Increased risk of death associated with the use of proton-pump inhibitors in patients with dementia and controls - a pharmacoepidemiological claims data analysis.

BACKGROUND AND PURPOSE: The use of proton-pump inhibitors (PPIs) was reported to be associated with increased mortality risk and has been proposed as a potential risk factor for neurodegenerative diseases. We aimed to assess the impact of PPI use on survival in patients with dementia as compared with controls. METHODS: This register-based control-matched cohort study included 28 428 patients with dementia ascertained by the prescription of antidementia drugs and two control individuals matched by sex, age and area of residence for each patient with dementia during the study period from 1 January 2005 to 30 June 2016. Cumulative defined daily doses (DDDs) of PPIs were extracted from the health insurance prescription registries. A multivariate Cox regression model for non-proportional hazards was used to analyse mortality risk in dependence of PPI exposure, which was limited to 1 year preceding the date of cohort entry (index date) in order to avoid immortal time bias. RESULTS: The PPI exposure of 100 DDDs in the year before the index date was associated with an increased mortality risk in patients with dementia (adjusted hazard ratio, 1.07; 95% confidence intervals, 1.03-1.12), but also in controls (adjusted hazard ratio, 1.47; 95% confidence intervals, 1.31-1.64). The mortality risk in relation to PPI use was significantly lower in patients with dementia as compared with controls (P < 0.0001) and highest in the first 2 years after the index date in both cohorts. CONCLUSIONS: Our findings promote more stringent pharmacovigilance strategies to avoid PPI use in cases lacking a clear indication for therapy or where potential risks outweigh the benefits.

Use of proton pump inhibitors and mortality after hip fracture in a nationwide study.

We analyzed the association of proton pump inhibitors (PPIs) with mortality after osteoporosis-related hip fracture in Austria. PPIs were associated with reduced 90-day mortality but elevated mortality after half a year when initiated pre-fracture. Inpatients and discharged patients on PPIs showed lowered in-hospital and 90-day mortality, respectively. INTRODUCTION: We herein investigated use of proton pump inhibitors (PPIs) and mortality among hip fracture patients in a nationwide study in Austria. METHODS: In this retrospective cohort study, data on use of PPIs were obtained from 31,668 Austrian patients ≥50 years with a hip fracture between July 2008 and December 2010. All-cause mortality in patients without anti-osteoporotic drug treatment who had received their first recorded PPI prescription in the study period either before or after fracture was compared with hip fracture patients on neither PPIs nor anti-osteoporotic medication using logistic and Cox regression analysis. RESULTS: With PPI use, 90-day mortality was significantly reduced, both at initiation before (OR 0.66; p < 0.0001) and after hip fracture (OR 0.23; p < 0.0001). 90-day mortality was also reduced when PPIs were prescribed not until after discharge from the last recorded hip fracture-related hospital stay (OR 0.49; p < 0.0001) except for patients aged <70 years. In a sub-cohort of patients beginning PPIs during hospital stay, in-hospital mortality (0.2%) was substantially reduced relative to matched control patients (3.5%) (p < 0.0001). Longer-term mortality significantly increased after half a year post-fracture only among those who started PPI prescription before fracture. CONCLUSIONS: PPI use during and after hospital stay due to hip fracture is associated with a considerable decrease in mortality. These findings could have implications for hip fracture treatment.

Antiresorptive therapy and risk of mortality and refracture in osteoporosis-related hip fracture: a nationwide study.

UNLABELLED: We analyzed the association of bisphosphonate therapy with mortality and hip refracture incidence among osteoporosis-related hip fracture patients in Austria. Mortality was lower in primarily female bisphosphonate users, while hip refracture incidence was generally elevated relative to controls, indicating beneficial effects of bisphosphonates other than on bone. INTRODUCTION: The purpose of this study was to analyze mortality and hip refracture risk in osteoporotic hip fracture patients with and without antiosteoporotic medication. METHODS: We retrospectively analyzed data on 31,668 Austrian patients ≥50 years with a hip fracture between July 2008 and December 2010 for antiosteoporotic drug treatment with respect to outcome parameters all-cause mortality, hip refracture incidence, and hip refracture-free days. Outcomes when bisphosphonate (BP) treatment was begun before or after fracture were compared with an age- and sex-matched hip fracture control without antiosteoporotic medication. RESULTS: 27.69 % of patients (33.01 % of women, 13.13 % of men) were prescribed antiosteoporotic medication, primarily BPs. Females having initiated BP treatment before first fracture had lower odds for mortality 1 and 3 year(s) post-fracture, whereas hip refracture incidence under pre-fracture BP initiation was generally higher. Treatment that was started after fracture, however, entailed significantly lower mortality hazards for both genders (HR 0.43, 95 %CI 0.36-0.52, p < 0.0001 after 1 year) but significantly higher hip refracture incidence except for patients aged 50-69 years and more hip refracture free days for females. Hip refractures overall amounted to 29.22/1000 patient years differing significantly between women and men (31.03 vs. 23.89, respectively, p < 0.0001), and longer hip refracture free survival was observed for women than for men (499 vs. 466 median days, respectively, p < 0.0001). CONCLUSIONS: Although BP use is associated with reduced mortality after hip fracture, notably among women, hip refracture incidences are likewise elevated, which is most likely accounted for by a high probability of BP prescription to more comorbid patients suffering from more severe osteoporosis. Concomitantly, through possible effects other than on bone, BPs might be able to curtail mortality. Male hip fracture patients' low treatment frequency in particular reflects underdiagnosis and undertreatment of osteoporosis in Austria.

Cost comparison of epoetin alpha, epoetin beta and darbepoetin alpha for cancer patients with anaemia in the clinical practice setting.

BACKGROUND AND OBJECTIVE: Cost control is becoming an increasingly important consideration for clinicians when planning how to provide the best treatment for anaemic cancer patients. Administration of erythropoiesis stimulating agents (epoetin alpha, epoetin beta and darbepoetin alpha) has become the standard of care for treatment of anaemia in cancer patients. However, only limited information is available on the economic comparability of epoetin alpha, epoetin beta and darbepoetin alpha, and thus this study was conducted to compare cost per patient of each of these agents for anaemic cancer patients. METHODS: All prescriptions of the agents over 1 year were analysed by two Austrian regional public health insurance associations and cost per patient for each agent was calculated from invoicing data. Data from the two regions were combined to obtain total mean drug costs per patient per year. RESULTS AND DISCUSSION: Analyses showed significantly lower costs for epoetin alpha ( 2,743.27 euros) than for darbepoetin alpha (3,627.98 euros ) or epoetin beta ( 3,292.28 euros): epoetin alpha vs. darbepoetin alpha (P < 0.0001); epoetin beta vs. darbepoetin alpha (P = 0.0001); epoetin alpha vs. epoetin beta (P = 0.0009). As costs of the three agents in Austria are identical for therapeutically equivalent doses, the higher cost of darbepoetin alpha was believed to be due mainly to longer treatment duration to target haemoglobin level. CONCLUSION: The finding of a cost difference favouring epoetin alpha over darbepoetin alpha suggests the need for prospective randomized studies comparing efficacy and cost effectiveness of all three agents to obtain more definitive data.

Procalcitonin: a new marker for diagnosis of acute rejection and bacterial infection in patients after heart and lung transplantation.

UNLABELLED: The aim of the study was to investigate the reliability of procalcitonin (PCT), a new potential marker for detection of bacterial, fungal and protozoal infections, in order to differentiate these from viral infections and early rejections in heart, heart-lung and lung transplanted patients. PCT is a propeptide of calcitonin with unknown origin which is not detectable in plasma of healthy subjects. It increases rapidly and significantly under severe microbial infections. METHODS: PCT plasma levels were measured using an immuno-luminescence assay. C-reactive protein and white blood cells were quantified to validate the PCT values. RESULTS: Increased levels of PCT were found in all transplant patients with bacterial, fungal and protozoal infections. The magnitude of the values were clearly associated with the severity of the infection. Trauma of operation or inflammatory events such as viral infections and rejections did not trigger PCT-production. The release of PCT did not depend on the type of pathogens even though Aspergillum resulted in the highest levels measured. Sensitivity, specificity and prognostic value of PCT for systemic infections were higher than of the other parameters investigated. CONCLUSION: PCT is a highly specific analyte which shows significant diagnostic validities when nonviral infections are compared with rejection episodes. PCT discriminates between inflammatory events such as rejection or viral infections and nonviral-infections including bacterial, fungal and protozoal infections. The half-life of PCT is 24 h indicating clearly a competent antibiotic treatment. Unnecessary antibiotic therapy can be avoided due to the early exclusion of bacterial and fungal infections.

Mediators of exocrine pancreatic secretion induced by intraduodenal application of bile and taurodeoxycholate in man.

The aim of the study was to investigate whether cholecystokinin, neurotensin, and cholinergic mechanisms act as mediators of bile salt-stimulated exocrine pancreatic secretion. Ten fasting healthy subjects provided with a double-lumen tube received 2, 4, and 6 g cattle bile and 200, 400, and 600 mg Na-taurodeoxycholate (TDC) into the duodenum at 65-min intervals, respectively. The application of TDC was repeated in another 10 subjects after intravenous bolus injection of 2.5 micrograms/kg b.w. atropine followed by continuous infusion of 5 micrograms/kg.h. Secretions of volume, bicarbonate, trypsin, and lipase were determined in 10-min fractions of duodenal juice. Plasma samples were analysed for cholecystokinin-like immunoreactivity (CCK-LI) and neurotensin with radioimmunoassays. Volume, bicarbonate, trypsin, and lipase secretion rates were significantly increased by 4 g and 6 g bile and by all doses of TDC. Incremental volume and bicarbonate output was dose-dependently enhanced by bile and TDC, and trypsin and lipase output by bile. Atropine significantly decreased the baseline values and all responses to TDC. Plasma concentrations and integrated CCK-LI and neurotensin significantly increased after 4 and 6 g bile and after 400 and 600 mg TDC. Atropine did not significantly influence peptide release. It is concluded that both hydrokinetic and ecbolic pancreatic secretion stimulated by intraduodenal bile and TDC are dependent on a cholinergic tone. CCK and probably also neurotensin act as further mediators of the ecbolic effect.

Suppression of vagus-mediated pancreatic polypeptide release by the mu-opiate receptor agonist loperamide in man.

1. Morphine suppresses the release of pancreatic polypeptide, a hormone under vagal cholinergic control. The intention of the study was to detect whether the mu-opiate receptor agonist loperamide is also able to inhibit pancreatic polypeptide release, and to define its site of action. 2. In groups of healthy subjects (n = 6 each) stimulation of pancreatic polypeptide was assessed in five different tests: (i) insulin-hypoglycaemia; (ii) modified sham feeding; (iii) intravenous infusion of the cholecystokinin analogue ceruletide; (iv) injection of corticotropin releasing hormone; (v) infusion of the muscarinic acetylcholine agonist bethanechol. All tests were performed after oral application of either a placebo or loperamide (16 mg), tests (ii) and (iii) were repeated with loperamide in smaller doses (2 and 6 mg), with loperamide plus naloxone, with naloxone alone, and with infusion of atropine. Plasma concentrations of pancreatic polypeptide were measured radioimmunologically. 3. Release of pancreatic polypeptide in test (i) to (iv) was completely blocked by 16 mg loperamide, whereas bethanechol-stimulated release (test 5) was not influenced. Tests (ii) and (iii) showed that the inhibition was dose-dependent and could be attenuated by naloxone. The inhibitory effect of loperamide was comparable with that of atropine. 4. We conclude that loperamide causes a dose-dependent inhibition of pancreatic polypeptide release mediated by vagal-cholinergic pathways, but does not have an atropine-like peripheral action.

The decrease in growth hormone (GH) response after repeated stimulation with GH-releasing hormone is partly caused by an elevation of somatostatin tonus.

Repeated injection of GHRH leads to a decrease in the GH response in normal subjects. Arginine (Arg) stimulates GH secretion by suppression of hypothalamic somatostatin. To confirm these findings, eight normal men were examined in a series of five settings: test 1 (GHRH/GHRH-TRH), 100 micrograms GHRH injected iv, followed by 100 micrograms GHRH, iv, after 120 min and 200 micrograms TRH, iv, after 150 min; test 2 (GHRH/Arg-TRH), like test 1, but instead of the second GHRH injection, a 30 g Arg infusion over 30 min; test 3 (GHRH/GHRH-Arg-TRH), like test 1, but additionally a 30 g Arg infusion after 120 min; test 4 (GHRH-Arg-TRH), iv GHRH and Arg infusion initially, followed by iv TRH after 30 min; and test 5 (TRH), 200 micrograms TRH, iv, at 0 min. For statistical evaluation, the area under the GH curve (AUC) from 0-120 min was compared with the AUC from 120-240 min. The GH response to the second administration of GHRH was significantly lower (P < 0.02) than the first increase [AUC, 0.5 +/- 0.01 min.mg/L (mean +/- SE) vs. 1.2 +/- 0.3]. No significant differences were found between the GH responses to either GHRH or Arg alone (AUC, 0.9 +/- 0.2 min.mg/L vs. 0.9 +/- 0.2). A larger GH increase (P < 0.02) was seen after GHRH-Arg compared to GHRH alone (AUC, 1.9 +/- 0.4 min.mg/L vs. 1.2 +/- 0.3). The GH response (P < 0.02) to GHRH-Arg stimulation was lower after previous GHRH injection than after GHRH-Arg stimulation alone (AUC, 1.9 +/- 0.4 min.mg/L vs. 3.5 +/- 0.9). There was a statistically significant difference between the TRH-stimulated TSH response in test 4 compared to that in test 5. We could show that decreasing GH responses to repeated GHRH can be avoided by a combined stimulation with GHRH/Arg. These findings suggest that the decreased GH response to a second GHRH bolus may be partly due to an elevated hypothalamic somatostatin secretion, which can be suppressed by Arg. The lower GH response to GHRH-Arg stimulation after a previous GHRH bolus suggests, furthermore, that the readily available GH pool in the human pituitary may be limited.

Immunoreactive inhibin in human follicular fluid in an ovarian hyperstimulation programme for in vitro fertilization: correlations and different forms.

UNLABELLED: The inhibin concentration in 131 samples of human follicular fluid obtained from 31 women undergoing ovarian hyperstimulation for in vitro fertilization was measured using specific double antibody radioimmunoassay. We used the synthetic 1-32-alpha-inhibin as standard and radioiodinated 1-32-Tyr-alpha-inhibin as tracer. Antibodies were raised in rabbits by immunization with the synthetic peptide. Estradiol and progesterone concentrations were measured using commercial radioimmunoassays. RESULTS: The inhibin concentration correlated with the estradiol (r = 0.57, N = 88, p < 0.0001) and progesterone (r = 0.82, N = 88, p < 0.0001) concentrations in human follicular fluid. The dosage of human menopausal gonadotropin given to individual patients correlated with the average inhibin concentration measured in their follicles (r = 0.72, N = 23, p < 0.0001). Similarly, the size of follicles correlated with their inhibin content (r = 0.75, N = 131, p < 0.0001). Nineteen samples of human follicular fluid originating from follicles of different size and volume were examined using gel-chromatography. In each human follicular fluid the main form of inhibin (32 kDa) was recovered. In small follicles (3 ml) we found 12.8 +/- 9.1% (mean +/- SD) of the whole immunoreactive inhibin eluting in the area of Vo (> or = 80 kDa). In the larger follicles (4-7 ml), however, only 4.4 +/- 4.2% of this large inhibin form could be found. CONCLUSIONS: Our data confirm that human menopausal gonadotropin stimulates ovarian inhibin production. In addition to the estradiol and progesterone concentrations, the inhibin concentration may be an index of granulosa cell function and follicular maturation. The occurrence of large molecular weight forms of inhibin in small follicles remains unclear. They may represent large precursor molecules which are proteolytically cleaved in more mature follicles.

Biologic aggressiveness of palpable and nonpalpable prostate cancer: assessment with endosonography.

The biologic aggressiveness of palpable versus nonpalpable prostate cancer was evaluated in 666 patients studied with endosonography over a 24-month period. Biologic aggressiveness was defined by a combined histologic and grade-stage category score. In 314 patients suspected of having prostate cancer 328 biopsies were performed. Carcinoma was detected in 99 patients, by means of both palpation and endosonography (n = 80), endosonography alone (n = 9), and palpation alone (n = 8); two cancers were not detected with either palpation or endosonography. All patients with normal results of digital examination had a combined grade-stage category score lower than 9. Fifty-five of 69 patients (80%) with abnormal results of digital examination and available histologic data had a histologic score of 6 or higher; 38 of these patients (69%) had a combined grade-stage category score of 9 or higher. Although the number of patients is small, these data suggest that nonpalpable cancers are biologically less aggressive than palpable ones and that the advantage of endosonography over palpation in detection of clinically significant cancers is limited.

Fast and slow blockade of sodium channels by flecainide in rabbit cardiac Purkinje fibres.

The electrophysiological effects of flecainide were tested using the two-microelectrode voltage-clamp technique and Vmax-measurements in isolated rabbit cardiac Purkinje fibres. Flecainide predominantly unfolds its sodium-channel blocking action during the upstroke phase of the cardiac action potential, because its Vmax-depressant effects are independent of the duration of the depolarizing interval. Very long lasting depolarizations caused a second, very slow blocking activity. Starting from a steady-state block, recovery from block was tested and yielded a time constant of 7.3 s for a membrane potential of -105 mV. The strong blockade of sodium-channels combined with a delayed recovery behaviour of the drug-associated channels gives reasons for the observation of a marked use-dependent block. This block increased when the cycle length was shortened or the holding potential was less negative. Additional application of lidocaine in several concentrations did not significantly increase or attenuate the phasic block caused by flecainide alone. Under special conditions we investigated flecainide's depression and shift of the Vmax/Vm-relation and we observed that the concentration dependence of both parameters could be described by simple 1:1 binding reaction. The effects of flecainide are largely reversible often greater than or equal to 15 min. Flecainide could be characterized as an open channel blocker with a very slow inactivated channel blocking activity. For the qualitative description of the sodium-channel block by flecainide we used the "modulated-receptor hypothesis", whereas for reconstructions of the use-dependent action we applied the "guarded-receptor hypothesis", which enables computations of phasic block with the knowledge of only one forward and one reverse rate constant.

Pirmenol, a new antiarrhythmic drug with potassium- and sodium-channel blocking activity; a voltage-clamp study in rabbit Purkinje fibres.

The target of this study was to characterize the effect of pirmenol hydrochloride on the electrophysiological properties of cardiac cells. Action potential studies were carried out using the standard microelectrode technique in isolated rabbit Purkinje fibres. Information about the effect of pirmenol on the fast sodium current was obtained by Vmax-measurement. Furthermore the delayed rectifying current ix was studied by the two microelectrode voltage clamp technique. In concentrations of 0.5-5 mumol/l pirmenol caused a marked prolongation of the action potential duration in isolated rabbit Purkinje fibres. Measurements of the delayed rectifying current ix displayed a strong depression with a KD-value of 1 mumol/l pirmenol. The steady-state current voltage relation showed that pirmenol also caused a reduction of the steady-state sodium window current and/or of the slowly decaying components of the sodium current. In concentrations of greater than or equal to 10 mumol/l pirmenol the action potential duration was diminished again and Vmax was depressed in a use-dependent manner. Furthermore pirmenol caused a depression and a negative shift of the Vmax/Em-relation. Pirmenol blocked sodium channels which recovered from block with a time constant of 6.7 s at a holding potential of -105 mV. Similar to quinidine and sotalol the prolongation of the action potential duration under pirmenol is essentially caused by a diminution of the delayed rectifying current ix. The depression of Vmax is mainly independent from the action potential duration indicating the dominance of an open channel block. Pirmenol is a new drug with class Ia antiarrhythmic action.

Standardized endosonographic evaluation of prostate cancer: receiver-operator-characteristic analysis.

A standardized endosonographic numeric method has been developed for the detection of prostate cancer. Eighty-six men were examined with a 5-MHz, 96-element linear-array probe. Mean gray-scale amplitudes were produced by a semiautomatic method for periprostatic fat and regions of interest within the external portion of the prostate gland that were visually suspicious for prostate cancer. Mean gray-scale amplitude ratios of visually abnormal areas of prostate to periprostatic fat (Ap/Af) were calculated. Pathologic confirmation of disease was obtained in all patients. Three different numeric Ap/Af ratios were compared with digital palpation and subjective visual interpretation of sonograms. The numeric method resulted in a consistently higher specificity, accuracy, and positive predictive value when compared with palpation and subjective interpretation. The initial results suggest that this technique may also detect atypical hyperplasia.

Improved aortocoronary bypass patency by low-dose aspirin (100 mg daily). Effects on platelet aggregation and thromboxane formation.

Prevention of aortocoronary bypass occlusion by aspirin (ASA, 1 X 100 mg per day) was studied in a prospective double-blind trial of 83 patients. 60 (72%) were randomly allocated to ASA or placebo starting 24 h after operation. 90% of grafts in the ASA group and 68% in the placebo group were patent at four months. At least one anastomosis was occluded in 62% of the patients on placebo and in 27% of those on aspirin. Ventricular arrhythmias increased after surgery in more patients on placebo (12/18) than in patients on ASA (5/17). Platelet thromboxane formation on collagen tested before operation was significantly higher in patients in whom bypass occlusion developed (occlusion: 40 +/- 19, no occlusion: 25 +/- 13 ng/ml). A 100 mg dose of ASA per day effectively blocked platelet thromboxane formation and thromboxane-supported aggregation on collagen and was safe in the postoperative phase. No side effects were reported throughout the trial. The reduced toxicity with full efficacy favours a low and infrequent dosage of aspirin.