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Macrophage depletion alleviates pain-related behaviors in osteoarthritic mice

ABSTRACT: Macrophage depletion alleviates pain-related behaviors in osteoarthritic mice

PROVIDER: PRJNA1032140 | ENA |

REPOSITORIES: ENA

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Project description:Benson2014 - FAAH inhibitors for the treatment of osteoarthritic pain Evaluation of fatty acid amide hydrolase (FAAH) as a target for osteoarthritic pain in humans, using an integrated systems pharmacology model. The SBML version of the model is obtained from the supplementary material of the corresponding paper (see below). This model is described in the article: A systems pharmacology perspective on the clinical development of Fatty Acid amide hydrolase inhibitors for pain. Benson N, Metelkin E, Demin O, Li GL, Nichols D, van der Graaf PH. CPT Pharmacometrics Syst Pharmacol. 2014 Jan 15;3:e91. Abstract: The level of the endocannabinoid anandamide is controlled by fatty acid amide hydrolase (FAAH). In 2011, PF-04457845, an irreversible inhibitor of FAAH, was progressed to phase II clinical trials for osteoarthritic pain. This article discusses a prospective, integrated systems pharmacology model evaluation of FAAH as a target for pain in humans, using physiologically based pharmacokinetic and systems biology approaches. The model integrated physiological compartments; endocannabinoid production, degradation, and disposition data; PF-04457845 pharmacokinetics and pharmacodynamics, and cannabinoid receptor CB1-binding kinetics. The modeling identified clear gaps in our understanding and highlighted key risks going forward, in particular relating to whether methods are in place to demonstrate target engagement and pharmacological effect. The value of this modeling exercise will be discussed in detail and in the context of the clinical phase II data, together with recommendations to enable optimal future evaluation of FAAH inhibitors. This model is hosted on BioModels Database and identified by: MODEL1402030000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Macrophage depletion alleviates pain-related behaviors in osteoarthritic mice

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