Pharmacogenetic information in Swiss drug labels - a systematic analysis.

Implementation of pharmacogenetics (PGx) and individualization of drug therapy is supposed to obviate adverse drug reactions or therapy failure. Health care professionals (HCPs) use drug labels (DLs) as reliable information about drugs. We analyzed the Swiss DLs to give an overview on the currently available PGx instructions. We screened 4306 DLs applying natural language processing focusing on drug metabolism (pharmacokinetics) and we assigned PGx levels following the classification system of PharmGKB. From 5979 hits, 2564 were classified as PGx-relevant affecting 167 substances. 55% (n = 93) were classified as "actionable PGx". Frequently, PGx information appeared in the pharmacokinetics section and in DLs of the anatomic group "nervous system". Unstandardized wording, appearance of PGx information in different sections and unclear instructions challenge HCPs to identify and interpret PGx information and translate it into practice. HCPs need harmonization and standardization of PGx information in DLs to personalize drug therapies and tailor pharmaceutical care.

Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure.

In two large genome-wide association studies, an intergenic single-nucleotide polymorphism (SNP; rs7294919) involved in TESC gene regulation has been associated with hippocampus volume. Further characterization of neurobiological effects of the TESC gene is warranted using multimodal brain-wide structural and functional imaging. Voxel-based morphometry (VBM8) was used in two large, well-characterized samples of healthy individuals of West-European ancestry (Münster sample, N=503; SHIP-TREND, N=721) to analyze associations between rs7294919 and local gray matter volume. In subsamples, white matter fiber structure was investigated using diffusion tensor imaging (DTI) and limbic responsiveness was measured by means of functional magnetic resonance imaging (fMRI) during facial emotion processing (N=220 and N=264, respectively). Furthermore, gene x environment (G × E) interaction and gene x gene interaction with SNPs from genes previously found to be associated with hippocampal size (FKBP5, Reelin, IL-6, TNF-α, BDNF and 5-HTTLPR/rs25531) were explored. We demonstrated highly significant effects of rs7294919 on hippocampal gray matter volumes in both samples. In whole-brain analyses, no other brain areas except the hippocampal formation and adjacent temporal structures were associated with rs7294919. There were no genotype effects on DTI and fMRI results, including functional connectivity measures. No G × E interaction with childhood maltreatment was found in both samples. However, an interaction between rs7294919 and rs2299403 in the Reelin gene was found that withstood correction for multiple comparisons. We conclude that rs7294919 exerts highly robust and regionally specific effects on hippocampal gray matter structures, but not on other neuropsychiatrically relevant imaging markers. The biological interaction between TESC and RELN pointing to a neurodevelopmental origin of the observed findings warrants further mechanistic investigations.

Compartment-specific gene regulation of the CAR inducer efavirenz in vivo.

Nuclear receptors such as the constitutive androstane receptor (CAR) are central factors that link drug exposure to the activities of drug metabolism and elimination. In order to determine the in vivo effects of efavirenz, a CAR activator, the expression of target genes was determined in duodenal biopsies obtained from 12 healthy volunteers before treatment and after 10 days of treatment with efavirenz; concomitant administration of the cholesterol inhibitor ezetimibe produced no significant difference. However, in in vitro studies, efavirenz significantly increased CYP2B6 expression in several cell types, suggesting that the drug transactivates CAR. This hypothesis is supported by our findings that there is significant induction of CAR target genes in in vivo peripheral blood mononuclear cells (PBMCs) isolated from healthy volunteers treated with multiple doses of efavirenz. The impact of efavirenz on hepatic metabolism in vivo was confirmed by significant changes in plasma 4ß-hydroxycholesterol and bilirubin levels and the area under the curve (AUC) of efavirenz. Induction of CYP2B6 mRNA expression correlated with the decrease in the AUC of efavirenz (r = 0.61; P = 0.036). Taken together, our results provide evidence that efavirenz exerts compartment-specific inductive capacity in vivo.

Impact of efavirenz on intestinal metabolism and transport: insights from an interaction study with ezetimibe in healthy volunteers.

Hypercholesterolemia frequently occurs in patients treated with efavirenz who cannot be treated adequately with statins because of drug interactions. These patients may benefit from cholesterol-lowering therapy with ezetimibe. This study determined the influence of single-dose and multiple-dose efavirenz (400 mg/day for 9 days) on the pharmacokinetics and sterol-lowering of ezetimibe (10 mg) in 12 healthy subjects. In addition, the influence of efavirenz on genome-wide intestinal expression and in vitro function of ABCB1, ABCC2, UGT1A1, and OATP1B1 was studied. Efavirenz (multiple dose) had no influence on the pharmacokinetics and lipid-lowering functions of ezetimibe. Intestinal expression of enzymes and transporters (e.g., ABCB1, ABCC2, and UGT1A1) was not affected by chronic efavirenz. Efavirenz (single dose) slightly increased ezetimibe absorption and markedly decreased exposure to ezetimibe-glucuronide (single dose and multiple dose), which may be explained by inhibition of UGT1A1 and ABCB1 (in vitro data). Ezetimibe had no effect on the disposition of efavirenz. Consequently, ezetimibe may be a safe and efficient therapeutic option in patients with HIV infection.

The effect of catechol-O-methyltransferase polymorphisms on pain is modified by depressive symptoms.

BACKGROUND: Variations within the catechol-O-methyltransferase (COMT) gene have been associated with pain severity in temporomandibular disorders (TMDs). Psychological factors such as personal conflicts, life stress and depression, are well known to be associated with onset, severity and chronicity of pain disorders. AIM: We hypothesized that the relationship between the COMT gene and TMD pain is modified by depressive symptoms. METHODS: Cross-sectional data from the population-based Study of Health in Pomerania (SHIP) in Germany were used to estimate additive interactions between depressive symptoms and 22 single-nucleotide polymorphisms (SNPs) of the COMT gene and the neighbouring thioredoxin reductase 2 (TXNRD2) gene on TMD pain. All participants were Caucasian subjects from a rural area in Northeast Germany. After exclusion of 79 subjects with antidepressant medication, 29.9% of the remaining 3904 subjects reported lifetime depressive symptoms. TMD pain was assessed by a standardized clinical examination. Among various TMD signs, only those that assessed muscle or joint pain on palpation were used as recommended. RESULTS: Six SNPs from the first of three COMT/TXNRD2 haploblocks interacted with depressive symptoms on TMD pain (smallest p-value: 2.7 × 10(-10) ). In subjects without depressive symptoms, rs5993882 was identified as the SNP most likely to be related to TMD pain. In subjects with symptoms of depression, rs1544325 was the corresponding top COMT SNP. CONCLUSIONS: Our results indicate that variants within the COMT gene are associated with pain perception. However, this association is highly moderated by the absence or presence of lifetime depressive symptoms.

In vitro and in vivo assessment of renal drug transporters in the disposition of mesna and dimesna.

Mesna and its dimer, dimesna, are coadministered for mitigation of ifosfamide- and cisplatin-induced toxicities, respectively. Dimesna is selectively reduced to mesna in the kidney, producing its protective effects. In vitro screens of uptake and efflux transporters revealed saturable uptake by renal organic anion transporters OAT1, OAT3, and OAT4. Efflux transporters breast cancer resistance protein; multidrug and toxin extrusion 1 (MATE1); multidrug resistance proteins MRP1, MRP2, MRP4, and MRP5; and P-glycoprotein (Pgp) significantly reduced dimesna accumulation. Further investigation demonstrated that renal apical efflux transporters MATE1, MRP2, and Pgp were also capable of mesna efflux. Administration of OAT inhibitor probenecid to healthy subjects significantly increased combined mesna and dimesna plasma exposure (91% ± 34%) while decreasing the renal clearance due to net secretion (67.0% ± 12.7%) and steady-state volume of distribution (45.2% ± 13.4%). Thus, the kidney represents a significant sink of total mesna, whereas function of renal drug transporters facilitates clearance in excess of glomerular filtration rate and likely the presence of active mesna in the urine. Loss of renal transporter function due to genetic variability or drug-drug interactions may decrease the efficacy of chemoprotectants, increasing the risk of ifosfamide- and cisplatin-induced toxicities.

Sensor-based fall risk assessment--an expert 'to go'.

BACKGROUND: Falls are a predominant problem in our aging society, often leading to severe somatic and psychological consequences, and having an incidence of about 30% in the group of persons aged 65 years or above. In order to identify persons at risk, many assessment tools and tests have been developed, but most of these have to be conducted in a supervised setting and are dependent on an expert rater. OBJECTIVES: The overall aim of our research work is to develop an objective and unobtrusive method to determine individual fall risk based on the use of motion sensor data. The aims of our work for this paper are to derive a fall risk model based on sensor data that may potentially be measured during typical activities of daily life (aim #1), and to evaluate the resulting model with data from a one-year follow-up study (aim #2). METHODS: A sample of n = 119 geriatric inpatients wore an accelerometer on the waist during a Timed 'Up & Go' test and a 20 m walk. Fifty patients were included in a one-year follow-up study, assessing fall events and scoring average physical activity at home in telephone interviews. The sensor data were processed to extract gait and dynamic balance parameters, from which four fall risk models--two classification trees and two logistic regression models--were computed: models CT#1 and SL#1 using accelerometer data only, models CT#2 and SL#2 including the physical activity score. The risk models were evaluated in a ten-times tenfold cross-validation procedure, calculating sensitivity (SENS), specificity (SPEC), positive and negative predictive values (PPV, NPV), classification accuracy, area under the curve (AUC) and the Brier score. RESULTS: Both classification trees show a fair to good performance (models CT#1/CT#2): SENS 74%/58%, SPEC 96%/82%, PPV 92%/ 74%, NPV 77%/82%, accuracy 80%/78%, AUC 0.83/0.87 and Brier scores 0.14/0.14. The logistic regression models (SL#1/SL#2) perform worse: SENS 42%/58%, SPEC 82%/ 78%, PPV 62%/65%, NPV 67%/72%, accuracy 65%/70%, AUC 0.65/0.72 and Brier scores 0.23/0.21. CONCLUSIONS: Our results suggest that accelerometer data may be used to predict falls in an unsupervised setting. Furthermore, the parameters used for prediction are measurable with an unobtrusive sensor device during normal activities of daily living. These promising results have to be validated in a larger, long-term prospective trial.

[Pharmacogenomics in routine medical care]. / Pharmakogenomik in der Praxis.

Pharmacogenomics investigates inherited differences in drug responses including beneficial and adverse reactions. While a considerable amount of evidence for genetic influences on drug responses has been accumulated within the last decade, predominantly in small studies, its value in routine therapy is still a matter of debate. The aim of this review is to discuss well established examples where pharmacogenomic techniques can improve routine treatment. Examples include genotyping of CYP2D6 in the context of antidepressant therapy, analysis of TPMT variants for the prediction of mercaptopurine-induced bone marrow depression, VKORC1 and CYP2C9 analyses for a better control of anticoagulant administration and the SLCO1B1 variant in the context of statin-induced myopathies.

A piece in the puzzle of personalized medicine.

Predicting individual drug response based on inherited factors remains a major challenge. Some examples of significant contributions of single genetic variants to overall therapeutic success of drugs in complex diseases are currently emerging. For most compounds, however, multiple genetic and nongenetic factors will modify drug action. Comprehensive integration of these factors will determine the role of pharmacogenomics for personalized medicine.

Predicting in-patient falls in a geriatric clinic: a clinical study combining assessment data and simple sensory gait measurements.

BACKGROUND: Falls are among the predominant causes for morbidity and mortality in elderly persons and occur most often in geriatric clinics. Despite several studies that have identified parameters associated with elderly patients' fall risk, prediction models -- e.g., based on geriatric assessment data -- are currently not used on a regular basis. Furthermore, technical aids to objectively assess mobility-associated parameters are currently not used. OBJECTIVES: To assess group differences in clinical as well as common geriatric assessment data and sensory gait measurements between fallers and non-fallers in a geriatric sample, and to derive and compare two prediction models based on assessment data alone (model #1) and added sensory measurement data (model #2). METHODS: For a sample of n=110 geriatric in-patients (81 women, 29 men) the following fall risk-associated assessments were performed: Timed 'Up & Go' (TUG) test, STRATIFY score and Barthel index. During the TUG test the subjects wore a triaxial accelerometer, and sensory gait parameters were extracted from the data recorded. Group differences between fallers (n=26) and non-fallers (n=84) were compared using Student's t-test. Two classification tree prediction models were computed and compared. RESULTS: Significant differences between the two groups were found for the following parameters: time to complete the TUG test, transfer item (Barthel), recent falls (STRATIFY), pelvic sway while walking and step length. Prediction model #1 (using common assessment data only) showed a sensitivity of 38.5% and a specificity of 97.6%, prediction model #2 (assessment data plus sensory gait parameters) performed with 57.7% and 100%, respectively. DISCUSSION AND CONCLUSION: Significant differences between fallers and non-fallers among geriatric in-patients can be detected for several assessment subscores as well as parameters recorded by simple accelerometric measurements during a common mobility test. Existing geriatric assessment data may be used for falls prediction on a regular basis. Adding sensory data improves the specificity of our test markedly.

[Reliability of basic geriatric assessment]. / Untersuchung zur Reliabilität des Geriatrischen Basisassessments.

This study investigates the Geriatric Basis Assessment (GBA) in terms of its reliability. Data from 1037 patients were collected. The reliability was estimated relating to the lambda 2 coefficient. It is necessary to define the items in different categories: the first variable means valuation 1 of each item and not 2, 3, 4; the second variable means valuation 1, 2 against 3, 4; the third variable means the valuation 1, 2, 3 and not 4. The table shows only little difference concerning the lambda 2 coefficients. In conclusion, 80% of the variability of the GBA items can be explained by differences in the patients themselves, while 20% is due to the inaccurate assessment system. For 343 patients, data for both Barthel index and GBA were available. As presumed, correlations between Barthel and connected GBA items were observed. However, the correlations were too weak to predict the Barthel scores from the corresponding GBA item accurately enough. The Barthel index appears to include similar, but not exactly the same aspects as the GBA. The reliability of the Barthel index (lambda 2 = 0.89 for the first variable) is slightly higher compared to the GBA but it is not suitable as a criterion of validity. Both the validity of the GBA and the Barthel index can not be determined lacking an external measure. As an example, a suitable criterion of validity could be the reintegration into the familiar surroundings preceding the hospital stay. When developing the GBA, it was not assumed that geriatric patients could be correctly diagnosed on the basis of an overall score alone or to allocate them to adequate care using that score as a sole indicator. Crucial for these purposes is the test profile as a whole, including the impairments, disabilities handicaps, and last but not least the diseases of the individual patient. Furthermore, the depiction of the GBA profile at admission and discharge allows one to identify those items, on which therapy has a significant influence and those which remain more or less stable. As presumed, items with minor initial deficits (e.g., motivation, eyesight, hearing, depression, capability of verbal expression, situative adaptability, understanding) showed only small differences between admission and discharge. On the other hand, items strongly influenced by geriatric treatment were, e.g., mobility (walking, transfer), functions of internal medicine, and domestic care. Prognostically significant are those items which are crucial for reintegration and describe a deficiency but cannot be altered reliably. Such items are the person, to whom the patient relates most closely, situative adaptability, motivation, orientation, capability of verbal expression, and possibly depression. All of these parameters are more difficult to influence than the activities of daily living assessed by the Barthel index. Further investigations should clarify whether the GBA can be a reliable tool for allocating a patient to adequate care. However, the requirement for such a criterion of validity is that this allocation is truly optimal for the patient.

Cerebrospinal fluid immune complexes in multiple sclerosis.

Using a C1q binding test, immune complexes have been detected in one half of cerebrospinal fluid samples from patients with multiple sclerosis. These results provide additional evidence for the participation of an immune reaction in the disease process.