Publications by authors named "Yuko Mori"

37 Publications

Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: phase 1 study.

Invest New Drugs 2021 Jun 23. Epub 2021 Jun 23.

National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

Background: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies.

Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib.

Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (C and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily.

Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).
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http://dx.doi.org/10.1007/s10637-021-01120-7DOI Listing
June 2021

Evaluation of the Association of Polymorphisms With Palbociclib-Induced Neutropenia: Pharmacogenetic Analysis of PALOMA-2/-3.

Oncologist 2021 07 7;26(7):e1143-e1155. Epub 2021 Jun 7.

Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Background: The most frequently reported treatment-related adverse event in clinical trials with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. Allelic variants in ABCB1 and ERCC1 might be associated with early occurrence (i.e., end of week 2 treatment) of grade 3/4 neutropenia. Pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms (SNPs) in these genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia.

Materials And Methods: ABCB1 (rs1045642, rs1128503) and ERCC1 (rs3212986, rs11615) were analyzed in germline DNA from palbociclib-treated patients from PALOMA-2 (n = 584) and PALOMA-3 (n = 442). SNP, race, and cycle 1 day 15 (C1D15) absolute neutrophil count (ANC) data were available for 652 patients. Univariate and multivariable analyses evaluated associations between SNPs, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Analyses were stratified by Asian (n = 122) and non-Asian (n = 530) ethnicity. Median progression-free survival (mPFS) was estimated using the Kaplan-Meier method. The effect of genetic variants on palbociclib pharmacokinetics was analyzed.

Results: ABCB1 and ERCC1_rs11615 SNP frequencies differed between Asian and non-Asian patients. Multivariable analysis showed that low baseline ANC was a strong independent risk factor for C1D15 grade 3/4 neutropenia regardless of race (Asians: odds ratio [OR], 6.033, 95% confidence interval [CI], 2.615-13.922, p < .0001; Non-Asians: OR, 6.884, 95% CI, 4.138-11.451, p < .0001). ABCB1_rs1128503 (C/C vs. T/T: OR, 0.57, 95% CI, 0.311-1.047, p = .070) and ERCC1_rs11615 (A/A vs. G/G: OR, 1.75, 95% CI, 0.901-3.397, p = .098) were potential independent risk factors for C1D15 grade 3/4 neutropenia in non-Asian patients. Palbociclib mPFS was consistent across genetic variants; exposure was not associated with ABCB1 genotype.

Conclusion: This is the first comprehensive assessment of pharmacogenetic data in relationship to exposure to a CDK4/6 inhibitor. Pharmacogenetic testing may inform about potentially increased likelihood of patients developing severe neutropenia (NCT01740427, NCT01942135).

Implications For Practice: Palbociclib plus endocrine therapy improves hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer outcomes, but is commonly associated with neutropenia. Genetic variants in ABCB1 may influence palbociclib exposure, and in ERCC1 are associated with chemotherapy-induced severe neutropenia. Here, the associations of single nucleotide polymorphisms in these genes and baseline characteristics with neutropenia were assessed. Low baseline absolute neutrophil count was a strong risk factor (p < .0001) for grade 3/4 neutropenia. There was a trend indicating that ABCB1_rs1128503 and ERCC1_rs11615 were potential risk factors (p < .10) for grade 3/4 neutropenia in non-Asian patients. Pharmacogenetic testing could inform clinicians about the likelihood of severe neutropenia with palbociclib.
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http://dx.doi.org/10.1002/onco.13811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265363PMC
July 2021

Feeling Unsafe at School and Associated Mental Health Difficulties among Children and Adolescents: A Systematic Review.

Children (Basel) 2021 Mar 17;8(3). Epub 2021 Mar 17.

INVEST Research Flagship Center, University of Turku, 20014 Turun Yliopisto, Finland.

This study systematically reviewed the literature on perceived school safety. We investigated the prevalence, factors and associated mental health difficulties, as well as cross-cultural findings. Five databases were searched up to 9 February 2021 for peer-reviewed papers published in English. We included quantitative studies that explored the perception of school safety among children and adolescents. The reference lists of the selected papers were also searched. We conducted a narrative synthesis of the included studies. The review included 43 papers. The mean prevalence of the students who felt unsafe at school was 19.4% and ranged from 6.1% to 69.1%. Their perceived safety was associated with a wide range of personal, school, and social factors. Not feeling safe at school was related to being victimized and mental health difficulties, including depressive symptoms and suicidal behavior. Higher perceived school safety was associated with measures such as the presence of a security officer and fair school rule enforcement. The results showed the lack of cross-cultural studies on perceived school safety. Empirical studies are needed that examine the mechanisms of school safety, using valid measures. A clear definition of school safety should be considered a key aspect of future studies.
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http://dx.doi.org/10.3390/children8030232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002666PMC
March 2021

Kynurenine 3-monooxygenase deficiency induces depression-like behavior via enhanced antagonism of α7 nicotinic acetylcholine receptors by kynurenic acid.

Behav Brain Res 2021 05 16;405:113191. Epub 2021 Feb 16.

Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Science, Aichi, Japan; Japanese Drug Organization of Appropriate Use and Research, Aichi, Japan.

Tryptophan (TRP) is metabolized via the kynurenine (KYN) pathway, which is related to the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the metabolism of KYN to 3-hydroxykynurenine. In rodents, KMO deficiency induces a depression-like behavior and increases the levels of kynurenic acid (KA), a KYN metabolite formed by kynurenine aminotransferases (KATs). KA antagonizes α7 nicotinic acetylcholine receptor (α7nAChR). Here, we investigated the involvement of KA in depression-like behavior in KMO knockout (KO) mice. KYN, KA, and anthranilic acid but not TRP or 3-hydroxyanthranilic acid were elevated in the prefrontal cortex of KMO KO mice. The mRNA levels of KAT1 and α7nAChR but not KAT2-4, α4nAChR, or β2nAChR were elevated in the prefrontal cortex of KMO KO mice. Nicotine blocked increase in locomotor activity, decrease in social interaction time, and prolonged immobility in a forced swimming test, but it did not decrease sucrose preference in the KMO KO mice. Methyllycaconitine (an α7nAChR antagonist) antagonized the effect of nicotine on decreased social interaction time and prolonged immobility in the forced swimming test, but not increased locomotor activity. Galantamine (an α7nAChR allosteric agonist) blocked the increased locomotor activity and prolonged immobility in the forced swimming test, but not the decreased social interaction time in the KMO KO mice. In conclusion, elevation of KA levels contributes to depression-like behaviors in KMO KO mice by α7nAChR antagonism. The ameliorating effects of nicotine and galantamine on depression-like behaviors in KMO KO mice are associated with the activation of α7nAChR.
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http://dx.doi.org/10.1016/j.bbr.2021.113191DOI Listing
May 2021

Investigation on the Epoxidation of Piperitenone, and Structure-activity Relationships of Piperitenone Oxide for Differentiation-inducing Activity.

J Oleo Sci 2020 Aug 9;69(8):951-958. Epub 2020 Jul 9.

Department of Applied Biological Science, Tokyo University of Science.

Piperitenone oxide, a major chemical constituent of the essential oil of spearmint, Mentha spicata, induces differentiation in human colon cancer RCM-1 cells. In this study, piperitenone oxide and trans-piperitenone dioxide were prepared as racemic forms by epoxidation of piperitenone. The relative configuration between two epoxides in piperitenone dioxide was determined to be trans by H NMR analysis and nuclear Overhauser effect spectroscopy (NOESY) in conjunction with density functional theory (DFT) calculations. Optical resolution of (±)-piperitenone oxide by high-performance liquid chromatography (HPLC) using a chiral stationary phase (CSP) afforded both enantiomers with over 98% enantiomeric excess (ee). Evaluation of the differentiation-inducing activity of the synthetic compounds revealed that the epoxide at C-1 and C-6 in piperitenone oxide is important for the activity, and (+)-piperitenone oxide has stronger activity than (-)-piperitenone oxide. The results obtained in this study provide new information on the application of piperitenone oxide and spearmint for differentiation-inducing therapy. Furthermore, natural piperitenone oxide was isolated from M. spicata. The enantiomeric excess of the isolated natural piperitenone oxide was 66% ee. Epoxidation of piperitenone with hydrogen peroxide proceeded in a phosphate buffer under weak basic conditions to give (±)-piperitenone oxide. These results suggest that the nonenzymatic epoxidation of piperitenone, which causes a decrease in the enantiomeric excess of natural piperitenone oxide, is accompanied by an enzymatic epoxidation in the biosynthesis of piperitenone oxide.
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http://dx.doi.org/10.5650/jos.ess19278DOI Listing
August 2020

High multi-azole-resistant Malassezia pachydermatis clinical isolates from canine Malassezia dermatitis.

Med Mycol 2020 Feb;58(2):197-200

Department of Veterinary Pathobiology, Nihon University College of Bioresource Sciences, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan.

Malassezia pachydermatis, a lipophilic and aerobic yeast, is a causative agent of Malassezia dermatitis, a common skin mycosis in dogs and cats. This fungus is also responsible for zoonotic fungal infections in human neonates. Ravuconazole (RVZ) is an antifungal azole compound and the active metabolite of fosravuconazole, which was approved for use in humans in Japan in 2018. In the present study, in vitro RVZ susceptibility and multi-azole resistance of 13 clinical M. pachydermatis strains was investigated using the modified Clinical and Laboratory Standards Institute M27-A3 test. The minimum inhibitory concentrations (MICs) for the 13 isolates ranged from 0.094 to >32 mg/L for itraconazole (ITZ) and from 0.5 to >32 mg/l for RVZ. Similarly, MICs for ITZ- or RVZ-resistant strains (MICs >32 mg/l) were also >32 mg/l for clotrimazole (CTZ), >32 mg/l for miconazole (MCZ), and 0.25 to >32 mg/L for voriconazole (VRZ). BLAST analysis using the NCBI database showed that ERG11 cDNA of the RVZ-resistant strain encoded Gly at codon 461 and Asp in cytochrome p450 encoded by M. pachydermatis ERG11 mRNA. This work is the first report to describe that an RVZ-resistant M. pachydermatis strain contains ERG11 mutations. The affinity of the protein encoded by ERG11 for RVZ may differ from that of ITZ. Therefore, RVZ has considerable therapeutic potential for treating ITZ-resistant canine Malassezia dermatitis. However, RVZ-resistant strains already exist in canine Malassezia dermatitis in Japan.
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http://dx.doi.org/10.1093/mmy/myz037DOI Listing
February 2020

Chronic unpredictable mild stress-induced behavioral changes are coupled with dopaminergic hyperfunction and serotonergic hypofunction in mouse models of depression.

Behav Brain Res 2019 10 6;372:112053. Epub 2019 Jul 6.

Department of Disease Control and Prevention, Fujita Health University, Graduate School of Health Sciences, Aichi, 470-1192, Japan; Japanese Drug Organization of Appropriate Use and Research, Aichi, 468-0069, Japan.

Accumulating evidence shows that stressful events evoke molecular alterations in the brain, considered a pathology in major depressive disorder (MDD). However, the abnormalities of neurotransmissions as well as intracellular signaling pathways affected by chronic stress in brain have not been fully explored. We investigated the effect of chronic unpredictable mild stress (CUMS) on the emotional behaviors, dopaminergic and serotoninergic function, and intracellular signaling in the nucleus accumbens, hippocampus and prefrontal cortex. Male C57BL/6J mice were exposed to CUMS for 4 weeks. CUMS was shown to induce hyperactivity in a novel environment, decrease interaction time in the social interaction test, prolong feeding latency in the novelty suppressed feeding test and enhance immobility in the forced swimming test. The levels of dopamine, its metabolites and turnover, and protein level of tyrosine hydroxylase (TH) were increased by CUMS in the nucleus accumbens (NAc). The level of serotonin and protein levels of tryptophan hydroxylase (TPH) and TH were decreased by CUMS in the hippocampus (HPC) and prefrontal cortex (PFC). Accompanying the increase in dopaminergic function, phosphorylation levels of extracellular signal-regulated kinases (ERK), protein kinase B (Akt) and cAMP response element-binding protein (CREB) were increased by CUMS in the NAc. Administration of fluoxetine (selective serotonin re-uptake inhibitor: 20 mg/kg i.p.) and aripiprazole (dopamine D receptor partial agonist: 0.1 mg/kg i.p.) during CUMS, prevented behavioral changes and increase of dopamine level in the NAc. These data suggest that CUMS-induced depression-like behaviors are coupled with dopaminergic hyperfunction in the NAc and serotonergic hypofunction in the HPC and PFC.
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http://dx.doi.org/10.1016/j.bbr.2019.112053DOI Listing
October 2019

Correction to: Neutropenia management with palbociclib in Japanese patients with advanced breast cancer.

Breast Cancer 2019 09;26(5):651

Kyoto University Graduate School of Medicine, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

The correct name of the last author should be "Masakazu Toi", and not ''Masakuzu Toi" as given in the original publication of the article.
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http://dx.doi.org/10.1007/s12282-019-00984-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828135PMC
September 2019

Neutropenia management with palbociclib in Japanese patients with advanced breast cancer.

Breast Cancer 2019 09 24;26(5):637-650. Epub 2019 May 24.

Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.

Background: The cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib, in combination with endocrine therapy (ET), significantly prolonged progression-free survival in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC) in PALOMA-2 and PALOMA-3. Neutropenia and palbociclib dose reductions/interruptions occurred more frequently in the Japanese versus overall populations. We evaluated neutropenia patterns, palbociclib dose management, and clinical responses after dose reduction in Japanese patients in PALOMA-2 and PALOMA-3 and a single-arm Japanese phase 2 study.

Methods: PALOMA-2 and the Japanese phase 2 study enrolled postmenopausal women with estrogen receptor-positive, HER2- ABC who had not received prior systemic therapy for advanced disease; PALOMA-3 enrolled women with HR+/HER2- ABC, regardless of menopausal status, whose disease had progressed after prior ET. Palbociclib (125 mg/day) was administered 3 weeks on/1 week off. Dose reduction/interruption, cycle delay, tumor response, and laboratory-assessed neutropenia were analyzed in Japanese patients who received palbociclib.

Results: A total of 101 Japanese patients received palbociclib + ET. Among Japanese patients in the 3 studies, the frequency of all-grade/grade 3/grade 4 neutropenia was 94%/53%/34%, 100%/69%/21%, and 100%/67%/26%, respectively. Twenty (63%), 28 (67%), and 15 (56%) patients required palbociclib dose reduction. Dose interruption or reduction did not affect palbociclib treatment duration, and durable tumor response was observed despite dose reduction.

Conclusion: Neutropenia was manageable with dose modifications, without affecting palbociclib treatment duration or efficacy.

Trial Registration: Pfizer (NCT01740427, NCT01684215, NCT01942135).
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http://dx.doi.org/10.1007/s12282-019-00970-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694088PMC
September 2019

Palbociclib Plus Letrozole as First-Line Therapy in Postmenopausal Asian Women With Metastatic Breast Cancer: Results From the Phase III, Randomized PALOMA-2 Study.

J Glob Oncol 2019 05;5:1-19

Kyoto University, Kyoto, Japan.

Purpose: In PALOMA-2, palbociclib plus letrozole significantly improved progression-free survival (PFS) as initial treatment of estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. We assessed the benefit of palbociclib plus letrozole in Asians.

Patients And Methods: Of 666 enrolled postmenopausal women with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (no prior treatment of advanced disease), 95 were Asian. Patients were randomly assigned 2:1 to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was investigator-assessed PFS. Secondary end points were overall survival, objective response, patient-reported outcomes, pharmacokinetics, and safety.

Results: Median PFS was significantly longer in Asian patients who received palbociclib plus letrozole versus placebo plus letrozole (25.7 months [95% CI, 19.2 months to not estimable] 13.9 months [95% CI, 7.4 to 22.0 months]; hazard ratio, 0.49; 95% CI, 0.27 to 0.87; = .007). The most common toxicities with palbociclib were hematologic and more frequent among Asians versus non-Asians: neutropenia (any grade, 95.4% 76.8%; grade 3/4, 89.2% 62.5%), leukopenia (43.1% 38.3%; 32.3% 23.5%), and thrombocytopenia (27.7% 13.5%; 4.6% 1.1%). No Asians had febrile neutropenia. Discontinuation rates as a result of adverse events were similar among Asian and non-Asian patients who received palbociclib plus letrozole (10.8% and 9.5%). In Asians, quality of life (QOL) was maintained with no significant differences observed between treatments from baseline in breast cancer-specific QOL and general health status scores. Change from baseline in EuroQol five dimensions index scores was significantly higher with palbociclib plus letrozole (0.013 -0.069; = .0132). Geometric mean palbociclib trough concentration values were higher in Asians versus non-Asians (93.8 61.7 ng/mL).

Conclusion: Consistent with the overall study population, the addition of palbociclib to letrozole significantly improved PFS in Asians. Hematologic toxicities were more frequent in Asians versus non-Asians but manageable with early dose modifications while maintaining QOL.
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http://dx.doi.org/10.1200/JGO.18.00173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550032PMC
May 2019

Palbociclib in combination with letrozole in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-2 subgroup analysis of Japanese patients.

Int J Clin Oncol 2019 Mar 4;24(3):274-287. Epub 2018 Dec 4.

Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: In PALOMA-2, palbociclib-letrozole significantly improved progression-free survival (PFS) vs placebo-letrozole in women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (ABC) in the first-line setting. We evaluated the efficacy, safety, and pharmacokinetics of palbociclib in Japanese women in PALOMA-2.

Methods: In this phase 3 study, 666 postmenopausal women with ER+/HER2- ABC were randomized 2:1 to palbociclib (125 mg/day [3 weeks on/1 week off]) plus letrozole (2.5 mg daily) or placebo plus letrozole. A prespecified, exploratory, subgroup analysis of Japanese patients (n = 46) was conducted to compare results with those of the overall population.

Results: At the February 26, 2016 cutoff, median PFS among the 46 Japanese patients was 22.2 months (95%CI, 13.6‒not estimable) with palbociclib-letrozole vs 13.8 months (5.6‒22.2) with placebo-letrozole (hazard ratio, 0.59 [95%CI, 0.26-1.34]). The most common adverse events (AEs) were hematologic and more frequent among Japanese patients than the overall population (neutropenia: 93.8% [87.5% grade 3/4] vs 79.5% [66.4%]; leukopenia: 62.5% [43.8%] vs 39.0% [24.8%]); no Japanese patients had febrile neutropenia. Palbociclib dose reductions due to toxicity (mainly neutropenia) were more common in Japanese patients (62.5% vs 36.0%); few permanently discontinued due to AEs. Although mean palbociclib trough concentration was higher in Japanese patients vs non-Asians (95.4 vs 61.7 ng/mL), the range of individual values of the Japanese patients was within that of non-Asians.

Conclusions: These results from PALOMA-2 suggest that palbociclib-letrozole merits consideration as a first-line treatment option for postmenopausal Japanese patients with ER+/HER2‒ ABC. ClinicalTrials.gov: NCT01740427.
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http://dx.doi.org/10.1007/s10147-018-1353-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399183PMC
March 2019

Palbociclib in combination with fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-3 subgroup analysis of Japanese patients.

Int J Clin Oncol 2019 Mar 3;24(3):262-273. Epub 2018 Nov 3.

Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.

Background: In the double-blind, phase 3 PALOMA-3 study, palbociclib-fulvestrant significantly prolonged progression-free survival versus placebo-fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) whose disease had progressed on prior endocrine therapy. The present study evaluated the efficacy, safety, and pharmacokinetics of palbociclib plus fulvestrant in Japanese patients enrolled in PALOMA-3.

Methods: Pre/peri/postmenopausal women with HR+/HER2- MBC were randomized 2:1 to fulvestrant (500 mg) and either palbociclib (125 mg/day; 3 weeks on/1 week off; n = 347) or placebo (n = 174). Prespecified exploratory analyses compared the efficacy (data cutoff: October 23, 2015), safety, and pharmacokinetics (data cutoff: December 5, 2014) in Japanese women versus the overall population.

Results: A total of 35 Japanese women were randomized to palbociclib-fulvestrant (n = 27) or placebo-fulvestrant (n = 8). Median progression-free survival was 13.6 months (95% CI, 7.5-not estimable) in the Japanese palbociclib-fulvestrant group and 11.2 months (95% CI, 5.6-not estimable) in the placebo-fulvestrant group. The most common adverse event (AE) in Japanese patients was neutropenia (all grades, 93%); no discontinuations were due to an AE. Geometric mean trough concentration values (within-subject mean steady state) for palbociclib were similar for Japanese Asian (excluding Japanese), and non-Asian patients (84.4 ng/mL, 86.3 ng/mL, and 74.8 ng/mL, respectively).

Conclusion(s): The results for the overall population and Japanese patients in PALOMA-3 suggest that palbociclib plus fulvestrant was effective and well tolerated in Japanese patients with HR+/HER2‒ MBC whose disease had progressed on prior endocrine therapy (Pfizer; NCT01942135).
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http://dx.doi.org/10.1007/s10147-018-1359-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399170PMC
March 2019

Palbociclib in combination with letrozole as first-line treatment for advanced breast cancer: A Japanese phase II study.

Cancer Sci 2018 Mar 22;109(3):803-813. Epub 2018 Feb 22.

Kyoto University Graduate School of Medicine, Kyoto, Japan.

This single-arm, open-label, phase II study in 42 Japanese postmenopausal patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer evaluated the efficacy, safety, and pharmacokinetics of first-line palbociclib (125 mg once daily, 3 weeks on/1 week off) coadministered with letrozole (2.5 mg once daily). Primary endpoint of investigator-assessed 1-year progression-free survival (PFS) probability was 75.0% (90% CI, 61.3%-84.4%), far surpassing the 40% lower limit of the 90% CI supporting efficacy. Median duration of treatment was 438 days. Among secondary efficacy measures, median PFS was not reached (95% CI, 16.7: not estimable), 17/42 patients (40.5%) had an objective response, 36/42 (85.7%) maintained disease control, and 27/42 (64.3%) remained in follow-up. Median overall survival was not reached, and 1-year survival probability was 92.9% (95% CI, 79.5%-97.6%). Results of intensive pharmacokinetics in a subset of 6 patients showed palbociclib steady-state mean area under the plasma concentration-time curve over the dosing interval [τ] and mean maximum plasma concentration were 1979 ng·h/mL and 124.7 ng/mL, respectively. For day 15 plasma samples from cycles 1 and 2, geometric mean of the within-patient mean trough concentration was 90.1 ng/mL. The most common treatment-related adverse events were neutropenia (100%) and stomatitis (73.8%). There was 1 case of treatment-related febrile neutropenia. Toxicities were generally tolerated and manageable by dose modifications and/or medical care. Efficacy and safety of first-line palbociclib plus letrozole therapy is supported in Japanese postmenopausal patients with treatment-naive ER+/HER2- advanced breast cancer.
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http://dx.doi.org/10.1111/cas.13507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834809PMC
March 2018

The Effect of Selective Transcranial Magnetic Stimulation with Functional Near-Infrared Spectroscopy and Intensive Speech Therapy on Individuals with Post-Stroke Aphasia.

Eur Neurol 2017 4;77(3-4):186-194. Epub 2017 Feb 4.

Department of Rehabilitation Medicine, The Jikei University School of Medicine, Tokyo, Japan.

Purpose: To examine the efficacy of selective repetitive transcranial magnetic stimulation (rTMS) therapy guided by functional near-infrared spectroscopy (fNIRS) combined with intensive speech therapy (iST) on post-stroke patients with aphasia.

Material And Methods: Eight right-handed patients with aphasia in the chronic stage after stroke were grouped into left and right hemisphere-activated for a language task based on pre-intervention fNIRS. Those with left hemisphere activation received 1-Hz TMS to the right inferior frontal gyrus (RtIFG; low-frequency rTMS [LFS] group), and those with right hemisphere activation received 10-Hz TMS to the RtIFG (high-frequency rTMS [HFS] group). The patients underwent an 11-day program of rTMS and iST.

Results: Both groups showed a significant improvement in language function as measured by Standard Language Test of Aphasia (SLTA) total score at post-intervention relative to pre-intervention. Furthermore, the pre-to-post SLTA change scores were not statistically different between the groups. Comparison of pre- and post-intervention fNIRS revealed a resolution of the imbalance of interhemispheric inhibition in the LFS group and activation of the target hemisphere in the HFS group.

Conclusions: The administration of fNIRS-guided selective rTMS therapy and iST to post-stroke patients with aphasia induced a significant improvement in language function, with both groups demonstrating a similar degree of improvement.
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http://dx.doi.org/10.1159/000457901DOI Listing
September 2017

High-voltage electron microscopy tomography and structome analysis of unique spiral bacteria from the deep sea.

Microscopy (Oxf) 2016 08 26;65(4):363-9. Epub 2016 May 26.

Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8673, Japan.

Structome analysis is a useful tool for identification of unknown microorganisms that cannot be cultured. In 2012, we discovered a unique deep-sea microorganism with a cell structure intermediate between those of prokaryotes and eukaryotes and described its features using freeze-substitution electron microscopy and structome analysis (quantitative and three-dimensional structural analysis of a whole cell at the electron microscopic level). We named it Myojin parakaryote Here we describe, using serial ultrathin sectioning and high-voltage electron microscopy tomography of freeze-substituted specimens, the structome analysis and 3D reconstruction of another unique spiral bacteria, found in the deep sea off the coast of Japan. The bacteria, which is named as 'Myojin spiral bacteria' after the discovery location and their morphology, had a total length of 1.768 ± 0.478 µm and a total diameter of 0.445 ± 0.050 µm, and showed either clockwise or counter-clockwise spiral. The cells had a cell surface membrane, thick fibrous layer, ribosomes and inner fibrous structures (most likely DNA). They had no flagella. The bacteria had 322 ± 119 ribosomes per cell. This ribosome number is only 1.2% of that of Escherichia coli and 19.3% of Mycobacterium tuberculosis and may reflect a very slow growth rate of this organism in the deep sea.
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http://dx.doi.org/10.1093/jmicro/dfw016DOI Listing
August 2016

Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients.

Cancer Sci 2016 Jun 11;107(6):755-63. Epub 2016 May 11.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.

This phase I study in Japanese patients evaluated the safety, pharmacokinetics, and preliminary efficacy of palbociclib, a highly selective and reversible oral cyclin-dependent kinase 4/6 inhibitor, as monotherapy for solid tumors (part 1) and combined with letrozole as first-line treatment of postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (part 2). Part 1 evaluated palbociclib 100 and 125 mg once daily (3 weeks on/1 week off; n = 6 each group) to determine the maximum tolerated dose. Part 2 evaluated palbociclib maximum tolerated dose (125 mg) plus letrozole 2.5 mg (n = 6). The most common treatment-related adverse event was neutropenia (all grades/grade 3/4): 100 mg, 83%/67%; 125 mg, 67%/33%; and palbociclib plus letrozole, 100%/83%. Heavier pretreatment with chemotherapy may have resulted in higher neutropenia rates observed with the 100-mg dose. Palbociclib exposure was higher with 125 vs 100 mg (mean area under the plasma concentration-time curve over dosing interval [τ]: 1322 vs 547.5 ng·h/mL [single dose], 2838 vs 1276 ng·h/mL [multiple dose]; mean maximum plasma concentration: 104.1 vs 41.4 ng/mL [single dose], 185.5 vs 77.4 ng/mL [multiple dose]). Half-life was 23-26 h. No drug-drug interactions between palbociclib and letrozole occurred. Four patients had stable disease (≥24 weeks in one patient with rectal cancer [100 mg] and one with esophageal cancer [125 mg]) in part 1; two patients had partial response and two had stable disease (both ≥24 weeks) in part 2. Palbociclib at the 125-mg dose (schedule 3/1) was tolerated and is the recommended dose for monotherapy and letrozole combination therapy in Japanese patients. The trials are registered with www.ClinicalTrials.gov: A5481010 and NCT01684215.
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http://dx.doi.org/10.1111/cas.12932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968608PMC
June 2016

Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson's disease.

Neurobiol Aging 2015 Dec 7;36(12):3306-3313. Epub 2015 Sep 7.

Clinical Research Center and Department of Neurology, Utano National Hospital, Kyoto, Japan. Electronic address:

Homozygous mutations of the glucocerebrosidase gene (GBA) cause Gaucher disease (GD), and heterozygous mutations of GBA are a major risk factor for Parkinson's disease (PD). This study examined the impact of GBA mutations on the longitudinal clinical course of PD patients by retrospective cohort design. GBA-coding regions were fully sequenced in 215 PD patients and GD-associated GBA mutations were identified in 19 (8.8%) PD patients. In a retrospective cohort study, time to develop dementia, psychosis, wearing-off, and dyskinesia were examined. Survival time analysis followed a maximum 12-year observation (median 6.0 years), revealing that PD patients with GD-associated mutations developed dementia and psychosis significantly earlier than those without mutations (p < 0.001 and p = 0.017, respectively). Adjusted hazard ratios of GBA mutations were 8.3 for dementia (p < 0.001) and 3.1 for psychosis (p = 0.002). No statistically significant differences were observed for wearing-off and dyskinesia between the groups. N-isopropyl-p[(123)I] iodoamphetamine single-photon emission tomography pixel-by-pixel analysis revealed that regional cerebral blood flow was reduced in the bilateral parietal cortex, including the precuneus of GD-associated mutant PD patients, compared with matched PD controls without mutations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.08.027DOI Listing
December 2015

Highly efficient chiral resolution of DL-arginine by cocrystal formation followed by recrystallization under preferential-enrichment conditions.

Chemistry 2014 Aug 15;20(33):10343-50. Epub 2014 Jul 15.

Graduate School of Human and Environmental Studies, Kyoto University, Yoshida Nihonmatsu-cho, Sakyo-ku, Kyoto 606-8501 (Japan), Fax: (+81) 75-753-7915.

An excellent chiral symmetry-breaking spontaneous enantiomeric resolution phenomenon, denoted preferential enrichment, was observed on recrystallization of the 1:1 cocrystal of dl-arginine and fumaric acid, which is classified as a racemic compound crystal with a high eutectic ee value (>95 %), under non-equilibrium crystallization conditions. On the basis of temperature-controlled video microscopy and in situ time-resolved solid-state (13) C NMR spectroscopic studies on the crystallization process, a new mechanism of phase transition that can induce preferential enrichment is proposed.
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http://dx.doi.org/10.1002/chem.201402446DOI Listing
August 2014

Composite hyoid bone graft interposition for the treatment of laryngotracheal stenosis.

ORL J Otorhinolaryngol Relat Spec 2014 11;76(3):147-52. Epub 2014 Jul 11.

Departments of Otolaryngology - Head and Neck Surgery at National Defense Medical College, Saitama, Japan.

Introduction: Chronic laryngotracheal stenosis (LTS) remains a challenging problem for otolaryngologists. A composite hyoid bone interposition graft has the potential to be an ideal graft because the head and neck surgeon can obtain the graft in the same operative field with good vascular supply from the muscle pedicle.

Methods: A composite hyoid interposition graft was used to provide structural support for the reconstructed lumen of the larynx or trachea in 2 cases of LTS.

Results: Two patients underwent successful decannulation with acceptable laryngeal function over a long-term observation period.

Conclusion: This technique allows vascularized stable graft survival with minimal donor site morbidity. Furthermore, it can be performed for thyroid, cricoid, and tracheal stenosis without fear of damage to the recurrent laryngeal nerves.
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http://dx.doi.org/10.1159/000363576DOI Listing
May 2015

Plasmon-assisted water splitting using two sides of the same SrTiO₃ single-crystal substrate: conversion of visible light to chemical energy.

Angew Chem Int Ed Engl 2014 Sep 2;53(39):10350-4. Epub 2014 Jul 2.

Research Institute for Electronic Science, Hokkaido University N21, W10, CRIS Building, Kita-ku, Sapporo 001-0021(Japan) http://misawa.es.hokudai.ac.jp/index_en.html.

A plasmon-induced water splitting system that operates under irradiation by visible light was successfully developed; the system is based on the use of both sides of the same strontium titanate (SrTiO3) single-crystal substrate. The water splitting system contains two solution chambers to separate hydrogen (H2) and oxygen (O2). To promote water splitting, a chemical bias was applied by regulating the pH values of the chambers. The quantity of H2 evolved from the surface of platinum, which was used as a reduction co-catalyst, was twice the quantity of O2 evolved from an Au-nanostructured surface. Thus, the stoichiometric evolution of H2 and O2 was clearly demonstrated. The hydrogen-evolution action spectrum closely corresponds to the plasmon resonance spectrum, indicating that the plasmon-induced charge separation at the Au/SrTiO3 interface promotes water oxidation and the subsequent reduction of a proton on the backside of the SrTiO3 substrate. The chemical bias is significantly reduced by plasmonic effects, which indicates the possibility of constructing an artificial photosynthesis system with low energy consumption.
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http://dx.doi.org/10.1002/anie.201404926DOI Listing
September 2014

A Comparison of the Pharmacokinetics and Drug Safety Among East Asian Populations.

Ther Innov Regul Sci 2014 May;48(3):393-403

1 Pfizer Japan Inc, Tokyo, Japan Presented at the Drug Information Association's 48th annual meeting; June 28, 2012; Philadelphia, Pennsylvania, USA.

Global clinical studies conducted in various countries and regions are increasing. Race and extrinsic ethnic factors are key covariates that may affect the pharmacokinetics (PK), efficacy, and safety of the drug. Genetic similarity among East Asian populations has been confirmed; thus, PK, efficacy, and safety in these populations are expected to be similar, but this has not been confirmed. This study presents a comparison of PK and safety among East Asians from clinical studies sponsored by Pfizer. Four compounds with different characteristics, including mechanism of actions and PK profiles, were selected, and retrospective PK and safety comparisons in East Asians were conducted. No distinct differences were observed in PK and safety across the 4 compounds. These results are consistent with previous reports on PK comparisons and meet the expectations based on genetic similarity among East Asians. Extrapolation of these findings to other compounds should be done with caution, but these results should support the consideration of mutual use of clinical data among East Asian countries.
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http://dx.doi.org/10.1177/2168479013517892DOI Listing
May 2014

A clinical study of attention-deficit/hyperactivity disorder in preschool children--prevalence and differential diagnoses.

Brain Dev 2014 Oct 2;36(9):778-85. Epub 2013 Dec 2.

Center for Developmental Clinical Psychology and Psychiatry, Nagoya University, Nagoya, Japan.

Objective: We aimed to examine (1) the prevalence and characteristics of ADHD in preschool children, and (2) differential diagnoses among children who display symptoms of inattention and hyperactivity-impulsivity in early childhood.

Methods: The participants were children living in Kanie-cho, in Japan's Aichi Prefecture, who underwent their age 5 exams at the municipal health center between April 2009 and March 2011. We first extracted children who were observed to be inattentive or hyperactive-impulsive during their age 5 exams and considered as possibly having ADHD. We conducted follow-ups with these children using post-examination consultations, visits to preschools, and group rehabilitation. The results of the age 5 exams were combined with behavior observations and interview content obtained during subsequent follow-ups. A child psychiatrist and several clinical psychologists discussed these cases and made a diagnosis in accordance with the DSM-IV-TR.

Results: 91 (15.6%) of the 583 children selected were considered as possibly having ADHD; we were able to conduct follow-ups with 83 of the 91 children. Follow-up results showed that 34 children (5.8% of all participants) remained eligible for a diagnosis of ADHD. Diagnoses for the remaining children included: pervasive developmental disorders (six children, or 6.6% of suspected ADHD children), intellectual comprehension problems (four children, or 4.4%), anxiety disorders (seven children, or 7.7%), problems related to abuse or neglect (four children, or 4.4%), a suspended diagnosis for one child (1.1%), and unclear diagnoses for 29 children (31.9%).

Conclusions: ADHD tendencies in preschool children vary with changing situations and development, and the present study provides prevalence estimates that should prove useful in establishing a diagnostic baseline.
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http://dx.doi.org/10.1016/j.braindev.2013.11.004DOI Listing
October 2014

Prokaryote or eukaryote? A unique microorganism from the deep sea.

J Electron Microsc (Tokyo) 2012 28;61(6):423-31. Epub 2012 Sep 28.

Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.

There are only two kinds of organisms on the Earth: prokaryotes and eukaryotes. Although eukaryotes are considered to have evolved from prokaryotes, there were no previously known intermediate forms between them. The differences in their cellular structures are so vast that the problem of how eukaryotes could have evolved from prokaryotes is one of the greatest enigmas in biology. Here, we report a unique organism with cellular structures appearing to have intermediate features between prokaryotes and eukaryotes, which was discovered in the deep sea off the coast of Japan using electron microscopy and structome analysis. The organism was 10 µm long and 3 µm in diameter, having >100 times the volume of Escherichia coli. It had a large 'nucleoid', consisting of naked DNA fibers, with a single nucleoid membrane and endosymbionts that resemble bacteria, but no mitochondria. Because this organism appears to be a life form distinct from both prokaryotes and eukaryotes but similar to eukaryotes, we named this unique microorganism the 'Myojin parakaryote' with the scientific name of Parakaryon myojinensis ('next to (eu)karyote from Myojin') after the discovery location and its intermediate morphology. The existence of this organism is an indication of a potential evolutionary path between prokaryotes and eukaryotes.
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http://dx.doi.org/10.1093/jmicro/dfs062DOI Listing
July 2013

Increased de novo riboflavin synthesis and hydrolysis of FMN are involved in riboflavin secretion from Hyoscyamus albus hairy roots under iron deficiency.

Plant Physiol Biochem 2012 Sep 7;58:166-73. Epub 2012 Jul 7.

Graduate School of Science and Technology, Nagasaki University, Nagasaki 852-8521, Japan.

Riboflavin secretion by Hyoscyamus albus hairy roots under Fe deficiency was examined to determine where riboflavin is produced and whether production occurs via an enhancement of riboflavin biosynthesis or a stimulation of flavin mononucleotide (FMN) hydrolysis. Confocal fluorescent microscopy showed that riboflavin was mainly localized in the epidermis and cortex of the root tip and, at the cellular level, in the apoplast. The expressions of three genes involved in the de novo biosynthesis of riboflavin (GTP cyclohydrolase II/3,4-dihydroxy-2-butanone 4-phosphate synthase; 6,7-dimethyl-8-ribityllumazine synthase; riboflavin synthase) were compared between Fe-starved and Fe-replete roots over a time-course of 7 days, using RT-PCR. All three genes were found to be highly expressed over the period 1-7 days in the roots cultured under Fe deficiency. Since riboflavin secretion began to be detected only from 3 days, there was a lag phase observed between the increased transcript accumulations and riboflavin secretion. To determine whether FMN hydrolysis might contribute to the riboflavin secretion in Fe-deficient root cultures, FMN hydrolase activity was determined and was found to be substantially increased after 3 days, when riboflavin secretion became detectable. These results suggested that not only de novo riboflavin synthesis but also the hydrolysis of FMN contributes to riboflavin secretion under conditions of Fe deficiency. Respiration activity was assayed during the time-course, and was also found to be enhanced after 3 days under Fe deficiency, suggesting a possible link with riboflavin secretion. On the other hand, several respiratory inhibitors were found not to affect riboflavin synthase transcript accumulation.
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http://dx.doi.org/10.1016/j.plaphy.2012.07.001DOI Listing
September 2012

Resolution of vocal fold polyps with conservative treatment.

J Voice 2012 May 13;26(3):e107-10. Epub 2011 Nov 13.

Department of Otolaryngology, Seibo International Catholic Hospital, Tokyo, Japan.

Objectives: Vocal fold polyp is generally thought to require surgical removal. However, a certain proportion of polyps resolve with conservative treatment. This study was performed to clarify the frequency of spontaneous resolution of vocal fold polyp and identify features associated with polyps that are likely to resolve without surgery.

Study Design: Retrospective study.

Methods: A review of the medical records of patients diagnosed with vocal fold polyps in Tokyo Voice Center from January 2001 to December 2008.

Results: Of 644 patients with the diagnosis of vocal fold polyp, 132 received conservative treatment, 433 were treated surgically, and 79 dropped out without attending for further consultation after the initial visit. Of those treated conservatively, 55 experienced complete resolution after a mean of 5.1 months of follow-up from the outset, and 29 showed lesion shrinkage after a mean of 4.1 months of follow-up. Polyps that resolved with conservative therapy were more likely than those that remained unchanged or enlarged to occur in women, be smaller, and have a shorter duration of symptoms. We could not determine the superiority of voice therapy.

Conclusions: At least 9.7% of vocal fold polyps might resolve without surgery. Conservative treatment should be considered as an option for selected patients with smaller and more recent-onset polyps.
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http://dx.doi.org/10.1016/j.jvoice.2011.07.005DOI Listing
May 2012

Structome of Saccharomyces cerevisiae determined by freeze-substitution and serial ultrathin-sectioning electron microscopy.

J Electron Microsc (Tokyo) 2011 9;60(5):321-35. Epub 2011 Sep 9.

Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.

The cell structure has been studied using light and electron microscopies for centuries, and it is assumed that the whole structure is clarified by now. Little quantitative and three-dimensional analysis of cell structure, however, has been undertaken. We have coined a new word, 'structome', by combining 'structure' and '-ome', and defined it as the 'quantitative and three-dimensional structural information of a whole cell at the electron microscopic level'. In the present study, we performed structome analysis of Saccharomyces cerevisiae, one of the most widely researched biological materials, by using freeze-substitution and serial ultrathin-sectioning electron microscopy. Our analysis revealed that there were one to three mitochondria, ~220 000 ribosomes in a cell, and 13-28 endoplasmic reticula/Golgi apparatus which do not form networks in the cytoplasm in the G1 phase. Nucleus occupied ~10.5% of the cell volume; cell wall occupied ~17%; vacuole occupied ~5.8%; cytoplasm occupied ~64%; and mitochondria occupied only ~1.7% in the G1 phase. Structome analysis of cells would form a base for the post-genome research.
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http://dx.doi.org/10.1093/jmicro/dfr052DOI Listing
February 2012

A population approach to eplerenone pharmacokinetics and saturable protein binding.

Drug Metab Pharmacokinet 2010 15;25(6):551-9. Epub 2010 Oct 15.

Department of Clinical Pharmacology, Pfizer Global R&D, Tokyo Laboratories, Pfizer Japan Inc., Tokyo, Japan. yuko.mori@pfizer.com

Eplerenone deviates from linear pharmacokinetics at doses above the therapeutic dose range. In addition, saturable protein binding of eplerenone is observed in in vitro plasma protein binding studies. The purpose of the present study was to clarify the factors contributing to the nonlinear pharmacokinetics of eplerenone. Plasma concentration data for eplerenone and its metabolite SC-70303, to which eplerenone is reversibly converted, obtained from four phase I studies were analyzed using NONMEM. A population pharmacokinetic model incorporating protein binding and the reversible relationship between eplerenone and SC-70303 was developed. Models with linear and nonlinear protein binding were fitted to the observed concentration data. The observed concentration data of eplerenone and SC-70303 were best described by a model with nonlinear protein binding. The area under the plasma concentration-time curve of eplerenone simulated by the model increased less than proportionally with increasing dose, whereas that of SC-70303 increased proportionally with increasing dose, consistent with observations from the non-compartmental analysis. In conclusion, the nonlinear pharmacokinetics of eplerenone and the apparently linear pharmacokinetics of SC-70303 were described by applying a model with nonlinear protein binding to observed plasma eplerenone and SC-70303 concentrations, suggesting that nonlinear protein binding plays a role in the nonlinear kinetics.
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http://dx.doi.org/10.2133/dmpk.dmpk-09-rg-024DOI Listing
May 2011

Iron deficiency induces changes in riboflavin secretion and the mitochondrial electron transport chain in hairy roots of Hyoscyamus albus.

J Plant Physiol 2010 Jul 23;167(11):870-8. Epub 2010 Feb 23.

Graduate School of Science and Technology, Nagasaki University, Nagasaki 852-8521, Japan.

Hyoscyamus albus hairy roots secrete riboflavin under Fe-deficient conditions. To determine whether this secretion was linked to an enhancement of respiration, both riboflavin secretion and the reduction of 2,3,5-triphenyltetrazolium chloride (TTC), as a measure of respiration activity, were determined in hairy roots cultured under Fe-deficient and Fe-replete conditions, with or without aeration. Appreciable TTC-reducing activity was detected at the root tips, at the bases of lateral roots and in internal tissues, notably the vascular system. TTC-reducing activity increased under Fe deficiency and this increase occurred in concert with riboflavin secretion and was more apparent under aeration. Riboflavin secretion was not apparent under Fe-replete conditions. In order to examine which elements of the mitochondrial electron transport chain might be involved, the effects of the respiratory inhibitors, barbiturate, dicoumarol, malonic acid, antimycin, KCN and salicylhydroxamic acid (SHAM) were investigated. Under Fe-deficient conditions, malonic acid affected neither root growth, TTC-reducing activity nor riboflavin secretion, whereas barbiturate and SHAM inhibited only root growth and TTC-reducing activity, respectively, and the other compounds variously inhibited growth and TTC-reducing activity. Riboflavin secretion was decreased, in concert with TTC-reducing activity, by dicoumarol, antimycin and KCN, but not by SHAM. In Fe-replete roots, all inhibitors which reduced riboflavin secretion in Fe-deficient roots showed somewhat different effects: notably, antimycin and KCN did not significantly inhibit TTC-reducing activity and the inhibition by dicoumarol was much weaker in Fe-replete roots. Combined treatment with KCN and SHAM also revealed that Fe-deficient and Fe-replete roots reduced TTC in different ways. A decrease in the Fe content of mitochondria in Fe-deficient roots was confirmed. Overall, the results suggest that, under conditions of Fe deficiency in H. albus hairy roots, the alternative NAD(P)H dehydrogenases, complex III and complex IV, but not the alternative oxidase, are actively involved both in respiration and in riboflavin secretion.
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http://dx.doi.org/10.1016/j.jplph.2010.01.011DOI Listing
July 2010

Neuronal re-juvenilization in the nucleus ambiguus after vagal nerve injury.

Neurosci Res 2009 Dec 31;65(4):353-9. Epub 2009 Aug 31.

Department of Otolaryngology-Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 1608582, Japan.

Nestin is an intermediate filament expressed in immature cells in the CNS including neural stem/progenitor cells, reactive astrocytes and immature neurons in lesser amounts after injury. Nestin expression in the nucleus ambiguus following vagal nerve injury was studied using nestin-EGFP transgenic rats. We confirmed that EGFP immunoreactivity was evident at 6h to 8 days in ipsilateral nucleus ambiguus after nerve transection. Properties of these cells were examined immunohistochemically. These EGFP-immunoreactive cells were immunoreactive for Tuj1 and Hu, and exhibited ChAT activity. However, no immunoreactivity for GFAP or CNPase was observed. In normal development, the level of KCC2 expression is known to increase with maturation of neurons. In our study, decreased KCC2 expression was observed in nestin-EGFP-positive cells within the nucleus ambiguus on the lesioned side compared with the contralateral side. These EGFP-immunoreactive cells were immunonegative for BrdU. This is the first study to demonstrate the expression of a neural stem/progenitor cell-enriched marker, Nestin, in the nucleus ambiguus after vagal nerve injury. The present findings suggest that mature motoneurons are an origin of these Nestin-positive cells, which are induced after injury. Mature neurons in the nucleus ambiguus may thus have the potential to juvenilize after vagal/recurrent laryngeal nerve injury.
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http://dx.doi.org/10.1016/j.neures.2009.08.012DOI Listing
December 2009
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