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... Show moreThe 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. Show less
This thesis deals with emotional and social influences on childhood somatic complaints. Strong support is provided for the idea that negative affect contributes to the development of somatic... Show moreThis thesis deals with emotional and social influences on childhood somatic complaints. Strong support is provided for the idea that negative affect contributes to the development of somatic complaints in childhood. In addition, the studies described give information about the type and levels of negative affect associated with somatic complaints in childhood. When appraisal is characterized by the experience of little control over negative situations and emotions, this is likely to directly cause more feelings of negative affect and also to contribute to a more negative processing of emotions: children who feel little control evidently use more maladaptive emotion regulation strategies. This negative emotional processing further contributes to negative affect and subsequent somatic complaints. These relationships between negative affect and somatic complaints are even present at subclinical levels of emotional problems. With regard to social problems, it is found that they have an effect on somatic complaints that is fully mediated by aspects of children’s emotional functioning: self-perceived social problems indicate lower feelings of control and more maladaptive emotion regulation. Show less
The frequently diagnosed lumbar disc herniation can disappear by natural course, but still leads to high low back surgery rates. The optimal period of conservative care, before surgery is executed,... Show moreThe frequently diagnosed lumbar disc herniation can disappear by natural course, but still leads to high low back surgery rates. The optimal period of conservative care, before surgery is executed, was unknown. It is surprising that scientific evidence was lacking which justified “early” surgery. Surgery, after 6-12 weeks of sciatica, was compared to prolonged conservative care in 283 patients in a randomized study. Primary outcomes were perceived recovery, leg pain intensity and functioning. Early surgery resulted in a 2 times faster recovery rate, compared to prolonged conservative care. From the latter group 39 percent of patients could not evade surgery. Within one year, however, both groups presented similar recovery rates and outcome. The impossibility to sit, because of sciatica, seemed to be a good argument to decide for early surgery. Intense pain and disability were predictors for delayed surgery. Compared to men, females exhibited a 3 times higher odds to develop chronic pain. The higher medical costs of early surgery were fully compensated by quick resumption of working capacity. From a medical point of view one may favor a prolonged wait-and-see strategy but our western society urges patients to decide for early surgery to resume daily activities. Show less
