[Show abstract][Hide abstract] ABSTRACT: Generic substitution of narrow therapeutic index drugs can have unintended consequences. Generic switching is often driven by cost incentives, regulations and supply, but may raise concerns about equal bioavailability, therapeutic equivalence and about possible confusion for the patient. Integrated systems of care with active management of patient behaviors, including adherence, may minimize the impact of switching. This article is intended to present policy drivers and potential consequences of generic switching and the role of pharmacist education in minimizing patient risk using warfarin and the pharmaceutical distribution systems of the United States and Germany as examples.
[Show abstract][Hide abstract] ABSTRACT: Ginkgo biloba drugs (Gb) are reimbursed within the German statutory health insurance (SHI) scheme for treatment of dementia. In 2008, a novel Gb product containing 240 mg Ginkgo extract EGb761(R) per tablet was introduced aiming to facilitate medication use by incorporating the recommended daily dose in one single tablet. The aim of this study was to evaluate the relationship between dosage strength and persistence in a representative population of patients treated with Gb.
Retrospective cohort study in ambulatory drug claims database within the German SHI system. Persistence was defined as continuous treatment with an allowable gap of 20% between refills. Multivariate regression models were conducted to identify variables associated with persistence.
Among 13,810 patients initiating treatment with Gb in 2008, 430 (3.1%) received a dosage strength of 240 mg, 7,070 (51.2%) a dosage strength of 120 mg and 6,310 (45.7%) dosage strengths containing less than 120 mg Gb per tablet. After 6 months, persistence was highest for patients treated with the 240 mg dosage form (22.8% of patients), although persistence was low in general (5.7% and 0% of patients treated with 120 mg and less than 120 mg, respectively). Risk for non-persistence was reduced in patients receiving 240 mg products compared to 120 mg (HR = 0.63; 95%CI 0.57 -- 0.70).
Patients initially treated with Gb 240 mg were more persistent compared to those receiving lower dosage strengths. Nevertheless, persistence with Gb therapy is generally low and should be improved in order to better realize therapeutic effects.
BMC Complementary and Alternative Medicine 10/2013; 13(1):278. DOI:10.1186/1472-6882-13-278 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To design and test the feasibility of two questionnaires in German community pharmacies exploring self-reported adherence to antihypertensives.
Two self-report questionnaires were designed for patients treated with antihypertensives. The 29-item-questionnaire (long form, LF) was completed by pharmacists interviewing patients who were on the premises filling a prescription. The short form (SF; 19 items) was sent by pharmacies to patients via mail. The acceptance of the instruments by patients and pharmacists as well as the feasibility to measure medication-taking behaviour was investigated. Adherence was investigated by using a modified 5-(LF) or 6-item (SF) Morisky score.
Of 44 community pharmacies contacted, 18 agreed to participate. Patients' response rates were 428/915 (46.8%) for the SF and 249/760 (32.8%) for the LF. One hundred and seventy-nine patients (41.8%) and 70 patients (28.1%) reported adherence problems according to the SF and LF respectively.
To our knowledge, this is the first attempt to develop a self-report instrument for the detection of non-adherence in patients taking antihypertensives in this setting in Germany. Patients were willing to provide detailed information about their medication-taking behaviour. Underestimation of non-adherence may be more pronounced when applying the questionnaire in the pharmacy.
[Show abstract][Hide abstract] ABSTRACT: Sunitinib and sorafenib can induce serious adverse drug reactions (ADR) such as hypothyroidism. However, the incidence has not been reliably determined in clinical trials.
To determine incidence rates (IR) and hazard ratios (HR) of thyroid hormone (TH) therapy as a surrogate for sunitinib- and sorafenib-induced clinical hypothyroidism.
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).
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.
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.
European journal of cancer (Oxford, England: 1990) 02/2012; 48(7):974-81. DOI:10.1016/j.ejca.2012.01.036 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
International journal of clinical pharmacology and therapeutics 01/2012; 50(1):24-32. DOI:10.5414/CP201572 · 1.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For treatment success in chronic diseases such as hypertension, adequate adherence to long-term pharmacotherapy is a prerequisite. The purpose of this study was to evaluate whether switching from brand name ramipril to a generic product after patent expiry may negatively affect patients' refill compliance.
Claims data for ambulatory prescriptions within the statutory health insurance system were evaluated. Patients were included if they had filled a ramipril prescription (index) for either brand name or generic ramipril products between September 2003 and June 2004. Patients had to be continuously treated with ramipril for at least 12 months before and after the index date. Patients with a change from brand name to generic product or vice versa during follow-up after the index date were excluded from the analyses, as were patients who could not be unequivocally allocated to characteristics of covariates. Refill compliance was analysed by calculating the medication possession ratio (MPR), assuming that patients were prescribed one unit dose per day (MPR(UD)).
In total, 142,690 and 79,191 patients were classified as brand name or generic therapy, respectively. Median MPR(UD) values were 0.95 and 0.96 (P < 0.001). In a logistic regression model adjusting for covariates, the probability for noncompliance (MPR(UD) < 0.8) was marginally lower in the generic compared with the brand name group (odds ratio 0.926, 99% confidence interval 0.901-0.951, P < 0.001).
These results suggest that refill compliance is not negatively affected by a physician-induced switch from brand name to generic ramipril products after patent expiry.
Journal of Hypertension 09/2011; 29(9):1837-45. DOI:10.1097/HJH.0b013e32834942be · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: The emergence of safety concerns associated with the use of selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) led to market withdrawals of rofecoxib in September 2004 and valdecoxib in April 2005. These events were accompanied by safety alerts from drug authorities and recommendations from professional medical associations. This study analysed the temporal influence of these measures on drug use in Germany, with the objective to assess overall appropriateness of prescribing and to evaluate the potential for pharmaceutical interventions. Drug prescriptions for patients within the statutory health insurance system (GKV) were analysed based on the total amount of DDDs of single drug substances dispensed every month in German pharmacies. The market withdrawal of rofecoxib in September 2004 resulted initially in increased prescribing of other coxibs. New safety warnings on coxibs later in 2004 and the withdrawal of valdecoxib in April 2005 led to pronounced reductions in coxib prescribing. Comparing the third quarter of 2005 with 2004, coxib prescriptions dropped from 47.5 to 10.4 million DDDs. Conversely, in the same time frame, NSAID prescriptions increased by 19.0 million DDDs. This is mostly due to increased prescribing of ibuprofen, diclofenac and, to a lesser degree, meloxicam, acemetacin, piroxicam, and naproxen. However, total prescribing of inhibitors of cyclooxygenases decreased by about 8.4%, indicating a relative reluctance to prescribe these drugs after cardiovascular safety warnings have been issued by drug authorities. Unexpectedly, also prescribing of metamizol (dipyrone) increased by 2.8 million DDDs (20%), despite recommendations to limit its use by medical associations. Furthermore, increased prescribing of proton pump inhibitors of 12.6 million DDDs could be observed. NSAIDs and coxibs are to a larger extent prescribed by a broad range of medical specialist groups including orthopaedists and surgeons, whereas drugs used in gastrointestinal or cardiovascular disorders are mainly prescribed by general practitioners and internal specialists, respectively. Therefore, the individual physician may not always be aware of the risk profiles of their patients. Pharmacists can close this gap by providing comprehensive medication records and information on self medication used by the patient to prescribing practitioners, thereby contributing to improved patient safety.
[Show abstract][Hide abstract] ABSTRACT: Mutations in the presenilins (PS) account for the majority of familial Alzheimer disease (FAD) cases. To test the hypothesis that oxidative stress can underlie the deleterious effects of presenilin mutations, we analyzed lipid peroxidation products (4-hydroxynonenal (HNE) and malondialdehyde) and antioxidant defenses in brain tissue and levels of reactive oxygen species (ROS) in splenic lymphocytes from transgenic mice bearing human PS1 with the M146L mutation (PS1M146L) compared to those from mice transgenic for wild-type human PS1 (PS1wt) and nontransgenic littermate control mice. In brain tissue, HNE levels were increased only in aged (19-22 months) PS1M146L transgenic animals compared to PS1wt mice and not in young (3-4 months) or middle-aged mice (13-15 months). Similarly, in splenic lymphocytes expressing the transgenic PS1 proteins, mitochondrial and cytosolic ROS levels were elevated to 142.1 and 120.5% relative to controls only in cells from aged PS1M146L animals. Additionally, brain tissue HNE levels were positively correlated with mitochondrial ROS levels in splenic lymphocytes, indicating that oxidative stress can be detected in different tissues of PS1 transgenic mice. Antioxidant defenses (activities of antioxidant enzymes Cu/Zn-SOD, GPx, or GR) or susceptibility to in vitro oxidative stimulation was unaltered. In summary, these results demonstrate that the PS1M146L mutation increases mitochondrial ROS formation and oxidative damage in aged mice. Hence, oxidative stress caused by the combined effects of aging and PS1 mutations may be causative for triggering neurodegenerative events in FAD patients.
Free Radical Biology and Medicine 04/2006; 40(5):850-62. DOI:10.1016/j.freeradbiomed.2005.10.041 · 5.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Transgenic mice overexpressing the P301L mutant human tau protein exhibit an accumulation of hyperphosphorylated tau and develop neurofibrillary tangles. The consequences of tau pathology were investigated here by proteomics followed by functional analysis. Mainly metabolism-related proteins including mitochondrial respiratory chain complex components, antioxidant enzymes, and synaptic proteins were identified as modified in the proteome pattern of P301L tau mice. Significantly, the reduction in mitochondrial complex V levels in the P301L tau mice revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) brains. Functional analysis demonstrated a mitochondrial dysfunction in P301L tau mice together with reduced NADH-ubiquinone oxidoreductase activity and, with age, impaired mitochondrial respiration and ATP synthesis. Mitochondrial dys-function was associated with higher levels of reactive oxygen species in aged transgenic mice. Increased tau pathology as in aged homozygous P301L tau mice revealed modified lipid peroxidation levels and the up-regulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward beta-amyloid (Abeta) peptide insult, suggesting a synergistic action of tau and Abeta pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Abeta.
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress plays an important role in the pathogenesis of Alzheimer's disease. To determine which mechanisms cause the origin of oxidative damage, we analyzed enzymatic antioxidant defense (Cu/Zn-superoxide dismutase Cu/Zn-SOD, glutathione peroxidase GPx and glutathione reductase GR) and lipid peroxidation products malondialdehyde MDA and 4-hydroxynonenal HNE in two different APP transgenic mouse models at 3-4 and 12-15 months of age. No changes in any parameter were observed in brains from PDGF-APP695(SDL) mice, which have low levels of Abeta and no plaque load. In contrast, Thy1-APP751(SL) mice show high Abeta accumulation with aging and plaques from an age of 6 months. In brains of these mice, HNE levels were increased at 3 months (female transgenic mice) and at 12 months (both gender), that is, before and after plaque deposition, and the activity of Cu/Zn-SOD was reduced. Interestingly, beta-amyloidogenic cleavage of APP was increased in female Thy1-APP751(SL) mice, which also showed increased HNE levels with simultaneously reduced Cu/Zn-SOD activity earlier than male Thy1-APP751(SL) mice. Our results demonstrate that impaired Cu/Zn-SOD activity contributes to oxidative damage in Thy1-APP751(SL) transgenic mice, and these findings are closely linked to increased beta-amyloidogenic cleavage of APP.
Neurobiology of Disease 03/2005; 18(1):89-99. DOI:10.1016/j.nbd.2004.09.003 · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD) and since the age-adjusted incidence of AD is higher in females than males, we examined a possible influence of gender on antioxidant metabolism in brains from male and female AD patients and age-matched controls. Activities of copper/zinc-dependent superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-disulfide reductase (GR) were elevated in AD samples compared to controls. Upon in vitro stimulation, levels of malondialdehyde formation were significantly lower in AD samples, probably due to the increased antioxidant capacity. Overall, our results indicate that antioxidant metabolism is functionally still intact but increased in AD implying that oxidative damage is caused rather by overproduction than by insufficient detoxification of ROS. Among AD patients, a gender-specific partial upregulation of antioxidant defence was present: activities of SOD and GPx were even further increased in female patients, and levels of 4-hydroxynonenal, a marker of oxidative damage, were higher than in male patients. Importantly, our results are in line with epidemiological studies indicating a higher risk for AD in females. Thus, gender differences in oxidative stress parameters might be related to the higher prevalence of AD in females.
[Show abstract][Hide abstract] ABSTRACT: Mounting evidence indicates increased susceptibility to cell death and increased oxidative damage as common features in neurons from sporadic Alzheimer's 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 beta-amyloid (Abeta) production compared with wild-type APP (APPwt). Because APPsw cells secrete low Abeta 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, Abeta production, mitochondrial dysfunction with caspase pathway, and neuronal loss.
Annals of the New York Academy of Sciences 01/2004; 1010(1):604-9. DOI:10.1196/annals.1299.113 · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Cu-binding beta-amyloid precursor protein (APP), and the amyloid Abeta 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 Alzheimer's 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 Abeta 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 Abeta 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.
Proceedings of the National Academy of Sciences 12/2003; 100(24):14187-92. DOI:10.1073/pnas.2332818100 · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 Alzheimer's 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.