro Yamazaki, Kazuo Matsubara, Hisashi Sakaguchi, Kenji Minakata, Kyokun Uehara, Ryuzo Sakata, Kenji Minatoya, Shunsaku Nakagawa, Ikuko Yano, Atsushi Yonezawa, and Y. Kayano
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Male ,medicine.medical_specialty ,Time Factors ,Medication Therapy Management ,medicine.medical_treatment ,Hemorrhage ,030204 cardiovascular system & hematology ,Pharmacists ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Aortic valve replacement ,Mitral valve ,Thromboembolism ,medicine ,Humans ,Pharmacology (medical) ,cardiovascular diseases ,030212 general & internal medicine ,International Normalized Ratio ,Cardiac Surgical Procedures ,Aged ,Retrospective Studies ,Pharmacology ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,Mitral valve replacement ,Warfarin ,Anticoagulants ,Atrial fibrillation ,Middle Aged ,medicine.disease ,Surgery ,medicine.anatomical_structure ,Cohort ,Prothrombin Time ,Female ,Drug Monitoring ,business ,Pharmacy Service, Hospital ,Algorithms ,medicine.drug ,Blood sampling - Abstract
SummaryWhat is known and objective Anticoagulation therapy with warfarin requires periodic monitoring of prothrombin time-international normalized ratio (PT-INR) and adequate dose adjustments based on the data to minimize the risk of bleeding and thromboembolic events. In our hospital, we have developed protocol-based pharmaceutical care, which we called protocol-based pharmacotherapy management (PBPM), for warfarin therapy. The protocol requires pharmacists to manage timing of blood sampling for measuring PT-INR and warfarin dosage determination based on an algorithm. This study evaluated the efficacy of PBPM in warfarin therapy by comparing to conventional pharmaceutical care. METHODS From October 2013 to June 2015, a total of 134 hospitalized patients who underwent cardiovascular surgeries received post-operative warfarin therapy. The early series of patients received warfarin therapy as the conventional care (control group, n=77), whereas the latter received warfarin therapy based on the PBPM (PBPM group, n=68). These patients formed the cohort of the present study and were retrospectively analysed. RESULTS The indications for warfarin included aortic valve replacement (n=56), mitral valve replacement (n=4), mitral valve plasty (n=22) and atrial fibrillation (n=29). There were no differences in patients' characteristics between both groups. The percentage time in therapeutic range in the first 10 days was significantly higher in the PBPM group (47.1%) than that in the control group (34.4%, P
- Published
- 2017
21. Accumulation of alpha-fluoro-beta-alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia
- Author
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Kazuo Matsubara, Yoshitaka Nishikawa, Taro Funakoshi, Manabu Muto, Shin'ichi Miyamoto, Takeshi Matsubara, Atsushi Yonezawa, Motoko Yanagita, Takahiro Horimatsu, and Shunsaku Nakagawa
- Subjects
0301 basic medicine ,Male ,Cancer Research ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,medicine.medical_treatment ,Fluoroacetates ,Pharmacology toxicology ,Toxicology ,Gastroenterology ,End stage renal disease ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Ammonia ,Renal Dialysis ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Hyperammonemia ,Pharmacology (medical) ,Recurrent Colorectal Cancer ,Diabetic Nephropathies ,Alpha-fluoro-beta-alanine ,Aged ,Pharmacology ,Chemotherapy ,business.industry ,medicine.disease ,Combined Modality Therapy ,030104 developmental biology ,Endocrinology ,Oncology ,Fluorouracil ,030220 oncology & carcinogenesis ,beta-Alanine ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
High-dose 5-fluorouracil (5-FU) containing chemotherapy occasionally causes hyperammonemia and can be lethal. However, the mechanism of 5FU-associated hyperammonemia has not been known. The aim of this study was to reveal the pharmacokinetics of 5-FU-associated hyperammonemia in a recurrent colorectal cancer patient with end-stage renal disease (ESRD).We experienced a case of hyperammonemia during mFOLFOX6 plus bevacizumab therapy for recurrent colorectal cancer. He was a dialyzed patient due to diabetic nephropathy and was registered to prospective blood sampling for pharmacokinetics analysis during chemotherapy. Blood concentrations of 5-FU and its catabolites were determined by inductively coupled plasma-mass spectrometry.The patient developed hyperammonemia encephalopathy 41 h after the initiation of continuous 5-FU infusion (on the third day). Before onset of hyperammonemia encephalopathy, serum alpha-fluoro-beta-alanine (FBAL, 59.2 µg/ml) and fluoro mono acetate (FMA, 905.8 ng/ml) were gradually increased. After hemodialysis for hyperammonemia, FBAL and FMA were collaterally decreased and his symptom was improved. Other intermediate catabolites of 5-FU, dihydrofluorouracil, and alpha-fluoro-beta-ureidopropionic acid were not changed.We found increases of serum FBAL and FMA under the condition of hyperammonemia in the patient with ESRD during mFOLFOX6 plus bevacizumab therapy. This research supported the hypothesis that impairment of tricarboxylic acid (TCA) cycle by FMA would cause 5-FU-associated hyperammonemia.
- Published
- 2017
22. Pharmacokinetics and safety of FOLFOX therapy in patients undergoing hemodialysis
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Shunsaku Nakagawa, Takahiro Horimatsu, Motoko Yanagita, Yohei Harada, Taro Funakoshi, Manabu Muto, Masami Nakajima, Shigeki Kataoka, Toshihiko Kirishima, and Shina Sueki
- Subjects
medicine.medical_specialty ,Oncology ,FOLFOX ,business.industry ,medicine.medical_treatment ,medicine ,In patient ,Hematology ,Hemodialysis ,business ,medicine.drug ,Surgery - Published
- 2017
23. [The Contribution of GMP-grade Hospital Preparation to Translational Research]
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Tomohiro Omura, Shunsaku Nakagawa, Kazuo Matsubara, Atsushi Yonezawa, Ikuko Minami, and Moto Kajiwara
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Quality Control ,medicine.medical_specialty ,media_common.quotation_subject ,International Cooperation ,MEDLINE ,Pharmaceutical Science ,Pharmacy ,Translational research ,Translational Research, Biomedical ,Patient safety ,Japan ,Medicine ,Quality (business) ,Medical physics ,media_common ,Pharmacology ,Clinical Trials as Topic ,business.industry ,Sterilization ,Drugs, Investigational ,University hospital ,Clinical trial ,Clinical research ,Pharmaceutical Preparations ,Family medicine ,Patient Safety ,business ,Pharmacy Service, Hospital - Abstract
Translational research is important for applying the outcomes of basic research studies to practical medical treatments. In exploratory early-phase clinical trials for an innovative therapy, researchers should generally manufacture investigational agents by themselves. To provide investigational agents with safety and high quality in clinical studies, appropriate production management and quality control are essential. In the Department of Pharmacy of Kyoto University Hospital, a manufacturing facility for sterile drugs was established, independent of existing manufacturing facilities. Manuals on production management and quality control were developed according to Good Manufacturing Practices (GMP) for Investigational New Drugs (INDs). Advanced clinical research has been carried out using investigational agents manufactured in our facility. These achievements contribute to both the safety of patients and the reliability of clinical studies. In addition, we are able to do licensing-out of our technique for the manufacture of investigational drugs. In this symposium, we will introduce our GMP grade manufacturing facility for sterile drugs and discuss the role of GMP grade hospital preparation in translational research.
- Published
- 2015
24. mTOR inhibitor everolimus ameliorates progressive tubular dysfunction in chronic renal failure rats
- Author
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Satohiro Masuda, Shunsaku Nakagawa, Kumiko Nishihara, and Ken-ichi Inui
- Subjects
Male ,medicine.medical_specialty ,Urinary system ,Biochemistry ,Lesion ,Internal medicine ,medicine ,Animals ,Everolimus ,Rats, Wistar ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Pharmacology ,Sirolimus ,Kidney ,Protein synthesis inhibitor ,business.industry ,TOR Serine-Threonine Kinases ,medicine.disease ,Rats ,Endocrinology ,medicine.anatomical_structure ,Kidney Tubules ,Renal physiology ,Disease Progression ,Kidney Failure, Chronic ,medicine.symptom ,business ,Protein Kinases ,medicine.drug ,Kidney disease - Abstract
Responsible factors in progressive tubular dysfunction in chronic renal failure have not been fully identified. In the present study, we hypothesized that the mammalian target of rapamycin, mTOR, was a key molecule in the degenerative and progressive tubular damage in chronic renal failure. Everolimus, an mTOR inhibitor, was administered for 14 days in 5/6 nephrectomized (Nx) rats at 2 and 8 weeks after renal ablation. Marked activation of the mTOR pathway was found at glomeruli and proximal tubules in remnant kidneys of Nx rats. The reduced expression levels of the phosphorylated S6 indicated the satisfactory pharmacological effects of treatment with everolimus for 14 days. Everolimus suppressed the accumulation of smooth muscle alpha actin, infiltration of macrophages and expression of kidney injury molecule-1 in the proximal tubules. In addition, everolimus-treatment restored the tubular reabsorption of albumin, and had a restorative effect on the expression levels of membrane transporters in the polarized proximal tubular epithelium, when its administration was started at 8 weeks after Nx. These results indicate that the constitutively activated mTOR pathway in proximal tubules has an important role in the progressive tubular dysfunction, and that mTOR inhibitors have renoprotective effects to improve the proximal tubular functions in end-stage renal disease.
- Published
- 2009
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