Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

INTRODUCTION: Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE: The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS: Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS: Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION: It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving

De prognose van geopereerde hernia nuclei pulposi patiënten: een onderzoek naar aantoonbare factoren, van invloed op het houden van post-operatieve klachten en de mate van werkhervatting bij patiënt

Contains fulltext : mmubn000001_230564267.pdf (publisher's version ) (Open Access)Promotor : J. Prick110 p

Childhood Obesity; Medical, Cultural and Psychological Factors

The aim of this thesis was to examine medical, cultural and psychological factors of childhood obesity in a multi-ethnic cohort. Medical factors Several associations between weight measured and hormones were determined in obese children between 6 and 18 years. Thyroid stimulating hormone (TSH) was associated with age and sex standardized body mass index (Z-BMI), impaired fasting glucose, impaired glucose tolerance, high total cholesterol, high LDL-cholesterol and high triglycerides. There were no significant associations between albumin/creatinine ratio and any cardiometabolic risk factors. Moreover, there was a low prevalence of microalbuminuria (an early marker of kidney disease). In contrast, an alarmingly high prevalence of vitamin D deficiency was found in obese ethnic children (88%), while normal weight white children showed a prevalence of 20%. With a high loading dose of 25 000 IU weekly vitamin D3 supplementation, 84.4% of these children improved from deficiency (<50 nmol/L) to sufficiency (≥50 nmol/L). No side effects were reported, and the highest level reached was far below the threshold for toxicity. Cultural and family factors The radical change in lifestyle during Ramadan has shown to affect the weight, glucose and lipid metabolism in normal- and overweight adults. We found that Ramadan 2012 had no effect on Z-BMI or glucose metabolism in 25 obese adolescents. However, transient increases in total-, LDL-, HDL-cholesterol and hs-CRP were observed, all of which normalized 6 weeks after conclusion of Ramadan fast. Parental weight has proven to be one of the most important independent predictors of childhood obesity and therefore we determined the effect of gastric bypass on the weight and eating behaviors of their children. Surprisingly, no significant changes in eating behavior or Z-BMI of the children were found after one year. Psychological factors In addition to the physical health problems, obesity also poses a considerable risk of psychological problems. Indeed, health related quality of life and specifically the subscales physical wellbeing, moods & emotions and self-perception were markedly reduced in our obese cohort compared to an age and sex matched reference group. Parents reported consistently lower quality of life scores than the children themselves. Surprisingly, we did not find any ethnic specific differences in quality of life. Furthermore, obese children had more eating- and overall behavior problems compared to normal weight children. Moreover, obesity was significantly associated with poor intelligence, poor working memory and high response variability. Response variability was correlated with inattention, a well known symptom of attention-deficit/hyperactivity disorder (ADHD). These results suggest that ADHD like symptoms could be a risk factor for the development of obesity, which need to be confirmed by future longitudinal studies

Childhood obesity : medical, cultural and psychological factors

The aim of this thesis was to examine medical, cultural and psychological factors of childhood obesity in a multi-ethnic cohort. Medical factors Several associations between weight measured and hormones were determined in obese children between 6 and 18 years. Thyroid stimulating hormone (TSH) was associated with age and sex standardized body mass index (Z-BMI), impaired fasting glucose, impaired glucose tolerance, high total cholesterol, high LDL-cholesterol and high triglycerides. There were no significant associations between albumin/creatinine ratio and any cardiometabolic risk factors. Moreover, there was a low prevalence of microalbuminuria (an early marker of kidney disease). In contrast, an alarmingly high prevalence of vitamin D deficiency was found in obese ethnic children (88%), while normal weight white children showed a prevalence of 20%. With a high loading dose of 25 000 IU weekly vitamin D3 supplementation, 84.4% of these children improved from deficiency (<50 nmol/L) to sufficiency (≥50 nmol/L). No side effects were reported, and the highest level reached was far below the threshold for toxicity. Cultural and family factors The radical change in lifestyle during Ramadan has shown to affect the weight, glucose and lipid metabolism in normal- and overweight adults. We found that Ramadan 2012 had no effect on Z-BMI or glucose metabolism in 25 obese adolescents. However, transient increases in total-, LDL-, HDL-cholesterol and hs-CRP were observed, all of which normalized 6 weeks after conclusion of Ramadan fast. Parental weight has proven to be one of the most important independent predictors of childhood obesity and therefore we determined the effect of gastric bypass on the weight and eating behaviors of their children. Surprisingly, no significant changes in eating behavior or Z-BMI of the children were found after one year. Psychological factors In addition to the physical health problems, obesity also poses a considerable risk of psychological problems. Indeed, health related quality of life and specifically the subscales physical wellbeing, moods & emotions and self-perception were markedly reduced in our obese cohort compared to an age and sex matched reference group. Parents reported consistently lower quality of life scores than the children themselves. Surprisingly, we did not find any ethnic specific differences in quality of life. Furthermore, obese children had more eating- and overall behavior problems compared to normal weight children. Moreover, obesity was significantly associated with poor intelligence, poor working memory and high response variability. Response variability was correlated with inattention, a well known symptom of attention-deficit/hyperactivity disorder (ADHD). These results suggest that ADHD like symptoms could be a risk factor for the development of obesity, which need to be confirmed by future longitudinal studies

The hypomotility elicited by small doses of apomorphine seems exclusively mediated by dopaminergic systems in the nucleus accumbens

The reduction of motor activity elicited in rats by a subcutaneous injection of a small dose of apomorphine was reversed by pretreatment of the nucleus accumbens with haloperidol (10 pg), sulpride (10 pg) or desenkephalin-γ-endorphin (DEγE) (100 pg or 10 ng). These doses of the compounds did not change motor activity in placebo-treated rats. Pretreatment of the nucleus caudatus with the same neuroleptics or DEγE did not diminish the effect of subcutaneously administered low doses of apomorphine. A small dose of apomorphine decreased motor activity when it was injected directly into the nucleus accumbens. This effect was dose dependently antagonized by subcutaneous pretreatment with DEγE. It is suggested that the hypoactivity elicited by small doses of apomorphine is exclusively mediated by dopaminergic systems in the nucleus accumbens