Management of drug-disease interactions:a best practice from the Netherlands

Background Drug-disease interactions are situations where pharmacotherapy may have a negative effect on patients' comorbidities. In these cases, it can be necessary to avoid that drug, adjust its dose or monitor therapy. In the Netherlands, pharmacists have developed a best practice how to systematically evaluate drug-disease interactions based on pharmacological considerations and implement recommendations for specific drug-disease interactions. Aim To describe the development of recommendations for drug-disease interactions and the implementation in prescribing and dispensing practice in the Netherlands. Setting Pharmacies and physicians' practices in primary care and hospitals in the Netherlands. Development A multi-disciplinary expert panel assessed if diseases had clinically relevant drug-disease interactions and evaluated drug-disease interactions by literature review and expert opinion, and subsequently developed practice recommendations. Implementation The recommendations were implemented in all clinical decision support systems in primary care and hospitals throughout the Netherlands. Evaluation Recommendations were developed for 57 diseases and conditions. Cardiovascular diseases have the most drug-disease interactions (n = 12, e.g. long QT-syndrome, heart failure), followed by conditions related to the reproductive system (n = 7, e.g. pregnancy). The number of drugs with recommendations differed between 6 for endometriosis and tympanostomy tubes, and up to 1171 in the case of porphyria or even all drugs for pregnancy. Conclusion Practice recommendations for drug-disease interactions were developed, and implemented in prescribing and dispensing practice. These recommendations support both pharmacists and physicians by signalling clinically relevant drug-disease interactions at point of care, thereby improving medication safety. This practice may be adopted and contribute to safer medication use in other countries as well

Nutzung heterologer Transporter zur Steigerung der L-Threonin-Bildung mit Corynebacterium glutamicum\textit{Corynebacterium glutamicum}

Although the amino acids L-aspartate, L-serine and L-threonine are co-consumed together with glucose, transcriptome analysis did not reveal any distinct indication of increased expression of the amino acid importers involved in the uptake. However, a hitherto unknown transcriptional regulation of the genes $\textit{glyA}$ and $\textit{serA}$ encoding for serine hydroxymethyltransferase and 3-phosphoglycerate dehydrogenase by L-serine was discovered. Of the four analyzed transporters RhtA, RhtB, RhtC and YeaS from $\textit{Escherichia coli}$ the two transporters RhtA and RhtC could effectively catalyze the export of L-threonine in $\textit{C. glutamicum}$. Whereas the use of peptides without expression of RhtC led to the accumulation of up to 140 mM of cell-internal L-threonine, the cell-internal concentration was reduced to a maximum of 10 mM due to RhtC-mediated export. Under these conditions a maximal export rate of 8.9 nmol min$^{-1}$ mg TG$^{-1}$ was determined for RhtC and of 5.8 nmol min$^{-1}$ mg TG$^{-1}$ for RhtA. Moreover, it was shown that RhtA also exports L-serine in addition to L-threonine. In addition to the export, increased L-threonine accumulations were achieved in the strain background of $\textit{C. glutamicum}$ DM1800 pEC-T18 hom$^{fbr}$ $\textit{thrB thrE}$ pEKEx2 $\textit{rhtC}$. Inactivation of the threonine dehydratase resulted in a rise of 20%, increased transcription of the pyruvate carboxylase by 5% and reduced citrate synthase activity by 15%. The maximal export rate obtained was 13.3 nmol min$^{-1}$ mg TG$^{-1}$ and the maximal accumulation of L-threonine was 66 mM with a yield of 0.3 mol L-threonine per mol glucose. This is a 900% increase compared to the strain present at the beginning of this thesis. Due to the product spectrum and the internal concentration it can therefore be assumed that by using the heterologous transporter RhtC the export of L-threonine is no longer limiting