Browsing by Subject "pharmacogenomics"

There are significant inter-individual differences in the effects of drugs. These differences can be caused by, for example, other diseases, adherence to treatment, or drug-drug interactions. A drug-drug interaction can lead to an increase in the concentration of the active substance in the circulation (pharmacokinetic interactions) or a change in the effect of the drug without changes in plasma concentration (pharmacodynamic interactions). A drug-drug interaction can change the efficacy of a drug or affect the adverse drug reaction profile. The individual’s genetic background, such as diversity in drug-modifying enzymes (polymorphism), also has an effect on the efficacy and the risk for adverse drug reactions of some drugs. A pharmacogenetic test can be used to study how genetic factors affect drug treatments. The aim of this master's thesis was to examine the possibilities of personalized migraine pharmacotherapy from the perspective of pharmacogenomics and drug-drug interactions. Four online drug-drug interaction databases available in Finland were compared. Inxbase is the most widely used interaction database by physicians in Finland and it is also integrated into Finnish pharmacy systems. Other databases used in this study were the international professional database Micromedex as well as Medscape Drug Interaction Checker and Drugs.com Drug Interactions Checker. The latter two are open-access databases available for healthcare professionals and patients. Interaction searches were conducted in the selected databases between acute and prophylactic drugs used for the treatment of migraine (e.g. bisoprolol-sumatriptan). Fourteen acute and 12 prophylactic drugs were selected for this study based on the Current Care Guidelines in Finland (Käypä hoito), and the data were collected in Excel spreadsheets. The first search was completed in December 2019 and the second search in March 2020. In this study, many potential interactions were found between acute and prophylactic drugs used to treat migraine in Finland. For more than half of the drug pairs studied, a potential interaction was found in at least one of the databases. There were significant differences between the interaction databases regarding which interactions the database contains and how the severity of the interactions was classified. Of the interactions found, only 45% were found in all four databases, and each database contained interactions that were not found in the other databases. Even very serious interactions or drug pairs classified as contraindicated were not found to be consistently presented across all four databases. When selecting drug treatment for a migraine patient, potential drug-drug interactions between acute and prophylactic drugs as well as the patient's genetic background should be considered. Individualizing migraine treatment to achieve the best efficacy and to reduce the risk for adverse drug reactions is important because migraine as a disease causes a heavy burden on individuals, healthcare, and society. Pharmacogenetic tests particularly developed to help choosing migraine treatment are not yet available, but tests are available for few other indications in both public and private healthcare. The use of these tests in clinical practice will increase as physicians’ pharmacogenetic knowledge and scientific evidence on pharmacogenetic tests increase. Utilization of pharmacogenetic data requires that test results are stored in electronic health records so that they are available in the future, when changes are made to drug treatment of individuals. More studies are warranted to better understand the clinical impact of pharmacogenomics and drug-drug interactions in migraine care.

Farmakogeneettisen tiedon hyödyntäminen ja farmakogeneettisten geenimuunnosten testaaminen suomalaisessa terveydenhuollossa on vielä vähäistä. Tämän syventävien opintojen tutkielman tarkoituksena on selvittää farmakogeneettisesti merkittävien lääkehoitojen yleisyyttä HUS:n hoitojaksoilla ja potilailla sekä tekijöitä, jotka liittyvät näiden lääkeaineiden määräämiseen tutkituilla hoitojaksoilla. Tämän tutkielman aineisto perustui FINRISKI-tutkimuksen aineistoon sekä HUS:n sähköisiin potilasasiakirjoihin. FINRISKI-tutkimukseen osallistuneiden tutkimushenkilöiden joukosta poimittiin ne potilaat, joille oli merkitty vähintään yhden vuorokauden mittainen hoitojakso johonkin HUS:n yksikköön vuosien 2010 ja 2017 välillä. Tutkittavat lääkeaineet valittiin mukaan Kliinisen farmakogenetiikan implementaatiokonsortion (CPIC) farmakogeneettisten suositusten perusteella. Tutkittujen lääkeaineiden yleisyydet määritettiin erikseen HUS:n hoitojaksoilla ja potilailla, jonka lisäksi määritettiin lääkehoitojen yleisyys eri erikoisalojen hoitojaksoilla. Logistisen binäärisen regressiomallin avulla etsittiin tekijöitä, jotka liittyivät farmakogeneettisesti merkittävän lääkehoidon saamiseen HUS:n hoitojaksoilla. Kaikkiaan 52,8 %:lla 5433 hoitojaksosta ja 56,9 %:lla 2567 potilaasta oli merkintä farmakogeneettisesti merkittävästä lääkeaineesta. Viisi yleisintä tutkittua lääkeainetta hoitojaksoilla olivat ondansetroni (21,2 %), simvastatiini (16,4 %), kodeiini (12,9 %), varfariini (11,4 %) ja klopidogreeli (5,4 %). Tutkitut lääkeaineet olivat myös hyvin yleisiä eri erikoisalojen hoitojaksoilla. Farmakogeneettisesti merkittävään lääkehoitoon liittyviä tekijöitä tunnistettiin kaikkiaan 18 kappaletta. Potilaan hoitojakson aikaisella diagnoosilla verenkiertoelinten sairauksista oli vahvin yhteys farmakogeneettisesti merkittävän lääkehoidon saamisen hoitojakson aikana. Farmakogeneettisesti merkittävä lääkehoito oli hyvin yleistä HUS:n hoitojaksoilla ja potilailla. Suuri osa yliopistosairaalan potilaista voisi potentiaalisesti hyötyä farmakogeneettisten geenimuunnosten määrittämisestä ennen lääkehoidon aloittamista.

Nitai Peled1, Miao Zefeng1, Tuija Tapaninen1,2, Pertti J. Neuvonen1,2 and Mikko Niemi1,2 1Department of Clinical Pharmacology, University of Helsinki, Finland 2HUSLAB, Helsinki University Central Hospital, Helsinki, Finland Rifampicin is a broad spectrum antibiotic used in the treatment of tuberculosis and staphylococcal infections. Through activation of pregnane X receptor (PXR), rifampicin induces the expression of several drug metabolizing enzymes and drug transporters. Previous studies suggest that rifampicin can induce the expression of certain drug transporters (e.g., ABCB1) in blood. Our aim was to investigate possible effects of rifampicin on drug transporter gene expression in whole blood. In a randomized crossover study, 12 healthy volunteers took 600 mg rifampicin or placebo once daily for 5 days (Tapaninen et al 2010). On the morning of day 6, a venous blood RNA sample was collected from each participant into a PaxGene® tube. The expression of 18 ABC, 24 SLC and 10 SLCO transporters was investigated using reverse transcription quantitative real-time PCR (RT-qPCR) with OpenArray® technology on a QuantStudio™ 12 K Flex Real-Time PCR system (Life Technologies, Paisley, UK). FPGS, TRAP1, DECR1 and PPIB served as reference genes. A total of 16 ABC transporters, 18 SLC transporters and 4 SLCO transporters were expressed above the quantification limit in most samples. Rifampicin had no significant effect on the expression of any transporter. However, SLC5A6 (sodium-dependent multivitamin transporter, SMVT) and ABCB4 (multidrug resistance protein 3, MDR3) expression tended to be increased by rifampicin (by 19% and 18%; P=0.066 and P=0.096, respectively). In conclusion, multiple drug transporter genes are expressed in whole blood, but rifampicin has limited effects on their expression. References: Tapaninen T, Neuvonen PJ, Niemi M. Rifampicin reduces the plasma concentrations and the renin-inhibiting effect of aliskiren. Eur J Clin Pharmacol 2010;66:497-502.