Down syndrome (DS) is associated with increased susceptibility to infections, auto-immunity, immunodeficiency and haematological malignancies. The exact underlying immunological pathophysiology is... Show moreDown syndrome (DS) is associated with increased susceptibility to infections, auto-immunity, immunodeficiency and haematological malignancies. The exact underlying immunological pathophysiology is still unclear. The immunophenotype and clinical characteristics of DS resemble those of Activated PI3K Delta Syndrome (APDS), in which the PI3K/AKT/mTOR pathway is overactivated. We hypothesized that T cell exhaustion and the hyperactivation of the AKT signalling pathway is also present in immune cells of children with DS. In this observational non-interventional cohort study we collected blood samples of children with DS (n=22) and healthy age-matched controls (n=21) for flowcytometric immunophenotyping, phospho-flow AKT analysis and exhaustion analysis of T cells. The median age was 5 years (range 1-12y). Total T and NK cells were similar for both groups, but absolute values and transitional B cells, naive memory B cells and naive CD4+ and CD8+ T cells were lower in DS. pAKT and AKT were increased for CD3+ and CD4+ T cells and CD20+ B cells in children with DS. Total AKT was also increased in CD8+ T cells. Children with DS showed increased expression of inhibitory markers Programmed cell dealth-1 (PD-1), CD244 and CD160 on CD8+ T cells and increased PD-1 and CD244+ expression on CD4+ T cells, suggesting T cell exhaustion. Children with DS show increased pAKT and AKT and increased T cell exhaustion, which might contribute to their increased susceptibility to infections, auto immunity and haematological malignancies. Show less
Weltings, S.; Buddingh, K.T.; Diepen, D.C. van; Pelger, R.C.M.; Putter, H.; Rad, M.; ... ; Roshani, H. 2020
Purpose To investigate whether placebo is non-inferior to continuous infusion of butylscopolamine in patients with renal colic. Methods We conducted a placebo-controlled, multicenter, double-blind... Show morePurpose To investigate whether placebo is non-inferior to continuous infusion of butylscopolamine in patients with renal colic. Methods We conducted a placebo-controlled, multicenter, double-blind randomized clinical trial (RCT) including 128 patients with renal colic (confirmed by ultrasound or CT-scan). Patients were randomized to receive either continuous IV butylscopolamine 100 mg/24 h or placebo (saline). Primary outcome is the amount of opioid escape medication used, measured in doses administered. Secondary outcomes are pain measured on a Numeric Rating Scale (NRS), side effects, and time of drug administration. Non-inferiority was assessed using linear regression with robust standard errors, with non-inferiority limit set at 0.5 units of escape medication. Results Median number of doses of escape medication was one in both groups. The number of extra doses in the placebo group compared with the butylscopolamine group was 0.05, with a 95% robust confidence interval (CI) of 0.38-0.47. Upper limit of the CI remained below the non-inferiority limit of 0.5 (p = 0.04). No differences in secondary endpoints were seen between the groups. Conclusion Placebo is non-inferior to continuous IV butylscopolamine for pain relief in patients with renal colic. Based on this study and previous evidence, there is no role for continuous butylscopolamine IV in the treatment of renal colic. Trial NL7819 Show less
Weltings, S.; Buddingh, K.T.; Diepen, D.C. van; Pelger, R.C.M.; Putter, H.; Rad, M.; ... ; Roshani, H. 2020
Purpose To investigate whether placebo is non-inferior to continuous infusion of butylscopolamine in patients with renal colic. Methods We conducted a placebo-controlled, multicenter, double-blind... Show morePurpose To investigate whether placebo is non-inferior to continuous infusion of butylscopolamine in patients with renal colic. Methods We conducted a placebo-controlled, multicenter, double-blind randomized clinical trial (RCT) including 128 patients with renal colic (confirmed by ultrasound or CT-scan). Patients were randomized to receive either continuous IV butylscopolamine 100 mg/24 h or placebo (saline). Primary outcome is the amount of opioid escape medication used, measured in doses administered. Secondary outcomes are pain measured on a Numeric Rating Scale (NRS), side effects, and time of drug administration. Non-inferiority was assessed using linear regression with robust standard errors, with non-inferiority limit set at 0.5 units of escape medication. Results Median number of doses of escape medication was one in both groups. The number of extra doses in the placebo group compared with the butylscopolamine group was 0.05, with a 95% robust confidence interval (CI) of 0.38-0.47. Upper limit of the CI remained below the non-inferiority limit of 0.5 (p = 0.04). No differences in secondary endpoints were seen between the groups. Conclusion Placebo is non-inferior to continuous IV butylscopolamine for pain relief in patients with renal colic. Based on this study and previous evidence, there is no role for continuous butylscopolamine IV in the treatment of renal colic. Trial NL7819 Show less
Non-oral delivery of ethinyl estradiol (EE) does not reduce its biochemical impact compared to oral treatment. This is in contrast to non-EE oestrogens for which differential effects of route of... Show moreNon-oral delivery of ethinyl estradiol (EE) does not reduce its biochemical impact compared to oral treatment. This is in contrast to non-EE oestrogens for which differential effects of route of delivery have been described in the literature. Furthermore, non-oral non-EE oestrogens seem to have less unfavourable impact on haemostasis parameters and SHBG than non-oral EE, as do oral non-EE oestrogens compared to oral EE. Although these conclusions follow from an indirect comparison of results, they are in line with findings on oral and non-oral hormone replacement therapy and that the risk of venous thrombo-embolism is not reduced by non-oral routes of administration of EE-containing combined hormonal contraceptives. So far, no gold standard exists for estimating the risk of cardiovascular disease during the course of development of hormonal contraceptives. This is mainly due to the lack of data on the exact mechanism of steroid-induced disease. This has resulted in a lack of consensus on which biomarkers or biomarker fractions to study. The solution would be to investigate biomarkers and the relevant clinical outcome prospectively in one study. Such a study will entail a great deal of expense, but will provide with reliable information and prove more efficient in the long term. Show less
Hoever, P.; Hay, J.; Rad, M.; Cavallaro, M.; Gerven, J.M. van; Dingemanse, J. 2013
UNLABELLED WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Several lines of evidence suggest a possible role of 5-HT(6) receptor antagonists in dementia or cognitive dysfunction of schizophrenia. SB... Show moreUNLABELLED WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Several lines of evidence suggest a possible role of 5-HT(6) receptor antagonists in dementia or cognitive dysfunction of schizophrenia. SB-742457 is a potent 5-HT(6) antagonist and has shown efficacy in different animal models of cognitive impairment. It is currently in development as a cognitive enhancer. Risperidone, commonly used to control agitation and psychotic features in both schizophrenia and Alzheimer's disease, is a D(2)/5-HT(2A ) antagonist with low affinity for 5-HT(6) receptors and limited effects on cognitive parameters. WHAT THIS STUDY ADDS • As the combination of risperidone and SB-742457 may constitute a reasonable combination in cognitively impaired patients, pharmacodynamic interaction effects were investigated in this study. The only significant drug-drug interaction was a small increase of electroencephalogram (EEG) alpha and beta bands, which might suggest mild arousing activity of SB-742457 on the central nervous system-depressant effects of risperidone. The clinical relevance of these findings in patients remains to be established. Additionally, this study provided an extensive multidimensional pharmacodynamic profile of risperidone in healthy volunteers, showing that this antipsychotic suppresses motor performance (eye-hand coordination, finger tapping and postural stability), alertness, memory and neurophysiological functions (saccadic eye movements and EEG power spectrum). AIM Several lines of evidence suggest a possible role of 5-HT(6 ) receptor antagonists in cognitive dysfunction of schizophrenia. Atypical antipsychotics, such as risperidone, are currently used in these disorders. Therefore, the pharmacological interactions between the 5-HT(6) antagonist SB-742457 and risperidone were investigated in the light of possible co-medication. METHODS A randomized, double-blind, two-way crossover design was used to study the interaction between multiple doses SB-742457 50 mg and a single dose risperidone 2 mg in 18 healthy subjects. RESULTS Treatment was well tolerated. The most common adverse event was somnolence in 83% during the combination vs. 50% of subjects after risperidone, 32% after placebo and 11% after SB-742457. Combination treatment produced a statistically significant increase in the maximum plasma concentration of risperidone and had no effect on SB-742457 pharmacokinetics. Risperidone decreased saccadic peak velocity, finger tapping, adaptive tracking, subjective alertness, delayed word recognition and body sway and increased electroencephalogram (EEG) theta power and prolactin. The only pharmacodynamic interaction of risperidone and SB-742457 was an increase of absolute EEG alpha (ratio = 1.25, 95% CI = 1.11, 1.40, P= 0.0004) and beta power (ratio = 1.14, 95% CI = 1.03, 1.27, P= 0.016). No significant effects of SB-742457 alone were found. CONCLUSION The pharmacokinetic interactions between SB-742457 and risperidone detected in this study were not clinically relevant. The increase in EEG alpha and beta power is incompatible with enhanced risperidone activity, but could point to mild arousing effects of the combination. Most pharmacodynamic changes of risperidone are consistent with previously reported data. The potential cognitive effects of SB-742457 remain to be established. Show less
