The revised role of left ventricular dilatation and ACE-inhibition after myocardial infarction

It has generally been accepted that a myocardial infarction is complicated by extensive LVdilatation and that the main mechanism by which ACE-inhibitors produce their beneficial effects after myocardial infarction is attenuation of LV dilatation. This thesis tests both theories in an era where the primary prevention strategy after myocardial infarction has become the re-opening of the infarct related artery by administration of thrombolytic therapy or primary percutaneous coronary intervention (PCI). This thesis aims 1) to develop an adequate statistical model to describe the process of left ventricular (LV) dilatation after myocardial infarction, 2) to develop a prediction model to predict which patients are at risk of long-term LV dilatation, and 3) to investigate the effects of acute angiotensin converting enzyme (ACE) inhibitor treatment (administrated within 9 hours after myocardial infarction) on LV dilatation and clinical outcome in thrombolysed patients

Sublingual allergen immunotherapy with a liquid birch pollen product in patients with seasonal allergic rhinoconjunctivitis with or without asthma

Background: Sublingual allergen immunotherapy (SLIT) has been demonstrated to be both clinically efficacious and safe. However, in line with the current regulatory guidance from the European Medicines Agency, allergen immunotherapy (AIT) products must demonstrate their efficacy and safety in pivotal phase III trials for registration. Objective: We sought to investigate the efficacy and safety of sublingual high-dose liquid birch pollen extract (40,000 allergy units native [AUN]/mL) in adults with birch pollen allergy. Methods: A randomized, double-blind, placebo-controlled, parallel-group multicenter trial was conducted in 406 adult patients with moderate-to-severe birch pollen-induced allergic rhinoconjunctivitis with or without mild-to-moderate controlled asthma. Treatment was started 3 to 6 months before the birch pollen season and continued during the season in 40 clinical study centers in 5 European countries. For primary end point assessment, the recommended combined symptom and medication score of the European Academy of Allergy and Clinical Immunology was used. Secondary end points included quality-of-life assessments, immunologic parameters, and safety. Results: Primary efficacy results demonstrated a significant (P < .0001) and clinically relevant (32%) reduction in the combined symptom and medication score compared with placebo after 3 to 6 months of SLIT. Significantly better rhinoconjunctivitis quality-of-life scores (P < .0001) and the patient's own overall assessment of his or her health status, including the visual analog scale score (Euro Quality of Life Visual Analogue Scale; P = .0025), were also demonstrated. In total, a good safety profile of SLIT was observed. Conclusion: This study confirmed both the clinical efficacy and safety of a sublingual liquid birch pollen extract in adults with birch pollen allergy in a pivotal phase III trial (EudraCT: 2013-005550-30; ClinicalTrials. gov: NCT02231307)

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

Aardbevingen en de regionale woningmarkt: gevolgen voor eigenaren, huurders en verhuurders

Bijdrage aan docentendag Vastgoed en Makelaardij, Groningen, 31 januari 201

Shaping Modern Vaccines: Adjuvant Systems Using MicroCrystalline Tyrosine (MCT®).

The concept of adjuvants or adjuvant systems, used in vaccines, exploit evolutionary relationships associated with how the immune system may initially respond to a foreign antigen or pathogen, thus mimicking natural exposure. This is particularly relevant during the non-specific innate stage of the immune response; as such, the quality of this response may dictate specific adaptive responses and conferred memory/protection to that specific antigen or pathogen. Therefore, adjuvants may optimise this response in the most appropriate way for a specific disease. The most commonly used traditional adjuvants are aluminium salts; however, a biodegradable adjuvant, MCT®, was developed for application in the niche area of allergy immunotherapy (AIT), also in combination with a TLR-4 adjuvant-Monophosphoryl Lipid A (MPL®)-producing the first adjuvant system approach for AIT in the clinic. In the last decade, the use and effectiveness of MCT® across a variety of disease models in the preclinical setting highlight it as a promising platform for adjuvant systems, to help overcome the challenges of modern vaccines. A consequence of bringing together, for the first time, a unified view of MCT® mode-of-action from multiple experiments and adjuvant systems will help facilitate future rational design of vaccines while shaping their success

The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders

The duration of anticoagulant treatment after a first episode of venous thromboembolism primarily depends on the risk of recurrence, Variability of recurrence rates in factor (F) V Leiden carriers may be due to concomitant thrombophilic disorders. A retrospective study was performed in 329 FV Leiden carriers with a history of venous thromboembolism (262 probands, 67 relatives). The annual rate of first recurrence was estimated in relatives. The contribution of concomitant thrombophilic disorders to the recurrence rate was evaluated in probands and relatives by a nested case-control analysis in 10 5 matched pairs of carriers either with or without recurrence, The overall annual recurrence rate was 2.3 per 100 patient-years, The adjusted risk of recurrence for concomitant thrombophilic disorders was: 9.1 (1.3-62.8) for the FII mutation; 1.0 (0.2-4.9) for homozygosity for FV Leiden; 1.5 (0.2-9.5) for inherited deficiencies of protein C or S: 1.8 (0.7-4.9) for FVIII coagulant activity (FVIII:C) levels > 122%.; 5.4 (1.6-18.6) for fasting homocysteine levels > 15.2 mumol/l: and 4.4 (1.0-18.7) for loading homocysteine levels >45.8 mumol/l. Of these disorders, only the FII mutation and hyperhomocysteinaemia significantly increased the risk of recurrence in FV Leiden carriers. The estimated recurrence rate ranged from 0.45 per 100 patient-years after a secondary first event in the absence of concomitant disorders to 4.8 per 100 patient-years when a spontaneous first event was combined with concomitant disorders, Our study provides supportive evidence that the incidence of recurrent venous thromboembolism in heterozygous FV Leiden carriers depends on the concomitance of other thrombophilic disorders. in addition to whether the first thrombotic event occurred spontaneousl

Approaches to statistical analysis of repeated echocardiographic measurements after myocardial infarction and its relation to heart failure:Application of a random-effects model

Background: Extensive left ventricular (LV) dilatation after myocardial infarction (MI) is associated with increased heart failure risk. Aims: To investigate whether the power to demonstrate the relation between LV dilatation and heart failure depends on the method applied to predict LV dilatation after MI. Methods: A random-effects model and ANOVA model for repeated measurements (MANOVA) were applied to predict LV volume index during I year for 298 post-MI patients. Spearman correlation coefficients (r) were calculated and Cox regression analysis was used to calculate risk ratio's (RR). Results: LV volume indices were more accurately predicted by a random-effects model than by a MANOVA model (systolic/diastolic respectively r=0.93/0.91 vs. r=0.67/0.64). Furthermore, patients with high LV volume index as predicted by the random-effects model, had significantly increased heart failure risk (systolic RR 2.04 (95% CL 1.31 to 3.17; P=0.001), diastolic RR 1.80 (95% Cl: 1.16 to 2.78; P=0.007). Using the same data, MANOVA failed to demonstrate this relation significantly (systolic RR 1.77 (95% CL 0.79 to 3.98; P=0.16), diastolic RR 1.49 (95% Cl: 0.68 to 3.30; P=0.31). Conclusion: When analyzing repeated measurement data, random-effect models are more powerful in detecting clinical relations than are MANOVA models, especially in the presence of missing values. (C) 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved

Dogmas, challenges, and promises in phase III allergen immunotherapy studies

The concept of treatment of an allergy with the offending allergen was introduced more than a century ago. Allergen immunotherapy (AIT) is the only disease modifying treatment of allergic diseases caused by inhalational allergens and insect venoms. Despite this, only few AIT products have reached licensure in the US or an official marketing authorization status in European countries. Moreover, most of these AIT products are provided on an individual patient basis as named patient products (NPP) in Europe, while individualized preparations of (mixed) allergenic extract vials for subcutaneous administration (compounding) is common practice in the US. AIT products are generally considered safe and well tolerated, but the major practical clinical development challenge is to define the optimal dose and prove the efficacy and safety of these products using state-of-the art Phase II and pivotal Phase III studies. In planning Phase II-III AIT studies, a thorough understanding of the study challenges is essential (e.g. variability and non-validated status of subjective primary endpoints, limitations of pollen season definitions) and dogmas of these products (e.g., for sublingual immunotherapy (SLIT) trials double-blinding conditions cannot be maintained, resulting in stronger placebo responses in the active treatment group and inflated treatment effects in Phase III). There is future promise for more objective biomarker endpoints (e.g. basophil activation (CD63 and CD203c), subsets of regulatory dendritic, T and B cells, IL-10-producing group 2 innate lymphoid cells; alone or in combination) to overcome several of these dogmas and challenges; innovation in AIT clinical trials can only progress with integral biomarker research to complement the traditional endpoints in Phase II-III clinical development. The aim of this paper is to provide an overview of these dogmas, challenges and recommendations based on published data, to facilitate the design of Phase III studies and improve the evidence basis of safe and effective AIT products. Keywords: Allergen immunotherapy; Biomarker; Blinding; Phase III; Placebo effect