The Development of Practice Recommendations for Drug-Disease Interactions by Literature Review and Expert Opinion

Background: Drug-disease interactions negatively affect the benefit/risk ratio of drugs for specific populations. In these conditions drugs should be avoided, adjusted, or accompanied by extra monitoring. The motivation for many drug-disease interactions in the Summary of Product Characteristics (SmPC) is sometimes insufficiently supported by (accessible) evidence. As a consequence the translation of SmPC to clinical practice may lead to non-specific recommendations. For the translation of this information to the real world, it is necessary to evaluate the available knowledge about drug-disease interactions, and to formulate specific recommendations for prescribers and pharmacists. The aim of this paper is to describe a standardized method how to develop practice recommendations for drug-disease interactions by literature review and expert opinion. Methods: The development of recommendations for drug-disease interactions will follow a six-step plan involving a multidisciplinary expert panel (1). The scope of the drug-disease interaction will be specified by defining the disease and by describing relevant effects of this drug-disease interaction. Drugs possibly involved in this drug-disease interaction are selected by checking the official product information, literature, and expert opinion (2). Evidence will be collected from the official product information, guidelines, handbooks, and primary literature (3). Study characteristics and outcomes will be evaluated and presented in standardized reports, including preliminary conclusions on the clinical relevance and practice recommendations (4). The multidisciplinary expert panel will discuss the reports and will either adopt or adjust the conclusions (5). Practice recommendations will be integrated in clinical decision support systems and published (6). The results of the evaluated drug-disease interactions will remain up-to-date by screening new risk information, periodic literature review, and (re)assessments initiated by health care providers. Actionable Recommendations: The practice recommendations will result in advices for specific DDSI. The content and considerations of these DDSIs will be published and implemented in all Clinical Decision Support Systems in the Netherlands. Discussion: The recommendations result in professional guidance in the context of individual patient care. The professional will be supported in the decision making in concerning pharmacotherapy for the treatment of a medical problem, and the clinical risks of the proposed medication in combination with specific diseases

Werkplaats Kindergemeenschap Bilthoven:een aangepast procesontwerp voor nieuwbouw van een scholengemeenschap

Dit verslag is het resultaat van een case-study naar het nieuwbouwproject van De Werkplaats Kindergemeenschap te Bilthoven (WP). De WP is een bijzondere scholengemeenschap waar het kind centraal staat en waar gefocust wordt op samenwerking en zelfwerkzaamheid van de leerlingen. De nieuwbouw, die momenteel (september 2005) in volle gang is, werd aangrepen om het onderwijsconcept te vernieuwen. De ontwikkeling van een nieuw gebouw, in combinatie met een nieuw onderwijsconcept en een daarbij veranderende organisatie bleek zeer complex. Dit complexe proces is geanalyseerd waarbij verbeterpunten zijn gegeven. Tevens is een procesontwerp voor toekomstige projecten gemaakt. De opdracht voor deze studie is afkomstig van de huisvestingsadviseur van de WP, de heer Meijer van M3V, en uitgevoerd door vijf cursisten van Architectural Design Management Systems (ADMS).De opdracht luidt: "Het maken van één of meerdere zo generiek mogelijke ontwerpen voor een optimaal besluitvormings- (inclusief participatie-) proces vanaf aanvang van visie- en conceptontwikkeling tot en met gereed ontwerp voor de nieuwbouw van een scholengemeenschap voor VMBO-t, HAVO en VWO, naar aanleiding van het gelopen traject van de Werkplaats Kindergemeenschap te Bilthoven." Het onderzoek is gestart met een evaluatie van het gelopen traject van de WP. Deze evaluatie is gedaan middels interviews met betrokkenen en door bestudering van de projectdocumentatie. Hieruit zijn een aantal onderzoeksvelden naar voren gekomen. Naar deze onderzoeksvelden, allen aspecten van besluitvorming bij nieuwbouw, is literatuuronderzoek verricht. Door vervolgens de verbeterpunten binnen de onderzoeksvelden naast de theorie te leggen, kon een diagnose gesteld worden over het nieuwbouwproces van de WP. Voor de problemen uit de diagnose is in de procesontwerpfase een mogelijke oplossing gevonden. Deze oplossing is gegoten in de vorm van een handzaam hulpmiddel dat gebruikt kan worden door het projectmanagement bij de start en gedurende de eerste fases van een nieuwbouwproject bij scholenbouw

Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients

Contains fulltext : 203020.pdf (publisher's version ) (Open Access

Crop Rotation and Soil Amendment Alters Sorghum Grain Quality

Soybean [Glycine max (L.) Merr.] rotation enhances grain sorghum [Sorghum bicolor (L.) Moench] yield, but infl uence on grain quality has not been measured. The objective was to determine the effect of cropping sequence (CS) and soil amendment (SA) on grain yield and quality. Sorghum grain yield and quality, soil NO3–N and water were measured in a rotation study in 2003 and 2004 on a Sharpsburg silty clay loam (fine, smectitic, mesic Typic Argiudoll). Cropping sequences were continuous sorghum, and sorghum rotated with non-nodulating and nodulating soybean. Soil amendments consisted of no amendment, manure (17–26 Mg dry matter ha−1 yr−1), and N (84 kg ha−1 yr−1). CS × SA interaction effects were found for most parameters. Rotation with non-nodulating soybean without SA increased yield by 2.6 to 2.8 Mg ha−1 over continuous sorghum without SA. Rotation without SA with nodulating soybean further increased yield by 1.7 to 1.8 Mg ha−1 over rotation with non-nodulating soybean. Grain N increased by 0.5 to 1.0, 2.5 to 5.0, and 3.3 to 4.9 g kg−1 for N application to continuous sorghum and sorghum rotated with non-nodulating and nodulating soybean, respectively. Tangential abrasive dehulling device (TADD) removal indicated that continuous sorghum without SA produced the softest grain with 43 to 44% TADD removal, and sorghum rotated with nodulating soybean with manure produced the hardest grain with 22 to 27% TADD removal. As food end-use opportunities for sorghum grain evolve, use of crop rotation and SA application will be important to produce grain with desirable quality attributes. Includes corrected Table 4

Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer

Background: Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C&gt;T, ABCG2 421C&gt;A and 34G&gt;A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+ NSCLC patients. Methods: Patients who started treatment with osimertinib for EGFRm+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. Findings: From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11–0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p = 0.010). Interpretation: ABCG2 34G&gt;A and ABCB1 3435C&gt;T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C&gt;A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G&gt;A should be studied further, to prevent new CNS metastases during osimertinib treatment. Funding: No funding was received for this trial.</p