Evaluation of pharmaceutical concerns in Germany: frequency and potential reasons.

BACKGROUND: Generic substitution can have unintended consequences. In Germany, brand name to generic or generic to generic switching is mainly driven by rebate contracts. Frequent switching may raise concerns about bio- and therapeutic equivalence. Expected patient confusion may result in compromised medication adherence or new onset of other drug-related problems. Since 2008, pharmacists are allowed to deviate from rebate contracts by denying substitution due to pharmaceutical concerns on an individual basis. OBJECTIVES: To explore the frequency of documented pharmaceutical concerns in Germany between July 2011 and December 2013 and to identify the medicines most frequently related to pharmaceutical concerns in 2013. METHODS: We analyzed documented pharmaceutical concerns in all prescribed drugs at the expense of any statutory health insurance company requiring pharmacies' generic substitution according to rebate contracts. RESULTS: Since July 2011, the frequency of documented pharmaceutical concerns in relation to prescribed drug products with rebate contracts requiring substitution increased consistently and doubled between July 2011 and July 2013. Overall in 2013, the trend of the two previous years continued and reached approximately 1.5%. The most affected drugs/drug classes were thyroid hormones (in particular combinations with iodide; 15.9%) followed by ondansetron (12.5%), and levothyroxine (11.3%). For all drugs/drug classes under investigation, product-, patient- or disease-related aspects could be identified which are potential reasons to deny substitution and to document pharmaceutical concerns. CONCLUSIONS: Although there is no electronic recording of the specific reasons for pharmaceutical concerns in claims data, our analyses support the assumption that pharmacists make use of this instrument based on individual clinical decisions and as required by contract. Pharmaceutical concerns are, therefore, an important instrument for pharmacies to refuse generic substitution. They are considered to prevent compromised medication safety and to assure pharmacotherapy effectiveness in a generic substitution environment driven by low drug prizes above all

a correlation with theirphotosensitizing potential based on published literature

Background: Drug‐induced photosensitivity refers to the development of cutaneous adverse events due to interaction between a pharmaceutical compound and sunlight. Although photosensitivity is a very commonly listed side‐effect of systemic drugs, reliable data on its actual incidence are lacking so far. Objectives: A possible approach to evaluate the real‐life extent of drug‐induced photosensitivity would be an analysis of the frequency of exposure to a given photosensitizing drug combined with an indicator of its photosensitizing potential. This could serve as a basis for developing a pharmaceutical ‘heatmap’ of photosensitivity. Methods: The present study investigated the number of reimbursed dispensed packages of potentially photosensitizing drugs in Germany (DE) and Austria (AT) between 2010 and 2017 based on nationwide health insurance‐based databases. In addition, an indicator for the photosensitizing potential was established for each drug based on the number of reports on photosensitivity in the literature. Results: This analysis includes means of 632 826 944 (+/−14 894 918) drug dispensings per year in DE and 113 270 754 (+/−1 964 690) in AT. Out of these, the mean percentage of drugs that enlist photosensitivity as a potential side‐effect was 49.5% (±0.7) in DE and 48.2% (±1.2) in AT. When plotting the number of reimbursed dispensed packages vs. the number of reports on photosensitivity, two categories of drugs show high numbers for both parameters, that is diuretics and non‐steroidal anti‐inflammatory drugs (NSAIDs). Conclusions: Diuretics and NSAIDs appear to be responsible for the greatest part of exposure to photosensitizing drugs with potential implication on public health

The frequency of photosensitizing drug dispensings in Austria and Germany: a correlation with their photosensitizing potential based on published literature.

BACKGROUND:Drug-induced photosensitivity refers to the development of cutaneous adverse events due to interaction between a pharmaceutical compound and sunlight. Although photosensitivity is a very commonly listed side-effect of systemic drugs, reliable data on its actual incidence are lacking so far. OBJECTIVES:A possible approach to evaluate the real-life extent of drug-induced photosensitivity would be an analysis of the frequency of exposure to a given photosensitizing drug combined with an indicator of its photosensitizing potential. This could serve as a basis for developing a pharmaceutical 'heatmap' of photosensitivity. METHODS:The present study investigated the number of reimbursed dispensed packages of potentially photosensitizing drugs in Germany (DE) and Austria (AT) between 2010 and 2017 based on nationwide health insurance-based databases. In addition, an indicator for the photosensitizing potential was established for each drug based on the number of reports on photosensitivity in the literature. RESULTS:This analysis includes means of 632 826 944 (+/-14 894 918) drug dispensings per year in DE and 113 270 754 (+/-1 964 690) in AT. Out of these, the mean percentage of drugs that enlist photosensitivity as a potential side-effect was 49.5% (±0.7) in DE and 48.2% (±1.2) in AT. When plotting the number of reimbursed dispensed packages vs. the number of reports on photosensitivity, two categories of drugs show high numbers for both parameters, that is diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). CONCLUSIONS:Diuretics and NSAIDs appear to be responsible for the greatest part of exposure to photosensitizing drugs with potential implication on public health

Comparing outpatient oral antibiotic use in Germany and the Netherlands from 2012 to 2016.

PURPOSE: Overuse of antibiotics is of concern, but may differ between European countries. This study compares outpatient use of oral antibiotics between Germany (DE) and the Netherlands (NL). METHODS: For DE, we used the DAPI database with information on dispensings at the expense of the Statutory Health Insurance Funds from > 80% of community pharmacies. For NL, data were obtained from the Dutch Foundation for Pharmaceutical Statistics. Use of oral antibiotics was estimated as defined daily doses per 1000 inhabitants per day (DID), except for age comparisons as packages per 1000 inhabitants annually. National time trends were assessed with linear regression, stratified for the major antibiotic classes, and individual substances. RESULTS: From 2012 to 2016, outpatient antibiotic use was lower in NL than in DE (9.64 vs 14.14 DID in 2016) and non-significantly decreased slightly over time in both countries. In DE, dispensings of oral antibiotics to children were higher compared with NL for the age groups 2 to 5 (2.0-fold in 2016) and 6 to 14 years (2.7-fold in 2016). Use of cephalosporins was very low in NL (0.02 DID in 2016), but the second most frequently dispensed class in DE (2.95 DID in 2016). CONCLUSION: From 2012 to 2016, outpatient use of oral antibiotics was lower in NL than in DE. Differences were primarily observed in the age groups 2 to 5 and 6 to 14 years, although the recommendations of evidence-based guidelines in both countries were in agreement

Quality Appraisal of Ambulatory Oral Cephalosporin and Fluoroquinolone Use in the 16 German Federal States from 2014-2019.

Background: Despite concerns about causing bacterial resistance and serious side effects, oral cephalosporins and fluoroquinolones are still frequently prescribed in Germany. We aimed to test a method for the detection of regional quality differences in the use of oral cephalosporins and fluoroquinolones and to apply this to the German federal states. Methods: Use of antibiotics from 2014–2019 was analyzed using dispensing data from community pharmacies claimed to the statutory health insurance (SHI) funds. Quality of regional antibiotic use in 2019 was assessed by calculating indicators based on defined daily doses per 1000 SHI-insured persons per day (DID). Oral cephalosporin and fluoroquinolone use was followed by linear regression analyses. Results: The method used was suitable to find meaningful quality differences in ambulatory oral cephalosporin and fluoroquinolone use between the German federal states. In 2019, DID varied from 1.62 in Brandenburg to 3.17 in Rhineland-Palatinate for cephalosporins and from 0.47 in Brandenburg to 0.89 in Saarland for fluoroquinolones. The city-states Hamburg, Bremen, and Berlin showed highest quality with the applied indicator set. From 2014–2019, a significant decrease in utilization of oral cephalosporins was found in all federal states. During 2017–2019, all states showed a significant decline of fluoroquinolone us

Studies of aging and HV break down problems during development and operation of MSGC and GEM detectors for the Inner Tracking System of HERA-B

The results of five years of development of the inner tracking system of the HERA-B experiment and first experience from the data taking period of the year 2000 are reported. The system contains 184 chambers, covering a sensitive area of about 20 * 20 cm2 each. The detector is based on microstrip gas counters (MSGCs) with diamond like coated (DLC) glass wafers and gas electron multipliers (GEMs). The main problems in the development phase were gas discharges in intense hadron beams and aging in a high radiation dose environment. The observation of gas discharges which damage the electrode structure of the MSGC led to the addition of the GEM as a first amplification step. Spurious sparking at the GEM cannot be avoided completely. It does not affect the GEM itself but can produce secondary damage of the MSGC if the electric field between the GEM and the MSGC is above a threshold depending on operation conditions. We observed that aging does not only depend on the dose but also on the spot size of the irradiated area. Ar-DME mixtures had to be abandoned whereas a mixture of 70% Ar and 30% CO2 showed no serious aging effects up to about 40 mC/cm deposited charge on the anodes. X-ray measurements indicate that the DLC of the MSGC is deteriorated by the gas amplification process. As a consequence, long term gain variations are expected. The Inner Tracker has successfully participated in the data taking at HERA-B during summer 2000.Comment: 29 pages, 22 figure

Learnings from Regional Market Dynamics of Originator and Biosimilar Infliximab and Etanercept in Germany.

Drug budget and prescription control measures are implemented regionally in Germany, meaning that the uptake of pharmaceuticals, including biosimilars, can vary by region. We examine regional market dynamics of tumor necrosis factor alpha (TNFα) inhibitor originators and biosimilars in Germany and studied the influence of biosimilar policies on these dynamics. This study is based on: (1) a literature review in which German biosimilar policies are identified, (2) the analysis of dispensing data (2010-2018) for the class of TNFα inhibitors, and (3) ten semi-structured interviews investigating prescribers' and insurers' views on factors potentially influencing biosimilar uptake. The analysis of biosimilar market shares of infliximab and etanercept revealed wide variations across the 17 German Regional Associations of Statutory Health Insurance Accredited Physicians (PA regions). Quantitative analyses indicated that biosimilar market shares for infliximab and etanercept were significantly lower in former East Germany when compared to former West Germany regions. Through qualitative interview analyses, this study showed that the use of infliximab and etanercept biosimilars across Germany is primarily influenced by (1) the regional-level implementation of biosimilar quotas and the presence of monitoring/sanctioning mechanisms to ensure adherence to these quotas, (2) the different insurer-manufacturer discount contracts, and (3) gainsharing arrangements established at the insurer-prescriber level

Comparison of contrast enhanced color Doppler targeted biopsy to conventional systematic biology: Impact on Gleason score

Purpose: Prostate cancer grading with Gleason score is an important prognostic factor. This prospective randomized study compares ultrasound systematic biopsy vs contrast enhanced color Doppler targeted biopsy for the impact on Gleason score findings. Materials and Methods: We examined 690 men (mean age 56 years, range 41 to 77) with a serum total prostate specific antigen of 1.25 ng/ml or greater, a free-to-total prostate specific antigen ratio less than 18% and/or a suspicious digital rectal examination. Contrast enhanced color Doppler targeted biopsies with a limited number of cores (5 or less) were performed in hypervascular areas of the peripheral zone during administration of the ultrasound contrast agent SonovueTM(Bracco, Milano, Italy). Ten systematic biopsies were obtained in a standard spatial distribution. Cancer detection rates and Gleason score were compared. Results: Prostate cancer was identified in 221 of 690 subjects (32%) with a mean prostate specific antigen of 4.6 ng/ml (range 1.4 to 35.0). Prostate cancer was detected in 180 of 690 subjects (26%) with contrast enhanced color Doppler targeted biopsy and in 166 of 690 patients (24%) with systematic ultrasound biopsy. The Gleason score of all 180 cancers detected on contrast enhanced color Doppler targeted biopsy was 6 or higher (mean 6.8). The Gleason score of all 166 cancers detected on systematic biopsy ranged from 4 to 6 and mean Gleason score was 5.4. Contrast enhanced color Doppler targeted biopsy detected significantly higher Gleason scores compared to systematic biopsy (Wilcoxon rank sum test p \u3c0.003). Conclusions: Contrast enhanced color Doppler targeted biopsy detected cancers with higher Gleason scores and more cancer than systematic biopsy. Therefore, contrast enhanced color Doppler seems to be helpful in the grading of prostate cancer, which is important for defining prognosis and deciding treatment

Lef1 regulates caveolin expression and caveolin dependent endocytosis, a process necessary for Wnt5a/Ror2 signaling during Xenopus gastrulation

The activation of distinct branches of the Wnt signaling network is essential for regulating early vertebrate development. Activation of the canonical Wnt/β-catenin pathway stimulates expression of β-catenin-Lef/Tcf regulated Wnt target genes and a regulatory network giving rise to the formation of the Spemann organizer. Non-canonical pathways, by contrast, mainly regulate cell polarization and migration, in particular convergent extension movements of the trunk mesoderm during gastrulation. By transcriptome analyses, we found caveolin1, caveolin3 and cavin1 to be regulated by Lef1 in the involuting mesoderm of Xenopus embryos at gastrula stages. We show that caveolins and caveolin dependent endocytosis are necessary for proper gastrulation, most likely by interfering with Wnt5a/Ror2 signaling. Wnt5a regulates the subcellular localization of receptor complexes, including Ror2 homodimers, Ror2/Fzd7 and Ror2/dsh heterodimers in an endocytosis dependent manner. Live-cell imaging revealed endocytosis of Ror2/caveolin1 complexes. In Xenopus explants, in the presence of Wnt5a, these receptor clusters remain stable exclusively at the basolateral side, suggesting that endocytosis of non-canonical Wnt/receptor complexes preferentially takes place at the apical membrane. In support of this blocking endocytosis with inhibitors prevents the effects of Wnt5a. Thus, target genes of Lef1 interfere with Wnt5a/Ror2 signaling to coordinate gastrulation movements

Issues and Opportunities in Exotic Hadrons

The last few years have been witness to a proliferation of new results concerning heavy exotic hadrons. Experimentally, many new signals have been discovered that could be pointing towards the existence of tetraquarks, pentaquarks, and other exotic configurations of quarks and gluons. Theoretically, advances in lattice field theory techniques place us at the cusp of understanding complex coupled-channel phenomena, modelling grows more sophisticated, and effective field theories are being applied to an ever greater range of situations. It is thus an opportune time to evaluate the status of the field. In the following, a series of high priority experimental and theoretical issues concerning heavy exotic hadrons is presented.Comment: White paper from INT workshop, "Modern Exotic Hadrons". References added. Version to appear in Chinese Physics