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Testerink J.,Manchester Metropolitan University | Testerink J.,VU University Amsterdam | Degens H.,VU University Amsterdam | Rittweger J.,Manchester Metropolitan University | And 5 more authors.
Journal of Physiology and Pharmacology | Year: 2011

Vitamin D deficiency is associated with muscle weakness. It is unknown, however, how supra-physiological levels of vitamin D affect skeletal muscle. To investigate the effects of increased serum vitamin D (1,25 (OH)2D3 or 1,25D) levels on the contractile properties of the medial gastrocnemius muscle, adult and old female Fischer344 × Brown Norway F1 rats were orally treated with vehicle or the vitamin D analogue alfacalcidol for 1 or 6 weeks. Alfacalcidol treatment resulted in elevated 1,25D serum levels. This was accompanied by hypercalcaemia and a reduction in body mass, the latter largely attributable to a reduced food intake. However, kidney function, as reflected by normal creatinine serum levels, as well as heart mass were unaffected. The 17% reduction in maximal isometric force and power was explicable by a similar loss of muscle mass. The force-frequency relationship of the 6-week-treated old rats was shifted to the left, but neither the shape of the force-velocity relationship nor the fatigability of the muscle were altered. Supraphysiological doses of vitamin D were accompanied by significant reductions in body and muscle mass, but not by an improvement in muscle functioning. Weight loss was largely due to a reduced food intake, while the left shift in the force-frequency relation may be due to increased 1,25D levels.

Morcos P.N.,Roche Holding AG | Yu L.,Roche Holding AG | Bogman K.,Roche Holding AG | Sato M.,Chugai Pharmaceuticals Co. | And 9 more authors.
Xenobiotica | Year: 2016

1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor. 2. The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50 μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600 mg oral dose of alectinib in the first period, and a single 600 mg/67 μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects. 3. The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5 L/h, volume of distribution was 475 L and the hepatic extraction ratio was low (0.14). 4. Near-complete recovery of administered radioactivity was achieved within 168 h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively. 5. This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

Fujita F.,Experimental Cancer Chemotherapy Research Laboratories Co. | Shirane M.,Chugai Pharmaceuticals Co. | Mori K.,Chugai Pharmaceuticals Co. | Koike M.,Experimental Cancer Chemotherapy Research Laboratories Co. | Fujita M.,Association for Anticancer Drug Search
Japanese Journal of Cancer and Chemotherapy | Year: 2010

We carried out gene expression profiling of forty human tumor cells for research choice method of the most fitting anticancer drug, using unsupervised hierarchal clustering analysis. This clustering analysis is based on a tumor growth inhibition panel of nine antitumor drugs (MMC, CDDP, ACNU, CPT-11, CPA, FT-207, UFT, 5′-DFUR and ADM) for forty human cancers. These cancers (eleven stomach, seven colon, six breast, three pancreas, five lung, two esophageal carcinomas, one liver, one renal cell carcinoma, one uterus, two ovarian, and one melanoma) have been maintained by serial s. c. passages in nude mice of the same sex of donor patients. Nine antitumor drugs were divided into two groups, a 5-FU-related drug group (5′-DFUR, FT-207 and UFT) and another group. On the other hands, forty cells were clustered into four groups. By using GeneChip® (Hu95Av2, Affymetrix), we investigated gene expression profiling of the matched tumor cells and selected specific genes in each group. Interestingly, a pathway analysis revealed that expressions of p53-related genes were up-regulated in the 5-FU-sensitive groups. This result suggested that chemosensitivity was predicted by gene expression profiling of tumor cells. We considered that microarray analysis would be a good tool for further tailor-made medications.

Niikura N.,Tokai University | Iwamoto T.,Okayama University | Masuda S.,Nihon University | Kumaki N.,Tokai University | And 8 more authors.
Cancer Science | Year: 2012

The objective of this study was to examine the association between the immunohistochemical Ki67 labeling index (IHC Ki67), Ki67 mRNA expression level, and first-generation gene signatures in a cohort of breast cancer patients. We assessed associations between IHC Ki67 and first-generation gene signatures in a panel of 39 tumor samples, using an oligonucleotide microarray. Gene expression analyses included Ki67 alone (MKi67), 21-gene signature, mitosis kinome score signature, and genomic grade index. Correlation coefficients were calculated by Spearman's rank correlation test. In all cases, IHC Ki67, MKi67, and three genetic markers were highly correlated (ρ, 0.71-0.97). Estrogen receptor (ER)-positive cases showed strong correlations between IHC Ki67 and other signatures (ρ, 0.79-0.83). The ER-negative cases showed slightly lower correlations (ρ, 0.58-0.73). In ER-positive cases, the low IHC Ki67 group showed significantly longer relapse-free survival than the high IHC Ki67 group (P = 0.007). This difference was confirmed by multivariate analysis. Our data indicate that IHC Ki67 shows similar predictive power for proliferation in ER-positive cancers as genomic markers. Further study of IHC Ki67 is needed to define prognostic factors and predictive factors for chemotherapy using central laboratory assessment. © 2012 Japanese Cancer Association.

Ogawa K.,Chugai Pharmaceuticals Co. | Kato M.,Chugai Pharmaceuticals Co. | Houjo T.,Chugai Research Institute for Medical Science Inc. | Ishigai M.,Chugai Pharmaceuticals Co.
Xenobiotica | Year: 2013

1. Focusing on the genetic similarity of CYP3A subfamily enzymes (CYP3A4 and CYP3A5) between monkeys and humans, we have attempted to provide a single-species approach to predicting human hepatic clearance (CLh) of CYP3A4 substrates using pharmacokinetic parameters in cynomolgus monkeys following intravenous administrations. 2. Hepatic intrinsic clearance (CL int,h) of six CYP3A4 substrates (alprazolam, clonazepam, diltiazem, midazolam, nifedipine, and quinidine), covering a wide range of clearance, in monkeys correlated well with that cited in literature for humans (R = 0.90) with a simple equation of Y = 0.165X (Y: human CLint,h, X: monkey CL int,h, represented in mL/min/kg). 3. To verify the predictability of human CLint,h, monkey CLint,h of a test set of CYP3A4 substrates cited in literature (dexamethasone, nifedipine, midazolam, quinidine, tacrolimus, and verapamil) was applied to the equation and human CL int,h was calculated. The human CLint,h of all the substrates was predicted within 3-fold error (fold error: 0.35-2.77). 4. The predictability of human CLh by our method was superior to common in vivo prediction methods (allometry and liver blood flow method). These results suggest that human hepatic clearance of CYP3A4 substrates can be predicted by applying cynomolgus monkey CLint,h obtained following intravenous administrations in each laboratory to the simple equation. © 2013 Informa UK, Ltd.

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