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Katsume A.,Tokyo Metropolitan Institute of Medical Science | Katsume A.,Chugai Pharmaceutical Co. | Tokunaga Y.,Tokyo Metropolitan Institute of Medical Science | Hirata Y.,Tokyo Metropolitan Institute of Medical Science | And 14 more authors.
Gastroenterology | Year: 2013

Background & Aims Host cell lipid rafts form a scaffold required for replication of hepatitis C virus (HCV). Serine palmitoyltransferases (SPTs) produce sphingolipids, which are essential components of the lipid rafts that associate with HCV nonstructural proteins. Prevention of the de novo synthesis of sphingolipids by an SPT inhibitor disrupts the HCV replication complex and thereby inhibits HCV replication. We investigated the ability of the SPT inhibitor NA808 to prevent HCV replication in cells and mice. Methods We tested the ability of NA808 to inhibit SPT's enzymatic activity in FLR3-1 replicon cells. We used a replicon system to select for HCV variants that became resistant to NA808 at concentrations 4- to 6-fold the 50% inhibitory concentration, after 14 rounds of cell passage. We assessed the ability of NA808 or telaprevir to inhibit replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in mice with humanized livers (transplanted with human hepatocytes). NA808 was injected intravenously, with or without pegylated interferon alfa-2a and HCV polymerase and/or protease inhibitors. Results NA808 prevented HCV replication via noncompetitive inhibition of SPT; no resistance mutations developed. NA808 prevented replication of all HCV genotypes tested in mice with humanized livers. Intravenous NA808 significantly reduced viral load in the mice and had synergistic effects with pegylated interferon alfa-2a and HCV polymerase and protease inhibitors. Conclusions The SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers. It might be developed for treatment of HCV infection or used in combination with pegylated interferon alfa-2a or HCV polymerase or protease inhibitors. © 2013 by the AGA Institute.

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.

Sakamoto H.,Chugai Pharmaceutical Co. | Tsukaguchi T.,Chugai Pharmaceutical Co. | Hiroshima S.,Chugai Research Institute for Medical Science Inc. | Kodama T.,Chugai Pharmaceutical Co. | And 6 more authors.
Cancer Cell | Year: 2011

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors. © 2011 Elsevier Inc.

Yamaguchi K.,Chugai Pharmaceutical Co. | Kato M.,Chugai Pharmaceutical Co. | Suzuki M.,Chugai Pharmaceutical Co. | Hagita H.,Chugai Research Institute for Medical Science Inc. | And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

To evaluate the relationship between the in vitro and in vivo potency of sodium-glucose cotransporter (SGLT) inhibitors, a pharmacokinetic and pharmacodynamic (PK-PD) study was performed using normal rats. A highly selective SGLT2 inhibitor, tofogliflozin, and four other inhibitors with different in vitro inhibition potency to SGLT2 and selectivity toward SGLT2, versus SGLT1 were used as test compounds, and the time courses for urinary glucose excretion (UGE) and the plasma glucose and compound concentrations were monitored after administration of the compounds. A PK-PD analysis of the UGE caused by SGLT inhibition was performed on the basis of a nonlinear parallel tube model that took into consideration the consecutive reabsorption by different glucose transport properties of SGLT2 and SGLT1. The model adequately captured the time course of cumulative UGE caused by SGLT inhibition; then, the in vivo inhibition constants (Ki) of inhibitors for both SGLT1 and SGLT2 were estimated. The in vivo selectivity toward SGLT2 showed a good correlation with the in vitro data (r 5 0.985; P < 0.05), with in vivo K i values for SGLT2 in the range of 0.3-3.4-fold the in vitro data. This suggests that in vitro inhibition potency to both SGLT2 and SGLT1 is reflected in vivo. Furthermore, the complementary role of SGLT1 to SGLT2 and how selectivity toward SGLT2 affects the inhibitory potency for renal glucose reabsorption were discussed using the PK-PD model. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Kawase Y.,Chugai Research Institute for Medical Science Inc. | Suzuki H.,Obihiro University of Agriculture and Veterinary Medicine
Journal of Reproduction and Development | Year: 2011

This review describes the study of freeze-dried mouse sperm for practical application in preserving and transporting genetic resources. Freeze-dried sperm can be used to preserve and transport genetic resources; however, there still remain many areas which need to be studied. In particular, it is essential to assure long-term preservation over several decades or centuries. Recently, the theory of accelerated degradation kinetics to freeze-dried mouse sperm has been applied, and found that long-term preservation by conventional methods requires temperatures lower than -80 C. When the relationship between the pressure at primary drying and the preservation potential of freezedried mouse sperm was examined, a pressure of 0.37 mbar at primary drying significantly improved the developmental rate to the blastocyst stage. In addition, it has been shown that freeze-dried sperm stored at -80 C with and without transportation can retain their ability to generate viable offspring after storage for up to 2 years. Sperm chromatin structure assay (SCSA) was applied to mouse sperm freeze-dried under several conditions and compared the results with the embryonic developmental rates of freeze-dried sperm after intracytoplasmic sperm injection (ICSI) and with comet assay results. Furthermore, SCSA might be useful for estimation of developmental potential of fertilized eggs derived from ICSI using freeze-dried sperm in mice. © 2011 by the Society for Reproduction and Development.

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