Faculty Profiles - ARIYOSHI Noritaka

Papers - ARIYOSHI Noritaka

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Adverse events of nivolumab plus ipilimumab versus nivolumab plus cabozantinib: a real-world pharmacovigilance study. Reviewed International journal

Yurie Oka, Jun Matsumoto, Tatsuaki Takeda, Naohiro Iwata, Takahiro Niimura, Aya Fukuma Ozaki, Kensuke Bekku, Hirofumi Hamano, Motoo Araki, Keisuke Ishizawa, Yoshito Zamami, Noritaka Ariyoshi

International journal of clinical pharmacy 2024.4

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: No head-to-head clinical trials have compared the differences in adverse events (AEs) between nivolumab plus ipilimumab (NIVO-IPI) and nivolumab plus cabozantinib (NIVO-CABO) in the treatment of metastatic renal cell carcinoma (mRCC). AIM: We analysed the two largest real-world databases, the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the World Health Organization's VigiBase, to elucidate the differences in AEs between NIVO-IPI and NIVO-CABO. METHOD: In total, 40,376 and 38,022 records were extracted from FAERS and VigiBase, and 193 AEs were analysed. The reporting odds ratios (ROR) with 95% confidence interval were calculated using a disproportionality analysis (NIVO-CABO/NIVO-IPI). RESULTS: The reported numbers of immune-related AEs, including myocarditis, colitis, and hepatitis, were significantly higher with NIVO-IPI (ROR = 0.18 for FAERS and 0.13 for VigiBase). Contrarily, the reported numbers of other AEs, including gastrointestinal disorders (ROR = 2.68 and 2.92) and skin and subcutaneous tissue disorders (ROR = 2.94 and 3.55), considered to be potentiated by the combination of NIVO and CABO, were higher with NIVO-CABO. CONCLUSION: Our findings contribute to the selection and clinical management of NIVO-IPI and NIVO-CABO, which minimizes the risk of AEs for individual patients with mRCC by considering distinctive differences in the AE profiles.

DOI： 10.1007/s11096-024-01713-1

A comparison between the adverse event profiles of patients receiving palbociclib and abemaciclib: analysis of two real-world databases. Reviewed International journal

Tatsuaki Takeda, Shiho Sugimoto, Jun Matsumoto, Naohiro Iwata, Akihiko Nakamoto, Aya Fukuma Ozaki, Hirofumi Hamano, Noritaka Ariyoshi, Yoshito Zamami

International journal of clinical pharmacy 2024.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Palbociclib and abemaciclib are cyclin-dependent kinase (CDK) 4/6 inhibitors currently used to treat breast cancer. Although their therapeutic efficacies are considered comparable, differences in adverse event (AE) profiles of the two drugs remain unclear. AIM: We analysed two real-world databases, the World Health Organization's VigiBase and the Food and Drug Administration Adverse Event Reporting System (FAERS), to identify differences in AE profiles of palbociclib and abemaciclib. METHOD: Data of patients with breast cancer receiving palbociclib or abemaciclib recorded until December 2022 were extracted from the VigiBase and FAERS databases. In total, 200 types of AEs were analysed. The reporting odds ratios were calculated using a disproportionality analysis. RESULTS: Cytopenia was frequently reported in patients receiving palbociclib, whereas interstitial lung disease and diarrhoea were frequently reported in those receiving abemaciclib. Moreover, psychiatric and nervous system disorders were more common in the palbociclib group, whereas renal and urinary disorders were more common in the abemaciclib group. CONCLUSION: This study is the first to show comprehensively the disparities in the AE profiles of palbociclib and abemaciclib. The findings highlight the importance of considering these differences when selecting a suitable CDK4/6 inhibitor to ensure safe and favourable outcomes for patients with breast cancer.

DOI： 10.1007/s11096-023-01687-6

Significance of UGT1A6, UGT1A9, and UGT2B7 genetic variants and their mRNA expression in the clinical outcome of renal cell carcinoma. Reviewed International journal

Jun Matsumoto, Anzu Nishimoto, Shogo Watari, Hideo Ueki, Shoya Shiromizu, Naohiro Iwata, Tatsuaki Takeda, Soichiro Ushio, Makoto Kajizono, Masachika Fujiyoshi, Toshihiro Koyama, Motoo Araki, Koichiro Wada, Yoshito Zamami, Yasutomo Nasu, Noritaka Ariyoshi

Molecular and cellular biochemistry 478 ( 8 ) 1779 - 1790 2023.8

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

UDP-glucuronosyltransferase (UGT) metabolizes a number of endogenous and exogenous substrates. Renal cells express high amounts of UGT; however, the significance of UGT in patients with renal cell carcinoma (RCC) remains unknown. In this study, we profile the mRNA expression of UGT subtypes (UGT1A6, UGT1A9, and UGT2B7) and their genetic variants in the kidney tissue of 125 Japanese patients with RCC (Okayama University Hospital, Japan). In addition, we elucidate the association between the UGT variants and UGT mRNA expression levels and clinical outcomes in these patients. The three representative genetic variants, namely, UGT1A6 541A > G, UGT1A9 i399C > T, and UGT2B7-161C > T, were genotyped, and their mRNA expression levels in each tissue were determined. We found that the mRNA expression of the three UGTs (UGT1A6, UGT1A9, and UGT2B7) are significantly downregulated in RCC tissues. Moreover, in patients with RCC, the UGT2B7-161C > T variant and high UGT2B7 mRNA expression are significantly correlated with preferable cancer-specific survival (CSS) and overall survival (OS), respectively. As such, the UGT2B7-161C > T variant and UGT2B7 mRNA expression level were identified as significant independent prognostic factors of CSS and CSS/OS, respectively. Taken together, these findings indicate that UGT2B7 has a role in RCC progression and may, therefore, represent a potential prognostic biomarker for patients with RCC.

DOI： 10.1007/s11010-022-04637-4

Derivation of a Novel Scoring System Predicting High Platelet Reactivity on Prasugrel in Patients with Coronary Artery Disease Reviewed

Yuichi Saito, Takeshi Nishi, Shinichi Wakabayashi, Yuji Ohno, Hideki Kitahara, Noritaka Ariyoshi, Yoshio Kobayashi

Journal of Atherosclerosis and Thrombosis 29 ( 11 ) 1625 - 1633 2022.11

Adverse Events of Axitinib plus Pembrolizumab Versus Lenvatinib plus Pembrolizumab: A Pharmacovigilance Study in Food and Drug Administration Adverse Event Reporting System. Reviewed International journal

Jun Matsumoto, Naohiro Iwata, Shogo Watari, Soichiro Ushio, Shoya Shiromizu, Tatsuaki Takeda, Hirofumi Hamano, Makoto Kajizono, Motoo Araki, Yasutomo Nasu, Noritaka Ariyoshi, Yoshito Zamami

European urology focus 9 ( 1 ) 141 - 144 2022.7

Language：English Publishing type：Research paper (scientific journal)

No head-to-head postmarket surveillance study has compared the differences in adverse events (AEs) between two combination therapies, axitinib (AXI) + pembrolizumab (PEMBRO) and lenvatinib (LEN) + PEMBRO, against metastatic renal cell carcinoma. This study aims to highlight the comprehensive differences in AEs between these two therapies based on the real-world big data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. In total, 28 937 records were extracted from the FAERS database, and 139 AEs grouped into the System Organ Class according to the Medical Dictionary for Regulatory Activities were analysed. Logistic regression analyses were performed, and the reporting odds ratio with a 95% confidence interval was determined. We found that the incidences of cardiac and hepatobiliary disorders for AXI + PEMBRO, and blood and lymphatic system, metabolism and nutrition, and vascular disorders for LEN + PEMBRO, all of which were associated with serious AEs, were higher than those for LEN + PEMBRO and AXI + PEMBRO, respectively. The differences in the AEs between AXI + PEMBRO and LEN + PEMBRO were not derived merely from those between AXI and LEN monotherapies. Furthermore, remarkable AE potentiation was observed for AXI + PEMBRO. As FAERS is a spontaneous reporting system comprising partially limited information, analysing more detailed relationships between AEs and patient or treatment characteristics was challenging in this study. The present study is the first to show the overall real-world postmarketing differences in AEs between AXI + PEMBRO and LEN + PEMBRO. Our novel findings will substantially improve clinical practice; we recommend comparing patients' conditions associated with the above AEs when selecting between these two therapies. PATIENT SUMMARY: Herein, we highlight the differences in adverse events (AEs) between axitinib + pembrolizumab and lenvatinib + pembrolizumab therapies using data from the real-world Food and Drug Administration Adverse Event Reporting System database aimed at patients with metastatic renal cell carcinoma. We identified AEs that needed attention in each combination. We recommend the differences in AEs to be considered when selecting these two therapies.

DOI： 10.1016/j.euf.2022.07.003

Differential Impact of Clinical and Genetic Factors on High Platelet Reactivity in Patients with Coronary Artery Disease Treated with Clopidogrel and Prasugrel. Reviewed

Yuichi Saito, Takeshi Nishi, Shinichi Wakabayashi, Yuji Ohno, Hideki Kitahara, Noritaka Ariyoshi, Yoshio Kobayashi

Journal of atherosclerosis and thrombosis 29 ( 7 ) 1031 - 1039 2022.7

Language：English Publishing type：Research paper (scientific journal)

AIM: High platelet reactivity (HPR) is associated with increased risks of thrombotic events in patients with coronary artery disease. The recently developed ABCD-GENE score identified five clinical and genetic factors (age, body mass index, chronic kidney disease, diabetes, and the CYP2C19 loss-of-function allele) for HPR, although the significance of various stages of each factor is unclear. METHODS: Four prospective studies were pooled, in which platelet reactivity was measured using the VerifyNow assay with clopidogrel and prasugrel; genotyping of CYP2C19 was also performed. Each component of the ABCD-GENE score was divided into three subcategories. VerifyNow P2Y12 reactivity units ＞208 were defined as HPR. RESULTS: A total of 184 patients were included, of which 111 (60%) and 51 (28%) had HPR with clopidogrel and prasugrel. Chronic kidney disease had an impact on HPR on both clopidogrel and prasugrel, whereas the impact of diabetes was more evident in patients treated with prasugrel. Although the number of CYP2C19 loss-of-function alleles was clearly associated with a likelihood of HPR with clopidogrel, P2Y12 reactivity units with prasugrel treatment were also significantly and progressively higher in patients with more CYP2C19 loss-of-function alleles. CONCLUSIONS: Clinical and genetic factors had a differential effect on a P2Y12 inhibitor reactivity with clopidogrel and prasugrel in patients with coronary artery disease. The severity of the factors also had a different impact on HPR.

DOI： 10.5551/jat.63035

Blood concentrations of tacrolimus upon conversion from rabeprazole to vonoprazan in renal transplant recipients: Correlation with cytochrome P450 gene polymorphisms. Reviewed International journal

Shogo Watari, Motoo Araki, Jun Matsumoto, Kasumi Yoshinaga, Takanori Sekito, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Koichiro Wada, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Shinji Kitamura, Hitoshi Sugiyama, Noritaka Ariyoshi, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

Drug metabolism and pharmacokinetics 40 100407 - 100407 2021.10

Language：English Publishing type：Research paper (scientific journal)

We evaluated the impact of vonoprazan on blood concentrations of tacrolimus via a retrospective analysis of 52 renal transplant recipients who took tacrolimus and converted from rabeprazole to vonoprazan between August 2018 and September 2019. We compared tacrolimus trough levels upon conversion among groups that were classified based on cytochrome P450 (CYP) gene polymorphisms. CYP3A5 groups were heterozygous or homozygous for CYP3A5∗1 and CYP3A5∗3 alleles. CYP2C19 genotypes were classified as extensive (∗1/∗1), intermediate (∗1/∗2 and ∗1/∗3) or poor metabolizers (∗2/∗2, ∗2/∗3 and ∗3/∗3). Tacrolimus trough levels increased only 0.3 ng/mL upon conversion in the CYP3A5∗3/∗3 group: 5.8 [3.4-7.2] vs 6.1 [3.8-7.9]; p = 0.06. No statistically significance changes in tacrolimus levels also occurred in the CYP3A5∗1/∗1 or CYP3A5∗1/∗3 groups. Subgroup analyses of CYP3A5∗3/∗3 demonstrated low changes for all three CYP2C19 subgroups: 5.2 [4.3-6.5] vs 6.2 [4.3-7.9]; p = 0.07, 6.1 [3.4-7.2] vs 6.7 [4.6-7.9]; p = 0.12 and 5.4 [3.6-6.5] vs 4.7 [3.8-6.3]; p = 1.00, respectively. Conversion to vonoprazan thus resulted in little increase of tacrolimus trough levels, even in the group predicted to be most susceptible (CYP3A5∗3/∗3 and 2C19∗1/∗1), thus supporting the safety of concomitant use of vonoprazan with tacrolimus.

DOI： 10.1016/j.dmpk.2021.100407

Relevance of CYP3A5 Expression on the Clinical Outcome of Patients With Renal Cell Carcinoma. Reviewed International journal

Jun Matsumoto, Yumi Kotera, Shogo Watari, Koichi Takeuchi, Hideo Ueki, Toshihiro Koyama, Koichiro Wada, Masachika Fujiyoshi, Yasutomo Nasu, Noritaka Ariyoshi

Anticancer research 41 ( 5 ) 2511 - 2521 2021.5

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/AIM: This study aimed to elucidate the detailed characteristics of CYP3A5 expression and the association between CYP3A5 expression and clinical outcomes in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: This study retrospectively enrolled 124 Japanese patients with RCC treated at the Okayama University Hospital. The commonest CYP3A5 gene polymorphism, CYP3A5*3, and expression levels of CYP3A5 mRNA and protein in each tissue were examined. RESULTS: Expression of CYP3A5 mRNA and protein in RCC tissues was significantly down-regulated compared to that in adjacent normal tissues. High level of CYP3A5 mRNA expression significantly extended cancer-specific survival (p=0.004) and overall survival (p=0.002). The CYP3A5 mRNA expression level was identified as a significant independent prognostic factor for both cancer-specific survival and overall survival. CONCLUSION: CYP3A5 could serve as a potential marker for prognostication and treatment planning for patients with RCC.

DOI： 10.21873/anticanres.15029

Validation of the ABCD-GENE score to identify high platelet reactivity in east Asian patients undergoing percutaneous coronary intervention. Reviewed International journal

Yuichi Saito, Takeshi Nishi, Shinichi Wakabayashi, Yuji Ohno, Hideki Kitahara, Noritaka Ariyoshi, Yoshio Kobayashi

International journal of cardiology 327 15 - 18 2021.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: High platelet reactivity (HPR) is associated with subsequent thrombotic events in patients undergoing percutaneous coronary intervention (PCI). Recently, the ABCD-GENE score was developed to identify patients at risk for HPR, incorporating both clinical and genetic factors. However, this score was derived and validated in mostly Caucasian subjects and it has not been validated in an East Asian population. METHOD: Individual patient data from 4 prospective studies were pooled, in which platelet reactivity was measured using the VerifyNow assay on clopidogrel and genotyping of CYP2C19 was performed after PCI. Study populations included patients with general stable coronary artery disease, hemodialysis, age ≥75 and/or body weight <50 kg, and acute coronary syndrome. VerifyNow P2Y12 reactivity units >208 was defined as HPR. RESULTS: Of 184 patients, 111 (60%) had HPR on clopidogrel. In the receiver operating characteristics curve analyses, the ABCD-GENE score significantly predicted HPR on clopidogrel (AUC 0.78, best cut-off value 9, p < 0.001). Across the 4 studies and their combinations, the diagnostic ability and cut-off values of ABCD-GENE score for HPR on clopidogrel were consistent. CONCLUSIONS: The ABCD-GENE score had significant and moderate diagnostic ability for HPR on clopidogrel in Japanese patients undergoing PCI. The predictivity was consistent across a broad spectrum of patient populations, suggesting the applicability of this novel scoring system in clinical practice worldwide.

DOI： 10.1016/j.ijcard.2020.11.022

【コロナ禍における医療人育成】薬学領域コロナ禍における薬学実務実習での工夫

猪田宏美, 藤吉正哉, 西原茂樹, 松本准, 有吉範高, 千堂年昭

医学教育 51 ( 5 ) 541 - 543 2020.10

Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro: a different effect on asunaprevir versus daclatasvir and beclabuvir. Reviewed International journal

Jun Matsumoto, Su Nwe San, Masachika Fujiyoshi, Ayano Kawauchi, Natsumi Chiba, Ran Tagai, Ryoko Sanbe, Shiho Yanaka, Hiroaki Sakaue, Yoshinori Kato, Hiroyoshi Nakamura, Harumi Yamada, Noritaka Ariyoshi

Journal of human genetics 65 ( 2 ) 143 - 153 2020.1

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Direct-acting antivirals, asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are known to be mainly metabolized by CYP3A enzymes; however, the differences in the detailed metabolic activities of CYP3A4 and CYP3A5 on these drugs are not well clarified. The aim of the present study was to elucidate the relative contributions of CYP3A4 and CYP3A5 to the metabolism of ASV, DCV, and BCV, as well as the effect of CYP3A5*3 genetic variant in vitro. The amount of each drug and their major metabolites were determined using LC-MS/MS. Recombinant CYP3As and CYP3A5*3-genotyped human liver microsomes (CYP3A5 expressers or non-expressers) were used for the determination of their metabolic activities. The contribution of CYP3A5 to ASV metabolism was considerable compared to that of CYP3A4. Consistently, ASV metabolic activity in CYP3A5 expressers was higher than those in CYP3A5 non-expresser. Moreover, CYP3A5 expression level was significantly correlated with ASV metabolism. In contrast, these observations were not found in DCV and BCV metabolism. To our knowledge, this is the first study to directly demonstrate the effect of CYP3A5*3 genetic variants on the metabolism of ASV. The findings of the present study may provide basic information on ASV, DCV, and BCV metabolisms.

DOI： 10.1038/s10038-019-0685-2

A randomized controlled, open-label early phase II trial comparing incidence of FOLFIRI.3-induced diarrhoea between Hangeshashinto and oral alkalization in Japanese patients with colorectal cancer. Reviewed International journal

Kaori Yamazaki, Noritaka Ariyoshi, Hideaki Miyauchi, Gaku Ohira, Noriko Kaneya, Kohei Yamamoto, Kenichi Arai, Shingo Yamazaki, Hisahiro Matsubara, Takaaki Suzuki, Itsuko Ishii

Journal of clinical pharmacy and therapeutics 44 ( 6 ) 946 - 951 2019.12

Language：English Publishing type：Research paper (scientific journal)

WHAT IS KNOWN AND OBJECTIVE: We conducted a pilot clinical trial to investigate whether Hangeshashinto (TJ-14) could be substituted for oral alkalization in patients scheduled to undergo chemotherapy by FOLFIRI.3 regimen for colorectal cancer (CRC). METHODS: Patients with CRC were randomized 1:1 to a TJ-14 (7.5 g/day) group or an oral alkalization (sodium bicarbonate, 1.8 g/day; ursodeoxycholic acid, 300 mg/day) group. The primary endpoint was incident of late-onset diarrhoea. A total of 30 patients were randomized to either the TJ-14 group or the alkalization group. RESULTS AND DISCUSSION: There was no statistical difference in age, concomitantly used drugs or UGT1A1 genotypes between the groups. In the alkalization group (n = 15), the frequency of grade 0/1/2 and grade 3 diarrhoea was 73% and 27%, respectively. In the TJ-14 group (n = 14), the frequency of grade 0/1/2 and grade 3 diarrhoea was 79% and 21%, respectively. Grade 4 diarrhoea was not observed in either group. There was no statistically significant difference in other adverse events or in response to FOLFIRI.3 between the groups. WHAT IS NEW AND CONCLUSION: This pilot trial suggests that TJ-14 is a promising alternative treatment option to reduce FOLFIRI.3-induced late-onset diarrhoea, although additional clinical study with a larger number of patients is necessary to confirm these results.

DOI： 10.1111/jcpt.13020

Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro. Reviewed International journal

Su Nwe San, Jun Matsumoto, Yumi Saito, Masako Koike, Hiroaki Sakaue, Yoshinori Kato, Masachika Fujiyoshi, Noritaka Ariyoshi, Harumi Yamada

Xenobiotica; the fate of foreign compounds in biological systems 49 ( 8 ) 935 - 944 2019.8

Language：English Publishing type：Research paper (scientific journal)

Paritaprevir (PTV) is a non-structural protein 3/4A protease inhibitor developed for the treatment of hepatitis C disease as a fixed dose combination of ombitasvir (OBV) and ritonavir (RTV) with or without dasabuvir. The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on in vitro PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5) and human liver microsomes (HLMs) genotyped as either CYP3A5*1/*1, CYP3A5*1/*3 or CYP3A5*3/*3. The intrinsic clearance (CLint, Vmax/Km) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism in CYP3A5*1/*1 and CYP3A5*1/*3 HLMs expressing CYP3A5 was comparable to that in CYP3A5*3/*3 HLMs, which lack CYP3A5. CYP3A4 expression level was significantly correlated with PTV disappearance rate and metabolite formation. In contrast, there was no such correlation found for CYP3A5 expression level. This study represents that the major CYP isoform involved in PTV metabolism is CYP3A4, with CYP3A5 having a minor role in PTV metabolism. The findings of the present study may provide foundational information on PTV metabolism, and may further support dosing practices in HCV-infected patients prescribed PTV-based therapy.

DOI： 10.1080/00498254.2018.1524947

A proposed simple screening method to determine relative contributions of CYP3A4 and CYP3A5 to drug metabolism in vitro. Reviewed

Matsumoto J, Nakamura H, San NS, Sato H, Takezawa M, Kishi R, Kito Y, Sugano J, Izuki M, Yanagisawa N, Ikeda N, Saito Y, Kato Y, Yamada H, Fujiyoshi M, Ariyoshi N

Pers Med Univers. 8 41 - 44 2019.7

High residual platelet reactivity after switching from clopidogrel to low-dose prasugrel in Japanese patients with end-stage renal disease on hemodialysis. Reviewed International journal

Yuji Ohno, Hideki Kitahara, Kenichi Fujii, Yukinori Kohno, Noritaka Ariyoshi, Takeshi Nishi, Yoshihide Fujimoto, Yoshio Kobayashi

Journal of cardiology 73 ( 1 ) 51 - 57 2019.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: High on-treatment platelet reactivity (HPR) under clopidogrel treatment is frequently observed in hemodialysis (HD) patients. In such patients, 10mg of prasugrel has reportedly inhibited platelet reactivity more adequately compared with 75mg of clopidogrel. However, the efficacy of 3.75mg prasugrel in Japanese HD patients is largely unknown. METHODS: A total of 41 Japanese coronary artery disease patients under HD who received aspirin and clopidogrel were enrolled. Clopidogrel was switched to 3.75mg prasugrel. At day 14, prasugrel was switched to clopidogrel. Platelet reactivity was measured using VerifyNow assay (Accumetrics, San Diego, CA, USA) at baseline, day 14, and day 28. VerifyNow P2Y12 reaction units (PRU) >208 was defined as HPR. RESULTS: The PRU level on prasugrel therapy was significantly lower than that on clopidogrel therapy before switching (219.1±62.3 PRU vs. 238.2±68.0 PRU, p=0.02). Although the prevalence of HPR was numerically lower on prasugrel therapy compared with clopidogrel therapy before and after switching, the differences did not reach a statistical significance (57.6% vs. 75.7% vs. 74.2%, p=0.13). Even under prasugrel treatment, more than half of patients showed HPR. CONCLUSIONS: Although low-dose prasugrel had somewhat better antiplatelet effect than clopidogrel, it could not significantly improve the prevalence of HPR in Japanese HD patients. Higher doses of prasugrel might be needed to achieve adequate platelet inhibition in this high thrombotic risk population.

DOI： 10.1016/j.jjcc.2018.07.001

Efficacy of 2.5-mg Prasugrel in Elderly or Low-Body-Weight Patients. Reviewed

Shinichi Wakabayashi, Noritaka Ariyoshi, Hideki Kitahara, Kenichi Fujii, Yoshihide Fujimoto, Yoshio Kobayashi

Circulation journal : official journal of the Japanese Circulation Society 82 ( 9 ) 2326 - 2331 2018.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Due to concern about bleeding complications, a maintenance dose of prasugrel 2.5 mg may be used in elderly or low-body-weight patients in Japan. There is little information, however, on the efficacy and safety of a 2.5-mg maintenance dose of prasugrel. Methods and Results: In this single-center, prospective, open-label, cross-over study, a total of 44 elderly (≥75 years old) or low body-weight (<50 kg) Japanese patients >1 month after percutaneous coronary intervention who were treated with aspirin 81-100 mg and clopidogrel 75 mg were randomized to either prasugrel 2.5 mg or 3.75 mg instead of clopidogrel for 14 days, with a cross-over directly to the alternate treatment for another 14 days. Platelet inhibition was assessed with the VerifyNow assay (Accumetrics, San Diego, CA, USA) at 3 time points: baseline; day 14; and day 28. P2Y12 reaction units (PRU) ≤95 was defined as low on-treatment platelet reactivity (LPR), and PRU ≥262 as high on-treatment platelet reactivity (HPR). The prevalence of LPR was 2.2% in patients treated with clopidogrel, 2.2% in those with prasugrel 2.5 mg, and 22.7% in those with prasugrel 3.75 mg (P<0.001). Clopidogrel resulted in the higher prevalence of HPR compared with 2.5-mg and 3.75-mg prasugrel (40.9% vs. 18.2% vs. 6.8%, P<0.001). CONCLUSIONS: Prasugrel 2.5 mg may be more appropriate in elderly or lower-body-weight Japanese patients.

DOI： 10.1253/circj.CJ-18-0337

Platelet inhibition after loading dose of prasugrel in patients with ST-elevation and non-ST-elevation acute coronary syndrome. Reviewed

Shinichi Wakabayashi, Hideki Kitahara, Takeshi Nishi, Kazumasa Sugimoto, Takashi Nakayama, Yoshihide Fujimoto, Noritaka Ariyoshi, Yoshio Kobayashi

Cardiovascular intervention and therapeutics 33 ( 3 ) 239 - 246 2018.7

Language：English Publishing type：Research paper (scientific journal)

The PRASFIT-ACS study showed the antiplatelet effect 2-4 h after prasugrel loading. However, there is little information about the antiplatelet effect <2 h after prasugrel loading dose, especially in patients with acute coronary syndrome (ACS). There had not been any comparison between ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation ACS (NSTE-ACS). Fifty patients with ACS (15 with STEMI and 35 with NSTE-ACS) were enrolled. They received a 20-mg prasugrel loading dose followed by a maintenance dose of 3.75 mg. Platelet reactivity [P2Y12 reaction units (PRU)] was evaluated by the VerifyNow assay at baseline, 30 min, 1, 2, 4, and 6 h, 1 week under prasugrel, and at 1 month after switching to clopidogrel. The primary end point was the change of PRU compared to the baseline. Furthermore, PRU after prasugrel loading between STEMI and NSTE-ACS was compared. A significant reduction in PRU from baseline was observed at ≥2 h after administration of prasugrel. In STEMI patients, a significant reduction in PRU was observed at 4 h after prasugrel loading. STEMI patients had higher PRU compared to NSTE-ACS patients at 2, 4, and 6 h after prasugrel loading. Utilizing >208 PRU as a cutoff value, STEMI patients had a higher prevalence of high on-treatment platelet reactivity at 2-6 h and 1 week after loading. Rapid antiplatelet effect is not achieved by low-dose prasugrel loading in STEMI patients. Platelet inhibition occurs earlier in NSTE-ACS patients, although it takes ≥2 h after loading in the majority of patients.

DOI： 10.1007/s12928-017-0475-8

HPLC-UVを用いたソホスブビルの定量法の確立(Determination of sofosbuvir via a high-performance liquid chromatography method using ultraviolet detection)

Su Nwe San, 松本准, 小池雅子, 斎藤祐実, 坂上弘明, 加藤芳徳, 有吉範高, 山田治美

国際医療福祉大学学会誌 23 ( 1 ) 130 - 136 2018.3

Language：English Publisher：国際医療福祉大学学会

Sofosbuvir(SOF)は、C型肝炎ウイルスの増殖を阻害するヌクレオチドアナログ薬である。本研究において、我々は、水溶液およびヒト血漿中SOF濃度の簡便、特異的、高感度および精密なUV検出を用いた高速クロマトグラフィー法による測定方法の確立を試みた。0.25mLの水溶液またはヒト血漿からアセトニトリルを含む抽出液で抽出し、C18逆相カラムを用いて分析した。ソラフェニブを内標準物質(IS)とし、移動相は酢酸アンモニウム緩衝液、メタノールおよびアセトニトリルを用いた。流速は1.0mL/min、UV検出波長は265nmとした。SOFとISの検出時間はそれぞれ7.8minおよび9.1min、1検体の測定時間は15.0minであった。検量線は、0.1-10.0μg/mLの範囲で直線性を得た。それぞれの検出限界は0.1μg/mL、ヒト血漿試料からの回収率は99%以上であった。水溶液およびヒト血漿中の日内、日間変動係数はそれぞれ1.41-10.06%および0.21-6.53%であった。日内、日間精度はそれぞれ92.71-98.41%および89.31-101.21%であった。本方法は、非常に簡便でかつ試料から良好な回収が可能でありSOFの薬物動態研究を行うために用いることができる。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J05958&link_issn=&doc_id=20180426420014&doc_link_id=http%3A%2F%2Fid.nii.ac.jp%2F1065%2F00000857%2F&url=http%3A%2F%2Fid.nii.ac.jp%2F1065%2F00000857%2F&type=%8D%91%8D%DB%88%E3%97%C3%95%9F%8E%83%91%E5%8Aw%81F%8D%91%8D%DB%88%E3%97%C3%95%9F%8E%83%91%E5%8Aw%83%8A%83%7C%83W%83g%83%8A&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80077_3.gif

An extremely high bioavailability of orally administered vancomycin in a patient with severe colitis and renal insufficiency Reviewed

Shingo Yamazaki, Takaaki Suzuki, Tatsuya Suzuki, Hirokazu Takatsuka, Masayuki Ishikawa, Noriyuki Hattori, Takeshi Fujishiro, Hideaki Miyauchi, Takehiko Oami, Noritaka Ariyoshi, Shigeto Oda, Hisahiro Matsubara, Itsuko Ishii

JOURNAL OF INFECTION AND CHEMOTHERAPY 23 ( 12 ) 848 - 851 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Because there is little absorption of orally administered vancomycin hydrochloride (VCM) through the normal intestinal microvillus membrane, the pharmacokinetics of VCM absorbed from the digestive tract are mostly unknown. Here we report a case of severe colitis and renal insufficiency in which the serum concentration of VCM reached the supratherapeutic range after oral administration. A 54-year-old man receiving outpatient chemotherapy for rectal cancer was admitted to our hospital for severe sepsis and acute renal failure. Multimodal therapy including continuous renal replacement therapy (CRRT) and mechanical ventilation was initiated, and oral VCM administration (0.5 g every 6 h) was begun for suspected severe pseudomembranous colitis with large amounts of watery stool. Despite continued CRRT, the serum VCM concentration increased to 30.6 mg/mL after 4 days. Based on pharmacokinetic analysis, the bioavailability of VCM was estimated to be over 54.5%. Colonoscopy showed that the mucosa was severely damaged throughout the large intestine, resulting in considerable exudation of plasma and blood. This case indicates the need for careful and early monitoring during high-dose oral VCM administration to patients with severe mucosal injury and renal insufficiency. (C) 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2017.08.004

Impact of chronic kidney disease on platelet inhibition of clopidogrel and prasugrel in Japanese patients. Reviewed International journal

Takeshi Nishi, Noritaka Ariyoshi, Takashi Nakayama, Yoshihide Fujimoto, Kazumasa Sugimoto, Shinichi Wakabayashi, Hideki Hanaoka, Yoshio Kobayashi

Journal of cardiology 69 ( 5 ) 752 - 755 2017.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The impact of chronic kidney disease (CKD) on the antiplatelet effect of clopidogrel and low-dose (3.75mg) prasugrel in Japanese patients is largely unknown. METHODS: A total of 53 consecutive Japanese patients with stable coronary artery disease who received aspirin and clopidogrel were enrolled, and categorized by estimated glomerular filtration rate (eGFR): CKD group (n=15, eGFR<60ml/min/1.73m2) and non-CKD group (n=38, eGFR≥60ml/min/1.73m2). Clopidogrel was switched to 3.75mg prasugrel. Platelet reactivity measurement using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA, USA) was performed at baseline (on clopidogrel) and day 14 (on prasugrel). RESULTS: The VerifyNow P2Y12 reaction units (PRU) during clopidogrel therapy was significantly higher in the CKD group than that in the non-CKD group (185.2±51.1 PRU vs. 224.3±57.0 PRU, p=0.02), whereas, the PRU with the prasugrel therapy in the CKD group and non-CKD group were not significantly different (149.9±51.1 PRU vs. 165.3±61.8 PRU, p=0.36). The PRU was significantly lower with the prasugrel therapy compared to that with the clopidogrel therapy both in the CKD group and in the non-CKD group. CONCLUSIONS: Antiplatelet effect of clopidogrel but not prasugrel is attenuated in patients with CKD. Prasugrel achieves a consistently lower platelet reactivity compared with clopidogrel regardless of the presence of mild to moderate CKD.

DOI： 10.1016/j.jjcc.2016.07.017

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