Katrin Schüssel

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

The Cu-binding β-amyloid precursor protein (APP), and the amyloid Aβ peptide have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced Cu homeostasis with a causative or diagnostic link to Alzheimers disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in Aβ levels in APP-transfected cells in vitro. To investigate the influence of bioavailable Cu, transgenic APP23 mice received an oral treatment with Cu-supplemented sucrose-sweetened drinking water (1). Chronic APP overexpression per se reduced superoxide dismutase 1 activity in transgenic mouse brain, which could be restored to normal levels after Cu treatment (2). A significant increase of brain Cu indicated its bioavailability on Cu treatment in APP23 mice, whereas Cu levels remained unaffected in littermate controls (3). Cu treatment lowered endogenous CNS Aβ before a detectable reduction of amyloid plaques. Thus, APP23 mice reveal APP-induced alterations linked to Cu homeostasis, which can be reversed by addition of dietary Cu.

Mitochondrial dysfunction, apoptotic cell death, and Alzheimer’s disease

Being major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and might therefore be particularly susceptible to oxidative injury. Mitochondrial damage may play a pivotal role in the cell death decision. Bolstered evidence indicates that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress occurring in Alzheimers disease (AD) finally contributing to synaptic failure and neuronal degeneration. Accumulation and oligomerization of amyloid beta (Abeta) is also thought to play a central role in the pathogenesis of this disease by probably directly leading to mitochondrial dysfunction. Moreover, numerous lines of findings indicate increased susceptibility to apoptotic cell death and increased oxidative damage as common features in neurons from sporadic AD patients but also from familial AD (FAD) cases. Here we provide a summary of recent work demonstrating some key abnormalities that may initiate and promote pathological events in AD. Finally, we emphasize a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, and Abeta production with mitochondrial dysfunction, caspase pathway, and neuronal loss.

Increased Apoptotic Cell Death in Sporadic and Genetic Alzheimer's Disease

Abstract: Mounting evidence indicates increased susceptibility to cell death and increased oxidative damage as common features in neurons from sporadic Alzheimers disease (AD) patients but also from familial AD (FAD) cases. Autosomal dominant forms of FAD are caused by mutations of the amyloid precursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2 (PS1/2). We investigated the effect of the Swedish APP double mutation (APPsw) on oxidative stress‐induced cell death mechanisms in PC12 cells. This mutation results in from three‐ to sixfold increased β‐amyloid (Aβ) production compared with wild‐type APP (APPwt). Because APPsw cells secrete low Aβ levels similar to the situation in FAD brains, our cell model represents a very suitable approach to elucidate the AD‐specific cell death pathways under more likely physiological conditions. We found that APPsw‐bearing cells show decreased mitochondrial membrane potential after exposure to hydrogen peroxide. In addition, activity of the executor caspase 3 after treatment with hydrogen peroxide was elevated in APPsw cells, which seems to be the result of an enhanced activation of both intrinsic and extrinsic apoptosis pathways. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a consequence of an increased vulnerability of neurons by mitochondrial abnormalities resulting in activation of different apoptotic pathways as a consequence to elevated oxidative stress levels. Finally, we propose a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, Aβ production, mitochondrial dysfunction with caspase pathway, and neuronal loss.

Adherence to Disease Modifying Drugs among Patients with Multiple Sclerosis in Germany: A Retrospective Cohort Study.

Background Long-term therapies such as disease modifying therapy for Multiple Sclerosis (MS) demand high levels of medication adherence in order to reach acceptable outcomes. The objective of this study was to describe adherence to four disease modifying drugs (DMDs) among statutorily insured patients within two years following treatment initiation. These drugs were interferon beta-1a i.m. (Avonex), interferon beta-1a s.c. (Rebif), interferon beta-1b s.c. (Betaferon) and glatiramer acetate s.c. (Copaxone). Methods This retrospective cohort study used pharmacy claims data from the data warehouse of the German Institute for Drug Use Evaluation (DAPI) from 2001 through 2009. New or renewed DMD prescriptions in the years 2002 to 2006 were identified and adherence was estimated during 730 days of follow-up by analyzing the medication possession ratio (MPR) as proxy for compliance and persistence defined as number of days from initiation of DMD therapy until discontinuation or interruption. Findings A total of 52,516 medication profiles or therapy cycles (11,891 Avonex, 14,060 Betaferon, 12,353 Copaxone and 14,212 Rebif) from 50,057 patients were included into the analysis. Among the 4 cohorts, no clinically relevant differences were found in available covariates. The Medication Possession Ratio (MPR) measured overall compliance, which was 39.9% with a threshold MPR≥0.8. There were small differences in the proportion of therapy cycles during which a patient was compliant for the following medications: Avonex (42.8%), Betaferon (40.6%), Rebif (39.2%), and Copaxone (37%). Overall persistence was 32.3% at the end of the 24 months observation period, i.e. during only one third of all included therapy cycles patients did not discontinue or interrupt DMD therapy. There were also small differences in the proportion of therapy cycles during which a patient was persistent as follows: Avonex (34.2%), Betaferon (33.4%), Rebif (31.7%) and Copaxone (29.8%). Conclusions Two years after initiating MS-modifying therapy, only 30–40% of patients were adherent to DMDs.

Incidence of thyroid hormone therapy in patients treated with sunitinib or sorafenib: a cohort study.

BACKGROUND Sunitinib and sorafenib can induce serious adverse drug reactions (ADR) such as hypothyroidism. However, the incidence has not been reliably determined in clinical trials. AIMS To determine incidence rates (IR) and hazard ratios (HR) of thyroid hormone (TH) therapy as a surrogate for sunitinib- and sorafenib-induced clinical hypothyroidism. METHODS A cohort study was performed using claims data for prescriptions covering >80% of German pharmacies. Patients with a first prescription of sunitinib or sorafenib in the period between June 2006 and December 2007 were followed until incident prescription of any TH (event of interest) or censoring (due to loss to follow-up, discontinuation or switch of therapy, prescription of antithyroid drugs or the end of the study). RESULTS One-hundred and seventy eight of 1295 sunitinib patients (13.7%) versus 77 of 1214 sorafenib patients (6.3%) received a TH. IR were 24.2 and 12.1 per 100 person-years, respectively. Unadjusted HR for TH therapy was 2.0 (95%confidence interval (CI) 1.5-2.6) for sunitinib compared to sorafenib and remained significant after adjustment for covariates, i.e. type of prescriber, region, insurance status, type of insurance fund, and relevant co-medication. CONCLUSIONS Sunitinib- and sorafenib-induced hypothyroidism is a more frequent ADR than currently labelled. Furthermore, patients treated with sunitinib have a two-fold increased risk of requiring TH therapy compared to sorafenib. Patients being treated with sunitinib or sorafenib are, therefore, at risk of thyroid function disturbances and routine monitoring both at baseline and throughout treatment with sunitinib and sorafenib is justified.

Strategies to improve medication adherence

Up to 50 % of patients with chronic diseases do not take their medication regularly. Poor adherence to drug therapy is associated with higher morbidity and mortality. A selective literature search using the terms adherence, compliance, concordance, persistence, medication management, and pharmaceutical care was performed. Evidence for improving adherence has been provided for the following principles: individual counselling of patients and care givers, medication management including simplifying dosing and use of combination tablets as well as the use of individual unit doses, e. g. blister cards. The effectiveness has only been shown for the duration of the interventions. The improvement of medication adherence represents an area of research with high impact on outcomes and cost. Measures to improve adherence may be as important as the development of novel therapies. However, prospective clinical evaluations with clinical endpoints are missing especially for the German health care system in order to develop recommendations for clinical practice. Joint efforts of physicians and pharmacists are needed.

Treatment duration (persistence) of basal insulin supported oral therapy (BOT) in Type-2 diabetic patients: comparison of insulin glargine with NPH insulin

OBJECTIVE To compare the persistence (treatment duration) of basal insulin supported oral therapy (BOT) using insulin glargine (GLA) or NPH insulin (NPH) in Type-2 diabetic patients. METHODS This retrospective cohort study reports results from an analysis of claims data from prescriptions for ambulatory patients within the German Statutory Health Insurance scheme. The study is based on claims data from more than 80% of German community pharmacies. Treatment duration until switching to a basal bolus treatment regimen (intensified conventional insulin therapy: ICT) was determined in insulin-naïve patients who began treatment with BOT using GLA or NPH between 01/2003 and 12/2006. RESULTS A total of 97,998 patients (61,070 GLA and 36,928 NPH) were included. Within the observation period, 23.5% of GLA patients and 28.0% of NPH patients switched from BOT to ICT. The upper quartile of probability of continuation of therapy (the 75th percentile) was reached after 769 days in GLA patients and after 517 days in NPH patients. Therefore, the risk of switching to ICT was significantly higher with NPH compared to GLA: hazard ratios were 1.34 (99% CI: 1.29-1.38; unadjusted) and 1.22 (99% CI: 1.18-1.27) after adjustment for predefined covariates. Various sensitivity analyses using modified inclusion criteria and endpoint definitions were applied and these confirmed the initial results. CONCLUSION Type-2 diabetic patients under BOT with GLA stayed significantly longer on the initial therapy before switching to ICT than patients on BOT using NPH.

Adherence to antihypertensives: feasibility of two self-report instruments to investigate medication-taking behaviour in German community pharmacies

To design and test the feasibility of two questionnaires in German community pharmacies exploring self‐reported adherence to antihypertensives.