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

BACKGROUND/AIM: Everolimus-resistant Caki/EV and 786/EV cells have been established from human derived renal cell carcinoma cells, Caki-2 and 786-O, respectively. These cells exhibit resistance to everolimus and to other mTOR inhibitors and erlotinib. However, the sensitivity of these resistant cells to classical and cytotoxic anticancer drugs remain unclear. The aim of the study was to examine sensitivity of Caki/EV and 786/EV cells to classical and cytotoxic anticancer drugs. MATERIALS AND METHODS: Sensitivity to classical and cytotoxic anticancer drugs in Caki/EV and 786/EV cells was evaluated using the WST-1 (tetrazolium salts) colorimetric assay and was compared to those of the corresponding parental cells. The mRNA expression levels were measured using SYBR® green based quantitative reverse transcription-polymerase chain reaction. RESULTS: Sensitivity to vinblastine, vincristine, paclitaxel, doxorubicin, etoposide, SN-38 (active metabolite of irinotecan), 5-fluorouracil, cisplatin, and carboplatin varied in the resistant cells. Sensitivity to carboplatin and SN-38 was comparable between resistant cells and their parental cells, whereas sensitivity to vinca alkaloids, etoposide, 5-fluorouracil, and cisplatin decreased in the resistant cells. However, sensitivity to paclitaxel and doxorubicin was remarkably enhanced in both resistant cells compared to that of parental cells, this could be partially explained by down-regulation of ABCB1 mRNA expression. CONCLUSION: The everolimus-resistant Caki/EV and 786/EV cells showed cross-resistance to classical and cytotoxic anticancer drugs. However, Caki/EV and 786/EV cells exhibited a remarkable increase in sensitivity to paclitaxel and doxorubicin, and ABCB1 mRNA was down-regulated in response to long-term exposure to everolimus.

DOI： 10.21873/anticanres.17099

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PURPOSE: Although several potential radioprotectants have been explored, radiation esophagitis is still difficult to control. Further development of supportive therapies is required. Our purpose was to investigate the efficacy and safety of cystine and theanine for esophagitis in non-small cell lung cancer (NSCLC) patients undergoing chemoradiotherapy (CRT). METHODS: This study is a prospective observational study. The participants were recruited from unresectable locally advanced NSCLC who had scheduled to receive weekly paclitaxel or nab-paclitaxel/carboplatin plus radiation therapy (60 Gy in 30 fractions) for 6 weeks. They took an oral amino acid supplement containing 700 mg cystine and 280 mg theanine once daily regardless of CRT timing from the start of CRT until completion. The primary endpoint was the incidence of any grade esophagitis. The secondary endpoints were quality of life (QoL) and adverse events (AEs). RESULTS: A total of 26 patients were evaluated. All participants completed 60 Gy of RT in 30 fractions. The overall incidence of esophagitis was 73%; however, no ≥ grade 3 was reported. There were no AEs likely to be related to cystine and theanine. The mean EuroQoL 5-Dimension 5-Level health index score before and after chemoradiotherapy was 0.952 ± 0.0591 and 0.952 ± 0.0515 (P = 0.89), and the mean Visual Analogue Scale scores before and after treatment were 67.9 ± 15.4 and 79.4 ± 13.2 (P = 0.0047), respectively. CONCLUSION: Our study showed no severe esophagitis, any AEs, nor QoL decrease in NSCLC patients receiving CRT. Cystine and theanine are potentially effective to reduce severe CRT-induced esophagitis. TRIAL REGISTRATION: UMIN000052622, 26 October 2023, retrospectively registered.

DOI： 10.1007/s00520-024-08613-0

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Language：Japanese   Publisher：(一社)日本医療薬学会  

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

Everolimus is used for immunosuppression after renal transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model of everolimus using therapeutic drug monitoring (TDM) data of patients under long-term multiple immunosuppressive therapy, including tacrolimus. To develop the model, 185 renal transplant recipients with 3358 everolimus blood concentrations during a median postoperative period of 35.3 months were included. The PopPK model is described as a one-compartment model with first-order absorption. The population mean of apparent clearance is 8.92 L/h (relative standard error = 3.6%), and this negatively correlated with the dose-normalized concentration (C/D) of tacrolimus and hematocrit value, and positively correlated with a daily dose of everolimus (i.e. TDM effect). The usefulness of dose adjustment using the final popPK model was assessed by a simulation study. The ratio of the first trough measurement within the therapeutic range of 3-8 ng/mL increased from 69.8% in the original dose to 87.9% in the individual dose calculated by the final PopPK model. The tacrolimus C/D ratio before initiating everolimus therapy and the hematocrit value were useful to estimate the initial dose of everolimus and can improve the safety and effectiveness of immunosuppressive therapy involving everolimus.

DOI： 10.1016/j.dmpk.2024.101009

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Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.

DOI： 10.1007/s10637-024-01432-4

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BACKGROUND: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine. METHODS: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery. RESULTS: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%. CONCLUSIONS: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.

DOI： 10.1097/FTD.0000000000001197

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Language：Japanese   Publisher：(一社)日本病院薬剤師会  

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BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody, can cause infusion reactions (IRs), especially during the initial rituximab infusion therapy. Generally, patients are administered a histamine H1-receptor antagonist before the rituximab infusion, along with an antipyretic analgesic, to prevent or reduce IRs. Multiple retrospective case-control studies indicate that the second generation of histamine H1-receptor antagonists might be more effective than the first generation in suppressing IRs caused by the rituximab infusion. OBJECTIVE: This study aimed to assess the efficacy of first- and second-generation histamine H1-receptor antagonists for preventing IRs resulting from the initial infusion of rituximab in patients diagnosed with non-Hodgkin lymphoma. METHODS: This is a phase II, double-blind, active-controlled randomized trial. It will be a multicenter study conducted across 3 facilities that aims to enroll a total of 40 patients diagnosed with non-Hodgkin lymphoma who will receive their initial rituximab infusion. Participating patients will be administered hydroxyzine pamoate or bepotastine besilate, representing first- or second-generation histamine H1-receptor antagonists, respectively. This will be combined with 400-mg acetaminophen tablets taken approximately 30 minutes before the first infusion of rituximab. The primary end point of this trial is to assess severe IRs, equivalent to grade 2 or higher as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, that occur within a 4-hour period after the initiation of rituximab infusion. The secondary end points include assessing the severity of the initial IR, the maximum severity of the IR, and the duration between rituximab infusion initiation and the onset of the first IR within a 4-hour period. Additionally, the trial will evaluate histamine H1-receptor antagonist-induced drowsiness using the visual analogue scale, with each patient providing their individual response. RESULTS: This study began with patient recruitment in April 2023, with 17 participants enrolled as of November 12, 2023. The anticipated study completion is set for February 2026. CONCLUSIONS: This study is the first randomized controlled trial comparing the effects of oral first- and second-generation histamine H1-receptor antagonists in preventing IRs induced by the initial administration of rituximab. The findings from this study hold the potential to establish the rationale for a phase III study aimed at determining the standard premedication protocol for rituximab infusion. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051220169; https://jrct.niph.go.jp/latest-detail/jRCTs051220169. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54882.

DOI： 10.2196/54882

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Language：Japanese   Publisher：(一社)日本医療薬学会  

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DOI： 10.1007/s10157-023-02436-9

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本薬学会  

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DOI： 10.1007/s10157-023-02415-0

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BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) inhibitors represent the standard of care for metastatic renal cell carcinoma (RCC). However, treatment outcomes are relatively poor, suggesting a potential problem with tolerating mTOR inhibitors. The aim of this study was to establish everolimus-resistant sublines and to compare their molecular characteristics with those of their counterparts. MATERIALS AND METHODS: Human-derived RCC, Caki-2, and 786-O cells were continuously exposed to everolimus at 1 μM, and the established resistant sublines were designated as Caki/EV and 786/EV, respectively. Cellular characteristics were compared between both cells. RESULTS: Caki/EV and 786/EV cells showed a decrease in sensitivity to everolimus as well as other mTOR inhibitors. Expression of mTOR and its effectors exhibited no alteration in resistant sublines and their counterparts. However, phosphorylation of S6K, an index of mTOR activity, decreased in resistant sublines. PCR array analysis of mTOR signaling pathway-related factors indicated that the expression of INSR, TP53, and IGFBP3 increased in Caki/EV cells, whereas that of TELO2, HRAS, and SGK1 was up-regulated in 786/EV cells. The levels of DDIT4, DEPTOR, HIF1A, and PLD1 mRNAs decreased in both cell lines. CONCLUSION: The novel everolimus-resistant Caki/EV and 786/EV cells exhibited cross-resistance to other mTOR inhibitors and decreased mTOR activity. Furthermore, down-regulation of DDIT4, DEPTOR, HIF1A, and PLD1 may contribute to everolimus resistance.

DOI： 10.21873/anticanres.16630

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The prevalence of CKD may be higher in patients with cancer than in those without due to the addition of cancer-specific risk factors to those already present for CKD. In this review, we describe the evaluation of kidney function in patients undergoing anticancer drug therapy. When anticancer drug therapy is administered, kidney function is evaluated to (1) set the dose of renally excretable drugs, (2) detect kidney disease associated with the cancer and its treatment, and (3) obtain baseline values for long-term monitoring. Owing to some requirements for use in clinical practice, a GFR estimation method such as the Cockcroft-Gault, MDRD, CKD-EPI, and the Japanese Society of Nephrology's GFR estimation formula has been developed that is simple, inexpensive, and provides rapid results. However, an important clinical question is whether they can be used as a method of GFR evaluation in patients with cancer. When designing a drug dosing regimen in consideration of kidney function, it is important to make a comprehensive judgment, recognizing that there are limitations regardless of which estimation formula is used or if GFR is directly measured. Although CTCAEs are commonly used as criteria for evaluating kidney disease-related adverse events that occur during anticancer drug therapy, a specialized approach using KDIGO criteria or other criteria is required when nephrologists intervene in treatment. Each drug is associated with the different disorders related to the kidney. And various risk factors for kidney disease associated with each anticancer drug therapy.

DOI： 10.1007/s10147-023-02372-4

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This comprehensive review discusses the dosing strategies of cancer treatment drugs for patients with impaired kidney function, specifically those with chronic kidney disease (CKD), undergoing hemodialysis, and kidney transplant recipients. CKD patients often necessitate dose adjustments of chemotherapeutic agents, e.g., platinum preparations, pyrimidine fluoride antimetabolites, antifolate agents, molecularly targeted agents, and bone-modifying agents, to prevent drug accumulation and toxicity due to diminished renal clearance of the administered drugs and their metabolites. In hemodialysis patients, factors such as drug removal from hemodialysis and altered pharmacokinetics demand careful optimization of anticancer drug therapy, including dose adjustment and timing of administration. While free cisplatin is removed by hemodialysis, most of the tissue- and protein-bound cisplatin remains in the body and rebound cisplatin elevations are observed after hemodialysis. It is not recommended hemodialysis for drug removal, regardless of timing. Kidney transplant patients encounter unique challenges in cancer treatment, as maintaining the balance between reduction of immunosuppression, switching to mTOR inhibitors, and considering potential drug interactions with chemotherapeutic agents and immunosuppressants are crucial for preventing graft rejection and achieving optimal oncologic outcomes. The review underscores the importance of personalized, patient-centric approaches to anticancer drug therapy in patients with impaired kidney function.

DOI： 10.1007/s10147-023-02377-z

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BACKGROUND: Optimised antithrombotic therapy requires clinical experience and an understanding of the current guidelines. This retrospective study aimed to evaluate whether pharmacist interviews and interventions with patients taking oral antithrombotic drugs in the pharmaceutical outpatient cardiology clinic had favourable clinical outcomes including decreased bleeding. METHODS: The participants included patients visiting the outpatient clinic of cardiovascular internal medicine at the Kobe University Hospital from January-December 2017, and were taking oral antithrombotic medication. The observation period was from the first visit to the outpatient clinic to October 2021 or death. Patients who received pharmacist intervention more than twice were defined as the pharmacist intervention group. Two control patients per one pharmacist intervention group individual were selected from the non-intervention pool matched for age, gender and antithrombotic medication type. RESULTS: Of the 895 eligible patients, 132 were in the pharmacist intervention group and 264 were selected for the matched non-intervention group. Bleeding events according to the Bleeding Academic Research Consortium criteria over type 2 were significantly lower in the pharmacist intervention group compared with the non-intervention group (17.4% versus 28.4%, P = 0.019). There were no significant differences in mortality and heart failure hospitalisation frequency, stroke, or cardiovascular events between the groups. Multivariate analysis identified age (≥ 65 years) and pharmacist intervention as factors associated with bleeding (odds ratio = 2.29 and 0.51, respectively). CONCLUSION: Pharmacist intervention in the outpatient clinic of cardiovascular internal medicine was effective in reducing the risk of bleeding in patients undergoing antithrombotic therapy.

DOI： 10.1186/s40780-023-00296-9

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DOI： 10.1016/j.dmpk.2023.100529

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Language：Japanese   Publisher：(一社)日本緩和医療薬学会  

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Parkinson's Disease (PD) is caused by many factors and endoplasmic reticulum (ER) stress is considered as one of the responsible factors for it. ER stress induces the activation of the ubiquitin-proteasome system to degrade unfolded proteins and suppress cell death. The ubiquitin ligase 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation 1 (HRD1) and its stabilizing molecule, the suppressor/enhancer lin-12-like (SEL1L), can suppress the ER stress via the ubiquitin-proteasome system, and that HRD1 can also suppress cell death in familial and nonfamilial PD models. These findings indicate that HRD1 and SEL1L might be key proteins for the treatment of PD. Our study aimed to identify the compounds with the effects of upregulating the HRD1 expression and suppressing neuronal cell death in a 6-hydroxydopamine (6-OHDA)-induced cellular PD model. Our screening by the Drug Gene Budger, a drug repositioning tool, identified luteolin as a candidate compound for the desired modulation of the HRD1 expression. Subsequently, we confirmed that low concentrations of luteolin did not show cytotoxicity in SH-SY5Y cells, and used these low concentrations in the subsequent experiments. Next, we demonsrated that luteolin increased HRD1 and SEL1L mRNA levels and protein expressions. Furthermore, luteolin inhibited 6-OHDA-induced cell death and suppressed ER stress response caused by exposure to 6-OHDA. Finally, luteolin did not reppress 6-OHDA-induced cell death when expression of HRD1 or SEL1L was suppressed by RNA interference. These findings suggest that luteolin might be a novel therapeutic agent for PD due to its ability to suppress ER stress through the activation of HRD1 and SEL1L.

DOI： 10.1007/s11064-023-04019-2

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pharmaceutical Society of Japan  

DOI： 10.1248/bpb.b22-00794

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BACKGROUND: Sarcopenia is defined as the loss of skeletal muscle mass and function and is associated with increased mortality. Certain genetic polymorphisms represent risk factors used to assess the incidence of sarcopenia; however, few studies have evaluated the association between genetic polymorphisms and sarcopenia after kidney transplantation (KTx). We examined single-nucleotide polymorphisms (SNPs) in the genes involved in sarcopenia after KTx. METHODS: Sixty-five patients who underwent KTx were enrolled in this study. We used the psoas mass index (PMI; the cross-sectional area of the bilateral psoas muscle/height) as a surrogate marker for assessing the extent of sarcopenia. We determined the PMI before KTx and 1 year after KTx, and we identified 5 SNPs in 5 genes associated with sarcopenia in the general population. Finally, the link between the changes in PMI 1 year after KTx and each SNP was examined. RESULTS: The median PMI before KTx and 1 year after KTx was 7.4 (4.6-13.2) and 7.0 (3.6-13.6), respectively. The PMI decreased in 43 patients (66.2%). The alpha-actinin-3 rs1815739 genotype was associated with changes in PMI; the distribution of CT+TT genotypes in the PMI decrease group was significantly higher than that of the CC genotype (odds ratio, 4.23; 95% CI 0.05-0.97; P = 0.025). Moreover, the T allele frequency was significantly higher in the PMI decrease group than in the PMI increase group (odds ratio, 2.34; 95% CI 0.18-0.950; P = 0.025). CONCLUSION: The alpha-actinin-3 rs1815739 genotype may represent a genetic risk factor for sarcopenia after KTx.

DOI： 10.1016/j.transproceed.2023.03.020

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

BACKGROUND/AIM: Osimertinib is a key drug for treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Genetic differences may be associated to adverse events (AEs) induced by osimertinib. This retrospective observational multicenter study evaluated the association of genotypes, including STAT3 -1697C>G, CYP3A5 6986A>G, and ABCG2 421C>A, with the incidence of osimertinib-induced AEs in patients with EGFR mutation-positive NSCLC. PATIENTS AND METHODS: A total of 85 patients treated with osimertinib (Institution A: 33 patients, Institution B: 52 patients) were enrolled in the study. Single nucleotide polymorphisms were determined by real-time PCR, and the incidence of AEs was compared for each genotype. RESULTS: Paronychia incidence was 59% for the CC genotype, 19% for the CG genotype, and 19% for the GG genotype at STAT3 -1697C>G. A genotype-related trend was observed (Cochran-Armitage test, p=0.009). Multivariate analysis showed that the CC genotype at STAT3 -1697C>G and female sex were significant independent factors associated with paronychia [odds ratio (OR)=6.41, 95% confidence interval (CI)=1.94-21.20 and OR=3.40, 95%CI=1.03-11.22, respectively]. The incidence of diarrhea was 53% for the CC genotype, 30% for the AC genotype, and 29% for the AA genotype at ABCG2 421C>A, and a genotype-related trend was observed (p=0.048). However, the CC genotype at ABCG2 421C>A was not a significant independent factor associated with diarrhea in multivariate analysis. No significant associations were detected between other polymorphisms and the incidence of AEs. CONCLUSION: STAT3 -1697C>G may be a novel risk factor for osimertinib-induced paronychia in patients with NSCLC.

DOI： 10.21873/anticanres.16331

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

BACKGROUND/AIM: Lenvatinib is a multiple-tyrosine kinase inhibitor used to treat hepatocellular carcinoma (HCC), and its systematic concentration varies according to liver function. The albumin-bilirubin (ALBI) grade is a novel indicator for predicting liver function in patients with hepatic disease. This study aimed to investigate the relationship between ALBI grade and HCC patients' lenvatinib treatment duration. PATIENTS AND METHODS: This is a retrospective cohort study of patients with HCC and Child-Pugh A treated with lenvatinib between April 2018 and December 2019. The baseline liver function was determined using the ALBI grade. The primary outcome was discontinuation owing to adverse events. The risk factors for discontinuation owing to adverse effects were analyzed using logistic regression. RESULTS: This investigation included 48 HCC patients. Patients with ALBI grade 2 had a significantly shorter time of discontinuation due to adverse events than those with grade 1 (p=0.036). However, the time of treatment failure did not differ between the groups. Multiple logistic regression analysis showed that ALBI grade 2 and non-use of antihypertensive drugs were independent factors for discontinuation due to adverse events [odds ratio (OR)=14.1, 95% confidence interval (CI)=1.46-135, p=0.022 and OR=5.48, 95% CI=1.13-23.9, p=0.024, respectively]. CONCLUSION: The ALBI grades may be useful in predicting adverse events caused by lenvatinib in patients with HCC and Child-Pugh A.

DOI： 10.21873/anticanres.16279

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

This study aimed to determine the effects of pregnancy and ontogeny on risperidone and paliperidone pharmacokinetics by assessing their serum concentrations in two subjects and constructing a customized physiologically-based pharmacokinetic (PBPK) model. Risperidone and paliperidone serum concentrations were determined in a pregnant woman and her newborn. PBPK models for risperidone and paliperidone in adults, pediatric, and pregnant populations were developed and verified using the Simcyp simulator. These models were then applied to our two subjects, generating their "virtual twins." Effects of pregnancy on both drugs were examined using models with fixed pharmacokinetic parameters. In the neonatal PBPK simulation, 10 different models for estimating the renal function of neonates were evaluated. Risperidone was not detected in the serum of both pregnant woman and her newborn. Maternal and neonatal serum paliperidone concentrations were between 2.05-3.80 and 0.82-1.03 ng/ml, respectively. Developed PBPK models accurately predicted paliperidone's pharmacokinetics, as shown by minimal bias and acceptable precision across populations. The individualized maternal model predicted all observed paliperidone concentrations within the 90% prediction interval. Fixed-parameter simulations showed that CYP2D6 activity largely affects risperidone and paliperidone pharmacokinetics during pregnancy. The Flanders metadata equation showed the lowest absolute bias (mean error: 22.3% ± 6.0%) and the greatest precision (root mean square error: 23.8%) in predicting paliperidone plasma concentration in the neonatal population. Our constructed PBPK model can predict risperidone and paliperidone pharmacokinetics in pregnant and neonatal populations, which could help with precision dosing using the PBPK model-informed approach in special populations.

DOI： 10.1111/cts.13473

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Oral lichen planus (OLP) is a type of chronic and refractory stomatitis characterized by abnormal keratinization, which is often painful. There is no consensus regarding treatment options for OLP, particularly in the presence of pain. The current study protocol focuses on the short-term efficacy and long-term safety of an ibuprofen gargle for pain management in patients with OLP. Patients (n = 24) with painful OLP will be enrolled. During a crossover study period, patients in the ibuprofen–placebo (IP) group will receive an ibuprofen gargle (0.6%) on day 1, a placebo gargle on day 2, and an ibuprofen gargle on days 3–5 at least once daily. Patients in the placebo–ibuprofen (PI) group will receive a placebo gargle on day 1, an ibuprofen gargle on day 2, and an ibuprofen gargle on days 3–5 at least once daily. The primary endpoint of the crossover study period is the change in pain level as measured by a visual analogue scale score from before gargle administration to 5 min after gargle administration on days 1 and 2. The primary endpoint of the long-term extension study is assessment of long-term safety. The results of this study may support existing evidence regarding the effectiveness of ibuprofen rinses in treating OLP.

DOI： 10.3390/mps6010007

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Language：Japanese   Publisher：(一社)日本病院薬剤師会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Background

Hand-foot skin reaction (HFSR) induced by multiple tyrosine kinase inhibitors (TKIs) is a serious side effect that can cause treatment interruption or decreased dosing. This study was conducted to evaluate the safety and efficacy of bis-glyceryl ascorbate (Amitose bis(di)-glyceryl ascorbate [DGA])-containing cream (DGA cream) for the prevention of sunitinib-induced HFSR.

Methods

A single-arm, open-label phase I/II study was conducted, targeting patients with metastatic renal cell carcinoma (mRCC) who were receiving sunitinib therapy with a schedule of 2 weeks on/1 week off. The participants applied DGA cream to both palmar and plantar surfaces in combination with a moisturizing agent as standard-of-care prophylaxis during two sunitinib treatment cycles (6 weeks). The primary endpoint in phase I was safety defined as dermatological abnormalities and it was determined in the first five participants. The primary endpoint in phase II was efficacy defined as development of grade 1 or higher HFSR defined by Common Terminology Criteria for Adverse Events within 6 weeks and it was determined on a full analysis set (FAS) defined as the population including all participants who used DGA cream once in the study duration. Efficacy in the per protocol set (PPS) defined as the population excluding seven patients whose study treatment was interrupted was evaluated as a secondary endpoint.

Results

Twenty-four patients were enrolled as a FAS. No dermatological abnormalities occurred in the first 5 patients enrolled in the phase I study. Three patients developed HFSR (grade 1: n = 2, grade 2: n = 1) in the observation period. The HFSR incidence rate was 12.5% (3/24; 95% confidence interval [CI]: 2.7%-32.4%) in the FAS, which was significantly lower than the incidence rate predefined as a threshold of 33.3% by a previous report from our hospital (P = .030). The incidence rate in the 17 patients of the PPS was 17.6% (3/17; 95%CI: 3.8%-43.4%).

Conclusion

DGA cream may be safe and effective in the prophylaxis of HFSR in mRCC patients who receive sunitinib therapy (Trial ID: jRCTs051180051).

DOI： 10.1093/oncolo/oyab067

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

We evaluated the association of signal transducer and activator of transcription 3 (STAT3) polymorphisms with the incidence of mammalian target of rapamycin (mTOR) inhibitor-induced interstitial lung disease (ILD) in patients with renal cell carcinoma (RCC). We also used lung-derived cell lines to investigate the mechanisms of this association. Japanese patients with metastatic RCC who were treated with mTOR inhibitors were genotyped for the STAT3 polymorphism, rs4796793 (1697C/G). We evaluated the association of the STAT3 genotype with the incidence of ILD and therapeutic outcome. In the 57 patients included in the primary analysis, the ILD rate within 140 days was significantly higher in patients with the GG genotype compared with those with other genotypes (77.8% vs. 23.1%, odds ratio=11.67, 95% confidential interval=3.0644.46). There were no significant differences in progression-free survival or time-to-treatment failure between the patients with the GG genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the GG genotype exhibited an increase in the expression of mesenchymal markers, such as fibronectin, N-cadherin, and vimentin, and decreases in E-cadherin, which is an epithelial marker associated with exposure to everolimus, although STAT3 expression and activity were not related to the genotype. In conclusion, the GG genotype of the STAT3 rs4796793 polymorphism increases the risk of mTOR inhibitor-induced ILD, supporting its use as a predictive marker for RCC.

DOI： 10.3727/096504022X16418911579334

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Potentially inappropriate medications (PIMs) and polypharmacy in older adults lead to increase the risk of adverse drug events. This study aimed to evaluate the effectiveness of pharmacist intervention combining the criteria for detecting PIMs with the deprescribing algorithm on correcting PIMs, reducing the number of medications, and readmissions.

Methods

A prospective observational study was conducted at a Japanese University Hospital enrolling new inpatients aged ≥65 years prescribed ≥1 daily medication. Pharmacists detected PIMs based on the criteria combined the screening tool of older persons’ potentially inappropriate prescriptions criteria version 2 with the screening tool for older persons’ appropriate prescriptions for Japanese, examined changes using the deprescribing algorithm, and suggested changes to the physician. The proportion of patients whose number of medications was reduced at discharge and the rate of readmissions within 30 and 90 days were compared between patients without PIMs (without PIMs group), patients who were not suggested to change PIMs (no suggestions group), and patients who were suggested to change PIMs (suggested group).

Results

The study enrolled 544 patients (median age 75.0 years, 54.4% males, median number of medications 6.0/patient). The number of patients with PIMs was 240 (44.1%), and 304 patients had no PIMs (without PIMs group). Among the patients with PIMs, 125 (52.1%) patients received pharmacist suggestions to change ≥1 PIMs (suggested group), and 115 patients received no suggestions for change (no suggestions group). The total number of PIMs was 432, of which changes were suggested for 189 (43.8%). Of these 189 cases, 172 (91.0%) were changed. The proportion of patients whose number of medications was reduced was significantly higher in the suggested group than in the without PIMs group and the no suggestions group [56.8% (71/125) vs. 26.6% (81/304) and 19.1% (22/115), respectively; P < 0.001 in both comparisons]. There were no significant differences in the rates of readmissions within 30 and 90 days among the three groups.

Conclusions

Pharmacist intervention combining the criteria for detecting PIMs with the deprescribing algorithm was effective for correcting PIMs and may be associated with a reduction in the number of medications.

DOI： 10.1186/s40780-022-00243-0

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Other Link： https://link.springer.com/article/10.1186/s40780-022-00243-0/fulltext.html

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WHAT IS KNOWN AND OBJECTIVE: Sunitinib is used as a first-line therapy for metastatic renal cell carcinoma. The primary aim of this study was to determine the optimal total sunitinib (sunitinib plus N-desethyl sunitinib) trough concentration for the alternative dosing schedule: 2-week-on and 1-week-off schedule (2/1 schedule). METHODS: Patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib, whose total sunitinib concentrations were available, were recruited for this study. Out of 19 patients, 17 whose sunitinib dosage was not changed until the measurement of drug concentration were eligible for the analysis of the relationship between total sunitinib concentration and clinical outcome. Individual pharmacokinetic parameters in 19 patients were estimated via the Bayesian analysis. RESULTS: The onset of severe (grade ≥3) adverse effects among 17 patients during 3 weeks as a first course of sunitinib therapy was observed in 7 (41.2%) patients. The median total sunitinib concentration in patients with severe adverse effects was significantly higher compared with that in patients without severe adverse effects [median: 119 (113-131) vs. 87.8 (77.4-102) ng/mL, p = 0.01]. According to the receiver operating characteristic analysis of the onset of severe adverse effects, the cut-off value of the total sunitinib concentration was 108 ng/mL. Patients with a total sunitinib concentration lower than 108 ng/mL had a longer time to first dose reduction or withdrawal due to adverse effects compared with those with a total sunitinib concentration of 108 ng/mL or higher (p = 0.03). The probability without treatment failure was not significantly different between the two concentration groups. In addition, the estimated sunitinib apparent oral clearance (CL/F) was significantly lower in the severe adverse effects group. Our simulation demonstrated that 0.67-time dose is needed for patients with approximately 90.0 ng/mL of sunitinib concentration on day 7 to maintain the concentration at the same level as the patients with higher CL/F. WHAT IS NEW AND CONCLUSION: Maintaining the total sunitinib trough concentrations of less than 108 ng/mL is safe to avoid the onset of serious adverse effects without increasing the treatment failure in patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib.

DOI： 10.1111/jcpt.13517

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The gut microbiome influences tumor response to immune checkpoint inhibitors (ICIs). The proton pump inhibitors (PPI) significantly impair diversity of the gut microbiota and can affect the efficacy of ICIs. Therefore, the present study aimed to evaluate the influence of PPI on survival in patients with metastatic or unresectable urothelial carcinoma receiving pembrolizumab. We conducted a retrospective cohort study of patients with metastatic or unresectable urothelial carcinoma receiving pembrolizumab. The use of PPI was defined as any administration for ≥30 d within 60 d prior and/or 30 d after treatment initiation. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and Cox proportional hazards regression analysis was performed to investigate prognostic factors based on patient characteristics. Seventy-nine patients were included in the analysis, and 34 patients (43.0%) received PPI. There were no significant differences in OS and PFS between PPI users and nonusers (median OS: 8.2 months vs. 11.2 months, hazard ratio (HR): 1.36, 95% confidence interval (CI): 0.75-2.42, p = 0.296; median PFS: 3.5 months vs. 5.1 months, HR: 1.63, 95% CI: 0.95-2.80, p = 0.069). In the multivariable analysis, PPI use was not associated with OS (HR 0.80, 95% CI 0.40-1.56, p = 0.526) or PFS (HR 1.44, 95% CI 0.79-2.60, p = 0.233). In conclusion, the estimated effect size of PPI use on survival in Japanese patients with metastatic or unresectable urothelial carcinoma treated with pembrolizumab was not reproducible.

DOI： 10.1248/bpb.b21-00939

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

BACKGROUND/AIM: Resistance to venetoclax, a selective inhibitor of BCL2 apoptosis regulator (BCL2), is regarded as a clinical problem. However, it is unclear whether resistance to venetoclax induces cross-resistance to other drugs. MATERIALS AND METHODS: Venetoclax-resistant HL60/VEN cells were newly established through continuous exposure of human acute promyelocytic leukemia HL60 cells to venetoclax, and drug sensitivity, apoptotic activity, and mRNA expression were compared between HL60 and HL60/VEN cells. RESULTS: HL60/VEN cells displayed approximately 3-fold resistance to venetoclax, maintained their ability to synthesize DNA and had low apoptotic activity. HL60/VEN cells also exhibited diverse sensitivity to cytotoxic drugs, especially resistance to ATP binding cassette subfamily B member 1 (ABCB1) substrates, and up-regulation of ABCB1 mRNA. However, the sensitivity of HL60/VEN cells to venetoclax was not restored by ABCB1 inhibitor. ABCB1-overexpressing cells did not show resistance to venetoclax. CONCLUSION: HL60/VEN cells exhibited up-regulation of ABCB1 in addition to an alteration in apoptotic activity, and cross-resistance to ABCB1 substrates was clarified. However, sensitivity to venetoclax was hardly affected by ABCB1.

DOI： 10.21873/anticanres.15228

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BACKGROUND: A multicenter investigation of neonate exposure to potentially harmful excipients (PHEs) in neonatal intensive care units (NICUs) in Japan has not been conducted. METHODS: A multicenter nationwide observational study was conducted. Neonate patient demographic data and information on all medicines prescribed and administered during hospitalization on 1 day between November 2019 and March 2021 were extracted from the medical records. Nine PHEs, paraben, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol, benzalkonium chloride, and aspartame, were selected. PHEs were identified from the package insert and the Interview Form. The quantitative daily exposure was calculated if quantitative data were available for each product containing the PHE. RESULTS: Prescription data was collected from 22 NICUs in Japan. In total, 343 neonates received 2360 prescriptions for 426 products containing 228 active pharmaceutical ingredients. PHEs were found in 52 (12.2%) products in 646 (27.4%) prescriptions for 282 (82.2%) neonates. Benzyl alcohol, sodium benzoates, and parabens were the most common PHEs in parenteral, enteral, and topical formulations, respectively. Quantitative analysis showed that 10 (10%), 38 (42.2%), 37 (94.9%), and 9 (39.1%) neonates received doses exceeding the acceptable daily intake of benzyl alcohol, polysorbate 80, propylene glycol, and sorbitol, respectively. However, due to the lack of quantitative information for all enteral and topical products, accurate daily PHE exposure could not be quantified. CONCLUSIONS: Neonates admitted to NICUs in Japan were exposed to PHEs, and several of the most commonly prescribed medicines in daily clinical practice in NICUs contained PHEs. Neonate PHE exposure could be reduced by replacing these medicines with available PHE-free alternatives.

DOI： 10.1186/s40780-021-00208-9

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OBJECTIVE: It was reported that the administration of tramadol in patients with cancer pain who have a higher interleukin 6 (IL-6) serum level led to insufficient pain relief. Cytokines produced by tumors, including IL-6, are associated with cancer cachexia. However, whether nonresponse to tramadol is related to cancer cachexia is unknown. The purpose of this study was to examine the relationship between tramadol response and cancer cachexia in patients with cancer pain. METHODS: We conducted a retrospective cohort study of patients with cancer who received tramadol treatment for mild to moderate pain from January 2016 to June 2019. Patients who experienced <20% pain reduction based on the numeric rating scale from baseline to day 7 after treatment with tramadol were defined as nonresponders. Univariate and multivariate logistic regression analyses were conducted to examine the relationships between tramadol response and various patient characteristics, including cancer cachexia. RESULTS: Of 115 patients, 79 were included in the analysis. A total of 24 patients experienced cancer cachexia, and 22 patients were nonresponders. In the univariate logistic analysis, cancer cachexia (odds ratio [OR]: 6.04, 95% confidence interval [CI]: 2.06-17.7), higher white blood cell counts (× 103/μL; OR: 1.28, 95% CI: 1.04-1.61), and lower body mass index (OR: 0.79, 95% CI: 0.66-0.96) were significantly associated with nonresponse to tramadol. The multivariate logistic analysis revealed that cancer cachexia (OR: 5.27, 95% CI: 1.75-15.9) was the only significant factor associated with nonresponse to tramadol. CONCLUSIONS: Cancer cachexia in patients with cancer pain can be associated with nonresponse to tramadol.

DOI： 10.1177/1049909120945570

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

Hand-foot skin reaction (HFSR) is a common side effect caused by several tyrosine kinase inhibitors, including sunitinib. However, the nature of the cornifying factors related to the molecular biological mechanisms underlying HFSR remains poorly understood. We used human keratinocyte models to investigate the key cornifying factors for dermatological and biological abnormalities induced by sunitinib. On the basis of the results of microarray analysis using the three-dimensional (3D) human epidermal model, keratin (KRT)6A, serine protease inhibitor (SERPIN)B1, KRT5, and SERPIN Kazal-type 6 were selected as candidate genes related to HFSR. Sunitinib treatment significantly decreased the expression of SERPINB1 and KRT6A in the immunohistochemical staining of the 3D epidermal model. In PSVK1 cells, but not in normal human epidermal keratinocyte cells, both of which are human normal keratinocyte cell lines, sunitinib decreased the expression of KRT6A with a concomitant decrease in levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated p38 mitogen-activated protein kinase (MAPK). Inhibitors of the ERK and p38 MAPK signal pathways also significantly decreased KRT6A expression. Sunitinib-induced decrease in KRT6A expression was suppressed by the inhibition of glycogen synthase kinase-3β by enhancing ERK1/2 and p38 MAPK phosphorylation. Thus, sunitinib reduces the expression of KRT6A and SERPINB1 by inhibiting the ERK1/2 and p38 MAPK signalling pathways in the skin model. These changes in expression contribute to the pathology of HFSR.

DOI： 10.1111/exd.14230

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Endoplasmic reticulum (ER) stress has been reported as a cause of Parkinson's disease (PD). We have previously reported that the ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and its stabilizing factor suppressor/enhancer lin-12-like (SEL1L) participate in the ER stress. In addition, we recently demonstrated that neuronal cell death is enhanced in the cellular PD model when SEL1L expression is suppressed compared with cell death when HRD1 expression is suppressed. This finding suggests that SEL1L is a critical key molecule in the strategy for PD therapy. Thus, investigation into whether microRNAs (miRNAs) regulate SEL1L expression in neurons should be interesting because relationships between miRNAs and the development of neurological diseases such as PD have been reported in recent years. In this study, using miRNA databases and previous reports, we searched for miRNAs that could regulate SEL1L expression and examined the effects of this regulation on cell death in PD models created by 6-hydroxydopamine (6-OHDA). Five miRNAs were identified as candidate miRNAs that could modulate SEL1L expression. Next, SH-SY5Y cells were exposed to 6-OHDA, following which miR-101 expression was found to be inversely correlated with SEL1L expression. Therefore, we selected miR-101 as a candidate miRNA for SEL1L modulation. We confirmed that miR-101 directly targets the SEL1L 3' untranslated region, and an miR-101 mimic suppressed the 6-OHDA-induced increase in SEL1L expression and enhanced cell death. Furthermore, an miR-101 inhibitor suppressed this response. These results suggest that miR-101 regulates SEL1L expression and may serve as a new target for PD therapy.

DOI： 10.3389/fnmol.2021.748026

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本医療薬学会  

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The safety of the coadministration of sunitinib with tacrolimus and everolimus with regard to therapeutic drug monitoring has not been demonstrated. Here, we report a patient who showed high sunitinib concentrations, in addition to pharmacokinetic changes in tacrolimus and everolimus after sunitinib therapy. A living-donor renal transplant patient treated with tacrolimus and everolimus was diagnosed with pulmonary and pleural metastases of renal cell carcinoma. The patient received sunitinib therapy (37.5 mg/day, 2 weeks on and 1 week off). This patient exhibited a high total sunitinib concentration (sunitinib, 105.8 ng/mL; N-desethyl sunitinib, 27.9 ng/mL) on day 10 postinitiation and experienced grade 3 diarrhea. The observed sunitinib concentrations were a little higher than those reported in the 421C>A polymorphism of the ATP-binding cassette subfamily G member 2 gene carrier. The observed concentrations of both tacrolimus and everolimus gradually decreased compared with the Bayesian-predicted values after the onset of sunitinib therapy, and the doses of tacrolimus and everolimus were increased. Careful therapeutic drug monitoring of sunitinib, tacrolimus, and everolimus concentrations is necessary during combination therapy, especially after episodes of diarrhea.

DOI： 10.1016/j.dmpk.2020.05.006

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本臨床衛生検査技師会  

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Background: Oral mucositis frequently occurs in cancer patients treated with chemotherapy and chemoradiotherapy (CRT). This study examined the safety and efficacy of ibuprofen gargle in healthy volunteers and patients with chemotherapy- and concomitant CRT-induced oral mucositis. Methods: We enrolled healthy volunteers and patients with chemotherapy- and CRT-induced oral mucositis. In cohort I, single and multiple doses of ibuprofen gargle (0.6% or 1.0%) were administered to healthy volunteers on day 1 and days 4-10. In cohort II, multiple doses of ibuprofen gargle (0.6%) were administered to patients with complicated grade 2-3 oral mucositis based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary endpoint of cohort I was the treatment-related adverse events (TRAEs) as defined by CTCAE version 4.0. The primary endpoint of cohort II was the change in the visual analogue scale (VAS) pain score from before to 15 min after gargle use on day 3. The incidence and severity of TRAEs were assessed based on the CTCAE version 4.0 and a subjective rating scale completed by healthy volunteers and patients. Results: In cohort I, 9 of 10 healthy volunteers were evaluable for safety. All 9 healthy volunteers reported the TRAE of oral irritation with single or multiple use of the gargle. In cohort II, 10 patients were enrolled and evaluable for safety and 7 of 10 patients were evaluable for efficacy. The mean change in the VAS pain score from before to 15 min after using the gargle on day 3 was - 1.28 (95% confidence interval: - 2.06, - 0.51), and all patients experienced some degree of pain relief (range: - 0.2 to - 2.5). All 10 patients reported the TRAE of oral irritation. No other TRAEs of ibuprofen gargle were observed in the healthy volunteers and patients. Conclusion: Despite oral irritation, the ibuprofen gargle appeared to be safe and effective for the pain related to chemo- or CRT-induced oral mucositis. However, ibuprofen-related oral irritation warrants further formulation improvement. Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000014433).

DOI： 10.1186/s40780-020-00168-6

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本医療薬学会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Sustained benzodiazepine use during pregnancy can induce neonatal abstinence syndrome (NAS). In this study, the association between NAS and plasma alprazolam concentration was examined using the measured neonatal concentrations in the time series as well as simulated plasma concentrations of pregnant woman and neonate by physiologically based pharmacokinetic (PBPK) modeling. A neonate born to a mother taking alprazolam daily throughout pregnancy exhibited symptoms such as apnea and vomiting from 9 h to 4 days after birth. Finnegan score was 7 at birth and decreased to 0 by day 4. Apnea improved by 24 h post-delivery and gastrointestinal symptoms disappeared by day 4. The plasma alprazolam concentration in the neonate was 15.2 ng/mL immediately after birth and gradually decreased over 3 days. Measured neonate and estimated maternal plasma alprazolam concentrations were within the 90% prediction intervals of each concentration by PBPK simulation using "pregnancy" and "pediatrics" population parameters including in Simcyp population-based ADME simulator. In conclusion, NAS symptoms such as apnea and digestive events disappeared in parallel with the decrease of the neonate's plasma alprazolam concentrations. Moreover, PBPK modeling and simulation is a useful methodology for toxicological assessment in special characteristics populations lacking specific experimental data.

DOI： 10.1016/j.dmpk.2019.09.002

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AIM: This study aimed to evaluate the efficacy of pharmacists' assessment and intervention using the Screening Tool for Older Persons' Appropriate Prescriptions for Japanese (STOPP-J) to detect and correct potentially inappropriate medications (PIM) compared with the Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (STOPP) criteria version 2. METHODS: A prospective observational study was carried out at a medical unit of Cardiovascular Surgery and Cardiovascular Internal Medicine in a Japanese university hospital involving new inpatients aged ≥65 years prescribed one or more daily medication. Pharmacists detected PIM based on STOPP-J and STOPP criteria version 2, and corrected them with physicians. The number of patients with PIM, the content and changes in PIM were compared between both criteria. RESULTS: Overall, 230 patients were included (mean age 75.4 years, 162 men, mean number of medications 8.3). STOPP-J detected significantly more patients with PIM than STOPP criteria version 2 (122 [53%] vs 75 [33%], P < 0.001). The number of PIM based on STOPP-J was 232, the physicians were recommended to change 61 (26%) and 50 (22%) were changed. Meanwhile, the number of PIM based on STOPP criteria version 2 was 133, the physicians were recommended to change 61 (46%) and 54 (41%) were changed. Several medications detected as PIM using STOPP-J were not detected using STOPP criteria version 2. CONCLUSIONS: STOPP-J detected significantly more patients with PIM than STOPP criteria version 2, and pharmacists' assessment and intervention based on STOPP-J were suggested to be effective for detecting and correcting PIM. Geriatr Gerontol Int 2019; 19: 1101-1107.

DOI： 10.1111/ggi.13773

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本病院薬剤師会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J04451&link_issn=&doc_id=20190805190012&doc_link_id=%2Fdg4hppha%2F2019%2F005508%2F012%2F0964-0968%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg4hppha%2F2019%2F005508%2F012%2F0964-0968%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JMIR Publications  

Background: Hand-foot skin reaction (HFSR) is a serious side effect induced by multiple-tyrosine kinase inhibitors (TKIs). HFSR can cause treatment interruption or decreased dosing. HFSR also markedly decreases quality of life and is associated with the therapeutic efficacy of multiple-TKIs. Therefore, the management and prevention of HFSR is an important issue; however, an effective method for its prevention has not been established. Specific ascorbic acid derivatives can reverse multiple-TKI-induced keratinocyte growth and pathological changes in vitro. Objective: This study was designed to evaluate the safety of bis-glyceryl ascorbate (Amitose DGA), a novel, hydrosoluble, and moisturizing ascorbic acid derivative, in patients with renal cell carcinoma (RCC) receiving sunitinib therapy. This study was also designed to evaluate Amitose DGA's preventive efficacy for sunitinib-induced HFSR. Methods: This is a Phase I/II, single-center, uncontrolled, single-arm, open-label trial. We will recruit a total of 30 patients with RCC receiving sunitinib therapy, with a 2-week-on and 1-week-off schedule. The participants will apply Amitose DGA-containing cream over both palmar and plantar surfaces within two treatment cycles (ie, 6 weeks) of sunitinib in combination with a general moisturizing agent, in addition to standard-of-care processes. Safety assessments will include dermatological abnormalities, clinical laboratory tests, and incidence of adverse events. Efficacy assessments will include development of HFSR and therapeutic outcomes associated with sunitinib. Results: Recruitment to the study began in August 2017 and is ongoing in Japan. To date, 21 subjects have been recruited. Study completion is expected in 2021. Conclusions: This is the first clinical study of Amitose DGA-containing cream in patients with RCC who are receiving sunitinib therapy. The single-center, single-arm, open-label design was selected to maximize subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable and preliminary evidence of the effects of Amitose DGA-containing cream on HFSR.

DOI： 10.2196/14636

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The purpose of the study was to evaluate the ability of different beverages to mask the bitterness of zopiclone and eszopiclone in tablet formulations using the artificial taste sensor and human gustatory sensation testing. The beverages tested for bitterness-masking effects were: Mugicha, Sports beverage, Lactic acid drink, Orange juice and a diluted simple syrup (an 8.5% sucrose solution). The bitterness intensities estimated by the taste sensor of zopiclone or eszopiclone one-tablet solutions mixed with the various beverages, corresponded well with the observed bitterness intensities measured by gustatory sensation testing. The Sports beverage, Lactic acid drink and Orange juice significantly suppressed the bitterness intensity of both zopiclone and eszopiclone 1-tablet solutions compared with water when tested in the artificial taste sensor. Sports beverage, Lactic acid drink and Orange juice all contain citric acid as acidifier, so it was postulated that citric acid was involved in the mechanism of bitterness intensity suppression of zopiclone and eszopiclone 1-tablet solutions by these three beverages. It was then shown that citric acid suppressed the bitterness intensity of a zopiclone one-tablet sample solution in a dose-dependent manner. 1H-NMR spectroscopic analysis of mixtures of citric acid with zopiclone suggested that the carboxyl groups of citric acid interact with the amine group on zopiclone. This study therefore showed that the bitterness intensities of zopiclone and eszopiclone can be suppressed by citric-acid-contained beverages and suggests that this bitterness suppression is due to a direct electrostatic interaction between citric acid and the two drugs.

DOI： 10.1248/cpb.c18-00502

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本臨床衛生検査技師会  

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Language：Japanese   Publisher：(一社)日本臨床化学会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag France  

DOI： 10.1007/s11523-018-0563-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier USA  

DOI： 10.1016/j.transproceed.2018.01.042

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本医療薬学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J03520&link_issn=&doc_id=20180525340005&doc_link_id=%2Fdb5pharm%2F2018%2F004405%2F005%2F0236-0243%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdb5pharm%2F2018%2F004405%2F005%2F0236-0243%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Humana Press Inc.  

DOI： 10.1007/s12032-017-1077-0

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Background: Risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene encoding CYP2D6 is highly polymorphic. The average steady-state plasma concentration of risperidone active moiety is higher in the CYP2D6 intermediate metabolizers (IMs) compared with that in the extensive metabolizers (EMs). An association between drug-induced extrapyramidal symptoms scale (DIEPSS) score and CYP2D6 polymorphisms has not been reported to date. This study investigates the association of CYP2D6 polymorphisms with the severity of extrapyramidal symptoms in schizophrenia patients receiving risperidone therapy. Methods: Schizophrenia patients undergoing risperidone treatment were recruited for the study in the Kobe University Hospital. We evaluated extrapyramidal symptoms of schizophrenia using the DIEPSS. CYP2D6*10 and CYP2D6*14 were analyzed using TaqMan® assays, and CYP2D6*5 was analyzed using the long-PCR method. Patients with CYP2D6*1/*5, *1/*14, *5/*10, *10/*10, and *10/*14 were classified as IMs, and patients with CYP2D6*1/*1 and *1/*10 were classified as EMs. Patients with CYP2D6*5/*5, *5/*14, and *14/*14 were classified as poor metabolizers (PMs). Results: A total of 22 patients were included in the study. No patients were classified as PMs. The dose of risperidone (mg/day) was not significantly different between EMs (n = 15) and IMs (n = 7) (median with the interquartile range: 4.0 (2.0-6.0) vs. 4.0 (2.0-7.0) mg, p = 0.31). The age and disease duration of schizophrenia were not significantly different between the EMs and IMs. The DIEPSS score in the IMs was significantly higher than that in the EMs (median with the interquartile range: 5.0 (3.5-6.5) vs. 0.0 (0.0-3.0), p < 0.001). The multiple regression analysis showed that CYP2D6 IMs is a significant risk factor for the DIEPSS (p < 0.05). Conclusion: Special attentions should be paid to the onset of extrapyramidal symptoms in schizophrenia patients identified as CYP2D6 IM undergoing risperidone therapy.

DOI： 10.1186/s40780-018-0126-y

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1248/bpb.b17-00386

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DOI： 10.24546/81009873

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本医薬品情報学会  

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DOI： 10.1111/jcpt.12496

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

DOI： 10.1248/bpb.b16-00875

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

DOI： 10.1016/j.bbrc.2017.02.107

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本医療薬学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本病院薬剤師会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本病院薬剤師会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12032-016-0733-0

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本医療薬学会  

DOI： 10.5649/jjphcs.42.78

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s11523-015-0382-9

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

DOI： 10.1124/jpet.115.226639

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

DOI： 10.1002/ptr.5305

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0102110

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本薬剤師会  

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Other Link： http://search.jamas.or.jp/link/ui/2014041013

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central  

DOI： 10.1186/1756-9966-32-83

Scopus

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

DOI： 10.3892/mmr.2011.734

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

DOI： 10.1371/journal.pone.0030697

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

DOI： 10.1016/j.ejps.2011.11.023

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DOI： 10.1111/j.1447-0594.2011.00729.x

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

DOI： 10.3109/02652040903515482

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

DOI： 10.1016/j.canlet.2008.12.033

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

DOI： 10.1080/01480540903130658

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Language：Japanese   Publisher：(一社)日本臨床薬理学会  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00296&link_issn=&doc_id=20221118310002&doc_link_id=%2Fab8gtkrc%2F2022%2F004911%2F002%2F1183-1187%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2022%2F004911%2F002%2F1183-1187%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：日本腎臓病薬物療法学会  

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Language：Japanese   Publisher：(株)日本メディカルセンター  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01864&link_issn=&doc_id=20220419290009&doc_link_id=20220610100021&url=http%3A%2F%2Fsearch.jamas.or.jp%2Flink%2Fbc%2F20220610100021&type=jamaslink&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F99999_1.gif

Language：Japanese   Publisher：(株)東京医学社  

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J-GLOBAL

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Language：Japanese   Publisher：日本腎臓病薬物療法学会  

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Language：Japanese   Publisher：(株)じほう  

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Language：Japanese   Publisher：(株)南山堂  

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Language：Japanese   Publisher：日本腎臓病薬物療法学会  

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Language：Japanese   Publisher：(株)診断と治療社  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

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Language：Japanese   Publisher：(株)医薬ジャーナル社  

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Language：Japanese   Publisher：医薬ジャーナル社  

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Language：Japanese   Publisher：(株)じほう  

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Language：Japanese   Publisher：(一社)日本医療薬学会  

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Language：Japanese   Publisher：(株)北隆館  

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Language：Japanese   Publisher：(公財)薬学研究奨励財団  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本TDM学会  

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Language：Japanese   Publisher：(公財)政策医療振興財団  

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Language：Japanese   Publisher：日本医療薬学会  

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Language：Japanese   Publisher：日本医療薬学会  

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Language：Japanese   Publisher：(公財)政策医療振興財団  

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Language：Japanese   Publisher：(株)日本医学館  

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Language：Japanese   Publisher：日本医療薬学会  

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Language：Japanese   Publisher：日本医療薬学会  

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publisher：医薬ジャーナル社  

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Other Link： http://search.jamas.or.jp/link/ui/2012368624

Language：Japanese   Publisher：日本医療薬学会  

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Language：Japanese  

J-GLOBAL

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Event date： 2021.3.14

Language：Japanese   Presentation type：Poster presentation  

Venue：WEB開催  

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Event date： 2021.3.14

Language：Japanese   Presentation type：Poster presentation  

Venue：WEB開催  

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Event date： 2021.3.14

Language：Japanese   Presentation type：Poster presentation  

Venue：WEB開催  

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Event date： 2021.3.14

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Venue：WEB開催  

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Event date： 2021.1.30 - 2021.1.31

Language：Japanese   Presentation type：Poster presentation  

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Event date： 2020.12.14 - 2020.12.28

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2020.10.24 - 2020.11.1

Language：English   Presentation type：Poster presentation  

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Event date： 2020.10.24 - 2020.11.1

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：WEB開催  

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Event date： 2020.10.24 - 2020.11.1

Language：Japanese   Presentation type：Poster presentation  

Venue：WEB開催  

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Event date： 2020.10.24 - 2020.11.1

Language：Japanese   Presentation type：Poster presentation  

Venue：WEB開催  

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Event date： 2020.10.24 - 2020.11.1

Language：Japanese   Presentation type：Poster presentation  

Venue：WEB開催  

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Event date： 2020.6.28 - 2020.7.10

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Venue：WEB開催  

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Event date： 2018.7

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Event date： 2016.5

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Event date： 2015

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Language：Japanese   Presentation type：Poster presentation  

Venue：WEB開催  

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Venue：WEB開催  

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

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Language：Japanese   Presentation type：Poster presentation  

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：English   Presentation type：Poster presentation  

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Award type：Award from Japanese society, conference, symposium, etc. 

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