研究等業績 - 原著論文 - 菊地 正史
-
Effect of isavuconazole on the concentration of tacrolimus in a patient with genotype CYP3A5*1/*3: a case report.
Hayato Yokota, Yumiko Akamine, Harumi Hatakeyama, Hideaki Kagaya, Sho Sakamoto, Mitsuru Saito, Masahide Takeda, Kazuhiro Sato, Katsutoshi Nakayama, Masafumi Kikuchi
Journal of pharmaceutical health care and sciences 11 ( 1 ) 20 - 20 2025年03月
研究論文（学術雑誌）
BACKGROUND: Azole antifungals are the standard treatment for pulmonary mycosis, which may develop during long-term immunotherapy for kidney transplant. Isavuconazole (ISCZ) is a cytochrome P450 (CYP) 3 A inhibitor that has a risk of interacting with the immunosuppressive drug tacrolimus (TAC). We report a case of simple pulmonary aspergilloma with renal dysfunction due to increased trough levels of TAC after ISCZ coadministration. CASE PRESENTATION: A male in his 60s was treated with TAC 3.0 mg/day orally to prevent graft rejection after kidney transplantation. He received a loading dose of ISCZ 600 mg/day orally for two days, followed by a maintenance dose of 200 mg/day for simple pulmonary aspergilloma. The TAC trough concentration increased markedly from 2.4 to 9.9 ng/mL on day 6 after coadministration. The creatinine level increased from 0.70 to 1.08 mg/dL, suggesting renal dysfunction due to TAC. Subsequently, the TAC dosage was reduced, leading to a decreased blood TAC concentration and improved renal function. The patient's genotype was CYP3A5*1/*3. CONCLUSIONS: In the early stages of ISCZ treatment, the blood TAC concentration is higher, and CYP3A5 polymorphisms may partially explain the extent of this interaction. We recommend more careful monitoring of TAC and serum creatinine levels for approximately one week after ISCZ administration.
-
Masahiro WATANABE, Masamitsu MAEKAWA, Toshihiro SATO, Yu SATO, Masaki KUMONDAI, Masafumi KIKUCHI, Nariyasu MANO
CHROMATOGRAPHY ( The Society for Chromatographic Sciences ) 2024年09月
研究論文（学術雑誌）
-
Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice.
Masaki Kumondai, Reika Ogawa, Nagomi Hayashi, Yurika Ishida, Hanae Oshikiri, Yuji Sato, Masafumi Kikuchi, Yu Sato, Toshihiro Sato, Masamitsu Maekawa, Nariyasu Mano
Pharmacology research & perspectives 12 ( 4 ) e1241 2024年08月
研究論文（学術雑誌）
Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β-hydroxycortisol, deoxycholic acid, and 1β-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.
-
Naldemedine-induced perforation of a diverticulum in the sigmoid colon of a patient with opioid-related constipation: a case report.
Hayato Yokota, Yumiko Akamine, Mizuki Kobayashi, Takuro Kitabayashi, Misato Horie, Tentaro Endo, Takechiyo Yamada, Masafumi Kikuchi
Journal of pharmaceutical health care and sciences 10 ( 1 ) 50 - 50 2024年08月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Naldemedine is an orally available peripherally acting μ-opioid receptor antagonist approved to treat opioid-induced constipation (OIC). It is contraindicated for patients with known or suspected gastrointestinal obstruction to protect against naldemedine-induced perforation. Here, we report a clinical case of suspected perforation of a diverticulum in the sigmoid colon associated with naldemedine. CASE PRESENTATION: The patient was a 65-year-old man with a history of oral cancer who had been prescribed oxycodone (20 mg/day) for cancer pain. On day 0, the patient started naldemedine 0.2 mg once daily before bedtime for OIC. The dose of oxycodone was increased for pain control up to 60 mg/day. On day 35 of naldemedine treatment, the patient developed fever and abdominal pain, and his frequency of defecation had decreased. Initial laboratory results showed a C-reactive protein (CRP) level of 28.5 mg/dL and white blood cell (WBC) count of 13,500/µL. On day 37, the patient still had tenderness in his lower abdomen. Abdominal computed tomography revealed free air in the abdominal cavity suggesting an intestinal perforation. A Hartmann procedure was performed. Histopathological findings showed numerous diverticula in the sigmoid colon, some of which were perforated. CONCLUSIONS: These results suggest that the effects of OIC may have compressed the intestinal tract, which was followed by naldemedine-activation of peristalsis, which led to the onset of intestinal perforation. In patients with pre-existing diverticular disease, we should monitor for increased WBC counts and CRP levels after the initiation of treatment with naldemedine, and consider performing appropriate tests early in the event of abdominal complaints.
-
Yu Sato, Hiroki Kondo, Yuji Sato, Ai Abe, Masafumi Kikuchi, Toshihiro Sato, Masaki Kumondai, Kohei Yoshikawa, Yoshihiro Hayakawa, Masamitsu Maekawa, Nariyasu Mano
Pharmaceutics 2024年08月 [査読有り]
研究論文（学術雑誌）
-
Development of a simultaneous LC-MS/MS analytical method for plasma: 16 antipsychotics approved in Japan and 4 drug metabolites.
Masamitsu Maekawa, Maki Yokota, Toshihiro Sato, Yu Sato, Masaki Kumondai, Yuji Sato, Masato Suzuka, Daisuke Kobayashi, Kotaro Sakamoto, Masaki Matsuura, Masafumi Kikuchi, Hiroshi Komatsu, Kumiko Fujii, Yuji Ozeki, Hiroaki Tomita, Nariyasu Mano
Analytical sciences : the international journal of the Japan Society for Analytical Chemistry 2024年06月
研究論文（学術雑誌）
The increased risk of adverse drug reactions due to the concomitant use of antipsychotics is problematic in the treatment of schizophrenia. Therefore, the simultaneous analysis of their plasma concentrations is required. In this study, we developed a simultaneous liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for analyzing plasma antipsychotics approved in Japan for therapeutic drug monitoring (TDM) applications. First, we counted the prescriptions for 16 antipsychotics and concomitant drugs used at the Tohoku University Hospital. LC-MS/MS was used for the simultaneous analysis of 16 antipsychotics and four drug metabolites. This analysis was conducted using a combination of selected reaction monitoring mode and reversed-phase chromatography. Following the examination of the MS/MS and LC conditions, an analytical method validation test was conducted. The developed method was used to analyze plasma antipsychotic levels in patients with schizophrenia. One-third of the patients received treatment with multiple antipsychotics. Under LC-MS/MS conditions, LC separation was performed using a combination of a C18 column and ammonium formate-based mobile phases with a gradient flow. The calibration curves were optimized by adjusting the ion abundance, and 11 compounds met the criteria for intra- and inter-day reproducibility tests. Some stability test results did not meet these criteria; therefore, further investigation is required. The developed method permitted the measurement of all the plasma parameters, including concentrations above the therapeutic range. Therefore, this method may be useful in the daily TDM practice of antipsychotics.
-
Association of the modified Glasgow prognostic score and prognostic nutritional index with duration of oral anamorelin administration in patients with cancer cachexia: a retrospective cohort study.
Kazuma Fujita, Yumiko Akamine, Haruka Igarashi, Yayoi Fukushi, Katsuya Sasaki, Koji Fukuda, Masafumi Kikuchi, Hiroyuki Shibata
Japanese journal of clinical oncology 2024年06月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: The modified Glasgow Prognostic Score (mGPS) and Prognostic Nutritional Index (PNI) are indicators of nutritional status in cancer patients; however, the effects of baseline mGPS and PNI on the duration of administration of the ghrelin receptor agonist anamorelin, which is used to treat cachexia in patients with cancer, are unclear. This study aimed to clarify the association of mGPS and PNI with the duration of oral anamorelin administration for patients who did not have beneficial effects from anamorelin. METHODS: The attending physician determined the duration of oral anamorelin administration based on discontinuation due to cancer progression, poor efficacy, adverse events, or death. RESULTS: The 12-week continuation rate of oral anamorelin was 30.4%. Univariate analysis revealed that an Eastern Cooperative Oncology Group performance status (ECOG-PS) of ≥2 (P < .001), concurrent chemotherapy (P = .002), albumin level (P = .005), C-reactive protein level (P = .013), and a mGPS of 2 (P = .014) were statistically significant predictors of the 12-week continuation rate of oral anamorelin. In the multivariate analysis, a mGPS of 2 remained a significant risk factor, and the ECOG-PS and concurrent chemotherapy had no effect on the association between the mGPS and 12-week continuation rate of oral anamorelin. CONCLUSION: Patients with a mGPS of 2, compared with mGPS of 0 or 1, are less likely to maintain oral anamorelin therapy, regardless of the ECOG-PS or concurrent chemotherapy. Therefore, it is necessary to consider initiating anamorelin administration at mGPS 0 or 1.
-
Case report of QT interval prolongation induced by anamorelin in an obese patient with non-small cell lung cancer.
Hayato Yokota, Ruriko Asahi, Yumiko Akamine, Mizuki Kobayashi, Hiyu Wakabayashi, Sho Sakamoto, Yuji Okuda, Kazuhiro Sato, Katsutoshi Nakayama, Masafumi Kikuchi
Journal of pharmaceutical health care and sciences 10 ( 1 ) 33 - 33 2024年06月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Anamorelin, a drug to treat cancer cachexia, binds to ghrelin receptors and improves body weight and appetite. In clinical trials in Japan, patients experienced a 10.7% frequency of stimulant conduction system depression as a severe side effect. Although rare, anamorelin sometimes causes fatal arrhythmias. Because patients with cancer cachexia are often underweight, data on the safety of anamorelin in obese patients are lacking. We report a case of QT interval prolongation after anamorelin administration to an obese patient with non-small cell lung cancer. CASE PRESENTATION: A female patient with a body mass index of 30 kg/m2 underwent immunotherapy for lung adenocarcinoma. She presented with severe weight loss, anorexia, and fatigue. She had no history of heart disease. On day 12, after administration of anamorelin 100 mg once daily, the patient developed nausea, diarrhea, and anorexia, which were considered cancer immunotherapy-induced immune-related adverse events, and she was admitted to the hospital. An electrocardiogram (ECG) on admission showed a QTc interval of 502 ms. On admission, her hepatic function was Child-Pugh class B, and anamorelin was discontinued the next day. On day 3 after anamorelin discontinuation, the QTc interval was prolonged by up to 557 ms, then decreased to 490 ms on day 6, and improved to 450 ms on day 16. Re-administration of anamorelin was avoided. CONCLUSIONS: When administering anamorelin to obese patients, we should be aware of the potential for stimulatory conduction system depression, as in underweight patients. Therefore, we should monitor patients by ECG from the early stages of anamorelin administration. Anamorelin is lipophilic, and its volume of distribution is increased in obese patients. Consequently, obese patients may continue to have QT interval prolongation after discontinuation of anamorelin, requiring long-term side-effect monitoring.
-
Toshihiro Sato, Ayaka Yagi, Minami Yamauchi, Masaki Kumondai, Yu Sato, Masafumi Kikuchi, Masamitsu Maekawa, Hiroaki Yamaguchi, Takaaki Abe, Nariyasu Mano
International Journal of Molecular Sciences 2024年01月
研究論文（学術雑誌）
-
多職種協働による最適ながん薬物療法の開発
菊地正史
秋田医学 51 ( 1 ) 29 - 36 2024年
研究論文（学術雑誌）
-
Plasma Venetoclax Concentrations in Patients with Acute Myeloid Leukemia Treated with CYP3A4 Inhibitors.
Ayaka Otsuki, Masaki Kumondai, Daisuke Kobayashi, Masafumi Kikuchi, Yugo Ueki, Yuji Sato, Nagomi Hayashi, Ayaka Yagi, Yasushi Onishi, Koichi Onodera, Satoshi Ichikawa, Noriko Fukuhara, Hisayuki Yokoyama, Masamitsu Maekawa, Nariyasu Mano
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 144 ( 7 ) 775 - 779 2024年
研究論文（学術雑誌）
Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.
-
簡易懸濁法を用いて在宅でオシメルチニブを経管投与した非小細胞肺癌の一例
水口敦史, 菊地正史, 成田佳奈, 宮内栄作, 眞野成康
医薬品相互作用研究 48 ( 1 ) 18 - 23 2024年 [査読有り]
研究論文（学術雑誌）
-
Keitaro Miyoshi, Eiji Hishinuma, Naomi Matsukawa, Yoshitaka Shirasago, Masahiro Watanabe, Toshihiro Sato, Yu Sato, Masaki Kumondai, Masafumi Kikuchi, Seizo Koshiba, Masayoshi Fukasawa, Masamitsu Maekawa, Nariyasu Mano
International Journal of Molecular Sciences ( MDPI AG ) 24 ( 21 ) 15642 - 15642 2023年10月
研究論文（学術雑誌）
Niemann–Pick disease type C (NPC) is an autosomal recessive disorder with progressive neurodegeneration. Although the causative genes were previously identified, NPC has unclear pathophysiological aspects, and patients with NPC present various symptoms and onset ages. However, various novel biomarkers and metabolic alterations have been investigated; at present, few comprehensive proteomic alterations have been reported in relation to NPC. In this study, we aimed to elucidate proteomic alterations in NPC and perform a global proteomics analysis for NPC model cells. First, we developed two NPC cell models by knocking out NPC1 using CRISPR/Cas9 (KO1 and KO2). Second, we performed a label-free (LF) global proteomics analysis. Using the LF approach, more than 300 proteins, defined as differentially expressed proteins (DEPs), changed in the KO1 and/or KO2 cells, while the two models shared 35 DEPs. As a bioinformatics analysis, the construction of a protein–protein interaction (PPI) network and an enrichment analysis showed that common characteristic pathways such as ferroptosis and mitophagy were identified in the two model cells. There are few reports of the involvement of NPC in ferroptosis, and this study presents ferroptosis as an altered pathway in NPC. On the other hand, many other pathways and DEPs were previously suggested to be associated with NPC, supporting the link between the proteome analyzed here and NPC. Therapeutic research based on these results is expected in the future.
-
High throughput LC/ESI-MS/MS method for simultaneous analysis of 20 oral molecular-targeted anticancer drugs and the active metabolite of sunitinib in human plasma
Tensei Hirasawa, Masafumi Kikuchi, Shinya Takasaki, Masaki Kumondai, Yu Sato, Toshihiro Sato, Eishi Imoto, Yoshihiro Hayakawa, Masamitsu Maekawa, Nariyasu Mano
Heliyon ( Elsevier BV ) 9 ( 6 ) e16926 - e16926 2023年06月 [査読有り]
研究論文（学術雑誌）
-
The prevalence of end-of-life chemotherapy and targeted therapy in Japan, assessed using a health claims database.
Masami Tsuchiya, Taku Obara, Masafumi Kikuchi, Nariyasu Mano
Cancer chemotherapy and pharmacology 2023年05月 [査読有り]
研究論文（学術雑誌）
PURPOSE: This study aimed to investigate the current status of end-of-life chemotherapy and targeted therapy and explore the aggressiveness of end-of-life care in Japan using the DeSC database, a large administrative claims database. METHODS: We identified fatal cases of at least one cancer-related diagnosis between April 2015 and November 2020. Patients prescribed at least one anticancer drug were analyzed, and chemotherapy regimens were categorized based on the combination of concomitant anticancer drugs prescribed. RESULTS: Among 1,095,713 individuals enrolled in the National Health Insurance database, 7,300 deaths with cancer-related diagnosis were identified. Of these, 4,010 cases were identified in which at least one anticancer drug was prescribed, and 11.6% of 7,300 death had been prescribed anticancer drugs in their last 30 days of life. The most commonly used regimen was S-1 (tegafur, gimeracil, and oteracil potassium combination) monotherapy, followed by nivolumab monotherapy and nab-paclitaxel plus gemcitabine. Immune checkpoint inhibitor monotherapy was more likely prescribed to patients whose last chemotherapy dose was in the last 30 days of life (p = 0.0066, chi-squared test). CONCLUSIONS: This study provides insights into the current status of end-of-life chemotherapy and targeted therapy in Japan, using a large administrative claims database. The results of this study will inform future research on end-of-life chemotherapy and targeted therapy, and help develop strategies to improve the quality of life of patients with advanced cancer.
-
Masaki Kumondai, Masamitsu Maekawa, Eiji Hishinuma, Yu Sato, Toshihiro Sato, Masafumi Kikuchi, Masahiro Hiratsuka, Nariyasu Mano
Biological and Pharmaceutical Bulletin ( Pharmaceutical Society of Japan ) 46 ( 3 ) 455 - 463 2023年03月 [査読有り]
研究論文（学術雑誌）
-
Therapeutic Drug Monitoring of Blood Sirolimus and Tacrolimus Concentrations for Polypharmacy Management in a Lymphangioleiomyomatosis Patient Taking Two Cytochrome P450 3A Inhibitors.
Masaki Kumondai, Masafumi Kikuchi, Atsushi Mizuguchi, Nagomi Hayashi, Masahiro Ui, Takashi Hirama, Yoshinori Okada, Yu Sato, Toshihiro Sato, Masamitsu Maekawa, Nariyasu Mano
The Tohoku journal of experimental medicine 260 ( 1 ) 29 - 34 2023年03月 [査読有り]
研究論文（学術雑誌）
Patients with lymphangioleiomyomatosis (LAM) and lung transplantations are treated with multiple drugs, such as tacrolimus, mycophenolate mofetil, prednisolone, and itraconazole, for long-term suppression of rejection response and prevention of infection. Additional drugs are required when lung transplant recipients develop graft complications. Therefore, managing polypharmacy is critical because of drug-drug interactions caused by various factors, including drug-metabolizing enzymes such as cytochrome P450 3A (CYP3A). The patient was a 48-year-old woman (height 144.9 cm and weight 38.4 kg) who underwent lung transplantation for LAM. Mycophenolate mofetil, tacrolimus (target blood concentration, 4.0-8.0 ng/mL), and prednisolone were administered for immunosuppression, and itraconazole and clarithromycin were administered to manage graft infection. The patient developed unilateral lymphedema, predominantly in the left leg; therefore, sirolimus was initiated with a target blood concentration of 3.0-5.0 ng/mL. In addition to 1.0 mg/day of sirolimus, tacrolimus (0.3 mg/day), itraconazole (100 mg/day), and clarithromycin (800 mg/day) were added. Blood sirolimus concentrations ranged from 18.8 to 36.9 ng/mL on days 6 to 9; thus, treatment with sirolimus was stopped because of over-target blood concentrations. Blood concentrations of sirolimus and tacrolimus were successfully managed without adverse events using therapeutic drug monitoring (TDM) and azole anti-fungal substitution of azithromycin instead of clarithromycin although sirolimus concentration was relatively lower compared to the target range. Thereby, frequent TDM, management of polypharmacy that influences CYP3A activity, and possibly CYP3A genotyping should be appropriately conducted for personalized medicine.
-
Kentaro Tajima, Tomofumi Ishikawa, Masami Tsuchiya, Masafumi Kikuchi, Taku Obara, Nariyasu Mano
Pharmacoepidemiology 2023年01月 [査読有り]
研究論文（学術雑誌）
-
Evaluation of a Capillary Microsampling Device for Analyzing Plasma Lenvatinib Concentration in Patients With Hepatocellular Carcinoma.
Akihiro Saito, Masafumi Kikuchi, Yuko Matsumoto, Erina Sugawara, Gesshu Takao, Hayato Inomata, Akane Takahashi, Yuji Sato, Masaki Kumondai, Yu Sato, Toshihiro Sato, Masashi Ninomiya, Jun Inoue, Masamitsu Maekawa, Nariyasu Mano
Therapeutic drug monitoring 44 ( 6 ) 771 - 776 2022年12月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: The anticancer drug, Lenvima (lenvatinib), has severe side effects. Therapeutic drug monitoring helps ensure its efficacy and safety. Regular and optimally timed blood sampling is tough, especially when lenvatinib is self-medicated. Microsampling using the easy to handle Microsampling Wing (MSW) may help circumvent this problem. However, current lenvatinib detection methods are not sensitive enough to detect its concentrations in microsamples (<50-250 μL). Thus, the aim of this study was 2-fold (1) develop an analytic method to estimate plasma lenvatinib concentrations in microsamples and (2) verify whether this method works on micro (5.6 μL) blood plasma samples obtained clinically through MSW from patients with unresectable hepatocellular carcinoma (HCC). METHODS: A simple, highly sensitive, and specific liquid chromatography-electrospray ionization tandem mass spectrometry method was developed. Using this novel protocol, the trough blood plasma concentration of lenvatinib was measured for both blood sampled conventionally and that using MSW. Thirty-five venous whole blood samples were obtained from 11 patients with HCC. Furthermore, the stability of lenvatinib in MSW samples during storage was evaluated. RESULTS: The mean plasma lenvatinib concentration estimates were not significantly different between the MSW and conventional venous blood samples. CV for interday and intraday assays was low. Up to day 5, the lenvatinib concentration in the MSW samples was 85%-115% of the initial day concentration (when stored at 25°C or 4°C). The interference of endogenous matrix components in the human plasma was low. CONCLUSIONS: These results indicate that the novel mass spectrometry protocol accurately measures lenvatinib in human plasma and is reproducible. Thus, MSW could be a useful microsampling device for lenvatinib therapeutic drug monitoring in patients with HCC when used in combination with this novel liquid chromatography-electrospray ionization tandem mass spectrometry detection method.
-
Masamitsu Maekawa, Keitaro Miyoshi, Aya Narita, Toshihiro Sato, Yu Sato, Masaki Kumondai, Masafumi Kikuchi, Katsumi Higaki, Torayuki Okuyama, Yoshikatsu Eto, Hiroshi Sakamaki, Nariyasu Mano
Biological and Pharmaceutical Bulletin ( Pharmaceutical Society of Japan ) 45 ( 9 ) 1259 - 1268 2022年09月 [査読有り]
研究論文（学術雑誌）
As Niemann-Pick disease type C (NPC) is difficult to diagnose owing to its various clinical symptoms; biomarker tests have been developed. Previously, we revealed urinary sulfated cholesterol metabolites as noninvasive biomarkers for NPC. However, LC/tandem mass spectrometry (LC/MS/MS) requires long separation time and large urine volumes. Recently, a basic mobile phase was reported to increase the MS intensity. Thus, we developed a highly sensitive and rapid LC/MS/MS method for analyzing urinary cholesterol metabolites using a basic mobile phase additive. 3β-Sulfooxy-7β-N-acetylglucosaminyl-5-cholenic acid, its glycine and taurine conjugates, 3β-sulfooxy-7β-hydroxy-5-cholenic acid, and 7-oxo form were measured, with selected reaction monitoring in negative ion mode. Oasis HLB and L-column 3 were used for column-switching LC/MS/MS and urine diluted 10-fold was employed as the sample. After trapping, gradient separation was performed using solutions containing 1% (v/v) ammonium solution. On average, a 16-fold increase in peak areas was observed compared to that obtained at pH 5.5 with the mobile phases. Although the previous method needed 60 min for separation from interference peaks, we succeeded to separate them in 7 min with optimized LC condition. Further, all compounds showed good linearity from 0.3-1000 ng/mL, with satisfactory intra- and inter-day reproducibility. The developed method was applied to the urinalysis of healthy participants and NPC patients. Overall, the concentrations of metabolites correlated with those obtained using the previous method. Therefore, we succeeded to increasing MS intensity and shorten LC running time; and the method is useful for the noninvasive diagnostic screening of patients with NPC.
-
Minami Yamauchi, Toshihiro Sato, Ayana Otake, Masaki Kumondai, Yu Sato, Masafumi Kikuchi, Masamitsu Maekawa, Hiroaki Yamaguchi, Takaaki Abe, Nariyasu Mano
International Journal of Molecular Sciences ( MDPI AG ) 23 ( 15 ) 8508 - 8508 2022年07月 [査読有り]
研究論文（学術雑誌）
Patients with liver diseases not only experience the adverse effects of liver-metabolized drugs, but also the unexpected adverse effects of renally excreted drugs. Bile acids alter the expression of renal drug transporters, however, the direct effects of bile acids on drug transport remain unknown. Renal drug transporter organic anion-transporting polypeptide 4C1 (OATP4C1) was reported to be inhibited by chenodeoxycholic acid. Therefore, we predicted that the inhibition of OATP4C1-mediated transport by bile acids might be a potential mechanism for the altered pharmacokinetics of renally excreted drugs. We screened 45 types of bile acids and calculated the IC50, Ki values, and bile acid–drug interaction (BDI) indices of bile acids whose inhibitory effect on OATP4C1 was >50%. From the screening results, lithocholic acid (LCA), glycine-conjugated lithocholic acid (GLCA), and taurine-conjugated lithocholic acid (TLCA) were newly identified as inhibitors of OATP4C1. Since the BDI index of LCA was 0.278, LCA is likely to inhibit OATP4C1-mediated transport in clinical settings. Our findings suggest that dose adjustment of renally excreted drugs may be required in patients with renal failure as well as in patients with hepatic failure. We believe that our findings provide essential information for drug development and safe drug treatment in clinics.
-
Tensei Hirasawa, Masafumi Kikuchi, Shinya Takasaki, Masaki Kumondai, Yu Sato, Toshihiro Sato, Eishi Imoto, Yoshihiro Hayakawa, Masamitsu Maekawa, Nariyasu Mano
Medical Mass Spectrometry ( (一社)日本医用マススペクトル学会 ) 6 ( 1 ) 52 - 63 2022年06月 [査読有り]
研究論文（学術雑誌）
-
Metabolic Alteration Analysis of Steroid Hormones in Niemann-Pick Disease Type C Model Cell Using Liquid Chromatography/Tandem Mass Spectrometry.
Ai Abe, Masamitsu Maekawa, Toshihiro Sato, Yu Sato, Masaki Kumondai, Hayato Takahashi, Masafumi Kikuchi, Katsumi Higaki, Jiro Ogura, Nariyasu Mano
International journal of molecular sciences 23 ( 8 ) 2022年04月 [査読有り]
研究論文（学術雑誌）
Niemann-Pick disease type C (NPC) is an autosomal recessive disease caused by a functional deficiency of cholesterol-transporting proteins in lysosomes, and exhibits various clinical symptoms. Since mitochondrial dysfunction in NPC has recently been reported, cholesterol catabolism to steroid hormones may consequently be impaired. In this study, we developed a comprehensive steroid hormone analysis method using liquid chromatography/tandem mass spectrometry (LC-MS/MS) and applied it to analyze changes in steroid hormone concentrations in NPC model cells. We investigated the analytical conditions for simultaneous LC-MS/MS analysis, which could be readily separated from each other and showed good reproducibility. The NPC phenotype was verified as an NPC model with mitochondrial abnormalities using filipin staining and organelle morphology observations. Steroid hormones in the cell suspension and cell culture medium were also analyzed. Steroid hormone analysis indicated that the levels of six steroid hormones were significantly decreased in the NPC model cell and culture medium compared to those in the wild-type cell and culture medium. These results indicate that some steroid hormones change during NPC pathophysiology and this change is accompanied by mitochondrial abnormalities.
-
宮城県における改訂薬学教育モデル・コアカリキュラムに基づく実務実習の実施状況と薬剤師の意識調査
大内 友季江, 中井 啓, 菊地 正史, 中村 浩規, 森川 昭正, 石澤 文章, 村井 ユリ子
医療薬学 ( (一社)日本医療薬学会 ) 47 ( 12 ) 674 - 687 2021年12月 [査読有り]
研究論文（学術雑誌）
2019年度に、改訂版薬学教育モデル・コアカリキュラム(改訂コアカリ)に基づく薬学実務実習(実習)の実施状況と薬剤師の意識に関するアンケート調査を行い、実習を受け入れた薬局27施設、薬局薬剤師69人、病院14施設、病院薬剤師151人から回答を得た。その結果、薬局では大学との直接的連携、病院では薬局や大学との直接的連携を望んでおり、改訂コアカリで求められる地域住民の薬物治療、在宅医療、セルフメディケーションの実習などは74.1%の薬局で、患者の薬物治療の経時的なモニタリングなどの実習は85.7%の病院でそれぞれ概ね対応できたと回答した。また、責任薬剤師や指導薬剤師以外の薬剤師の実習への関与は少なかった。改訂コアカリに基づく実習は改善の余地があり、施設全体の薬剤師が実習に関与するような体制構築、指導薬剤師の養成および好事例の共有に対応すべきと考えられた。
-
新型コロナウイルス感染症に対応した病院実務実習プログラムの評価
菊地 正史, 佐藤 裕, 佐藤 紀宏, 前川 正充, 眞野 成康
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 57 ( 11 ) 1256 - 1261 2021年11月 [査読有り]
研究論文（学術雑誌）
東北大学病院では、2020年度第II期の病院実務実習生25名に対して、Googleのオンラインシステムを活用し、新型コロナウイルス感染症に対応した病院実務実習プログラムを実践した。実習11週目の指導薬剤師による概略評価11項目の平均は2.5〜3.1であり、すべて臨床で実習を実施した2019年度と比べて、8項目において有意差が認められなかった。また、代表的8疾患にかかわった割合は92〜100%であり、2019年度と比べて有意差が認められなかった。さらに、Webアンケートでは、多くの実習項目の理解度と満足度は、2019年度と比べてともに高い傾向が認められた。個人情報を除いた実処方箋や実症例の情報などを用い、指導薬剤師が模擬医師や模擬患者となることで、特に知識を中心とする実習はオンラインで対応可能であることが示唆された。(著者抄録)
-
KRP-203 is a Desirable Immunomodulator for Islet Allotransplantation.
Ibrahim Fathi, Ryuichi Nishimura, Takehiro Imura, Akiko Inagaki, Norifumi Kanai, Akira Ushiyama, Masafumi Kikuchi, Masamitsu Maekawa, Hiroaki Yamaguchi, Masafumi Goto
Transplantation 106 ( 5 ) 963 - 972 2021年07月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: The current standard immunosuppressive regimens, calcineurin inhibitors, have diabetogeneic and anti-vascularization effects on islet grafts. KRP-203, a sphyngosine-1-phosphate functional antagonist, exerts its immunomodulatory function through lymphocyte sequestration. However, the effect of this antagonist on islets is unclear. We examined the effect of KRP-203 on the islet function and vascularization and sought a calcineurin-free regimen for islet allotransplantation. METHODS: KRP-203 was administered for 14 days to mice, then diabetogenic effect was evaluated by blood glucose levels and a glucose tolerance test. Static glucose stimulation, the breathing index, and insulin/DNA were examined using isolated islets. Islet neovascularization was evaluated using a multi-photon laser scanning microscope (MPLSM). After islet allotransplantation with either KRP-203 alone, Sirolimus alone, or both in combination, the graft survival was evaluated by blood glucose levels and immunohistochemical analyses. A mixed lymphocyte reaction was also performed to investigate the immunological characteristics of KRP-203 and Sirolimus. RESULTS: No significant differences in the blood glucose levels or glucose tolerance were observed between the control and KRP-203 groups. Functional assays after islet isolation were also comparable. The MPLSM showed no inhibitory effect of KRP-203 on islet neovascularization. Although allogeneic rejection was effectively inhibited by KRP-203 monotherapy (44%), combination therapy prevented rejection in most transplanted mice (83%). CONCLUSIONS: KRP-203 is a desirable immunomodulator for islet transplantation due to the preservation of the endocrine function and lack of interference with islet neovascularization. The combination of KRP-203 with low-dose Sirolimus may be promising as a calcineurin-free regimen for islet allotransplantation.
-
Enhancement and evaluation of a prescription audit system for direct oral anticoagulants using a check sheet.
Naoto Ishikawa, Hanae Oshikiri, Shinya Takasaki, Masafumi Kikuchi, Taku Obara, Kazutoshi Akasaka, Masaki Matsuura, Hiroaki Yamaguchi, Nariyasu Mano
Journal of pharmaceutical health care and sciences 7 ( 1 ) 22 - 22 2021年06月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Renal function and use of concomitant medications should be carefully monitored in patients subjected to treatment with direct oral anticoagulants (DOACs); the dose should be individually designed for each patient. Owing to the complex therapeutic indications and dose reduction criteria, pharmacists exercise caution when determining the optimal dose for each patient. A DOAC check sheet has been developed that is automatically printed in the dispensing room at the same time as the prescription and can be used by pharmacists to dispense DOACs promptly and correctly. The purpose of this study was to evaluate the system for dispensing DOACs using a check sheet. METHODS: The study was conducted at Tohoku University Hospital in Japan; prescriptions containing DOACs dispensed by the hospital pharmacists were evaluated. The DOAC check sheet described indications, dosage regimens, dose reduction criteria, and contraindications for each drug and included the patient's information. The check sheet was set to print automatically in the dispensing room at the same time as the prescription when an inpatient was prescribed DOACs. This check sheet was evaluated using a prescription survey and a questionnaire for pharmacists. RESULTS: The usefulness of this check sheet for the correct use of DOACs was evaluated. There were four inquiries out of 642 (0.6%) prescriptions from pharmacists to physicians regarding DOAC prescriptions, such as the dose introduced before DOAC check sheet utilization, and there were 21 out of 905 (2.3%) prescriptions when the DOAC check sheet was used it, showing a significant increase (p = 0.0089). After the introduction of this sheet, overdoses of DOACs were identified at the time of dispensing. Of the 52 pharmacists who responded to the questionnaire, 51 (98%) stated that the check sheet was useful. CONCLUSION: The use of the DOAC check sheet is likely to render safety to DOAC drug therapy for individual patients.
-
Establishment of an analytical method for simultaneous quantitation of CDK4/6 inhibitors, aromatase inhibitors, and an estrogen receptor antagonist in human plasma using LC-ESI-MS/MS.
Yu Sato, Kensuke Shigeta, Tensei Hirasawa, Toshihiro Sato, Jiro Ogura, Masamitsu Maekawa, Akiko Ebata, Yohei Hamanaka, Hiroshi Tada, Takanori Ishida, Masafumi Kikuchi, Nariyasu Mano
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 1173 122655 - 122655 2021年03月 [査読有り]
研究論文（学術雑誌）
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib, and ribociclib) are used to treat human epithelial growth factor receptor (HER)-2 negative and hormone receptor (HR) positive advanced breast cancer in combination with aromatase inhibitors (letrozole, anastrozole) or an estrogen receptor antagonist (fulvestrant). Administration of these drugs frequently causes severe side effects, such as neutropenia and diarrhea. Therefore, therapeutic drug monitoring (TDM) of CDK4/6 inhibitors, aromatase inhibitors, and the estrogen receptor antagonist is considered important for ensuring the efficacy and safety of these drugs. In this study, we describe a simple, highly sensitive, and specific liquid chromatography/electrospray ionization tandem mass spectrometry method for simultaneous quantitation of the concentrations of palbociclib, abemaciclib, ribociclib, letrozole, anastrozole, and fulvestrant. In addition, we analyzed plasma samples from patients with HER2-negative and HR-positive advanced breast cancer treated with these compounds using this novel method. In our method, the intra-assay relative error (RE) values ranged from -12.8% to 12.9%, the inter-assay RE values ranged from -4.8% to 6.2%, and the coefficient of variation (CV) values for intra- and inter-assay were ≤8.6% and ≤13.3%, respectively. The analytes showed good stability with RE values ranging from -13.5% to 13.6% and CV values <10.4%. Moreover, all the samples from patients were successfully quantified, and were within the range of measurement. This method can be used for TDM of routine anticancer drugs in clinical practice and for pharmacokinetics/pharmacodynamics research in future studies.
-
High-throughput liquid chromatography/electrospray ionization-tandem mass spectrometry method using in-source collision-induced dissociation for simultaneous quantification of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in human plasma.
Tensei Hirasawa, Masafumi Kikuchi, Kensuke Shigeta, Shinya Takasaki, Yu Sato, Toshihiro Sato, Jiro Ogura, Koichi Onodera, Noriko Fukuhara, Yasushi Onishi, Masamitsu Maekawa, Nariyasu Mano
Biomedical chromatography : BMC 35 ( 8 ) e5124 2021年03月 [査読有り]
研究論文（学術雑誌）
Recent studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKIs) could improve treatment efficacy and safety. A simple analytical method using high-performance LC/electrospray ionization-tandem mass spectrometry has been developed and validated for simultaneous quantification of BCR-ABL and Bruton's TKIs used for chronic leukemia (imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib) in human plasma. Although these structures and physical properties are similar, owing to their different linear ranges, simultaneously determining the plasma levels of these five TKIs by applying optimal MS parameters remains difficult. A quantitative range exceeding 60,000-fold was required, and the linear dynamic ranges of imatinib, bosutinib, and nilotinib were limited because of the presence of a saturated detection signal. In this study, we applied the in-source collision-induced dissociation technique to control the ion amounts in mass spectrometry. This new method allowed rapid determination within 5 min with simple pretreatment. The method was validated according to the US Food and Drug Administration guidelines. Moreover, all samples of patients with chronic leukemia were successfully measured and their values were within the linear range of measurement. Therefore, our high-throughput analytical system is useful to measure the plasma concentrations of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in clinical practice.
-
Development of a simultaneous analytical method for clozapine and its metabolites in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry with linear range adjusted by in-source collision-induced dissociation.
Toshihiro Sato, Masato Suzuka, Yuji Sato, Riko Iwabuchi, Daisuke Kobayashi, Jiro Ogura, Shinya Takasaki, Maki Yokota, Taku Tsukamoto, Yoshihiro Hayakawa, Masafumi Kikuchi, Masamitsu Maekawa, Nariyasu Mano
Biomedical chromatography : BMC 35 ( 7 ) e5094 2021年02月 [査読有り]
研究論文（学術雑誌）
Clozapine (CLZ) is a key drug in treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of CLZ and its metabolites, N-desmethylclozapine and clozapine N-oxide, is required to monitor and manage the risks of side effects. Although quantification methods for TDM have been developed for CLZ and its metabolites, they were not sufficiently accurate for the quantification of CLZ owing to the upper limits of the calibration curves. An analytical method using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry was developed and validated for the simultaneous measurement of CLZ and its metabolites in human plasma. To expand the concentration range of the calibration curves, we used a linear range shift technique using in-source collision-induced dissociation (CID). Using our approach, the linearity and quantitative range were improved compared to those reported by previous studies, and were sufficient for TDM in clinical practice. The intra- and inter-assay accuracy was 84.6%-114.8%, and the intra- and inter-assay precisions were ≤9.1% and ≤9.9%, respectively. Moreover, all samples from patients with treatment-resistant schizophrenia were successfully quantified. Therefore, our novel analytical method using in-source CID had the appropriate performance to measure the plasma concentrations of CLZ and its metabolites for TDM in clinical practice.
-
Simultaneous analysis of drugs administered to lung-transplanted patients using liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring.
Shinya Takasaki, Tensei Hirasawa, Yu Sato, Masamitsu Maekawa, Taku Tsukamoto, Masafumi Kikuchi, Jiro Ogura, Yoshihiro Hayakawa, Yasushi Matsuda, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Yoshinori Okada, Hiroaki Yamaguchi, Nariyasu Mano
Biomedical chromatography : BMC 35 ( 6 ) e5067 2021年01月 [査読有り]
研究論文（学術雑誌）
Several drugs are administered to lung-transplanted patients, which are monitored using therapeutic drug monitoring (TDM). Therefore, we developed and validated a liquid chromatography-tandem mass spectrometry method to simultaneously analyze immunosuppressive drugs such as mycophenolic acid, antifungal drugs such as voriconazole and itraconazole, and its metabolite hydroxyitraconazole. Chromatographic separation was achieved using a C18 column and gradient flow of mobile phase comprising 20 mM aqueous ammonium formate and 20 mM ammonium formate-methanol solution. A simple protein precipitation treatment was performed using acetonitrile/methanol and mycophenolic acid-2 H3 , voriconazole-2 H3 , itraconazole-2 H4 , and hydroxyitraconazole-2 H4 as internal standards. The linearity ranges of mycophenolic acid, voriconazole, itraconazole, and hydroxyitraconazole were 100-20,000, 50-10,000, 5-1000, and 5-1000 ng/mL, respectively. The retention time of each target was less than 2 min. The relative errors in intra- and inter-day were within ±7.6%, the coefficient of variation was 8.9% or less for quality control low, medium, and high, and it was 15.8% or less for lower limit of quantitation. Moreover, the patient samples were successfully quantified, and they were within the linear range of measurements. Therefore, our new method may be useful for TDM in lung-transplanted patients.
-
Takasaki, S., Kawasaki, Y., Kikuchi, M., Ito, A., Yamaguchi, H., Mano, N.
Journal of Pharmacy and Pharmaceutical Sciences 24 127 - 136 2021年
研究論文（学術雑誌）
PURPOSE: Therapeutic drug monitoring (TDM) is widely used in clinical practice to maximize drug efficacy and minimize toxicities. Currently, it is also practiced in the use of oral molecular targeted drugs. The objective of this study was to assess the clinical importance of measuring the systemic concentration of oral molecular targeted drugs used to treat renal cell carcinoma (RCC). METHODS: The systemic concentrations of the oral molecular targeted drugs sorafenib, sunitinib, axitinib, pazopanib, and everolimus used for RCC were useful for therapeutic interventions, and clinical outcomes were evaluated retrospectively. RESULTS: The interventional use of systemic drug concentration was confirmed in 26 of 87, and their categories are presented. The systemic concentration of sunitinib was useful in dose reduction and/or discontinuation (n = 10), dose escalation (n = 3), and adherence monitoring (n = 2). Nine of the 10 patients whose dose was reduced showed reduced adverse event. Two patients who were intervened in adherence monitor showed improved adherence. For axitinib, dose reduction and/or discontinuation (n = 1) and dose escalation (n = 6) were confirmed. For pazopanib, dose reduction and/or discontinuation (n = 1) and drug interaction detection (n = 1) were confirmed, both of them were confirmed to have reduced adverse events. For everolimus, dose reduction and/or discontinuation (n = 1) and drug interaction detection (n = 1) were confirmed, a patient with reduced dose recovered from adverse events. Interventions for sorafenib were not identified. CONCLUSIONS: This study demonstrated that systemic concentrations of oral molecular targeted drugs for RCC were considered to be clinically useful for dose adjustment, monitoring of treatment adherence, and the detection of drug interactions. Moreover, this information could be successfully used to guide individualized therapy to maximize the antitumor effects of these drugs.
-
新薬学教育6年制を考える 新型コロナウイルス感染症に対応した病院実務実習プログラムの構築と実践
菊地 正史, 佐藤 裕, 佐藤 紀宏, 前川 正充, 眞野 成康
医薬品相互作用研究 ( (一社)医薬品相互作用研究会 ) 44 ( 3 ) 191 - 195 2020年12月
研究論文（学術雑誌）
-
Plasma mycophenolic acid concentration and the clinical outcome after lung transplantation.
Hiroshi Yabuki, Yasushi Matsuda, Tatsuaki Watanabe, Shunsuke Eba, Fumihiko Hoshi, Takashi Hirama, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Akira Sakurada, Masafumi Kikuchi, Hiroaki Yamaguchi, Nariyasu Mano, Yoshinori Okada
Clinical transplantation 34 ( 12 ) e14088 2020年12月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: The therapeutic drug monitoring of mycophenolic acid (MPA) has been investigated for renal and heart transplantations; however, its usefulness in lung transplantation is unclear. METHODS: The MPA area under the plasma concentration-time curve (AUC) was calculated in 59 adult lung transplant recipients. The MPA AUC0-12 s were compared among the three groups determined by the presence of adverse events (no events, infection, and chronic lung allograft dysfunction [CLAD]). Next, MPA AUC0-12 thresholds for the adverse events were identified by receiver operating characteristic analysis. Cumulative occurrence rate of the adverse events was compared between two groups (adequate and inadequate groups) according to the thresholds. RESULTS: The MPA AUC0-12 s in the no event, infection, and CLAD groups were 30.3 ± 6.5, 36.8 ± 10.7, and 20.6 ± 9.6 µg·h/mL, respectively (P = .0027), while the tacrolimus trough levels were similarly controlled in the groups. The thresholds of MPA AUC0-12 for the occurrence of infection and CLAD were 40.5 and 22.8 µg·h/mL, respectively. The cumulative occurrence rate of adverse events of adequate group (15.3%) was significantly lower than that of inadequate group (56.0%) (P = .0050). CONCLUSIONS: The MPA AUC0-12 may affect the occurrence of adverse events in lung transplant recipients.
-
Development of a Diagnostic Screening Strategy for Niemann-Pick Diseases Based on Simultaneous Liquid Chromatography-Tandem Mass Spectrometry Analyses of N-Palmitoyl-O-phosphocholine-serine and Sphingosylphosphorylcholine.
Anna Iwahori, Masamitsu Maekawa, Aya Narita, Akie Kato, Toshihiro Sato, Jiro Ogura, Yu Sato, Masafumi Kikuchi, Atsuko Noguchi, Katsumi Higaki, Torayuki Okuyama, Tsutomu Takahashi, Yoshikatsu Eto, Nariyasu Mano
Biological & pharmaceutical bulletin 43 ( 9 ) 1398 - 1406 2020年09月 [査読有り]
研究論文（学術雑誌）
Early diagnosis of Niemann-Pick diseases (NPDs) is important for better prognosis of such diseases. N-Palmitoyl-O-phosphocholine-serine (PPCS) is a new NPD biomarker possessing high sensitivity, and with its combination with sphingosylphosphocholine (SPC) it may be possible to distinguish NPD-C from NPD-A/B. In this study, a rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method (method 1) and a validated LC-MS/MS analysis (method 2) of PPCS and SPC were developed, and we have proposed a diagnostic screening strategy for NPDs using a combination of serum PPCS and SPC concentrations. Nexera and API 5000 were used as LC-MS/MS systems. C18 columns with lengths of 10 and 50 mm were used for method 1 and 2, respectively. 2H3-Labeled PPCS and nor-SPC were used as internal standards. Selective reaction monitoring in positive-ion mode was used for MS/MS. Run times of 1.2 and 8 min were set for methods 1 and 2, respectively. In both methods 1 and 2, two analytes showed high linearity in the range of 1-4000 ng/mL. Method 2 provided high accuracy and precision in method validation. Serum concentrations of both analytes were significantly higher in NPD-C patients than those of healthy subjects in both methods. Serum PPCS correlated between methods 1 and 2; however, it was different in the case of SPC. The serum PPCS/SPC ratio was different in healthy subjects, NPD-C, and NPD-A/B. These results suggest that using a combination of the two LC-MS/MS analytical methods for PPCS and SPC is useful for diagnostic screening of NPDs.
-
Development of a precise quantitative method for monitoring sirolimus in whole blood using LC/ESI-MS/MS.
Kensuke Shigeta, Masafumi Kikuchi, Masaki Tanaka, Shinya Takasaki, Hisashi Oishi, Tetsu Sado, Yasushi Matsuda, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi
Biomedical chromatography : BMC 34 ( 8 ) e4853 2020年08月 [査読有り]
研究論文（学術雑誌）
Sirolimus is used on patients after solid organ transplantation and on lymphangioleiomyomatosis (LAM) patients, and therapeutic drug monitoring is required in clinical practice. We have previously reported an accurate method for quantitative determination of sirolimus, but its sample preparation step was complicated. In this study, we developed a modified liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for sirolimus quantification. A supported liquid extraction cartridge was used to purify sirolimus from whole blood and ion suppression was mostly prevented. The validation results met the acceptance criteria. This method was compared with the antigen conjugated magnetic immunoassay (ACMIA) and our previously reported method, using whole blood samples from LAM patients. Comparison of the Bland-Altman plots of the currently developed method and the previous method revealed no significant difference between the two methods (mean bias, -2.02%; 95% CI, -7.81-3.78). The values obtained using ACMIA were significantly higher than those obtained using the current method by 13.87% (95% CI, 6.49-21.25) owing to cross-reactivity. The degrees of cross reactivities in LAM patients and in organ transplant patients were similar, and our LC/ESI-MS/MS method precisely measured the blood concentrations of sirolimus.
-
Importance of Therapeutic Drug Monitoring to Detect Drug Interaction between Pazopanib and Warfarin: A Case Report.
Shinya Takasaki, Hisanobu Adachi, Yoshihide Kawasaki, Masafumi Kikuchi, Akihiro Ito, Nariyasu Mano
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 23 200 - 205 2020年 [査読有り]
研究論文（学術雑誌）
Pazopanib is an orally available multi-tyrosine kinase inhibitor and has been used to treat renal cell carcinoma (RCC). Here, we report the case of a patient with RCC with an increased prothrombin time- international normalized ratio (PT-INR) due to pazopanib therapy. In addition, we have reported the change in the blood levels of pazopanib. A 75-year-old man underwent a left nephrectomy for RCC. Four years later, his cancer recurred and pazopanib therapy was initiated. He was also taking warfarin for atrial fibrillation and his PT-INR was constant at approximately 2. His warfarin dose was reduced from 3.5 mg/day to 3.0 mg/day on day 10 because his PT-INR increased from 2.19 to 3.07 compared to that before starting pazopanib. On day 28, his PT-INR further increased to 4.34, and his aspartate aminotransferase, alanine transaminase, and alkaline phosphatase levels increased. The target concentration of pazopanib was 20.5 to 50.3 µg/mL, but his blood concentrations were 92.1 µg/mL on day 6 and 93.7 µg/mL on day 13. Therefore, both pazopanib and warfarin were discontinued. One week later, his laboratory tests recovered, and hence, warfarin treatment was resumed. However, pazopanib therapy was terminated due to concerns about liver dysfunction. His hepatic dysfunction and increased PT-INR were considered to be due to pazopanib treatment. Pazopanib has been reported to have no effect on the pharmacokinetics of warfarin in clinical patients. In this case, blood levels of pazopanib were abnormally high, possibly causing liver dysfunction and drug interactions, leading to his PT-INR prolongation. TDM monitoring, in addition to the recommended monitoring for pazopanib hepatotoxicity, may help identify patients at risk for drug interactions. For patients receiving concomitant pazopanib and warfarin, close monitoring of PT-INR is warranted.
-
Estimation of Blood Sirolimus Concentration Based on Tacrolimus Concentration/Dose Normalized by Body Weight Ratio in Lung Transplant Patients.
Masafumi Kikuchi, Kensuke Shigeta, Masaki Tanaka, Shinya Takasaki, Miki Akiba, Hisashi Oishi, Tetsu Sado, Yasushi Matsuda, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi
Therapeutic drug monitoring 41 ( 5 ) 615 - 619 2019年10月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Sirolimus and tacrolimus require accurate drug dosing based on their target blood levels to produce better clinical outcomes, specifically, the avoidance of drug-induced adverse effects and the maintenance of efficacy. However, because the ideal dose of sirolimus and the schedule for measuring its blood levels are unclear in lung transplant patients, an index is required for estimating sirolimus blood concentrations. The aim of this work is to study the correlation between the trough concentration/dose normalized by body weight (C0/D) ratios of sirolimus and tacrolimus in lung transplant patients. METHODS: Thirteen lymphangiomyomatosis patients who underwent lung transplantation and were treated with sirolimus and tacrolimus from February 2015 to July 2018 were divided into 2 groups, one receiving twice-daily (TD, n = 6) and the other once-daily (OD, n = 7) tacrolimus formulations. The correlation between the C0/D ratio of sirolimus and patient background was evaluated using Spearman's rank correlation coefficient. Correlations between sirolimus and tacrolimus C0/D ratios or doses were analyzed by single regression analysis. RESULTS: Significant correlations were found between the C0/D ratios of sirolimus and tacrolimus. The regression equations from the initial data of TD and OD groups at steady state were y = 1.880x + 32.636 (adjusted R = 0.743, P = 0.017) and y = 1.684x + 38.816 (adjusted R = 0.919, P < 0.001), respectively. In addition, the regression equations from all data of TD and OD groups were y = 1.883x + 4.170 (adjusted R = 0.546, P < 0.001) and y = 1.950x + 43.188 (adjusted R = 0.898, P < 0.001), respectively. A significant correlation between the dosage of sirolimus and tacrolimus was observed only in the OD group, with relatively low accuracy. CONCLUSIONS: Blood sirolimus concentrations can be estimated using the C0/D ratio of tacrolimus, suggesting that the C0/D ratio of tacrolimus is an index of required sirolimus dosage and the frequency of blood sirolimus concentration measurements.
-
Toward Personalized Cancer Therapy with Oral Molecular-targeted Agents
Hiroaki Yamaguchi, Shinya Takasaki, Masafumi Kikuchi, Yoshihide Kawasaki, Yoichi Arai, Nariyasu Mano
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN ( PHARMACEUTICAL SOC JAPAN ) 139 ( 6 ) 911 - 915 2019年06月 [査読有り]
研究論文（学術雑誌）
Oral molecular-targeted agents are used clinically for the treatment of various types of cancer. However, even when treatment is started at the dosage indicated in the medical package insert, we have experienced many cases in which treatment had to be stopped early owing to the occurrence of serious side effects or an insufficient therapeutic effect. In recent years, a wide range of studies has been conducted on the therapeutic drug monitoring (TDM) of oral molecular-targeted therapeutic agents to prevent serious side effects and maximize the therapeutic effect. In Japan, the TDM of imatinib has been covered by insurance since 2012, and the TDM of sunitinib has been covered since 2018. In contrast, tyrosine kinase inhibitors may have severe side effects, but their TDM is not covered by medical insurance. We aimed to identify a safe, highly effective chemotherapy regimen based on scientific evidence gathered from Japanese patients. We examined the relationship between the plasma concentration of drugs and clinical findings, such as side effects and treatment effects, at our hospital. In this symposium review, we introduce our results based on the treatment of patients with renal cell carcinoma.
-
Fundamental Study of Behaviors of In-Source Collision Induced Dissociation and Shifting the Linear Range of Calibration Curves of Various Drugs and the Metabolites Used for Therapeutic Drug Monitoring.
Maekawa M, Tsukamoto T, Takasaki S, Kikuchi M, Sato Y, Ogura J, Hayakawa Y, Yamaguchi H, Mano N
Chromatography 40 ( 2 ) 71 - 78 2019年05月 [査読有り]
研究論文（学術雑誌）
-
Limited Sampling Strategy for the Estimation of Mycophenolic Acid and its Acyl Glucuronide Metabolite Area under the Concentration-Time Curve in Japanese Lung Transplant Recipients.
Masaki Tanaka, Masafumi Kikuchi, Shinya Takasaki, Tensei Hirasawa, Kensuke Sigeta, Aoi Noda, Miki Akiba, Yasushi Matsuda, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 22 ( 1 ) 407 - 417 2019年 [査読有り]
研究論文（学術雑誌）
PURPOSE: The dose of mycophenolate mofetil (MMF) used to prevent rejection after lung transplantation is often adjusted based on the 12-hour area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). A limited sampling strategy (LSS) is useful to define the pharmacokinetic (PK) profiles of MPA and mycophenolic acid acyl glucuronide (AcMPAG). Therefore, this study aimed to design a LSS based on multiple linear regression for estimating the AUC0-12 of MPA and AcMPAG at the minimum blood sampling points in Japanese lung transplant patients with concomitant tacrolimus. METHODS: Forty-five lung transplantation recipients were enrolled in a PK study of MPA, mycophenolic acid glucuronide (MPAG), and AcMPAG. The plasma MPA, MPAG, and AcMPAG concentrations were determined just before and at 0.5, 1, 2, 4, 8, and 12 hours after dosing. The AUC0-12 of MPA and AcMPAG was calculated using a linear trapezoidal rule from the plasma concentration of each blood sampling time. LSS was used to develop models for estimated AUC in the model group (n = 23) and was evaluated in the validation group (n = 22). RESULTS: The best three time-point equation was 4.04 + 1.64·C1 + 3.08·C4 + 5.17·C8 for MPA, and -0.13 + 3.01·C1 + 3.51·C4 + 5.74·C8 for AcMPAG. The prediction errors (PE) and the absolute prediction errors (APE) were within the clinically acceptable ± 5% and 15% range, respectively (MPA: PE = 2.00%, APE = 11.66%, AcMPAG: PE = 0.98%, APE = 14.69%). The percentage of estimated AUC0-12 within ± 15% of the observed AUC0-12 was 77.27% for MPA and 81.82% for AcMPAG. CONCLUSION: LSS using three time-point (C1, C4, and C8) provides the most reliable and accurate simultaneous estimation of the AUC0-12 of MPA and AcMPAG in Japanese lung transplant patients.
-
Long-term relationship between everolimus blood concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma: a prospective study.
Shinya Takasaki, Hiroaki Yamaguchi, Yoshihide Kawasaki, Masafumi Kikuchi, Masaki Tanaka, Akihiro Ito, Nariyasu Mano
Journal of pharmaceutical health care and sciences 5 6 - 6 2019年 [査読有り]
研究論文（学術雑誌）
Background: Everolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Recently, personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. In this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC. Methods: Patients with mRCC were enrolled following treatment with everolimus at Tohoku University Hospital between April 2012 and December 2016. The relationship between everolimus trough blood concentration on day 8 of everolimus therapy and just before discontinuation or dose reduction, and their adverse events were evaluated. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the profiles of adverse events, and efficacy [time to treatment failure (TTF) and progression-free survival (PFS)] were evaluated. Results: The median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1-28.0) ng/mL and 14.8 (6.4-58.4) ng/mL, respectively, with no significant difference between these values (P = 0.3594). Patients (n = 6) with discontinuation or dose reduction following adverse events in everolimus therapy had significantly higher blood concentrations than patients (n = 4) with dose maintenance on both day 8 (median, 18.0 vs 8.2 ng/mL; P = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; P = 0.0142). Median TTF and PFS of the total patients (n = 10) were 96 days (95% confidence interval [CI], 26-288) and 235 days (95% CI, 28-291), respectively. Subgroup analysis showed that TTF of the patients with > 15.3 ng/mL (n = 5) was not significantly different from that of the patients with ≤15.3 ng/mL (n = 5; P = 0.5622). Similarly, PFS of the patients with > 15.3 ng/mL was not significantly different from that of the patients with ≤15.3 ng/mL (P = 0.3436). Conclusions: This study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and adverse events in Japanese patients with mRCC. Thus, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events for Japanese patients with mRCC.
-
Relationships between sunitinib plasma concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma.
Shinya Takasaki, Yoshihide Kawasaki, Masafumi Kikuchi, Masaki Tanaka, Masato Suzuka, Aoi Noda, Yuji Sato, Shinichi Yamashita, Koji Mitsuzuka, Hideo Saito, Akihiro Ito, Hiroaki Yamaguchi, Yoichi Arai, Nariyasu Mano
International journal of clinical oncology 23 ( 5 ) 936 - 943 2018年10月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: The aim was to investigate the relationships between total sunitinib plasma concentrations (sunitinib plus its active metabolite; N-desethyl sunitinib) and clinical outcomes in Japanese patients with metastatic renal cell carcinoma (mRCC). METHODS: Twenty patients with mRCC were enrolled following treatment with sunitinib. To assess safety, the total sunitinib concentration range up to discontinuation of treatment and dosage reduction associated with adverse events within 6 weeks from initiating administration were analyzed. The longest administered sunitinib dosage was defined as the maintenance dose, and the relationship between total sunitinib concentration at the maintenance dosage and sunitinib efficacy was investigated. RESULTS: Total sunitinib concentration was significantly higher in patients who discontinued treatment or had dosage reduction due to adverse events within 6 weeks after initiation of sunitinib than in patients who continued treatment with the initial dosage. The time to treatment failure, progression-free survival, and overall survival were better in patients with total sunitinib concentrations < 50 ng/mL than in those with concentrations ≥ 50 ng/mL. CONCLUSIONS: The present study demonstrated that the effective range of total sunitinib concentration in Japanese patients with mRCC was lower than 50-100 ng/mL which was previously reported. These results indicate that therapeutic drug monitoring could maintain the therapeutic effect of sunitinib while minimizing adverse events by personalizing sunitinib dosages for Japanese patients with mRCC.
-
乳がんFEC100療法におけるニューロキニン1受容体拮抗薬の費用効果分析の検討
中川 直人, 渡邊 桂子, 菊地 正史, 石田 孝宣, 木皿 重樹, Lai Leanne
医薬品相互作用研究 ( 医薬品相互作用研究会 ) 42 ( 2 ) 95 - 102 2018年06月 [査読有り]
研究論文（学術雑誌）
乳がんFEC100療法(Fluorouracil-Epirubicin-Cyclophosphamide)4コースを終えた外来患者62名(女性)を対象とし、アプレピタント(APR)を投与したA群、ホスアプレピタント(FOS)を投与したF群とした。A群1コースは合計9516円、F群1コースは合計12635円で、全体的にF群の方が直接医療費は高くなった。A群のCR率はF群よりも高く、また期待費用もF群より安価であることから、APRは優位(効果が大きく費用が安い)であった。感度分析を行い、FOSのCR率が仮に高くなっても、APRの優位性は揺るがないことが明らかとなった。
-
Simultaneous analysis of oral anticancer drugs for renal cell carcinoma in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry.
Shinya Takasaki, Masaki Tanaka, Masafumi Kikuchi, Masamitsu Maekawa, Yoshihide Kawasaki, Akihiro Ito, Yoichi Arai, Hiroaki Yamaguchi, Nariyasu Mano
Biomedical chromatography : BMC 32 ( 6 ) e4184 2018年06月 [査読有り]
研究論文（学術雑誌）
An analytical method using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry has been developed and validated for simultaneous measurement of four tyrosine kinase inhibitors used for renal cell carcinoma and their metabolites in human plasma. Despite their similar structures, it is difficult to measure plasma levels of these compounds simultaneously using optimal MS parameters for each compound because a quantitative range exceeding 50,000-fold is required. To overcome this problem, we used a linear range shift technique using in-source collision-induced dissociation. Linearity ranges of sorafenib, sorafenib N-oxide, sunitinib, N-desethyl sunitinib, axitinib and pazopanib were 100-10,000, 10-1,000, 1-100, 1-100, 1-100 and 500-50,000 ng/mL, respectively. The intra- and inter-day precision and accuracy were high, and coefficients of variation and relative error were <10.3% and within ±11.8%, respectively. The matrix effects of all analytes ranged from 87.7 to 114.8%. Extraction recoveries and overall recoveries showed small extraction loss (<15.0%) for all analytes. Moreover, all cancer patient samples used in this study were successfully quantified and fell within the linear range of measurement. Therefore, this novel analytical system using in-source collision-induced dissociation has sufficient performance to measure plasma concentrations of these four tyrosine kinase inhibitors and their metabolites for therapeutic drug monitoring.
-
M. Maekawa, M. Mori, M. Fujiyoshi, H. Suzuki, K. Yanai, A. Noda, M. Tanaka, S. Takasaki, M. Kikuchi, K. Akasaka, S. Kisara, M. Matsuura, K. Hisamichi, M. Sato, J. Goto, M. Shimada, H. Yamaguchi, N. Mano
Chromatography ( The Society for Chromatographic Sciences ) 39 ( 1 ) 41 - 47 2018年 [査読有り]
研究論文（学術雑誌）
-
Comparison of PETINIA and LC-MS/MS for determining plasma mycophenolic acid concentrations in Japanese lung transplant recipients.
Masafumi Kikuchi, Masaki Tanaka, Shinya Takasaki, Akiko Takahashi, Miki Akiba, Yasushi Matsuda, Masafumi Noda, Kanehiko Hisamichi, Hiroaki Yamaguchi, Yoshinori Okada, Nariyasu Mano
Journal of pharmaceutical health care and sciences 4 7 - 7 2018年 [査読有り]
研究論文（学術雑誌）
Background: Mycophenolic acid (MPA) treatment requires therapeutic drug monitoring to improve the outcome after organ transplantation. The aim of this study was to compare two methods, a particle enhanced turbidimetric inhibition immunoassay (PETINIA) and a reference liquid chromatography tandem mass spectrometry (LC-MS/MS) for determining plasma MPA concentrations from Japanese lung transplant recipients. Methods: Plasma MPA concentrations were determined from 20 Japanese lung transplant recipients using LC-MS/MS and the PETINIA on the Dimension Xpand Plus-HM analyzer. Results: The mean MPA concentration measured by PETINIA was significantly higher than that measured by LC-MS/MS (3.26 ± 2.73 μg/mL versus 2.82 ± 2.71 μg/mL, P < 0.0001). The result of the Passing Bablok analysis was a slope of 1.104 (95% confidence interval [CI], 1.036-1.150) and an intercept of 0.229 (95%CI, 0.144-0.315). Bland-Altman analysis revealed PETINIA overestimates plasma MPA concentration by 26.25% and 95%CI from 21.43 to 31.07%. Conclusion: The measurement of MPA by the PETINIA in Japanese lung transplant patients should evaluate the result with attention to positive bias.
-
Development of a Liquid Chromatography-Tandem Mass Spectrometric Method for Quantification of Mycophenolic Acid and Its Glucuronides in Dried Blood Spot Samples.
Hiromasa Iboshi, Hiroaki Yamaguchi, Hiroyuki Suzuki, Masafumi Kikuchi, Masaki Tanaka, Shinya Takasaki, Akiko Takahashi, Masamitsu Maekawa, Miki Shimada, Yasushi Matsuda, Yoshinori Okada, Nariyasu Mano
Therapeutic drug monitoring 39 ( 6 ) 648 - 653 2017年12月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Personalized immunosuppressive therapy, including accurate drug dosing based on the drug blood level, leads to better clinical outcomes, specifically regarding avoidance of drug-induced adverse effects and maintenance of efficacy. Mycophenolic acid (MPA) is used as an immunosuppressant in transplantation of various solid organs. The aim of this study was to develop a method for quantification of MPA and its metabolites, mycophenolic acid 7-O-glucuronide (MPAG) and mycophenolic acid acyl glucuronide, in dried blood spot (DBS) samples, using liquid chromatography/electrospray ionization/tandem mass spectrometry. METHODS: For sample preparation, a microwave-drying approach was used to deactivate enzymes and reduce drying time. Blood volume was calculated in a DBS disk of 3 mm diameter. Concentrations of analytes in plasma from patients receiving mycophenolate mofetil were compared with DBS samples after hematocrit correction. RESULTS: The method yielded good recoveries of all 3 analytes (90.3%-104.2%). Blood volume in the disk was calculated as 3.0 ± 0.2 μL. Linearity over concentration ranges of 0.1-30 mcg/mL MPA, 0.1-200 mcg/mL MPAG, and 0.125-10 mcg/mL mycophenolic acid acyl glucuronide was obtained with r ≥0.999. Intraday and interday variations were less than 14.6%, and accuracy was within ±11.9%. Passing-Bablok analysis showed no significant differences between plasma concentrations and DBS concentrations after hematocrit correction of MPA and MPAG. CONCLUSIONS: We developed and validated a liquid chromatography/electrospray ionization-tandem mass spectrometry method for analysis of MPA in DBS samples. The method is useful for monitoring the MPA blood level.
-
Severe toxicity induced by accumulation of active sunitinib metabolite in a Japanese patient with renal cell carcinoma: a case report.
Shinya Takasaki, Masafumi Kikuchi, Yoshihide Kawasaki, Akihiro Ito, Yoichi Arai, Hiroaki Yamaguchi, Nariyasu Mano
Journal of medical case reports 11 ( 1 ) 28 - 28 2017年02月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Sunitinib is a multi-targeted tyrosine kinase inhibitor that is approved for treatment of renal cell carcinoma as an oral anticancer drug. Therapeutic drug monitoring of total sunitinib (sunitinib and N-desethyl sunitinib) is used in our hospital to improve therapeutic efficacy, while preventing adverse effects. Here, we report the first case of a patient with metastatic renal cell carcinoma undergoing hemodialysis and presenting severe adverse events induced by the accumulation of N-desethyl sunitinib. CASE PRESENTATION: A 60-year-old Japanese man was diagnosed with metastatic renal cell carcinoma requiring hemodialysis. On day 26 of the first cycle of sunitinib therapy, our patient presented grade 3 thrombocytopenia and leukopenia, which required interruption of therapy although the plasma levels of total sunitinib in the patient were less than the effective concentration of 50 ng/mL. The elimination half-life of sunitinib was normal at 50.8 hours, but that of N-desethyl sunitinib was an extended 211.4 hours. Moreover, the N-desethyl sunitinib/sunitinib trough level ratio was higher than 1.0. We attribute our patient's severe adverse events to the excessive accumulation of N-desethyl sunitinib owing to its delayed excretion. Although the reason for the delayed excretion of N-desethyl sunitinib in this patient was unknown, it may have been caused by genetic polymorphisms related to the pharmacokinetics of sunitinib rather than the hemodialysis. In this case, the patient was homozygous for the ABCG2 421C allele, but was capable of potentially harboring polymorphisms in other genes, such as ABCB1, an efflux pump of sunitinib. In addition, even though there is no clear evidence, urinary excretion of the metabolic products of N-desethyl sunitinib could be inhibited by the interaction of transporters such as the organic ion transporter. CONCLUSIONS: The monitoring of not only total sunitinib concentration but also N-desethyl sunitinib concentration and their elimination half-lives during sunitinib therapy is recommended to avoid critical adverse events.
-
エベロリムス誘発肝機能障害により血中エベロリムス濃度高値と高血糖を示した腎細胞癌患者の1例
高崎 新也, 菊地 正史, 川崎 芳英, 伊藤 明宏, 荒井 陽一, 山口 浩明, 眞野 成康
癌と化学療法 ( (株)癌と化学療法社 ) 44 ( 1 ) 87 - 89 2017年01月 [査読有り]
研究論文（学術雑誌）
エベロリムス誘発肝機能障害により、血中エベロリムス濃度高値と高血糖を示した腎細胞癌患者の1例を経験したので報告する。症例は74歳、男性。右腎細胞癌、多発肺転移の診断で右腎摘除術後、インターフェロン、ソラフェニブにより治療されたが病勢進行となり、エベロリムスを開始した。エベロリムス投与15日目にgrade 3の肝機能障害および高血糖が認められ、血中エベロリムス濃度が58.4ng/mLと高値を示したことから、エベロリムスを休薬した。肝機能検査値の回復後にエベロリムスを減量して再開したが、再び肝機能障害が認められたため、エベロリムスの血中濃度が高値を示す前に投与を中止した。肝機能検査値の回復後にアキシチニブへ変更し、その後は肝機能障害および高血糖を認めなかった。腎細胞癌患者に対するエベロリムス治療において肝機能障害が認められた場合、血中エベロリムス濃度が高値を示す可能性が示唆された。したがって、血中エベロリムス濃度測定は有害事象の管理に重要であると考えられた。(著者抄録)
-
[A Case of Renal Cell Carcinoma with High Everolimus Blood Concentrations and Hyperglycemia Due to Everolimus-Induced Hepatic Dysfunction].
Shinya Takasaki, Masafumi Kikuchi, Yoshihide Kawasaki, Akihiro Ito, Yoichi Arai, Hiroaki Yamaguchi, Nariyasu Mano
Gan to kagaku ryoho. Cancer & chemotherapy 44 ( 1 ) 87 - 89 2017年01月 [査読有り]
研究論文（学術雑誌）
We report the case of a patient who had renal cell carcinoma with high everolimus blood concentrations and hyperglycemia due to everolimus-induced hepatic dysfunction. A 74-year-old man who underwent right nephrectomy for renal cell carcinoma was administered everolimus for multiple lung metastases. Everolimus caused grade 3 hepatic dysfunction and hyperglycemia; hence, high blood levels of everolimus were observed. Although the patient was re-administrated everolimus after recovering from hepatic dysfunction, hepatic function test values worsened again. Everolimus was discontinued before its blood concentration increased, and the patient was switched to axitinib treatment. Therefore, the measurement of everolimus blood level is considered useful for the management of adverse events in renal cell carcinoma.
-
がんの治療手帳の作成とセミナーの開催による多職種連携への取り組み
菊地 正史, 小林 美奈子, 中川 直人, 木皿 重樹, 松浦 正樹, 久道 周彦, 山田 卓郎, 佐々木 孝雄, 石岡 千加史, 眞野 成康
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 52 ( 12 ) 1493 - 1498 2016年12月 [査読有り]
研究論文（学術雑誌）
がん化学療法の外来化が進むなかで、安全で安心ながん治療の提供には、保険薬局を含めた地域における多職種連携が重要となっている。東北大学病院では、患者情報とがん化学療法の基礎知識の共有を目的に、がんの治療手帳(以下、治療手帳)を作成するとともに、宮城県薬剤師会と宮城県各地域における多職種連携セミナー(以下、セミナー)を開催した。治療手帳は、アンケート調査に基づく保険薬局薬剤師が必要とする情報ばかりか、患者自らが副作用の発現状況や経口抗がん薬の服薬状況を記入できる情報共有ツールとなった。また、セミナーの平均参加人数は約137名/回であり、アンケート調査の結果、参加者の約97%が内容に満足またはやや満足と回答し、90%以上がセミナーで得られた情報は抗がん薬の調剤や服薬指導時に有益であると回答した。今回の取り組みは、地域における多職種連携を強化し、安全で質の高いがん化学療法を実施するうえで役立つものと期待される。(著者抄録)
-
イトラコナゾールの併用によりシロリムスの全血中トラフ濃度が高値を示したリンパ脈管筋腫症患者の2例
菊地 正史, 野田 あおい, 田中 雅樹, 高橋 阿希子, 秋場 美紀, 松田 安史, 星川 康, 久道 周彦, 山口 浩明, 岡田 克典, 眞野 成康
TDM研究 ( (一社)日本TDM学会 ) 33 ( 3 ) 104 - 108 2016年09月 [査読有り]
研究論文（学術雑誌）
症例1:49歳、女性。リンパ脈管筋腫症(LAM)の進行に伴う右片肺移植施行後、シロリムス(SRL)を開始し、2mg/日の連日投与で全血中トラフ濃度は6.7〜7ng/mLで安定していた。深在性真菌症の予防にイトラコナゾール(ITCZ)50mg/日の連日投与を開始するため、SRL1mg/日の連日投与に減量したが、併用13日目に治療濃度域の上限(15ng/mL)に近い13.2ng/mLまで上昇した。SRLを1mg/日の隔日投与に変更し、併用17日目に8.6ng/mLまで低下した。症例2:40歳、女性。LAMの進行に伴う両肺移植施行後、深在性真菌症の予防にITCZを50mg/日で連日投与していた。SRLを1mg/日の連日投与で開始したところ、併用6日目の全血中トラフ濃度は治療濃度域の上限を超える28.4ng/mLとなった。SRLを1mg/日の3日毎投与に変更し、併用9日目に11.3ng/mLまで低下した。肺移植後のLAM患者において、SRLとITCZを併用する場合、SRLの減量や投与間隔の延長を検討し、全血中トラフ濃度を頻回に測定しながら投与量を調節することが重要である。(著者抄録)
-
肺移植後患者におけるミコフェノール酸モフェチル血中濃度測定の検討
矢吹 皓, 船橋 淳一, 岡田 克典, 渡邉 龍秋, 菊地 正史, 野津田 泰嗣, 新井川 弘道, 松田 安史, 野田 雅史, 桜田 晃, 星川 康
Organ Biology ( 一般社団法人 日本臓器保存生物医学会 ) 23 ( 2 ) 141 - 144 2016年
研究論文（学術雑誌）
Mycophenolate mofetil (MMF) has been used as a standard immunosuppressive agent after lung transplantation. MMF is rapidly metabolized to active constituent, mycophenolic acid (MPA), after intake. Gastrointestinal side- effects and leukocytopenia are common adverse effects of MMF. Although, therapeutic drug monitoring (TDM) for calcineurin inhibitors is widely used, the role of TDM for MPA is unclear in lung transplantation. We investigated the correlation among the blood concentration of MPA, the dosage of MMF and the number of leukocyte in lung transplant recipients. The correlation coefficient between the blood concentration of MPA and the dosage of MMF was not significant, so MMF might require TDM. On the other hand, neither the correlation coefficients between the number of leukocyte and the blood concentration of MPA nor the correlation coefficients between the number of leukocyte and the dosage of MMF were not significant. Further investigation is necessary to find the meanings of TDM for MPA after lung transplantation.
-
乳がんFEC100療法におけるホスアプレピタント注とアプレピタントカプセルの有効性と安全性の比較
渡邊 桂子, 菊地 正史, 木皿 重樹, 小笠原 喜美代, 久道 周彦, 石田 孝宣, 鈴木 直人, 村井 ユリ子, 島田 美樹, 富岡 佳久, 石岡 千加史, 眞野 成康
医薬品相互作用研究 ( 医薬品相互作用研究会 ) 39 ( 1 ) 29 - 35 2015年08月 [査読有り]
研究論文（学術雑誌）
乳がんFEC100療法におけるホスアプレピタント注(FOS)とアプレピタントカプセル(APR)の有効性と安全性について比較検討した。乳がんFEC100療法を施行し、FOSを末梢静脈から投与、またはAPRを内服し、制吐療法を施行した32例を対象とした。FOSを投与したFOS群19例、APRを内服したAPR群13例であった。急性および遅発性悪心は、それぞれFOS群7例、APR群5例およびFOS群13例、APR群6例に発現し、重症度は最大でgrade 2であった。急性嘔吐は、両群ともに0例で、遅発性嘔吐はFOS群の2例に発現し、重症度は最大でgrade 2であった。CR率は、FOS群36.8%、APR群76.9%で有意差を認めた。注射部位反応はFOS群の17例で発現し、血管痛や静脈炎が有意に高値であった。
-
PTX療法におけるラニチジン注とファモチジン注のアレルギー発現率の後方視的コホート研究
片岡 佑太, 菊地 正史, 中川 直人, 木皿 重樹, 高橋 哉子, 小笠原 喜美代, 我妻 恭行, 久道 周彦, 鈴木 直人, 村井 ユリ子, 富岡 佳久, 石岡 千加史, 島田 美樹, 眞野 成康
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 49 ( 10 ) 1091 - 1095 2013年10月 [査読有り]
研究論文（学術雑誌）
パクリタキセル注(以下、PTX)を用いるがん化学療法においては、アレルギー予防のためH2受容体拮抗薬のラニチジン注またはファモチジン注が前投薬されるが、ラニチジン注を用いた場合にしばしばそう痒感、蕁麻疹などが発現し、東北大学病院のがん化学療法に関するプロトコル審査委員会で問題提起された。そこで、ラニチジン注投与群175例(以下、R群)とファモチジン注投与群97例(以下、F群)について、両群間のアレルギー発現率を後方視的に比較検討した。その結果、前投薬中に発現したアレルギーはR群が12例(6.9%)、F群が0例(0%)であり、R群において有意に高頻度に発現していた(p<0.01)。一方、PTX投与中に発現したアレルギーは、R群で1例(0.6%)、F群で2例(2.1%)であり、両群に有意差は認められなかった。以上より、PTXの前投薬にはラニチジン注よりもファモチジン注のほうが安全に使用できることが示唆された。(著者抄録)
-
Structure and Cytotoxic Activity of Enzymatic Hydrolysis Products of Secoiridoid Glucosides, Isoligustroside and Isooleuropein
Masafumi Kikuchi, Yasunori Yaoita, Nariyasu Mano, Masao Kikuchi
CHEMISTRY & BIODIVERSITY ( WILEY-BLACKWELL ) 8 ( 4 ) 651 - 657 2011年04月 [査読有り]
研究論文（学術雑誌）
Hydrolysis of isoligustroside (1) and isooleuropein (2), secoiridoid glucosides, in the presence of beta-glucosidase provided 2-(4-hydroxyphenyl)methyl (2R,3S,4S)-3-formyl-3,4-dihydro-4-(2-methoxy-2-oxoethyl)-2-methyl-2H-pyran-5-carboxylate (3) and 2-(3,4-dihydroxyphenyl)methyl (2R,3S,4S)-3-formyl-3,4-dihydro-4-(2-methoxy-2-oxoethyl)-2-methyl-2H-pyran-5-carboxylate (4), respectively. The structures of 3 and 4 were elucidated on the basis of extensive spectral analyses, including 2D-NMR experiments. Compounds 3 and 4 were found to be new rearrangement products of the aglycones of 1 and 2. The cytotoxic activities of 3 and 4 were evaluated using a disease-oriented panel of 39 human cancer cell lines and showed moderate cytotoxic activity for 4, while 3 exhibited weaker activity compared to that of 4.
-
Cytotoxic and EGFR tyrosine kinase inhibitory activities of aglycone derivatives obtained by enzymatic hydrolysis of oleoside-type secoiridoid glucosides, oleuropein and ligustroside
Masafumi Kikuchi, Nariyasu Mano, Yoshimasa Uehara, Koichi Machida, Masao Kikuchi
JOURNAL OF NATURAL MEDICINES ( SPRINGER JAPAN KK ) 65 ( 1 ) 237 - 240 2011年01月 [査読有り]
研究論文（学術雑誌）
Hydrolysis of oleoside-type secoiridoid glucosides, oleuropein (1) and ligustroside (2), in the presence of beta-glucosidase provided their aglycones, named (5S,8R,9S)-7-3,4-dihydroxyphenethyl elenolate (3) and (5S,8R,9S)-7-4-hydroxyphenethyl elenolate (4), respectively. The structures of 3 and 4 were identified by spectroscopic means and optical rotation measurements. Evaluation of the cytotoxic and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activities of compounds 1-4 showed that compounds 3 and 4 exhibited moderate cytotoxicity against a disease-oriented panel of 39 human cancer cell lines in vitro, whereas compound 3 inhibited the enzyme.
-
Masafumi Kikuchi, Yasunori Yaoita Nariyasu Mano, Masao Kikuchi
Shoyakugaku Zasshi ( 日本生薬学会 ) 64 ( 2 ) 104 - 105 2011年01月 [査読有り]
研究論文（学術雑誌）
From the leaves of Syringa vulgaris L. (Oleaceae), nine known glycosides were isolated and identified: 3,4-dihydroxyphenethyl β-D-glucopyranoside (1), acteoside (2), echinacoside (3), oleoacteoside (4), oleoechinacoside (5), isooleoacteoside (6), syringopicroside B (7), syringalactone B (8), and 2"-epi-frameroside (9). This is the first time that compounds 6, 7 and 9 have been isolated from the leaves of S. vulgaris. The growth inhibitory activity of compounds 1-9 against 39 human cancer cell lines was evaluated.
-
New physiological function of secoiridoids: neuritogenic activity in PC12h cells
Kenzo Chiba, Matsumi Yamazaki, Masafumi Kikuchi, Rie Kakuda, Masao Kikuchi
JOURNAL OF NATURAL MEDICINES ( SPRINGER TOKYO ) 65 ( 1 ) 186 - 190 2011年01月 [査読有り]
研究論文（学術雑誌）
Previously, we have reported that geniposide isolated from an extract of Gardenia fructus has neuritogenic activity in PC12h cells, a subclone of rat pheochromocytoma cells. Furthermore, we have indicated that several geniposide-related iridoid compounds also had similar potent neuritogenic activity. In this study, we have examined the effects of various secoiridoid compounds [K-1, sweroside; K-2, swertiamarin; K-3, gentiopicroside; K-4, 6'-O-beta-d-glucopyranosylsweroside; K-5, 6'-O-beta-d-glucopyranosylgentiopicroside; K-6, 6'-O-beta-d-glucopyranosylswertiamarin; K-7, 5'-O-beta-d-glucopyranosylamarogentin; K-8, 5'-O-beta-d-glucopyranosylamaroswertin; H-1, n-butyl vogeloside; H-2, n-butyl epivogeloside; H-3, (7S)-secologanin butyl methyl acetal; H-4, (7R)-secologanin butyl methyl acetal; H-5, secologanin dimethyl acetal] isolated from various medicinal herbs. The secoiridoids H-1, H-2, H-3, H-4, and H-5 induced significant neurite outgrowth. Among these H-series compounds, H-2 was the most potent neuritogenic compound. Among the K-series compounds, K-1, K-2, K-3, and K-8 showed the most potent activity. These results suggest that secoiridoids have neuritogenic activity in PC12h cells and that these secoiridoid compounds are promising starting compounds for the development of neurotrophic factor-like and iridoid compounds.
-
ムラサキハシドイの葉のセコイリドイド配糖体の構造並びにヒトがん細胞株に対する増殖阻害活性について
八百板 康範, 菊地 正史, 菊地 正雄
東北薬科大学研究誌 ( 東北医科薬科大学 ) ( 57 ) 47 - 50 2010年12月 [査読有り]
研究論文（学術雑誌）
-
Three new glycosides from the leaves of Hydrangea macrophylla subsp serrata (THUNB.) MAKINO
Masao Kikuchi, Rie Kakuda, Masafumi Kikuchi, Yasunori Yaoita
CHEMICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 56 ( 4 ) 610 - 611 2008年04月 [査読有り]
研究論文（学術雑誌）
Three new glycosides, 7-deoxyloganic acid beta-D-glueopyranosyl ester (1), (3R)-hydrangenol 8,4'-di-O-beta-D-glu-copyranoside (2), and (6R,7E,9R)-megastigma-4,7-dien-3-one 9,13-di-O-beta-D-glueopyranoside (3), have been isolated from the leaves of Hydrangea macrophylla subsp. serrata (THUNB.) MAKINO (Saxifragaceae). The structures of 1-3 were elucidated on the basis of spectral data and chemical evidence.
-
Monohydroxy-Substituted Polyunsaturated Fatty Acids from Swertia japonica
Masafumi Kikuchi, Yasunori Yaoita, Masao Kiknchi
HELVETICA CHIMICA ACTA ( WILEY-V C H VERLAG GMBH ) 91 ( 10 ) 1857 - 1862 2008年 [査読有り]
研究論文（学術雑誌）
Fourteen monohydroxy-substituted polyunsaturated fatty acids, including two new compounds. (9Z,12S,13E,15Z)-12-hydroxyoetadeca-9,13,15-trienoic acid (10) and (9Z,12Z,14E,16R)-16-hydroxyoctadeca-9,12,14-trienoic acid acid (13), and 12 known ones. i.e., 1-9, 11, 12, and 14, were isolated from the whole plants of Swertia japonica MAKINO, and characterized as the corresponding methyl esters 1a- 14a. Their structures were elucidated by analysis of the corresponding spectroscopic data, and the absolute configurations of 10a and 13a were determined by the Mosher-ester method. The CD spectra (Table) of compounds 1a-14a are briefly discussed. This IS the first report oil the isolation of monohydroxy-substituted polyunsaturated fatty acids from the Swertia genus in Gentianaceae.
-
New secoiridoid glucosides from Swertia japonica
Masafumi Kikuchi, Rie Kakuda, Yasunori Yaoita, Masao Kikuchi
HELVETICA CHIMICA ACTA ( WILEY-V C H VERLAG GMBH ) 91 ( 7 ) 1236 - 1243 2008年 [査読有り]
研究論文（学術雑誌）
Four new secoiridoid glucosides, swertiajaposides C-F (1-4, resp.), were isolated from the whole plant of Swertia japonica MAKINO together with two known compounds, 8-hydroxy-10-hydrosweroside (5) and senburiside IV (6). The structures of 1-4 were elucidated on the basis of spectroscopic, chemical, and physicochemical evidence.
-
Neuritogenesis of herbal geniposide-related compounds in PC12h cells
Kenzo Chiba, Matsumi Yamazaki, Masafumi Kikuchi, Koichi Machida, Masao Kikuchi
JOURNAL OF HEALTH SCIENCE ( PHARMACEUTICAL SOC JAPAN ) 52 ( 6 ) 743 - 747 2006年12月 [査読有り]
研究論文（学術雑誌）
Previously, we have reported that geniposide, a compound isolated from an extract of Gardenia fructus, has neuritogenic activity in PC12h cells, a subclone of the rat pheochromocytoma cell. In this study, we have examined the effects of seven geniposide-related compounds (S-1, 6 alpha-hydroxygeniposide; S-2, 6 beta-hydroxygeniposide; S-3, 6 alpha-methoxygeniposide; S-4, 6 beta-methoxygeniposide; S-5, loganin; S-6, 7-ketologanin; and S-7, syringopicroside) isolated from various medicinal herbs. The geniposide-type iridoids S-1, S-2, S-3, and S-4, and S-7 induced neurite outgrowth that was similar or more potent to that of geniposide. S-2 and S-4, which are optical isomers of S-1 and S-3, respectively, were particularly potent. The 2 loganin-type iridoids, S-5 and S-6, showed less activity than geniposide. The neuritogenic activity of geniposide-type iridoids appears to be not necessarily correlated directly to their hydrophobicity. These results suggest that geniposide-type iridoids have potent neuritogenic activity and that specific configurations for the interactions between iridoid compounds and the target molecule are necessary for neuritogenic function.
-
A new iridoid diglycoside from Gentianae Scabrae Radix
Tomoko Kyoya, Masafumi Kikuchi, Rie Kakuda, Yasunori Yaoita, Masao Kikuchi
Natural Medicines ( 日本生薬学会 ) 59 ( 4 ) 178 - 180 2005年08月 [査読有り]
研究論文（学術雑誌）
A new iridoid diglycoside, gentianaside (1), was isolated together with two known compounds, 6'-O-β-D-glucopyranosylloganic acid (2) and 8-epikingiside (3), from Gentianae Scabrae Radix. The structure of the new compound was elucidated on the basis of spectral data.
-
Secoiridoid glycosides from Gentiana scabra
M Kikuchi, R Kakuda, M Kikuchi, Y Yaoita
JOURNAL OF NATURAL PRODUCTS ( AMER CHEMICAL SOC ) 68 ( 5 ) 751 - 753 2005年05月 [査読有り]
研究論文（学術雑誌）
Six new secoiridoid glycosides, gentiascabraside A (1), 6 beta-hydroxyswertiajaposide A (2), 1-O-beta-D-glucopyranosyl-4-epiamplexine (3), and scabrans G(3) (4), G(4) (5), and G(5) (6), have been isolated from the rhizomes and roots of Gentiana scabra together with a known compound, swertiajaposide A (7). The structures of the new Compounds were determined by spectroscopic (NMR, MS) and chemical means.
-
Studies on the constituents of Swertia japonica MAKINO II.(1)) - On the structures of new glycosides
M Kikuchi, M Kikuchi
CHEMICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 53 ( 1 ) 48 - 51 2005年01月 [査読有り]
研究論文（学術雑誌）
Two new secoiridoid glycosides, swertiajaposide A (1) and swertiajaposide B (2), a new unsaturated alcohol glycoside, 3-butenyl 6'-O-alpha-L-arabinopyranosyl-beta-D-glucopyranoside (3), and a new lignan glycoside, 7R,7'R,8S,8'S-(+)-neo-olivil-4-O-beta-D-glucopyranoside (4), were isolated together with six known compounds from the whole plants of Swertia japonica MAKINO. The structures of the new compounds were elucidated on the basis of chemical and spectroscopic evidence.
-
Studies on the constituents of Swertia japonica MAKINO I. On the structures of new secoiridoid diglycosides
M Kikuchi, M Kikuchi
CHEMICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 52 ( 10 ) 1210 - 1214 2004年10月 [査読有り]
研究論文（学術雑誌）
Eight new secoiridoid diglycosides, 6'-O-alpha-L-arabinopyranosylswertiamarin (1), 3'-O-P-D-glUeopyranosylswertiamarin (2), 4'-O-beta-D-glucopyranosylswertiamarin (3), 3'-O-beta-D-galactopyranosylswertiamarin (4), 6'-O-alpha-D-galactopyranosylswertiamarin (5), 6'-O-beta-D-mannopyranosylswertiamarin (6), 6'-O-beta-D-fructofuranosylswertiamarin (7) and 5"-O-beta-D-glucopyranosylamaroswerin (12), were isolated, together with five known compounds from the whole plants of Swertia japonica MAKINO. The structures of the new compounds were elucidated on the basis of chemical and spectroscopic evidence. Compounds 6 and 7 are the first naturally occuring iridoid diglycosides having an alpha-D-mannopyranosyl unit and beta-D-fructofuranosyl unit, respectively.
-
Triterpenoids from Gentianae Scabrae Radix and Gentianae Radix
Rie Kakuda, Chie Ueno, Nagisa Kobayashi, Masafumi Kikuchi, Yasunori Yaoita, Masao Kikuchi
Natural Medicines ( 日本生薬学会 ) 58 ( 1 ) 22 - 26 2004年02月 [査読有り]
研究論文（学術雑誌）
For new triterpenoids, uvaol 3-O-linoleate (1), uvaol 3-O-stearate (2), erythrodiol 3-O-linoleate (3) and erythrodiol 3-O-stearate (4), were isolated from Gentianae Scabrae Radix. Compounds 1 and 2, and an inseparable mixture of the new triterpenoids, α-amyrin 3-O-coriolate (5) and α-amyrin 3-O-dimorphecolate (6), were obtained from Gentianae Radix. The structures of the new compounds were elucidated on the basis of spectral data.
-
Studies on the constituents of Gentiana species. II. A new triterpenoid, and (S)-(+)- and (R)-(-)-gentiolactones from Gentiana lutea
R Kakuda, K Machida, Y Yaoita, M Kikuchi, M Kikuchi
CHEMICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 51 ( 7 ) 885 - 887 2003年07月 [査読有り]
研究論文（学術雑誌）
A new triterpenoid, 12-ursene-3beta, 11alpha-diol 3-O-palmitate (1), has been isolated from the rhizomes and roots of Gentiana lutea, together with the artificial diene derivative, 9 (11), 12-ursadien-3beta-ol 3-O-palmitate (1a) and five known compounds (3-7). Their structures were established on the basis of spectral analysis. In addition, (+/-)-gentiolactone [(+/-)-2], isolated from this plant, was successfully separated into its enantiomers [(+)-2, (-)-2] for the first time, and the absolute configurations at C-9 of (+)-2, (-)-2 were assigned as S and R, respectively, from the optical rotations and the circular dichroism (CD) spectral data.
-
New triterpenoids from Gentiana lutea
Y Toriumi, R Kakuda, M Kikuchi, Y Yaoita, M Kikuchi
CHEMICAL & PHARMACEUTICAL BULLETIN ( PHARMACEUTICAL SOC JAPAN ) 51 ( 1 ) 89 - 91 2003年01月 [査読有り]
研究論文（学術雑誌）
Three new triterpenoids, 2,3-seco-3-oxours-12-en-2-oic acid, 2,3-seco-3-oxoolean-12-en-2-oic acid, and betulin 3-O-palmitate, have been isolated from the rhizomes and roots of Gentiana lutea, together with five known ones. The structures of the new compounds were determined by spectral and chemical methods.
-
ゲンチアナの化学成分について(第3報)
上野稚恵, 角田利枝, 菊地正史, 八百板康範, 町田浩一, 菊地正雄
東北薬科大学研究誌 ( 50 ) 81 - 84 2003年 [査読有り]
研究論文（学術雑誌）
-
リュウタンの化学成分について(第3報)
小林渚, 角田利枝, 菊地正史, 八百板康範, 町田浩一, 菊地正雄
東北薬科大学研究誌 ( 50 ) 85 - 88 2003年 [査読有り]
研究論文（学術雑誌）
-
Sterol constituents from Poria cocos
Yasunori Yaoita, Masafumi Kikuchi, Masao Kikuchi
Natural Medicines ( 日本生薬学会 ) 56 ( 2 ) 63 - 63 2002年01月 [査読有り]
研究論文（学術雑誌）