Applied Pharmacology Research Laboratories

Leiderdorp, Netherlands

Applied Pharmacology Research Laboratories

Leiderdorp, Netherlands
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Heeringa M.,Global Clinical Pharmacology and Exploratory Development | Hastings A.,Applied Pharmacology Research Laboratories | Yamazaki S.,Astellas Pharma Inc. | De Koning P.,Global Clinical Pharmacology and Exploratory Development
Biomarkers in Medicine | Year: 2012

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease throughout the world. In the USA, approximately 3-5% of the population are affected, and the prevalence of this condition is increasing. NASH is associated with an increased risk of liver-related morbidity, such as cirrhosis and fibrosis, as well as cardiovascular disease, and in spite of several clinical studies investigating putative new drugs, no approved treatment is currently available. This is partly due to the nature of the disease. NASH is a complex, slowly progressing disease, and confirmatory clinical trials have long treatment durations and require invasive end points (a liver biopsy). Such invasive assessments are only accepted in confirmatory trials; clinical studies in the exploratory clinical development phase must rely on noninvasive biomarkers as the primary end point. Experimental and clinical research continues to achieve validation and qualification of biomarkers in NASH, which will hopefully assist the development of new treatments for NASH patients. © 2012 Future Medicine Ltd.


PubMed | Applied Pharmacology Research Laboratories
Type: Journal Article | Journal: Thrombosis and haemostasis | Year: 2012

We evaluated the relationship between antithrombotic effects and pharmacodynamic (PD) marker changes produced by the novel factor (F)Xa inhibitors darexaban (YM150) and rivaroxaban in a rabbit model of plaque disruption-induced arterial thrombosis. Animals were subjected to catheter-induced endothelial denudation via the femoral artery followed by a two-week high-cholesterol diet. Plaque disruption was induced by balloon angioplasty, and then stasis was achieved by ligation at the distal side of the injured segment. Darexaban and rivaroxaban were administered orally 1 hour (h) before and 9 h after plaque disruption, and their antithrombotic effects were evaluated 24 h after the initiation of ligation. Prothrombin time (PT), activated partial thromboplastin time (APTT), and plasma FXa activity were measured using blood samples collected before and 1h after administration. Darexaban and rivaroxaban significantly reduced thrombus formation. The thrombus weight obtained in the 30 mg/kg darexaban group was comparable to that in the 1 mg/kg rivaroxaban group (2.17 0.63 and 3.23 1.64 mg, respectively, vs. 8.01 1.08 mg in the control group). Plasma FXa activity correlated with the antithrombotic effects of darexaban and rivaroxaban, while PT only correlated with those of darexaban. Our findings suggest that the degree of plasma FXa inhibition may be useful for predicting antithrombotic effects of darexaban and rivaroxaban in arterial thrombosis. PT may also be useful in evaluating antithrombotic effects of darexaban in particular.


PubMed | Applied Pharmacology Research Laboratories
Type: Journal Article | Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] | Year: 2011

To investigate the preventive and therapeutic effects of tacrolimus on colonic inflammation in interleukin-10-deficient (IL-10(-/-)) mice, which spontaneously develop T-cell-mediated colitis.Tacrolimus or prednisolone, an anti-inflammatory glucocorticoid, was administered to IL-10(-/-) mice with pre- or post-symptomatic colitis. Effects on colonic inflammation were examined by measuring indices of colitis such as colonic weight/length ratio, cell infiltration, and goblet cell depletion. Effects on cytokine production in colonic lamina propria mononuclear cells (LPMCs) isolated from IL-10(-/-) mice were also examined.Tacrolimus prevented development of colitis and improved already-developed colitis. Prednisolone prevented the development of colitis, but had no effect on already-developed colitis. Tacrolimus completely inhibited IFN- and TNF- production of activated T-cells in LPMCs, but only partially inhibited IFN-, TNF-, and IL-12 production of activated monocytes/macrophages in LPMCs. Prednisolone inhibited cytokine production in both cell types but exhibited greater potency on monocytes/macrophages than on T-cells.These results suggest that the preventive and therapeutic effect of tacrolimus in IL-10(-/-) mice colitis might be attributed to the inhibition of colonic T-cell activation rather than monocyte/macrophage activation. T-cell immunosuppression may thus be a promising strategy for treating colonic inflammation.

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