[Pharmacological management of attention-deficit/hyperactivity disorders (ADHD) by generalists and specialists in Germany: a secondary data analysis]. / Pharmakotherapie von Aufmerksamkeitsdefizit-Hyperaktivitätsstörungen (ADHS) in der hausärztlichen und fachärztlichen Versorgung: eine Sekundärdatenanalyse.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common mental health disorders among children, and it is rapidly surging among adults as well. The aim of this study was to investigate the role of community neurologists and psychiatrists as well as general practitioners and paediatricians in prescribing ADHD medications in Germany and whether their role has changed over the 10-year period from 2008 and 2018. METHODS: In this secondary analysis of anonymized prescribing data, we calculated the absolute and relative frequencies of ADHD prescriptions by neurologists and psychiatrists, summarized as specialists, and family physicians and paediatricians, summarized as generalists, and how it has changed during the years 2008 to 2018. RESULTS: A total of 620 practices delivered data on 77,504 patients diagnosed with ADHD, 38% (29,396/77,504) of them had received a prescription for ADHD medicine at least once in the study period. Over time, we observed a shift from generalists to specialists. While 59% of patients received their prescription from a generalist and 41% from a specialist in 2008, there was reverse in the ratio in 2018: only 37% received their medication from a generalist and the vast majority (63%) from a specialist. This trend was particularly evident among adults: 58% of them received their ADHD medication from a specialist in 2008, but 80% in 2018. The proportion of children and adolescents who received their prescriptions from a specialist rose from 38% to 51% over the same period. CONCLUSION: There is a shift in drug prescription away from generalists to specialists, without any discussion of advantages or disadvantages so far. However, this would be desirable, not least because specialists alone may not have sufficient resources to care for all ADHD patients.

Role of private prescriptions in the long-term use of benzodiazepines and Z-drugs: A patient-related follow-up study.

PURPOSE: To analyse (1) how often patients insured under the statutory health insurance (SHI) scheme received repeated prescriptions for benzodiazepines or Z-drugs as private prescriptions and (2) how often doctors switched from SHI prescriptions to private prescriptions and vice versa when issuing repeat prescriptions. METHODS: On basis of anonymized prescriptions from 874 ambulatory practices in Germany, we analysed the percentage of private prescriptions for Z-drugs, benzodiazepines/anxiolytics, and benzodiazepines/hypnotics and sedatives over 6 years (2014 to 2020). RESULTS: Of 2 200 446 prescriptions for a benzodiazepine or Z-drug, 38% were private prescriptions. In case of Z-drugs, the rate of private prescriptions was 44.1% for single prescriptions and 48.9% for refills. The difference was smaller for anxiolytics (23.3% vs. 26.0%) and, for benzodiazepine/hypnotics and sedatives, the proportion of private prescriptions for refills was even lower than for single prescriptions. In case of Z-drugs, the proportion of private prescriptions was, on average, 42.7% for the first prescription of a series of repeat prescriptions and 49.6% for the tenth prescription. The increase was smaller for anxiolytics and negligible for benzodiazepine/hypnotics and sedatives. Doctors stayed with their initial decision in more than three quarters of repeat prescriptions, be it a SHI or private prescription. CONCLUSION: While we observed a large number of private prescriptions for benzodiazepines and Z-drugs, the proportion was only slightly higher for refills than for single prescriptions. Doctors do not seem to issue private prescriptions as a strategy to mask especially long-term use of these substances.

[Private Prescriptions In East And West Germany - A Secondary Data Analysis]. / Privatverordnungen von Benzodiazepinen und Z-Substanzen in Ost- und Westdeutschland ­ eine Sekundärdatenanalyse.

BACKGROUND AND OBJECTIVE: Benzodiazepines and Z-drugs are prescribed to a considerable extent as private prescription also for persons insured by a statutory health insurance (SHI), with formerly large differences between East and West Germany. The aim of the present study was to investigate whether these differences still exist today. METHOD: This secondary data analysis used anonymized prescription data from general practitioners (GPs), community neurologists, and psychiatrists. SHI-insured patients with at least one prescription for a benzodiazepine or Z-substance between 2014 and 2020 were included. Differences between East and West Germany in the proportion of private prescriptions were the central outcome. Multiple regression analyses were performed to test whether the factors region (eastern vs. western Germany) and specialist group (GPs vs. neurologists/psychiatrists) were statistically significant predictors of the proportion of private prescriptions - taking into account the age and gender composition of patients in a practice. RESULTS: From 867 practices, 2,200,446 prescriptions for Z-substances, benzodiazepine anxiolytics, and benzodiazepine hypnotics/sedatives were evaluated. More than 38% of these prescriptions were issued as private prescriptions: 53.6% in eastern Germany and 34.8% in western Germany. For Z-substances, the proportion of private prescriptions was particularly high (70.7% in eastern and 43.0% in western Germany). GPs issued private prescriptions far more frequently than neurologists and psychiatrists. The proportion of private prescriptions increased during the study period, comparatively strongly in the western states (from 33% to 39%) and slightly in the eastern states (from 53% to 54%). In the multivariate model, practice area (east/west) and specialist group were similarly strong predictors of the extent of private prescriptions, especially for Z-substances. CONCLUSION: Contrary to a general alignment in life expectancy, morbidity risks, and health behaviour in East and West Germany, there is, despite convergence, still a significant difference in the proportion of private prescriptions for benzodiazepines and especially for Z-substances between the two regions. The groups of physicians who mainly prescribe these substances, namely neurologists and psychiatrists, on the one hand, and GPs, on the other, also differ considerably in the proportion of their private prescriptions for these substances.

The 10-year trend in drug prescriptions for attention-deficit/hyperactivity disorder (ADHD) in Germany.

PURPOSE: The aim of this study was to analyse whether the global trend in drug prescriptions for attention-deficit hyperactivity disorders (ADHD), as observed during the last years and often criticized as medicalization, have remained stable or shifted. METHODS: This observational study was based on a secondary analysis of data from a large German database including patients with an ADHD diagnosis between 2008 and 2018. Prescription data comprised all important ADHD drugs. RESULTS: A total of 620 practices delivered data from a total of 77,504 patients (31% of them females) with a diagnosis of AHDH. Nearly 38% (29,396/77,504) of all patients received, at least, one prescription for an ADHS medicine between 2008 and 2018. The number of patients receiving a drug steadily increased annually until 2012 and then slowly fell, but unevenly distributed across the age groups. While the number of younger patients ( ≤ 16 years) receiving a prescription fell by 24% and the defined daily doses (DDDs) remained stable, the number of patients between 17 and 24 years receiving a prescription increased by 113% and the DDDs by 150%. Respectively, the number of older adults (≥ 25 years) with a prescription increased by 355% and the DDDs by 515%. Nearly one-third of older adults received an ADHD medicine only once. CONCLUSION: The ever-increasing prescription of ADHD medicines stopped some years ago for children. ADHS and its pharmacological management are increasingly observed among older adolescents and adults, with a different pattern of drug persistence compared with children.

Dual renin-angiotensin-aldosterone blockade: Implementation of published research and Dear Doctor letters in ambulatory care: A retrospective observational study using prescription data.

PURPOSE: This study aims to assess the implementation of published research, contraindications, and warnings on the prescription of dual renin-angiotensin-hormone system (RAS) blockade in ambulatory care in Germany. METHODS: Cohort study based on health claims data of 6.7 million subjects from 2008 to 2015. Yearly prevalence and incidence for dual RAS blockade with (a) angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers (ACEI + ARB) and (b) aliskiren and ACEI or ARB (aliskiren + ACEI/ARB) were calculated. We assessed prescriber specialty and associations between discontinuing dual RAS blockade with specialist (internal medicine, cardiology, nephrology) visits and hospital discharge in the previous year. RESULTS: A total of 2 984 517 patients were included (age 51.4 ± SD 18.4 y, 48.5% male). Prescription rates for ACEI + ARB decreased from 0.6% (n = 17 907) to 0.4% (n = 12 237) and for aliskiren + ACEI/ARB from 0.23% (n = 6634) to 0.03% (n = 818). Incident prescriptions decreased from 0.23% (n = 6705) to 0.19% (n = 5055) (ACE + ARB) and from 0.1% (n = 2796) to 0.005% (n = 142) (aliskiren + ACE/ARB); 59% of ACEI + ARB and 48% of aliskiren + ACE/ARB combinations were prescribed only by one physician. Of those, 73% (ACEI + ARB) and 58% (aliskiren + ACE/ARB) were primary care providers (PCPs). Discontinuing dual RAS blockade was associated with specialist care and hospital discharge in the previous year (specialist care: RR 1.4, 95% CI, 1.3-1.6; hospital visit: RR 1.5, 95% CI, 1.3-1.6). CONCLUSIONS: Our results suggest a delayed uptake of treatment recommendation for ACEI + ARB and a higher impact of Dear Doctor letters addressing PCPs directly compared with published research, contraindications, and warnings. Targeted continuous medical education, practice software alerts, and stronger involvement of pharmacists might improve the implementation of medication safety recommendations in ambulatory care.

Effects of expiring reimbursability of pentaerythrityl tetranitrate (PETN, pentalong®) on anti-anginal therapy: an observational study.

PURPOSE: Pentaerythrityl tetranitrate (PETN) was the most commonly prescribed long-acting nitrate in Germany. We aimed to assess whether the discontinuation of PETN reimbursability in 2011 resulted in alternative prescriptions of anti-anginal medications or in a discontinuation of anti-anginal therapy. METHODS: This is an observational study using health claims data from one German federal state analysing all patients discontinuing a PETN treatment. Patients starting a new alternative anti-anginal treatment (long-acting nitrates, molsidome, ivabradine and ranolazine) were compared with patients without a new anti-anginal treatment with respect to use of short-acting nitrates, beta blockers (BBs) and calcium channel blockers (CCBs). RESULTS: Out of 12,909 patients, 12,763 (99%) discontinued PETN until 12/2012. Of these, 52% started an alternative anti-anginal treatment, 43% did not receive any alternative treatment and 5% were excluded from analysis. Before termination of PETN reimbursability, 65% of patients received BBs, 29% CCBs and 10% short-acting nitrates. In patients started on alternative anti-anginal treatment, prescription rates for short-acting nitrates, BBs and CCBs remained constant after discontinuing PETN. In patients without any alternative anti-anginal treatment, prescription rates for BBs and CCBs did not change meaningfully (<3%), and prescription rates for short-acting nitrates decreased from 9% to 6%. CONCLUSIONS: Half of the patients discontinued PETN without alternative. This did not lead to increased prescription rates of standard IHD medications or total medication number indicating that there might still be a high percentage of ischaemic heart disease patients treated unnecessarily with long-acting nitrates. The undertreatment with prognostically relevant first-line medications indicates a need for better guideline implementation activities.

Persistence of antihypertensive drug use in German primary care: a follow-up study based on pharmacy claims data.

PURPOSE: To study drug persistence for antihypertensive treatment considering typical patient behaviour including extended drug holidays or irregular repeat prescriptions. METHODS: We used prescription data from a German statutory health insurance to follow up patients for 4 years. Medication persistence was defined as the continued use of a specific drug class, therapy persistence as the continued use of any antihypertensive drug. We applied 2 different interval criteria within which a repeat prescription had to be issued: 180 and 360 days. RESULTS: A total of 9,513 patients started an antihypertensive therapy between 2006 and 2008. Applying the 180-day (360-day) interval criterion, 28 % (66 %) of the patients starting therapy with a beta-blocker were still medication-persistent after 4 years. The rates were similar for angiotensin-II receptor blockers (ARBs; 30 % and 69 % respectively) or angiotensin-converting enzyme (ACE) inhibitors (28 % and 61 % respectively). Looking at therapy persistence, these rates were 44 % (79 %) when an ACE inhibitor was the initial drug, 46 % (82 %) for ARBs. On average, even of those who were defined as therapeutically persistent with the 360 days criterion, half received a repeat prescription within 96 days, three quarters within 131 days-with a median supply of 1.2 units per day and 1.25 defined daily doses. CONCLUSION: By applying more patient-orientated criteria, we found that many patients were therapy-persistent and received a prescription at the appropriate time. Therapy persistence was nearly independent of the initial agent; thus, drug persistence may not be an argument in favour of choosing a certain drug as a first-line option.

Discrepancies between prescribed and defined daily doses: a matter of patients or drug classes?

PURPOSE: Defined daily doses (DDD) are used for the measurement of drug utilisation. The aim of the study was to analyse whether differences between DDD and prescribed daily doses (PDD) exist for relevant drug classes such as antihypertensive drugs and, if so, whether they primarily depend on drug classes or patient-related factors. METHODS: Using the data of a large German statutory health insurance scheme, we analysed continuous prescriptions for the following antihypertensive drug classes: thiazide diuretics, beta-blockers, dihydropyridine calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs). We summed the doses of all dispensed drugs per person during a defined time frame. We calculated the PDD (= total dose divided by the number of days) and expressed them as the PDD:DDD ratio (= amount of DDD per day and person). RESULTS: During the study period, 149,704 patients continuously received an antihypertensive medication. The average PDD:DDD ratio ranged from 0.84 (beta-blockers) to 1.88 (ARBs) and 2.17 (ACEIs). The average prescribed dosage of each drug class remained unchanged, even if the patients had previously received another antihypertensive drug with another PDD:DDD ratio. For example, if patients were switched from a beta-blocker to an ACEI, the PDD:DDD ratio increased, on average, from 0.79 to 2.17. Vice versa, the ratio decreased for patients with a drug change from an ACEI to a beta-blocker from 2.06 to 0.75. CONCLUSIONS: Even large differences between DDD and PDD seem to be a matter of drug classes and not primarily of patient characteristics.

Appropriateness of treatment recommendations for PPI in hospital discharge letters.

PURPOSE: The reasons for the dramatic increase in proton pump inhibitors (PPI) prescriptions remain unclear and cannot be explained solely by increased morbidity, new indications or a decrease in alternative medication. Inappropriate use and discharge recommendations in hospitals are considered to be possible explanations. As the quality of PPI recommendations in hospital discharge letters in Germany has not been investigated to date, we have studied the appropriateness of these referrals. METHODS: Hospital discharge letters with recommendations for PPI medication from 35 primary care practices in the county of Mecklenburg-Western Pomerania (MV; North-east Germany) were collected and analysed, and the appropriateness of the PPI indication was rated. RESULTS: No information justifying the recommendation for continuous PPI medication could be identified in 54.5% of the discharge letters; in 12.7%, the indication was uncertain, and in 32.7%, we found an evidence-based indication for PPI medication. The most common indication for adequate PPI use was nonsteroidal anti-inflammatory drug-prophylaxis in high-risk patients. CONCLUSIONS: Inadequate recommendations for PPIs in discharge letters are frequent. This may lead to a continuation of this therapy in primary care, thereby unnecessarily increasing polypharmacy and the risk of adverse events as well as burdening the public health budget. Hospitals should therefore critically review recommendations for PPI medication and the dosage thereof in their discharge letters and clearly document the reason for PPI use and the need for continuous prescription in primary care.

Polypharmacy in primary care practices: an analysis using a large health insurance database.

PURPOSE: To ascertain the rate and range of continuous polypharmacy in German general practices and compare practice characteristics and prescribing profiles in practices with a high rate of polypharmacy patients (HPP) and a low rate of polypharmacy patients (LPP), respectively. METHODS: This observational study used a database composed of prescription data from a large German statutory health insurance. We defined polypharmacy as the continuous prescription of five or more drugs and calculated the percentage of polypharmacy patients for each practice to identify HPP and LPP. RESULTS: A total of 136 521 patients in 730 general practices received continuous medication. About 10% of these patients (14 293/136 521) received five or more different drugs. HPP had, on average, 15.1% polypharmacy patients compared to 4.2% in LPP. The total number of patients attending either a HPP or LPP was comparable (437 vs. 416; p = 0.102), but HPP had a higher number of patients with prescriptions (76.9% vs. 70.8%; p < 0.0001). The patients' age distribution was similar (68.0 in LPP vs. 68.8 in HPP) and there were slightly more female patients in LPP. Doctors in HPP prescribed proton pump inhibitors and NSAIDs more frequently than doctors in LPP, but there was no difference in the prescription of me-too drugs. CONCLUSION: The absolute differences in age and gender distribution between HPP and LPP were modest. Prescribing quality, as measured by the rate of me-too drug prescriptions, was similar across all practices. Therefore, differences in the rate of polypharmacy in general practice cannot sufficiently be explained by these factors.

The influence of hospitalisation on the initiation, continuation and discontinuation of benzodiazepines and Z-drugs - an observational study.

BACKGROUND AND OBJECTIVES: Hospitalisation influences drug therapy in ambulatory care and this influence is generally negatively perceived. The few studies that have explored changes in benzodiazepine or sleep medication use as a function of hospitalisation failed to precisely determine the hospital's role in initiating, continuing and discontinuing these drugs on a valid basis. The aim of the study was to ascertain the overall influence of hospitalisation on the prescription of benzodiazepines and Z-drugs in outpatient care with a special focus on the role of different hospital departments and drug classes. METHODS: In a secondary data analysis, we used prescription data for 181 037 patients who visited 127 hospitals and compared the numbers of patients with prescriptions of benzodiazepines and Z-drugs 50 days before and 50 or 100 days after hospitalisation. RESULTS: The proportion of patients who received benzodiazepines or Z-drugs increased from 3.1% before admission to 3.6% at 50 days after discharge and fell to the former level after an additional 50 days. A multivariable logistic regression showed that gender and department had an additional impact on these results. Of those patients without a prescription for a benzodiazepine or Z-drug before admission, 0.6% received a prescription in both time-windows after discharge. Of those patients who were prescribed a benzodiazepine, 38.0% received short-acting substances and 40.3% received long-acting substances before hospitalisation. After hospitalisation, these rates changed to favour short-acting substances (44.4% and 34.4%, respectively). CONCLUSIONS: The hospital effect on initiating and increasing hypnotic or sedative drug use seems to be only moderate and temporary. A change in favour of short-acting substances is even welcome. In less than 1% of patients, the hospital initiated the continuous use of benzodiazepines and Z-drugs, which may put pressure on primary care physicians. However, the widespread use of these drugs in hospitals does not seem to be continued on a large scale in primary care.

Comparison of therapy persistence for fixed versus free combination antihypertensives: a retrospective cohort study.

OBJECTIVES: The aim of the study was to compare therapy persistence among patients who started with one of three drug regimens: a monotherapy, or combination therapy either as a fixed combination (ie, 'single pill') or as a free combination (ie, two separate antihypertensive agents). DESIGN: In a secondary data analysis, we used descriptive statistics and multivariate logistic regression to measure the effect of the three therapy regimens on therapy persistence over 4 years. SETTING: Prescription data from a large German statutory health insurance provider. PARTICIPANTS: All patients who started with a new antihypertensive therapy in 2007 or 2008 (n=8032) were included and followed for 4 years. PRIMARY OUTCOME MEASURE: Therapy persistence, defined as receiving a refill prescription no later than within 180 days. RESULTS: The persistence rates after 4 years were nearly identical among patients who started with a monotherapy (40.3%) or a fixed combination of two drugs (39.8%). However, significantly more patients who started with free-drug combinations remained therapy persistent (56.4%), resulting in an OR of 2.00 (95% CI 1.6 to 2.5; p<0.0001) for free combinations versus fixed combinations. This trend was observed in all age groups and for men and women. At the end of the study period, the number of different antihypertensive agents was still similar between patients who started with a fixed combination (2.41) and patients who started with a free combination (2.28). CONCLUSIONS: While single-pill combinations make it easier to take different drugs at once, the risk is high that these several substances are stopped at once. Therapy persistence was significantly better for patients who started with a free-drug combination without taking much fewer different antihypertensive drugs as those with a fixed combination.

Understanding and reducing the prescription of hypnotics and sedatives at the interface of hospital care and general practice: a protocol for a mixed-methods study.

INTRODUCTION: Hypnotics and sedatives, especially benzodiazepines and Z-drugs, are frequently prescribed for longer periods than recommended-in spite of potential risks for patients. Any intervention to improve this situation has to take into account the interplay between different actors, interests and needs. The ultimate goal of this study is to develop-together with the professionals involved-ideas for reducing the use of hypnotics and sedatives and then to implement and evaluate adequate interventions in the hospital and at the primary and secondary care interface. METHODS AND ANALYSIS: The study will take place in a regional hospital in northern Germany and in some general practices in this region. We will collect data from doctors, nurses, patients and a major social health insurer to define the problem from multiple perspectives. These data will be explored and discussed with relevant stakeholders to develop interventions. The interventions will be implemented and, in a final step, evaluated. Both quantitative and qualitative data, including surveys, interviews, chart reviews and secondary analysis of social health insurance data, will be collected to obtain a full understanding of the frequency and the reasons for using hypnotics and sedatives. ETHICS AND DISSEMINATION: Approval has been granted from the ethics review committee of the University Medical Center Göttingen, Germany. Results will be disseminated to researchers, clinicians and policy makers in peer-reviewed journal articles and conference publications. One or more dissemination events will be held locally during continuous professional development events for local professionals, including (but not confined to) the study participants.

Troglitazone treatment increases protein kinase B phosphorylation in skeletal muscle of normoglycemic subjects at risk for the development of type 2 diabetes.

We investigated whether the effect of troglitazone on glucose disposal is associated with altered insulin signaling. Nondiabetic first-degree relatives of type 2 diabetic patients (age 30 +/- 2 years, BMI 30 +/- 1 kg/m(2); n = 20) were randomized in a double-blind manner to 3 months of troglitazone (200 mg/day) or placebo treatment. Before and after treatment, 3-h euglycemic-hyperinsulinemic glucose clamps (40 mU. m(-2). min(-1)) were performed, and muscle biopsies were obtained immediately before and after the clamps. In the biopsies, insulin receptor kinase (IRK) activity, insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI3K) activity, Ser(473) and Thr(308) phosphorylation of protein kinase B (PKB), and protein expression of IRS-1, IRS-2, phosphoinositol-dependent kinase-1 (PDK-1), PKB, and GLUT-4 were determined. After troglitazone treatment, insulin-stimulated glucose disposal was increased compared with pretreatment and placebo (279 +/- 37 vs. 211 +/- 26 and 200 +/- 25 mg. m(-2). min(-1); both P < 0.05). IRK and PI3K activities were not altered by troglitazone, but PKB Ser(473) phosphorylation was enhanced compared with pretreatment and placebo at the clamp insulin level (138 +/- 36 vs. 77 +/- 16 and 55 +/- 13 internal standard units; both P < 0.05) and with pretreatment at the basal level (31 +/- 9 vs. 14 +/- 4 internal standard units; P < 0.05). PKB Thr(308) phosphorylation also tended to be higher, but this was not statistically significant. Troglitazone did not alter insulin receptor number or IRS-1, IRS-2, PKB, PDK-1, or GLUT-4 protein expression. We conclude that increased PKB phosphorylation may contribute to the insulin-sensitizing effects of thiazolidinediones in human skeletal muscle.

The influence of hospitalisation on drug prescription in primary care--a large-scale follow-up study.

OBJECTIVE: To explore the influence of hospitalisation on the prescription of drugs in the primary care sector using prescription data of a major statutory health insurance (SHI) organisation, with a special focus on the so-called "Me-Too" drugs - in particular, 3-hydroxy-3-methyl-glutaryl (HMG) CoA reductase inhibitors (statins) and proton pump inhibitors (PPIs). METHODS: A comprehensive outpatient drug prescription analysis was conducted on members of a SHI who had been hospitalised during the first 3 months of 2004. The number and costs of all prescriptions of 2426 patients during a 3-month period before admission and after discharge, respectively, were compared using Wilcoxon's signed rank test. Data are shown in absolute and relative numbers as well as relative risks (RR) and their 95% confidence intervals (CIs). RESULTS: The total number of prescriptions before hospitalisation and after discharge remained nearly the same, while the number of different active substances prescribed per patient decreased by 4%. However, overall costs increased after discharge by 15% due to the higher cost per prescription. Changes in medication affected nearly every patient (98.1%), and 60% had at least five changes. Of the substances prescribed to an individual before admission, 57% were cancelled after discharge, and 55% of all substances prescribed after discharge were novel prescriptions. Significantly more patients received a PPI or statin after hospitalisation (RR for a PPI: 1.27; 95% CI: 1.12 -1.45; RR for a statin: 1.16; 95% CI: 1.02-1.32). The increase in PPI medication was due to a 58% increase in the number of patients receiving pantoprazole, a "Me-Too" drug. CONCLUSION: Hospitalisation exerts a marked influence on drug therapy in ambulatory care, with a significant increase in the prescription of novel, on-patent drugs instead of less expensive alternatives.

Differential modulation of insulin actions by dexamethasone: studies in primary cultures of adult rat hepatocytes.

BACKGROUND/AIMS: Steroid diabetes is associated with hepatic insulin resistance; in hepatic cell models, however, mainly insulin-permissive effects have been described. Here we investigate modulation by dexamethasone of a larger number of insulin actions. METHODS: Adult rat hepatocytes were cultured+/-dexamethasone for 48 h; insulin actions were studied subsequently. RESULTS: Stimulation of glycolysis by insulin but not by glucose required culture with dexamethasone. Activation of glycogen synthesis by insulin or glucose was strongly enhanced by dexamethasone, the insulin effects on glycogenolysis and amino acid uptake were not modulated. When dexamethasone was omitted from the culture, insulin was incapable to activate glycogen synthase, inactivate glycogen phosphorylase or elevate the level of fructose 2,6-bisphosphate. Dexamethasone did not alter insulin binding, insulin receptor number or kinase activity, insulin receptor substrate-1 and Akt protein expression/phosphorylation. Insulin-stimulated association of phosphatidylinositol 3-kinase with insulin receptor substrates-1 and -2 was increased with dexamethasone, the increased association with IRS-2 may, at least partially, be explained by higher IRS-2 protein expression. CONCLUSIONS: The steroid does not cause hepatic resistance in vitro. The differential attenuation under steroid deprivation points to defects in branches of the insulin signal chain and/or loss of hormonal regulation at the level of target enzymes.