Chronic pain is a significant health problem that greatly impacts the quality of life of individual patients and imparts high costs to society. Despite intense research effort and progress in our... Show moreChronic pain is a significant health problem that greatly impacts the quality of life of individual patients and imparts high costs to society. Despite intense research effort and progress in our understanding of the mechanistic and molecular basis of pain, chronic pain remains a significant clinical problem that has few effective therapies Throughout the various chapters we have highlighted some important conceptual and experimental flaws in the way that pain signalling and pharmacological activity are characterised and translated across species and disease conditions. The common denominator of the work presented here is the requirement for accurate characterisation of exposure-response relationships, without which the dose rationale for the progression of a molecule cannot justified, whether drugs are aimed at symptomatic relief, disease modification or prophylaxis. In addition to a comprehensive review of the mechanisms underlying pain signalling and symptoms, the work developed here focuses on three different aspects of research underpinning the use of pharmacokinetic-pharmacodynamic relationships. First, we have explored the requirements for the characterisation of behavioural measures of pain during the early screening of candidate molecules, shedding light onto the shortcomings of experimental protocols commonly used in preclinical research. Then we introduced the prerequisites for the parameterisation of pain behaviour to ensure accurate translation of the pharmacological properties across species as well as for bridging across different phases of development. Lastly, an attempt was made to model clinical response in chronic inflammatory pain and to establish correlations between symptom improvement and the underlying pharmacological effects using biomarkers. In addition our work showed how clinical trial simulations can be used as a design tool, enabling the evaluation of a variety of scenarios that disentangle the contribution of pharmacology from the confounding effects of placebo and disease dynamics. Show less
H2: Hensgens MP, Goorhuis A, Notermans DW, van Benthem BH, Kuijper EJ. Decrease of hypervirulent Clostridium difficile PCR ribotype 027 in the Netherlands. Euro Surveill. 2009 H3: Hensgens MP,... Show moreH2: Hensgens MP, Goorhuis A, Notermans DW, van Benthem BH, Kuijper EJ. Decrease of hypervirulent Clostridium difficile PCR ribotype 027 in the Netherlands. Euro Surveill. 2009 H3: Hensgens MP, Keessen EC, Squire M, Riley TV, Koene MG, de Boer E, Lipman LJ, Kuijper EJ. Clostridium difficile infection in the community: a zoonotic disease? Clin Microbiol Infect. 2012 H4: Hensgens MP / Goorhuis A, van Kinschot CM, Crobach MJ, Harmanus C, Kuijper EJ. Clostridium difficile infection in an endemic setting in the Netherlands. Eur J Clin Microbiol Infect Dis. 2011 H5: Hensgens MP, Goorhuis A, Dekkers OM, Kuijper EJ. Time-interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012 H7: Hensgens MP, Goorhuis A, Dekkers OM, van Benthem BH, Kuijper EJ. Outcome of nosocomial Clostridium difficile infections; results of a multicenter cohort study. Clin Infect Dis. 2013 H8: Hensgens MP / Bauer MP, Miller M, Gerding DN, Wilcox MH, Dale AP, Fawley WN, Kuijper EJ, Gorbach SL. Renal failure and leukocytosis are predictors of a complicated course of Clostridium difficile infection (CDI) if measured on day of diagnosis. Clin Infect Dis. 2012 H9: Hensgens MP, Kuijper EJ. Clostridium difficile infection due to binary toxin positive strains. Emerg Infect Dis. 2013 H10: Hensgens MP, Dekkers OM, Goorhuis A, Le Cessie S, Kuijper EJ. Predicting a severe course of Clostridium difficile infection at the bedside. Clin Microbiol Infect. 2012 Show less
