Beyond relief : biomarkers of the anti-inflammatory effect and dose selection of COX inhibitors in early drug development

Leiden Repository

Beyond relief : biomarkers of the anti-inflammatory effect and dose selection of COX inhibitors in early drug development

Type: Doctoral Thesis
Title: Beyond relief : biomarkers of the anti-inflammatory effect and dose selection of COX inhibitors in early drug development
Author: Huntjens, Dymphy Regien Hans
Publisher: Department Pharmacology, Leiden /Amsterdam Center for Drug Research (LACDR), Faculty of Science, Leiden University
Issue Date: 2008-11-18
Keywords: COX inhibitors
Biomarkers
Inflammation
Pain
PK-PD modelling
PGE2
Translational pharmacology
TXB2
Abstract: The main objective of the research described in this thesis is to demonstrate the relevance of biomarkers on the selection of the dose range of COX inhibitors for effective analgesic and anti-inflammatory response, as opposed to the focus on behavioural measures of pain and inflammation advocated by the current paradigm for the development of non-steroidal anti-inflammatory drugs (NSAIDs). To this end, the relationship between drug concentration and the corresponding inhibition of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) was investigated for a range of COX inhibitors with varying degrees of selectivity, and hence with differential effects on the selected biomarkers. Thanks to the use of a mechanism-based approach, attention is also given to translational pharmacology in drug development. We evaluate whether 1) estimates of drug action in vitro are predictive of the effect in vivo, 2) animal data in vivo reflect drug effect on biomarkers in humans and 3) whether inflammatory conditions modify the extent of drug effect as compared to healthy conditions. A recommendation and guideline for best practices in the development of COX inhibitors is anticipated from this analysis.
Description: Promotor: M. Danhof, Co-promotor: O.E. Della Pasqua
With summary in Dutch
Faculty: Faculteit der Wiskunde en Natuurwetenschappen
Citation: Huntjens, D.R.H., 2008, Doctoral thesis, Leiden University
ISBN: 9789085703136
Handle: http://hdl.handle.net/1887/13263
 

Files in this item

Description Size View
application/pdf Cover 2.507Mb View/Open
application/pdf Title page_Contents 56.30Kb View/Open
application/pdf Section I General introduction 12.71Kb View/Open
application/pdf Chapter 1 1.129Mb View/Open
application/pdf Chapter 2 2.872Mb View/Open Full text at publisher site
application/pdf Chapter 3 54.85Kb View/Open
application/pdf Section II PKPD modelling of biomarkers 14.06Kb View/Open
application/pdf Chapter 4 1.656Mb View/Open Full text at publisher site
application/pdf Chapter 5 1.584Mb View/Open Full text at publisher site
application/pdf Chapter 6 2.260Mb View/Open
application/pdf Chapter 7 1.479Mb View/Open
application/pdf Section III PKPD modelling of analgesia 13.48Kb View/Open
application/pdf Chapter 8 1.563Mb View/Open Full text at publisher site
application/pdf Chapter 9 2.367Mb View/Open
application/pdf Section IV Clin ... and inter-species scaling 13.53Kb View/Open
application/pdf Chapter 10 2.313Mb View/Open
application/pdf Section V Conclusions and perspectives 13.03Kb View/Open
application/pdf Chapter 11 591.4Kb View/Open
application/pdf Chapter 12 Summary in Dutch 58.77Kb View/Open
application/pdf List of publications_Curriculum vitae_Afterword 46.78Kb View/Open
application/pdf Propositions 40.48Kb View/Open

This item appears in the following Collection(s)