Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1... Show moreRimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide's anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6-11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies. Show less
In this thesis novel techniques are described which are developed to analyze or predict the efficacy of pharmacotherapy for pain. In Chapter 2 an overview is presented on recent pharmacokinetic... Show moreIn this thesis novel techniques are described which are developed to analyze or predict the efficacy of pharmacotherapy for pain. In Chapter 2 an overview is presented on recent pharmacokinetic pharmacodynamic (PKPD) modeling in acute and chronic pain. Chapter 3 describes the analgesic effect of a capsaicin patch in diabetic painful neuropathy (DPN) pain patients. A longitudinal population PD analysis is performed. In Chapter 4 a subgroup analysis is performed on pooled data from 4 multicenter trials on the effect of capsaicin 8% patch in post herpetic neuralgia (PHN). Apart from longitudinal and mixture analyses, covariates are examined to identify predictors of efficacy. In Chapter 5 the analgesic effect of orodispersible oxycodone versus orodispersible paracetamol for the management of breakthrough pain is quantified using a novel pharmacodynamic model. ________________________________Finally, Chapter 6 describes the effect of tapentadol versus morphine on conditional pain modulation (CPM) in healthy volunteers. A difference in CPM engagement between these two __opioids__ might proof the difference in mechanisms of action between the classical mu opioid receptor (MOR) agonist and the combined MOR-noradrenalin reuptake inhibitor (NRI) compound. Show less
This thesis describes the day to day interaction between propofol and midazolam as encountered in every day practice. The direct interaction of premedication given to patients before surgery has... Show moreThis thesis describes the day to day interaction between propofol and midazolam as encountered in every day practice. The direct interaction of premedication given to patients before surgery has profound implications. The propofol induction dose can be decreased with respect to the target BIS. Besides the interaction mechanisms of propofol and midazolam, the pharmacological backgrounds of propofol-opioid interactions are given. The future perspectives of PK-PD modeling and the use of additional informative techniques are given in the last chapter. Show less
