Controlling Prescribing through "Preferred Drug" Targets-The Bavarian Experience.

BACKGROUND: The rising costs of drugs are putting health care systems under pressure. We report on the Bavarian Drug Agreement, which employs prescribing targets for preferred and generic drugs in ambulatory care. Under this agreement, providers are regularly profiled with individual feedback but also possible sanctions. We investigated the degree to which targets were being met (or not) and why failure occurred. METHODS: We analysed prescribing data aggregated by practice for the quarter 1/2018. We chose eight specialisation groups and analysed their drug targets with a high prescribing volume, widely missed drug targets (<90%), and drugs preventing drug target achievement. Characterisation of drug targets and preventing drugs was undertaken. RESULTS: Drug targets with a high prescribing volume are mostly achieved, while highly missed drug targets mostly do not affect the main indication area of the specialisation groups considered. Generic drug targets seem to be more easily achieved than recommended drug targets. Paediatrics accounts for the largest number of missed drug targets. CONCLUSIONS: The Bavarian tool implemented uses the prescribing volume (DDD) and price components to evaluate the prescription behaviour of physicians. Well-established drugs with demonstrated effectiveness, safety, and lower costs are preferred. Nevertheless, me-too drugs, combination drugs, costly innovations with unclear value, and drugs with application methods of variable convenience challenge the drug prescribers and are reasons for missed drug targets.

The C-terminus of human Ca(v)2.3 voltage-gated calcium channel interacts with alternatively spliced calmodulin-2 expressed in two human cell lines.

Ca(v)2.3 containing voltage-activated Ca(2+) channels are expressed in excitable cells and trigger neurotransmitter and peptide-hormone release. Their expression remote from the fast release sites leads to the accumulation of presynaptic Ca(2+) which can both, facilitate and inhibit the influx of Ca(2+) ions through Ca(v)2.3. The facilitated Ca(2+) influx was recently related to hippocampal postsynaptic facilitation and long term potentiation. To analyze Ca(2+) mediated modulation of cellular processes more in detail, protein partners of the carboxy terminal tail of Ca(v)2.3 were identified by yeast-2-hybrid screening, leading in two human cell lines to the detection of a novel, extended and rarely occurring splice variant of calmodulin-2 (CaM-2), called CaM-2-extended (CaM-2-ext). CaM-2-ext interacts biochemically with the C-terminus of Ca(v)2.3 similar to the classical CaM-2 as shown by co-immunoprecipitation. Functionally, only CaM-2-ext reduces whole cell inward currents significantly. The insertion of the novel 46 nts long exon and the consecutive expression of CaM-2-ext must be dependent on a new upstream translation initiation site which is only rarely used in the tested human cell lines. The structure of the N-terminal extension is predicted to be more hydrophobic than the remaining CaM-2-ext protein, suggesting that it may help to dock it to the lipophilic membrane surrounding.

[Quality and Structure of Outpatient Care for Adults with ADHD (Attention Deficit Hyperactivity Disorder) - Results of the RAABE-Study [Retrospective Data Analysis of ADHD Treatment in Adults]]. / Qualität und Struktur der ambulanten Versorgung von erwachsenen Patienten mit ADHS (Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung).

OBJECTIVE: Data on the quality and structure of outpatient care for adults with ADHD in Germany are scarce. The study describes the reality of care and identifies possible measures for improvement. METHOD: A complete survey of adults ≥ 18 years of age with a diagnosis of ADHD (ICD-Code F90.0) covered by statutory health insurance was carried out in the outpatient setting in the German Free State of Bavaria in 2012. RESULTS: The analysis revealed a diagnostic prevalence of ADHD in adults in Bavaria of 0.1 %, which was lower than expected based on ADHD prevalence estimates in the general population (about 3 %). Patients were diagnosed by specialists for CNS disorders and by general practitioners. About 30 % of patients received a medication approved for the treatment of ADHD, and these were in approx. 75 % of cases prescribed by specialists for CNS disorders. About 50 % of the patients received psychotherapy. CONCLUSION: General practitioners play an important role for medical care of adult patients with ADHD. Continuous medical education programmes and collaboration between general practitioners and specialists is an urgent imperative for improving outpatient care of ADHD in adults.

GP130 activation induces myeloma and collaborates with MYC.

Multiple myeloma (MM) is a plasma cell neoplasm that results from clonal expansion of an Ig-secreting terminally differentiated B cell. Advanced MM is characterized by tissue damage that involves bone, kidney, and other organs and is typically associated with recurrent genetic abnormalities. IL-6 signaling via the IL-6 signal transducer GP130 has been implicated as an important driver of MM pathogenesis. Here, we demonstrated that ectopic expression of constitutively active GP130 (L-GP130) in a murine retroviral transduction-transplantation model induces rapid MM development of high penetrance. L-GP130-expressing mice recapitulated all of the characteristics of human disease, including monoclonal gammopathy, BM infiltration with lytic bone lesions, and protein deposition in the kidney. Moreover, the disease was easily transplantable and allowed different therapeutic options to be evaluated in vitro and in vivo. Using this model, we determined that GP130 signaling collaborated with MYC to induce MM and was responsible and sufficient for directing the plasma cell phenotype. Accordingly, we identified Myc aberrations in the L-GP130 MM model. Evaluation of human MM samples revealed recurrent activation of STAT3, a downstream target of GP130 signaling. Together, our results indicate that deregulated GP130 activity contributes to MM pathogenesis and that pathways downstream of GP130 activity have potential as therapeutic targets in MM.

Structural and biophysical determinants of single Ca(V)3.1 and Ca(V)3.2 T-type calcium channel inhibition by N(2)O.

We investigated the biophysical mechanism of inhibition of recombinant T-type calcium channels Ca(V)3.1 and Ca(V)3.2 by nitrous oxide (N(2)O). To identify functionally important channel structures, chimeras with reciprocal exchange of the N-terminal domains I and II and C-terminal domains III and IV were examined. In whole-cell recordings N(2)O significantly inhibited Ca(V)3.2, and - less pronounced - Ca(V)3.1. A Ca(V)3.2-prevalent inhibition of peak currents was also detected in cell-attached multi-channel patches. In cell-attached patches containing < or = 3 channels N(2)O reduced average peak current of Ca(V)3.2 by decreasing open probability and open time duration. Effects on Ca(V)3.1 were smaller and mediated by a reduced fraction of sweeps containing channel activity. Without drug, single Ca(V)3.1 channels were significantly less active than Ca(V)3.2. Chimeras revealed that domains III and IV control basal gating properties. Domains I and II, in particular a histidine residue within Ca(V)3.2 (H191), are responsible for the subtype-prevalent N(2)O inhibition. Our study demonstrates the biophysical (open times, open probability) and structural (domains I and II) basis of action of N(2)O on Ca(V)3.2. Such a fingerprint of single channels can help identifying the molecular nature of native channels. This is exemplified by a characterization of single channels expressed in human hMTC cells as functional homologues of recombinant Ca(V)3.1.