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Association between statin therapy and outcomes in critically ill patients: a nested cohort study
Al Harbi, Shmeylan A
Tamim, Hani M
Arabi, Yaseen M
BMC Clinical Pharmacology
The effect of statin therapy on mortality in critically ill patients is controversial, with some studies suggesting a benefit and others suggesting no benefit or even potential harm. The objective of this study was to evaluate the association between statin therapy during intensive care unit (ICU) admission and all-cause mortality in critically ill patients.
This was a nested cohort study within two randomised controlled trials conducted in a tertiary care ICU. All 763 patients who participated in the two trials were included in this study. Of these, 107 patients (14%) received statins during their ICU stay. The primary endpoint was all-cause ICU and hospital mortality. Secondary endpoints included the development of sepsis and severe sepsis during the ICU stay, the ICU length of stay, the hospital length of stay, and the duration of mechanical ventilation. Multivariate logistic regression was used to adjust for clinically and statistically relevant variables.
Statin therapy was associated with a reduction in hospital mortality (adjusted odds ratio [aOR] = 0.60, 95% confidence interval [CI] 0.36-0.99). Statin therapy was associated with lower hospital mortality in the following groups: patients >58 years of age (aOR = 0.58, 95% CI 0.35-0.97), those with an acute physiology and chronic health evaluation (APACHE II) score >22 (aOR = 0.54, 95% CI 0.31-0.96), diabetic patients (aOR = 0.52, 95% CI 0.30-0.90), patients on vasopressor therapy (aOR = 0.53, 95% CI 0.29-0.97), those admitted with severe sepsis (aOR = 0.22, 95% CI 0.07-0.66), patients with creatinine ≤100 μmol/L (aOR = 0.14, 95% CI 0.04-0.51), and patients with GCS ≤9 (aOR = 0.34, 95% CI 0.17-0.71). When stratified by statin dose, the mortality reduction was mainly observed with statin equipotent doses ≥40 mg of simvastatin (aOR = 0.53, 95% CI 0.28-1.00). Mortality reduction was observed with simvastatin (aOR = 0.37, 95% CI 0.17-0.81) but not with atorvastatin (aOR = 0.80, 95% CI 0.84-1.46). Statin therapy was not associated with a difference in any of the secondary outcomes.
Statin therapy during ICU stay was associated with a reduction in all-cause hospital mortality. This association was especially noted in high-risk subgroups. This potential benefit needs to be validated in a randomised, controlled trial.
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An evaluation of ciprofloxacin pharmacokinetics in critically ill patients undergoing continuous veno-venous haemodiafiltration
Spooner, Almath M
Deegan, Catherine
D'Arcy, Deirdre M
Gowing, Caitriona M
Donnelly, Maria B
Corrigan, Owen I
BMC Clinical Pharmacology
The study aimed to investigate the pharmacokinetics of intravenous ciprofloxacin and the adequacy of 400 mg every 12 hours in critically ill Intensive Care Unit (ICU) patients on continuous veno-venous haemodiafiltration (CVVHDF) with particular reference to the effect of achieved flow rates on drug clearance.
This was an open prospective study conducted in the intensive care unit and research unit of a university teaching hospital. The study population was seven critically ill patients with sepsis requiring CVVHDF.
Blood and ultrafiltrate samples were collected and assayed for ciprofloxacin by High Performance Liquid Chromatography (HPLC) to calculate the model independent pharmacokinetic parameters; total body clearance (TBC), half-life (t1/2) and volume of distribution (Vd). CVVHDF was performed at prescribed dialysate rates of 1 or 2 L/hr and ultrafiltration rate of 2 L/hr. The blood flow rate was 200 ml/min, achieved using a Gambro blood pump and Hospal AN69HF haemofilter.
Seventeen profiles were obtained. CVVHDF resulted in a median ciprofloxacin t1/2 of 13.8 (range 5.15-39.4) hr, median TBC of 9.90 (range 3.10-13.2) L/hr, a median Vdss of 125 (range 79.5-554) L, a CVVHDF clearance of 2.47+/-0.29 L/hr and a clearance of creatinine (Clcr) of 2.66+/-0.25 L/hr. Thus CVVHDF, at an average flow rate of ~3.5 L/hr, was responsible for removing 26% of ciprofloxacin cleared. At the dose rate of 400 mg every 12 hr, the median estimated Cpmax/MIC and AUC0-24/MIC ratios were 10.3 and 161 respectively (for a MIC of 0.5 mg/L) and exceed the proposed criteria of >10 for Cpmax/MIC and > 100 for AUC0-24/MIC. There was a suggestion towards increased ciprofloxacin clearance by CVVHDF with increasing effluent flow rate.
Given the growing microbial resistance to ciprofloxacin our results suggest that a dose rate of 400 mg every 12 hr, may be necessary to achieve the desired pharmacokinetic - pharmacodynamic (PK-PD) goals in patients on CVVHDF, however an extended interval may be required if there is concomitant hepatic impairment. A correlation between ciprofloxacin clearance due to CVVHDF and creatinine clearance by the filter was observed (r2 = 0.76), providing a useful clinical surrogate marker for ciprofloxacin clearance within the range studied.
Trial Registration
Current Controlled Trials ISRCTN52722850
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The effects of polyunsaturated fatty acids in alcohol dependence treatment - a double-blind, placebo-controlled pilot study
Fogaça, Marina N
Santos-Galduróz, Ruth F
Eserian, Jaqueline K
Galduróz, José Carlos F
BMC Clinical Pharmacology
The lipid fraction of cell membranes consists of polyunsaturated fatty acids (PUFAS), and chronic alcohol use alters it, modifying its permeability, what might contribute for the dysfunctional metabolism observed in the central nervous system of alcohol dependent patients. Therefore, the supplementation of PUFAS can be an important adjuvant in alcoholism treatment.
This was a placebo controlled, double blind, randomized study where, 80 alcohol dependent patients, according to DSM-IV, were allocated in four groups with 20 patient each: 'PUFAS', 'Naltrexone', 'Naltrexone + PUFAS' and 'Placebo'. Those substances were administered for 90 days and scales were applied to assess patients craving (OCDS) and alcohol dependence severity (SADD) at baseline and after 90 days. PUFAS serum levels were assessed before and after treatment by high performance liquid chromatography assay.
Forty-three patients completed the trial. There was a significant improvement over time on drinking days, SADD and OCDS scores in all groups (p < 0.001). The drinking days comparison between groups did not show statistical significant difference. The same effect was observed for compulsion (OCDS) and severity of dependence scale (SADD). The serum levels of PUFAS increased in all the supplemented groups after treatment, although not significantly.
The oral supplementation of 2 g PUFAS for 3 months did not significantly differ from placebo in reducing the amount of alcohol ingestion, or OCDS and SADD scores in a group of alcohol dependent patient.
Trial registration
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Comparative in vitro study of the antimicrobial activities of different commercial antibiotic products of vancomycin
Diaz, Jorge A
Silva, Edelberto
Arias, Maria J
Garzón, María
BMC Clinical Pharmacology
One of the most critical problems about antimicrobial therapy is the increasing resistance to antibiotics. Previous studies have shown that there is a direct relation between erroneous prescription, dosage, route, duration of the therapy and the antibiotics resistance. Other important point is the uncertainty about the quality of the prescribed medicines. Some physicians believe that generic drugs are not as effective as innovator ones, so it is very important to have evidence that shows that all commercialized drugs are suitable for therapeutic use.
Microbial assays were used to establish the potency, the Minimal Inhibitory Concentrations (MICs), the Minimal Bactericidal Concentration (MBCs), the critical concentrations, and the production of spontaneous mutants that are resistant to vancomycin.
The microbial assay was validated in order to determine the Vancomycin potency of the tasted samples. All the products showed that have potency values between 90 - 115% (USP requirement). The products behave similarly because the MICs, The MBCs, the critical concentrations, the critical concentrations ratios between standard and samples, and the production of spontaneous mutants don't have significant differences.
All products analyzed by microbiological tests, show that both trademarks and generics do not have statistical variability and the answer of antimicrobial activity Show also that they are pharmaceutical equivalents.
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Comparison of renal effects of ibuprofen versus indomethacin during treatment of patent ductus arteriosus in contiguous historical cohorts
Kushnir, Alla
Pinheiro, Joaquim MB
BMC Clinical Pharmacology
Ibuprofen treatment of patent ductus arteriosus (PDA) has been shown to be as effective as indomethacin in small randomized controlled trials, with possibly fewer adverse effects. However, adverse renal effects of ibuprofen have been noted in some trials and suspected in our practice.
The purpose of this study was to examine whether ibuprofen and indomethacin treatment of PDA have comparable effects on renal function as evidenced by urine output and serum creatinine.
Retrospective chart review of 350 patients. Serum creatinine and urine output were recorded prior to start of treatment, during each course and after the last course of treatment. Pre-treatment mean creatinine and urine output values were compared to treatment and post treatment means using 2-factor repeated measures ANOVA.
165 patients were treated with indomethacin (2005-2006) and 185 received ibuprofen (2007-2008). There was no difference between treatment groups in demographics or baseline renal function. For both groups, the number of treatment courses was inversely correlated with birth weight and gestational age. Analysis of the first course including all patients, revealed significant increase in creatinine and decrease in urine output with both drugs, with a more pronounced effect of indomethacin on creatinine. In the subgroup of 219 patients who received only one treatment course, there was a significant increase in creatinine after indomethacin, but not after ibuprofen. In the 131 who received 2 or more courses, the decrease in urine output and increase in creatinine were not different between drugs. There were significant decreases in urine output observed in the second and third courses of ibuprofen treatment (both by 0.9 mL/kg/hr).
Both drugs have a similar short-term effect on renal function. Indomethacin had a more prominent initial effect, while ibuprofen decreased renal function during the second and third courses similarly to indomethacin. The changes in renal function seen with ibuprofen treatment should be considered in fluid and electrolyte management, especially if treatment beyond one course is required.
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No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study
de Mey, Christian
Nassr, Nassr
Lahu, Gezim
BMC Clinical Pharmacology
Roflumilast is an oral, selective phosphodiesterase 4 inhibitor with anti-inflammatory effects in chronic obstructive pulmonary disease (COPD). The addition of roflumilast to long-acting bronchodilators improves lung function in patients with moderate-to-severe COPD. The present study investigated drug-drug interaction effects between inhaled formoterol and oral roflumilast.
This was a single-centre (investigational clinic), open, randomised, multiple-dose, parallel-group study. In Regimen A, healthy men were treated with roflumilast (500 μg tablet once daily; Day 2-18) and concomitant formoterol (24 μg twice daily; Day 12-18). In Regimen B, healthy men were treated with formoterol (24 μg twice daily; Day 2-18) and concomitant roflumilast (500 μg once daily; Day 9-18). Steady-state plasma pharmacokinetics of roflumilast, roflumilast N-oxide and/or formoterol (Cmax and AUC0-τ) as well as pharmacodynamics - blood pressure, transthoracic impedance cardiography (ZCG), 12-lead digital electrocardiography, peripheral blood eosinophils, and serum glucose and potassium concentrations - were evaluated through Day 1 (baseline), Day 8 (Regimen B: formoterol alone) or Day 11 (Regimen A: roflumilast alone), and Day 18 (Regimen A and B: roflumilast plus formoterol). Blood and urine samples were taken for safety assessment at screening, pharmacokinetic profiling days and Day 19. Adverse events were monitored throughout the study.
Of the 27 subjects enrolled, 24 were evaluable (12 in each regimen). No relevant pharmacokinetic interactions occurred. Neither roflumilast nor formoterol were associated with significant changes in cardiovascular parameters as measured by ZCG, and these parameters were not affected during concomitant administration. Formoterol was associated with a slight increase in heart rate and a corresponding shortening of the QT interval, without changes in the heart rate-corrected QTc interval. There were small effects on the other pharmacodynamic assessments when roflumilast and formoterol were administered individually, but no interactions or safety concerns were seen after concomitant administration. No severe or serious adverse events were reported, and no adverse events led to premature study discontinuation.
No clinically relevant pharmacokinetic or pharmacodynamic interactions were found when oral roflumilast was administered concomitantly with inhaled formoterol, including no effect on cardiac repolarisation. Roflumilast was well tolerated.
Trial Registration
Clinicaltrials.gov NCT00940329
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The future of pharmaceutical care in France: a survey of final-year pharmacy students' opinions
Perraudin, Clémence
Brion, Françoise
Bourdon, Olivier
Pelletier-Fleury, Nathalie
BMC Clinical Pharmacology
In the last decades, the provision of pharmaceutical care by community pharmacists has developed in OECD countries. These developments involved significant changes in professional practices and organization of primary care. In France, they have recently been encouraged by a new legal framework and favored by an increasing demand for health care (increase in the number of patients with chronic diseases) and reductions in services being offered (reduction in the number of general practitioners and huge regional disparities).
Objectives: This study aimed to investigate final-year pharmacy students' opinions on 1/expanding the scope of pharmacists' practices and 2/the potential barriers for the implementation of pharmaceutical care. We discussed these in the light of the experiences of pharmacists in Quebec, and other countries in Europe (United Kingdom and the Netherlands).
All final-year students in pharmaceutical studies, preparing to become community pharmacists, at the University Paris-Descartes in Paris during 2010 (n = 146) were recruited. All of them were interviewed by means of a questionnaire describing nine "professional" practices by pharmacists, arranged in four dimensions: (1) screening and chronic disease management, (2) medication surveillance, (3) pharmacy-prescribed medication and (4) participation in health care networks. Respondents were asked (1) how positively they view the extension of their current practices, using a 5 point Likert scale and (2) their perception of potential professional, technical, organizational and/or financial obstacles to developing these practices.
143 (97.9%) students completed the questionnaire. Most of practices studied received a greater than 80% approval rating, although only a third of respondents were in favor of the sales of over-the-counter (OTC) drugs. The most significant perceived barriers were working time, remuneration and organizational problems, specifically the need to create a physical location for consultations to respect patients' privacy within a pharmacy.
Despite remaining barriers to cross, this study showed that future French pharmacists were keen to develop their role in patient care, beyond the traditional role of dispensing. However, the willingness of doctors and patients to consent should be investigated and also rigorous studies to support or refute the positive impact of pharmaceutical care on the quality of care should be carried out.
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Drug safety of rosiglitazone and pioglitazone in France: a study using the French PharmacoVigilance database
Berthet, Stephanie
Olivier, Pascale
Montastruc, Jean-Louis
Lapeyre-Mestre, Maryse
BMC Clinical Pharmacology
Thiazolidinediones (TZDs), rosiglitazone (RGZ) and pioglitazone (PGZ) are widely used as hypoglycemic drugs in patients with type 2 diabetes mellitus. The aim of our study was to investigate the profile of adverse drug reactions (ADRs) related to TZDs and to investigate potential risk factors of these ADRs.
Type 2 diabetic patients were identified from the French Database of PharmacoVigilance (FPVD) between 2002 and 2006. We investigated ADR related to TZD, focusing on 4 ADR: edema, heart failure, myocardial infarction and hepatitis corresponding to specific WHO-ART terms.
Among a total of 99,284 adult patients in the FPVD, 2295 reports concerned type 2 diabetic patients (2.3% of the whole database), with 161 (7%) exposed to TZDs. The frequency of edema and cardiac failure was significantly higher with TZDs than in other patients (18% and 7.4% versus 0.8% and 0.1% respectively, p < 0.001) whereas the frequency of hepatitis was similar (5.9% versus 4%, NS). A multiple logistic regression model taking into account potential confounding factors (age, gender, drug exposure and co-morbidities) found that TZD exposure remained associated with heart failure and edema, but not with hepatitis or myocardial infarction.
Thiazolidinediones exposure is associated with an increased risk of edema and heart failure in patients with type 2 diabetes even when recommendations for use are respected. In contrast, the risk of hepatic reactions and myocardial infarction with this class of drugs seems to be similar to other hypoglycemic agents.
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Use, tolerability and compliance of spironolactone in the treatment of heart failure
Lachaine, Jean
Beauchemin, Catherine
Ramos, Elodie
BMC Clinical Pharmacology
Risk of morbidity and mortality in patients with severe heart failure (HF) is reduced by blockade of aldosterone receptors with spironolactone. However, benefits of spironolactone are potentially limited by treatment compliance and adverse events profile. The aim of this study was to estimate use of spironolactone by patients with HF, incidence of key adverse events, and patient compliance.
This study was performed using data from the Quebec provincial medical and drug plans (Régie de l'Assurance Maladie du Québec, RAMQ) for patients who had a diagnosis of HF. Relative incidence of gynecomastia and hyperkalemia was estimated for users and non-users of spironolactone. Treatment adherence was estimated for users of spironolactone and compared to adherence with angiotensin converting enzyme (ACE) inhibitors, beta-blockers (β-blockers), and angiotensin receptor blockers (ARBs).
RAMQ data were obtained for a total of 82,018 patients with a diagnosis of HF. Of these patients, 59.9% used an ACE inhibitor, 59.5% used a beta-blocker, 28.4% used an ARB, and 15.1% (n = 12,344) used spironolactone. Despite underestimation due to limitation of the database, the documented incidence of hyperkalemia (3.3% versus 1.4%) and gynecomastia (1.8% versus 0.7%) was significantly higher in spironolactone users than non-users (p < 0.001). Treatment compliance was significantly lower with spironolactone compared to ACE inhibitors, β-blockers, and ARBs (45.6% versus 56.1%, 59.7%, and 57.0%, respectively; p < 0.001). Persistence to treatment over a one-year period was also lower with spironolactone compared to ACE inhibitors, β-blockers, and ARBs (50.7% versus 64.5%, 70.4%, and 66.3%, respectively; p < 0.001).
Use of spironolactone is associated with an incidence of adverse events, which may have an impact on treatment compliance.
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Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies
Tomkinson, Helen
Kemp, John
Oliver, Stuart
Swaisland, Helen
Taboada, Maria
Morris, Thomas
BMC Clinical Pharmacology
Zibotentan (ZD4054) is a specific endothelin A (ETA) receptor antagonist being investigated for the treatment of prostate cancer. As zibotentan is eliminated by renal and metabolic routes, clearance may be reduced in patients with hepatic or renal impairment, leading to greater drug exposure.
Open-label studies investigated the PK and tolerability of zibotentan in subjects with hepatic or renal impairment, compared with those with normal organ function. In the hepatic and renal studies, respectively, subjects were divided into categories using Child-Pugh classification or 24-hour urine creatinine clearance (mild, moderate, or severe impairment and normal function). Each subject received a single oral dose of zibotentan 10 mg and PK sampling was undertaken. Within the hepatic study, AUC and Cmax were expressed as the ratio of geometric means and 90% CI for each impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure was considered if the upper 90% CI for the ratio exceeded 2. In the renal study, AUC, Cmax and t1/2 were analyzed using linear regression fitting effects for creatinine clearance and age.
In the hepatic and renal studies respectively, 32 subjects (eight per group) and 48 subjects received treatment (n = 18 normal, n = 12 mild, n = 9 moderate, n = 9 severe). Zibotentan Cmax was not significantly affected by hepatic or renal impairment. Compared with the normal function group, zibotentan AUC was 40% (1.40; 90% CI 0.91-2.17), 45% (1.45; 90% CI 0.94-2.24) and 190% (2.90; 90% CI 1.88-4.49) higher in subjects with mild, moderate and severe hepatic impairment, respectively, and 66% (1.66; 90% CI 1.38-1.99), 89% (1.89; 90% CI 1.50-2.39) and 117% (2.17; 90% CI 1.64-2.86) higher in subjects with mild, moderate and severe renal impairment, respectively. In both studies mean t1/2 increased and zibotentan clearance decreased with the degree of impairment. Headache was the most common AE in all groups.
Zibotentan absorption was unchanged, however, exposure was higher in subjects with hepatic or renal impairment due to slower clearance. This increased exposure did not result in differences in the range or severity of AEs observed.
Trial Registration
ClinicalTrials.gov: NCT00672581 and AstraZeneca study number D4320C00016 (renal trial; conducted in Germany).
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Constipation and diarrhoea - common adverse drug reactions? A cross sectional study in the general population
Fosnes, Gunvor S
Lydersen, Stian
Farup, Per G
BMC Clinical Pharmacology
Constipation and diarrhoea are common complaints and often reported as adverse drug reactions. This study aimed at finding associations between drugs and constipation and diarrhoea in a general population.
A selection of inhabitants in Oppland County, Norway participated in a cross-sectional survey. Information about demographics, diseases including gastrointestinal complaints classified according to the Rome II criteria and use of drugs were collected on questionnaires. Constipation was defined as functional constipation and constipation predominant Irritable Bowel Syndrome (IBS), and diarrhoea as functional diarrhoea and diarrhoea predominant IBS. Associations between drugs and constipation and diarrhoea were examined with multivariable logistic regression models. Based on the multivariable model, the changes in prevalence (risk difference) of the abdominal complaints for non-users and users of drugs were calculated.
In total 11078 subjects were invited, 4622 completed the questionnaires, 640 (13.8%) had constipation and 407 (8.8%) had diarrhoea. To start using drugs increased the prevalence of constipation and diarrhoea with 2.5% and 2.3% respectively. Polypharmacy was an additional risk factor for diarrhoea. Use of furosemide, levothyroxine sodium and ibuprofen was associated with constipation, and lithium and carbamazepine with diarrhoea. The excess drug related prevalence varied from 5.3% for the association between ibuprofen and constipation to 27.5% for the association between lithium and diarrhoea.
Use of drugs was associated with constipation and diarrhoea in the general population. The associations are most likely adverse drug reactions and show that drug-induced symptoms need to be considered in subjects with these complaints.
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Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer
Howes, Jan B
de Souza, Paul L
West, Leanne
Huang, Li Jiu
Howes, Laurence G
BMC Clinical Pharmacology
Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. This study reports the pharmacokinetics of phenoxodiol in patients with cancer.
The pharmacokinetics of phenoxodiol was studied following a single intravenous (iv) bolus dose and during a continuous intravenous infusion. Three men with prostate cancer and 3 women with breast cancer received IV bolus phenoxodiol (5 mg/kg) and plasma was sampled for free and total phenoxodiol levels. On a separate occasion 5 of the same patients received a continuous intravenous infusion of phenoxodiol (2 mg/kg/h) and plasma was again sampled for free and total phenoxodiol levels. Phenoxodiol was measured using gradient HPLC with ultraviolet detection.
Following bolus injection, free and total phenoxodiol appeared to follow first order pharmacokinetics. The elimination half-lives for free and total phenoxodiol were 0.67 ± 0.53 h and 3.19 ± 1.93 h, respectively, while the total plasma clearance rates were 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h, respectively. The respective apparent volumes of distribution were 1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg. During continuous intravenous infusion, free phenoxodiol accumulated rapidly to reach a mean concentration at steady state of 0.79 ± 0.14 μg/ml after 0.87 ± 0.18 h. The apparent accumulation half-life of free phenoxodiol was 0.17 ± 0.04 h while the plasma clearance during continuous infusion was 1.29 ± 0.23 L/h.
Phenoxodiol has a short plasma half-life, particularly in the free form, leading to a rapid attainment of steady state levels during continuous intravenous infusion.
Trial registration
Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000334000
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Increasing polypharmacy - an individual-based study of the Swedish population 2005-2008
Hovstadius, Bo
Hovstadius, Karl
Åstrand, Bengt
Petersson, Göran
BMC Clinical Pharmacology
An increase in the use of drugs and polypharmacy have been displayed over time in spite of the fact that polypharmacy represents a well known risk factor as regards patients' health due to the adverse drug reactions, drug-drug interactions, and low adherence to drug therapy arising from polypharmacy. For policymakers, as well as for clinicians, it is important to follow the developing trends in drug use and polypharmacy over time. We wanted to study if the prevalence of polypharmacy in an entire national population has changed during a 4-year period.
By applying individual-based data on dispensed drugs, we have studied all dispensed prescribed drugs for the entire Swedish population during four 3-month periods 2005-2008. Five or more (DP ≥5) and ten or more (DP ≥10) dispensed drugs during the 3-month period was applied as the cut-offs indicating the existence of polypharmacy and excessive polypharmacy respectively.
During the period 2005-2008, the prevalence of polypharmacy (DP≥5) increased by 8.2% (from 0.102 to 0.111), and the prevalence of excessive polypharmacy (DP≥10) increased by 15.7% (from 0.021 to 0.024).
In terms of age groups, the prevalence of polypharmacy and excessive polypharmacy increased as regards all ages with the exception of the age group 0-9 years. However, the prevalence of excessive polypharmacy displayed a clear age trend, with the largest increase for the groups 70 years and above. Furthermore, the increase in the prevalence of polypharmacy was, generally, approximately twice as high for men as for women. Finally, the mean number of dispensed drugs per individual increased by 3.6% (from 3.3 to 3.4) during the study period.
The prevalence of polypharmacy and excessive polypharmacy, as well as the mean number of dispensed drugs per individual, increased year-by-year in Sweden 2005-2008.
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The impact of generic substitution on the activities of pharmaceutical companies - a survey from the companies' perspective one year and five years after the introduction of generic substitution in finland
Timonen, Johanna
Bengtström, Marina
Karttunen, Pekka
Ahonen, Riitta
BMC Clinical Pharmacology
Mandatory generic substitution (GS) was introduced in Finland on 1 April 2003. The aim of this study was to explore and compare the impacts of GS on the activities of pharmaceutical companies representing mainly original or generic pharmaceutical products in Finland. The self-reported impact of GS from pharmaceutical companies' perspective was explored with a focus on the number of employees, the range of sales packages on the market, the marketing activities, the research and development of new pharmaceutical products and storage of pharmaceuticals.
A cross-sectional postal survey was conducted among pharmaceutical companies with an office in Finland and substitutable medicines in the Finnish pharmaceutical market one year (2004) and five years (2008) after the introduction of GS. Completed questionnaires were returned by 16 original and 7 generic product companies in 2004 (response rate 56%, n = 41) and by 16 original and 6 generic product companies in 2008 (response rate 56%, n = 39). Descriptive statistical analyses were performed.
The number of employees (2004: n = 6/16, 2008: n = 7/16) and the amount of prescription medicine marketing (2004: n = 7/16, 2008: n = 8/16) decreased in many of the original product companies after the introduction of GS. GS resulted in problems related to the storage of pharmaceuticals in the original product companies shortly after GS was introduced (p = 0.032 between 2004 and 2008). In the generic product companies, the prescription medicine representatives' visits to pharmacies increased at the beginning of GS (p = 0.021 between 2004 and 2008). In addition, GS caused problems with the storage of pharmaceuticals one year and five years after the reform (2004: n = 4/7, 2008: n = 3/6). The differences between original and generic product companies regarding the impacts of GS were not, however, statistically significant. GS did not affect on the range of sales packages on the market or the research activities of the majority of companies.
The study suggests that GS has had impacts on the activities of pharmaceutical companies in Finland. There were also some differences, although not statistically significant, between the surveyed original and generic product companies regarding the self-reported impacts of GS. More investigations are needed in this field.
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Comparison of the pharmacokinetics, safety and tolerability of two concentrations of a new liquid recombinant human growth hormone formulation versus the freeze-dried formulation
Liedert, Bernd
Forssmann, Ulf
Wolna, Peter
Golob, Michaela
Kovar, Andreas
BMC Clinical Pharmacology
Somatropin is recombinant human growth hormone (GH) used for the treatment of growth failure in children and GH deficiency in adults. Two concentrations of a liquid formulation have been developed: 5.83 and 8.0 mg/mL. This trial compared the pharmacokinetics (PK), safety and tolerability of these two liquid concentrations against the freeze-dried (FD) formulation in healthy volunteers.
In an open-label, single-centre, three-way crossover study, volunteers (aged 18-45 years) were given subcutaneous injections of the reconstituted FD and two liquid formulations in random sequential order, each at 4 mg/dose, with a 1-week wash-out period between doses. To suppress endogenous GH secretion, intravenous somatostatin was infused continuously 1 hour before to 24 hours after each dose, achieving a cumulative dose of 3 mg. Primary PK endpoints were area under the serum concentration-time curve (AUC0-t) and maximum serum concentration (Cmax). For each of the two liquid formulations, bioequivalence with the FD formulation was concluded if the 95% confidence intervals (CIs) for the estimated test/reference ratios of geometric means of AUC0-t and Cmax were within the standard pre-specified acceptance range (0.80-1.25).
Fifteen men and 15 women enrolled (safety population, n = 30; PK population, n = 28). Bioequivalence with the FD formulation could be shown for both liquid formulations. The ratios of geometric means (95% CI) were 1.046 (0.980, 1.117) and 0.991 (0.929, 1.058) for AUC0-t and 0.954 (0.875, 1.040) and 0.955 (0.876, 1.041) for Cmax for the 5.83 and 8.0 mg/mL formulations, respectively. No significant differences between the three treatments in half-lives, time to reach Cmax, clearance or volume of distribution were observed. After injection, the most common side-effects were pain or injection-site reactions (all of mild intensity). There were no clinically significant abnormal vital signs, ECG or laboratory findings. There were 56 treatment-related adverse events (AEs): 49 mild, 6 moderate and 1 severe (vomiting). No serious AEs occurred. The pattern of AEs was as expected and all resolved by study end.
Both concentrations of a new liquid multi-dose formulation are bioequivalent to the FD reference formulation and all are well tolerated.
Trial registration number
Related Articles
Pharmacokinetic comparability of Prolastin®-C to Prolastin® in alpha1-antitrypsin deficiency: a randomized study
Stocks, James M
Brantly, Mark L
Wang-Smith, Laurene
Campos, Michael A
Chapman, Kenneth R
Kueppers, Friedrich
Sandhaus, Robert A
Strange, Charlie
Turino, Gerard
BMC Clinical Pharmacology
Alpha1-antitrypsin (AAT) deficiency is characterized by low blood levels of alpha1-proteinase inhibitor (alpha1-PI) and may lead to emphysema. Alpha1-PI protects pulmonary tissue from damage caused by the action of proteolytic enzymes. Augmentation therapy with Prolastin® (Alpha1-Proteinase Inhibitor [Human]) to increase the levels of alpha1-PI has been used to treat individuals with AAT deficiency for over 20 years. Modifications to the Prolastin manufacturing process, incorporating additional purification and pathogen-reduction steps, have led to the development of an alpha1-PI product, designated Prolastin®-C (Alpha1-Proteinase inhibitor [Human]). The pharmacokinetic comparability of Prolastin-C to Prolastin was assessed in subjects with AAT deficiency.
In total, 24 subjects were randomized to receive 60 mg/kg of functionally active Prolastin-C or Prolastin by weekly intravenous infusion for 8 weeks before crossover to the alternate treatment for another 8 weeks. Pharmacokinetic plasma samples were drawn over 7 days following last dose in the first treatment period and over 10 days following the last dose in the second period. The primary end point for pharmacokinetic comparability was area under the plasma concentration versus time curve over 7 days post dose (AUC0-7 days) of alpha1-PI determined by potency (functional activity) assay. The crossover phase was followed by an 8-week open-label treatment phase with Prolastin-C only.
Mean AUC0-7 days was 155.9 versus 152.4 mg*h/mL for Prolastin-C and Prolastin, respectively. The geometric least squares mean ratio of AUC0-7 days for Prolastin-C versus Prolastin had a point estimate of 1.03 and a 90% confidence interval of 0.97-1.09, demonstrating pharmacokinetic equivalence between the 2 products. Adverse events were similar for both treatments and occurred at a rate of 0.117 and 0.078 per infusion for Prolastin-C (double-blind treatment phase only) and Prolastin, respectively (p = 0.744). There were no treatment-emergent viral infections in any subject for human immunodeficiency virus, hepatitis B or C, or parvovirus B19 during the course of the study.
Prolastin-C demonstrated pharmacokinetic equivalence and a comparable safety profile to Prolastin.
Trial Registration
ClinicalTrials.gov Identifier: NCT00295061
Related Articles
Efficacy and safety of combined prolonged-release oxycodone and naloxone in the management of moderate/severe chronic non-malignant pain: results of a prospectively designed pooled analysis of two randomised, double-blind clinical trials
Löwenstein, Oliver
Leyendecker, Petra
Lux, Eberhard A
Blagden, Mark
Simpson, Karen H
Hopp, Michael
Bosse, Björn
Reimer, Karen
BMC Clinical Pharmacology
Two randomised 12-week, double-blind, parallel-group, multicenter studies comparing oxycodone PR/naloxone PR and oxycodone PR alone on symptoms of opioid-induced bowel dysfunction in patients with moderate/severe non-malignant pain have been conducted.
These studies were prospectively designed to be pooled and the primary outcome measure of the pooled data analysis was to demonstrate non-inferiority in 12-week analgesic efficacy of oxycodone PR/naloxone PR versus oxycodone PR alone. Patients with opioid-induced constipation were switched to oxycodone PR and then randomised to fixed doses of oxycodone PR/naloxone PR (n = 292) or oxycodone PR (n = 295) for 12 weeks (20-80 mg/day).
No statistically significant differences in analgesic efficacy were observed for the two treatments (p = 0.3197; non-inferiority p < 0.0001; 95% CI -0.07, 0.23) and there was no statistically significant difference in frequency of analgesic rescue medication use. Improvements in Bowel Function Index score were observed for oxycodone PR/naloxone PR by Week 1 and at every subsequent time point (-15.1; p < 0.0001; 95% CI -17.3, -13.0). AE incidence was similar for both groups (61.0% and 57.3% of patients with oxycodone PR/naloxone PR and oxycodone PR alone, respectively).
Results of this pooled analysis confirm that oxycodone PR/naloxone PR provides effective analgesia and suggest that oxycodone PR/naloxone PR improves bowel function without compromising analgesic efficacy.
Trial registration numbers
ClinicalTrials.gov identifier: NCT00412100 and NCT00412152
Related Articles
Knowledge and adherence to antiretroviral therapy among adult people living with HIV/AIDS treated in the health care centers of the association "Espoir Vie Togo" in Togo, West Africa
Potchoo, Yao
Tchamdja, Kpatcha
Balogou, Agnon
Pitche, Vincent P
Guissou, Innocent P
Kassang, Etienne K
BMC Clinical Pharmacology
The efficiency of antiretroviral therapy (ART) depends on a near perfect level of patients' adherence. The level of adherence of adults HIV-infected patients treated in the HIV/AIDS health care centres of the association "Espoir Vie Togo" in Togo, West Africa is not properly documented. The aim of the present study was to examine by means of self-reports the knowledge, the adherence level and associated factors to antiretroviral therapy (ART) among these patients.
We conducted a cross-sectional survey among adult people living with HIV/AIDS (PLWHA) through a structured questionnaire.
A total of 99 patients were enrolled. Among them, 55.6% knew the name of antiretroviral agents of regimens prescribed. All patients had a good knowledge of treatment schedule. The treatment regimens based on 2 NRTIs + 1 NNRTI were used in 90% of patients. The average adherence rate was 89.8% of the total doses prescribed while 62.62% of patients showed an adherence rate of 95% or above. The treated groups were similar in term of median % of medication doses taken according to PLWHA epidemiological characteristics. However, patients reported forgetting (34.9%), travel (25.6%), cost of treatment (13.9%) and side effects (11.6%) as the main factors of missing at least once a dose intake.
These results should encourage the association and all the involved actors in the HIV/AIDS's program to strengthen counseling, education and information interventions for HIV-infected patients in order to overcome the potential barriers of poor adherence.
Related Articles
The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol
Tanner, Trevor
Aspley, Sue
Munn, Andrew
Thomas, Tracy
BMC Clinical Pharmacology
Ibuprofen and paracetamol differ in their mode of action and related therapeutic effects, suggesting that combined administration may offer improved analgesia. Reported here are the results of two studies on the pharmacokinetic properties of a novel ibuprofen (200 mg) and paracetamol (500 mg) fixed-dose combination tablet.
Both studies were open-label, randomised studies in healthy volunteers: Study 1 was a four-way crossover, single-dose study; Study 2 was a two-way cross-over, repeat-dose study.
Pharmacokinetic parameters for ibuprofen and paracetamol were similar for the combination and monotherapy tablets (values falling within the 80% to 125% acceptable bioequivalence range) except for the rate of absorption of paracetamol from the combination (tmax), which was significantly faster compared with monotherapy (median difference 10 minutes; p < 0.05). Mean plasma concentrations of both drugs were higher, earlier, following administration of the combination tablet compared with monotherapy. Mean plasma levels at 10 and 20 minutes were 6.64 μg.mL-1 and 16.81 μg.mL-1, respectively, for ibuprofen from the combination, compared with 0.58 μg.mL-1 and 9.00 μg.mL-1, respectively, for monotherapy. For paracetamol, mean plasma levels at 10 and 20 minutes were 5.43 μg.mL-1 and 14.54 μg.mL-1, respectively, for the combination compared with 0.33 μg.mL-1 and 9.19 μg.mL-1, respectively, for monotherapy. The rate of absorption of both ibuprofen and paracetamol was significantly delayed when the combination tablet was administered in the fed versus fasted state; median delay was 25 minutes for ibuprofen (p > 0.05) and 55 minutes for paracetamol (p < 0.001). The pharmacokinetic parameters were comparable irrespective of whether the combination tablet was given twice or three times daily; systemic exposure was, however, approximately 1.4 times greater for both drugs when given three times daily.
Administration of ibuprofen and paracetamol in a fixed-dose combination tablet does not significantly alter the pharmacokinetic profiles of either drug, except for enhancing the rate of paracetamol absorption, offering potential therapeutic benefits in relation to the onset of analgesia. Concentrations of both drugs reached previously reported therapeutic levels when the combination tablet was administrated in the fed or fasted state. Three times daily dosing may offer enhanced therapeutic effect for longer than twice daily dosing.
Related Articles
Traumeel S® for pain relief following hallux valgus surgery: a randomized controlled trial
Singer, Shepherd R
Amit-Kohn, Michal
Weiss, Samuel
Rosenblum, Jonathan
Maoz, Guy
Samuels, Noah
Lukasiewicz, Esther
Freedman, Laurence
Paltiel, Ora
Itzchaki, Menachem
Niska, Meir
Oberbaum, Menachem
BMC Clinical Pharmacology
In spite of recent advances in post-operative pain relief, pain following orthopedic surgery remains an ongoing challenge for clinicians. We examined whether a well known and frequently prescribed homeopathic preparation could mitigate post-operative pain.
We performed a randomized, double blind, placebo-controlled trial to evaluate the efficacy of the homeopathic preparation Traumeel S® in minimizing post-operative pain and analgesic consumption following surgical correction of hallux valgus. Eighty consecutive patients were randomized to receive either Traumeel tablets or an indistinguishable placebo, and took primary and rescue oral analgesics as needed. Maximum numerical pain scores at rest and consumption of oral analgesics were recorded on day of surgery and for 13 days following surgery.
Traumeel was not found superior to placebo in minimizing pain or analgesic consumption over the 14 days of the trial, however a transient reduction in the daily maximum post-operative pain score favoring the Traumeel arm was observed on the day of surgery, a finding supported by a treatment-time interaction test (p = 0.04).
Traumeel was not superior to placebo in minimizing pain or analgesic consumption over the 14 days of the trial. A transient reduction in the daily maximum post-operative pain score on the day of surgery is of questionable clinical importance.
Trial Registration
This study was registered at ClinicalTrials.gov. # NCT00279513
Related Articles
Assessing Safety Culture in Pharmacies: The psychometric validation of the Safety Attitudes Questionnaire (SAQ) in a national sample of community pharmacies in Sweden
Nordén-Hägg, Annika
Sexton, J Bryan
Kälvemark-Sporrong, Sofia
Ring, Lena
Kettis-Lindblad, Åsa
BMC Clinical Pharmacology
Safety culture assessment is increasingly recognized as an important component in healthcare quality improvement, also in pharmacies. One of the most commonly used and rigorously validated tools to measure safety culture is the Safety Attitudes Questionnaire; SAQ. This study presents the validation of the SAQ for use in Swedish pharmacies. The psychometric properties of the translated questionnaire are presented
The original English language version of the SAQ was translated and adapted to the Swedish context and distributed by e-mail. The survey was carried out on a national basis, covering all 870 Swedish community pharmacies. In total, 7,244 questionnaires were distributed. Scale psychometrics were analysed using Cronbach alphas and intercorrelations among the scales. Multiple group confirmatory factor analysis (CFA) was conducted.
SAQ data from 828 community pharmacies in Sweden, including 4,090 (60.22%) pharmacy personnel out of 6,683 eligible respondents, were received. There were 252 (28.97%) pharmacies that met the inclusion criteria of having at least 5 respondents and a minimum response rate of 60% within that pharmacy.
The coefficient alpha value for each of the SAQ scales ranged from .72 to .89. The internal consistency results, in conjunction with the confirmatory factor analysis results, demonstrate that the Swedish translation of the SAQ has acceptable to good psychometric properties. Perceptions of the pharmacy (Teamwork Climate, Job Satisfaction, Perceptions of Management, Safety Climate, and Working Conditions) were moderately to highly correlated with one another whereas attitudes about stress (Stress Recognition) had only low correlations with other factors. Perceptions of management showed the most variability across pharmacies (SD = 26.66), whereas Stress Recognition showed the least (SD = 18.58). There was substantial variability ranging from 0% to 100% in the percent of positive scores for each of the factors across the 252 pharmacies.
The Swedish translation of the SAQ demonstrates acceptable construct validity, for capturing the frontline perspective of safety culture of community pharmacy staff. The psychometric results reported here met or exceeded standard guidelines, which is consistent with previous studies using the SAQ in other healthcare settings and other languages.
Related Articles
Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis - An open clinical trial-
Kumagai, Kenji
Shirabe, Susumu
Miyata, Noriaki
Murata, Masakazu
Yamauchi, Atsushi
Kataoka, Yasuhumi
Niwa, Masami
BMC Clinical Pharmacology
Pentosan polysulfate sodium (pentosan) is a semi-synthetic drug manufactured from beech-wood hemicellulose by sulfate esterification of the xylopyranose hydroxyl groups. From in vitro and animal model studies, pentosan has been proposed as a disease modifying osteoarthritis drug (DMOAD). The objective of this study was to assess the efficacy, safety, and patient satisfaction in patients with mild radiographic knee osteoarthritis (OA) findings and OA-associated symptoms and signs.
Twenty patients were assessed clinically at Nagasaki University Hospital. The radiographic indications of OA were grade 1 to 3 using the Kellgren-Lawrence Grading System (K/L grade). Pentosan used in this study was manufactured and supplied in sterile injectable vials (100 mg/ml) by bene GmbH, Munich, Germany. The study was a single-center, open-label trial. Treatment consisted of 6 weekly subcutaneous injections (sc) of pentosan (2 mg/kg). Patients were clinically assessed at entry and 1 to 8, 11, 15, 24 & 52 weeks post treatment. The results were analyzed using one way ANOVA and Dunnett's method.
Hydrarthroses were reduced quickly in all cases. The clinical assessments, i.e., knee flexion, pain while walking, pain after climbing up and down stairs, etc, were improved significantly and these clinical improvements continued for almost one year. The dose used in this study affected the blood coagulation test, but was within safe levels. Slightly abnormal findings were noted in serum triglycerides.
Pentosan treatment in twenty patients with mild knee OA seemed to provide improvements in clinical assessments and C2C level of cartilage metabolism.
Trial Registration
UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002790
Related Articles
Use of analgesics in intentional drug overdose presentations to hospital before and after the withdrawal of distalgesic from the Irish market
Corcoran, Paul
Reulbach, Udo
Keeley, Helen S
Perry, Ivan J
Hawton, Keith
Arensman, Ella
BMC Clinical Pharmacology
Distalgesic, the prescription-only analgesic compound of paracetamol (325 mg) and dextropropoxyphene (32.5 mg) known as co-proxamol in the UK, was withdrawn from the Irish market as of January 2006. This study aimed to evaluate the impact of the withdrawal of distalgesic in terms of intentional drug overdose (IDO) presentations to hospital emergency departments (EDs) nationally.
A total of 42,849 IDO presentations to 37 of the 40 hospitals EDs operating in Ireland in 2003-2008 were recorded according to standardised procedures. Data on sales of paracetamol-containing drugs to retail pharmacies for the period 1998-2008 were obtained from IMS Health.
The withdrawal of distalgesic from the Irish market resulted in an immediate reduction in sales to retail pharmacies from 40 million tablets in 2005 to 500,000 tablets in 2006 while there was a 48% increase in sales of other prescription compound analgesics. The rate of IDO presentations to hospital involving distalgesic in 2006-2008 was 84% lower than in the three years before it was withdrawn (10.0 per 100,000). There was a 44% increase in the rate of IDO presentations involving other prescription compound analgesics but the magnitude of this rate increase was five times smaller than the magnitude of the decrease in distalgesic-related IDO presentations. There was a decreasing trend in the rate of presentations involving any paracetamol-containing drug that began in the years before the distalgesic withdrawal.
The withdrawal of distalgesic has had positive benefits in terms of IDO presentations to hospital in Ireland and provides evidence supporting the restriction of availability of means as a prevention strategy for suicidal behaviour.
Related Articles
EVITA: a tool for the early EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage
Püntmann, Isabel
Schmacke, Norbert
Melander, Arne
Lindberg, Gunnar
Mühlbauer, Bernd
BMC Clinical Pharmacology
New drugs are generally claimed to represent a therapeutic innovation. However, scientific evidence of a substantial clinical advantage is often lacking. This may be the result of using inadequate control groups or surrogate outcomes only in the clinical trials. In view of this, EVITA was developed as a user-friendly transparent tool for the early evaluation of the additional therapeutic value of a new drug.
EVITA does not evaluate a new compound per se but in an approved indication in comparison with existing therapeutic strategies. Placebo as a comparator is accepted only in the absence of an established therapy or if employed in an add-on strategy on top. The evaluation attributes rating points to the drug in question, taking into consideration both therapeutic benefit and risk profile. The compound scores positive points for superiority in efficiency and/or adverse effects as demonstrated in randomized controlled trials (RCTs), whilst negative points are awarded for inferiority and/or an unfavorable risk profile. The evaluation follows an algorithm considering the clinical relevance of the outcomes, the strength of the therapeutic effect and the number of RCTs performed. Categories for therapeutic aim and disease severity, although essential parts of the EVITA assessment, are attributed but do not influence the EVITA score which is presented as a color-coded bar graph. In case the available data were unsuitable for an EVITA calculation, a traffic-type yield sign is assigned instead to criticize such practice. The results are presented online http://www.evita-report.de together with all RCTs considered as well as the reasons for excluding a given RCT from the evaluation. This allows for immediate revision in response to justified criticism and simplifies the inclusion of new data.
As examples, four compounds which received approval within the last years were evaluated for one of their clinical indications: lenalidomide, pioglitazone, bupropion and zoledronic acid. Only the first achieved an EVITA score above zero indicating therapeutic advantage.
The strength of EVITA appears to lie in its speedy assessment of the potential therapeutic advantage of a new drug for a given indication. At the same time, this approach draws attention to the typical deficits of data used for drug approval. EVITA is not intended to replace classical health technology assessment reports but rather serves as a screening tool in the sense of horizon scanning.
Related Articles
Characteristics of primary health care units with focus on drug information from the pharmaceutical industry and adherence to prescribing objectives: a cross-sectional study
Carlzon, Daniel
Gustafsson, Lena
Eriksson, Anna L
Rignér, Karin
Sundström, Anders
Wallerstedt, Susanna M
BMC Clinical Pharmacology
Adherence to prescribing guidelines varies between primary health care units. The aim of the present study was to investigate correlations between characteristics of primary health care units and adherence to prescribing objectives for rational drug use with focus on drug information from the pharmaceutical industry.
A cross-sectional study was performed in all 25 primary health care units in Göteborg, Sweden. A questionnaire on characteristics of practice settings [(i) size of unit, (ii) profession of head, (iii) use of temporary physicians, (iv) drug information from the pharmaceutical industry, (v) producer-independent drug information, and (vi) education on prescribing for newly employed physicians] was sent to the heads of the units. A national sales register for prescribed drugs (Xplain) was used for evaluation of adherence to the six regional prescribing objectives concerning proton pump inhibitors (PPIs), angiotensin converting enzyme inhibitors (ACEIs), statins and antidepressants.
Twenty-two out of 25 primary health care units responded to the questionnaire (response rate 88%). A physician as head and presence of producer-independent drug information was positively correlated with adherence to the prescribing objectives (median number of prescribing objectives adhered to (25th - 75th percentile): 2.5 (1-3.25) vs 1 (0-2), P = 0.013; 2 (1-3) vs 0, P = 0.043, respectively. Presence of drug information from the pharmaceutical industry and education on prescribing for newly employed physicians was negatively associated with adherence to the prescribing objectives: 1 (0-2) vs 3.5 (2.25-4.75), P = 0.005; 1 (0-2) vs 3 (1.5-4), P = 0.034, respectively.
Several characteristics of the primary health care units correlated with adherence to prescribing objectives for rational drug use. Further research on this topic is needed and would constitute valuable information for health care decision makers.
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p>The folks behind our favorite letterpress studio designed these cheery turquoise and green coasters. Even if you aren't a grammar fiend, the ampersand motif is fun and stylish. Or try the cute moustaches, they're sure to make you smile. Grab a set to spruce up your coffee table. They're a hip way to keep your tables safe from stains!
I love that I was introduced to this brand. The art of Letterpress definitely interests me as there truly is nothing of better quality out there where stationary is concerned. I am very impressed with the two little coasters I recieved in my box this month and hope to order more soon. Thanks Birchbox and Two Paper Dolls!5


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Am I the only one...
...who has never heard the name "Ceglia" spoken aloud and when seeing it written down, hears it in their head as "Caligula"?
A firewood salesman who is locked in a legal spat with Facebook in a dispute over ownership of the dominant social network has lost another lawyer working on his case. Paul Ceglia reportedly instructed his now erstwhile lawyer Jeffery Lake "not to comply" with a court order issued by a judge in August. Lake, who has withdrawn …
...who has never heard the name "Ceglia" spoken aloud and when seeing it written down, hears it in their head as "Caligula"?
'Fraid so old chap.
I seem to recall that way back in 2002 I met Zuckerberg in a bar in Birmingham, we got chatting and I mentioned to him how cool it would be to have a myspace clone with its own API and aimed soley at impressionable young students.
I have no proof of this, however I believe Im entitled to 50% of facebook and I believe I also have the legal right to force Zuckerberg to change his name to Fuckerbeg.
That is all.
...and the chiselling cheapskate owes me big-time. I want at least 75% of FB.
... as Facebook's biggest demographic (in the UK at least) tends to be the late 20's to early 50's range.
(pedantic icon is nothing to do with grammer btw).


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- shop by theme
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Comments about ... Women's Gypsy Moon Adult Costume:
I ordered this costume to use in a school play. When it arrived I was delighted to see the appearance and quality were exceptional. The outfit was shipped in a full zippered garment bag and on a hanger for easy storage. What a great product. I\'d recommend this costume as well as Birthday in a Box to everyone!


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Product Information
Kong Ballistic Bone
A Strong and Unique Bone ToyDog bone toys are quite famous and if you want something strong then KONG Ballistic Bone is the toy for you. It's made using a multilayered design with three layers of material and eight rows of stitching that makes it extremely durable. This toy can be used for fetching and tug games. KONG Ballistic BoneComes with three layer materials for strength and durability Machine washableFloats on waterGentle on teeth and gums This bone toy can be used for indoor and outdoor fun. As it floats too, you can take it to beaches or just play with it in the pool. It also includes a squeaker that's secured using nylon pouches.A Closer Look: KONG Ballistic Bone is a tough and strong toy that's gentle on your pet s gums and teeth. It's covered with soft fleece material that prevents injuries.Made Specially for: Dogs of all ages
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We recently chaired a panel discussion about the many and varied uses of London maps – from aids to navigation, to works of art. London Maps: The Magical, The Methodical and the Multifaceted was held on 19 November 2011 at Air Gallery, in support of The Art of Mapping exhibition arranged by TAG Fine Arts.
Chaired by Londonist's Matt Brown, the evening featured three speakers:
- Stephen Walter, the acclaimed artist famous for his detailed hand-drawn maps of London
- John Kennedy, London taxi driver and chronicler of London's minutiae
- James Cheshire, digital mapper and Lecturer in Advanced Spatial Analysis at UCL
Londonist and TAG Fine Arts - The Art Of Mapping Talk by Londonist


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Hello to you here on Audiko.net! We offer you to download a free Paul Colman ringtones for your iPhone or mobile. Specify your favorite moment from your favorite music - lol, History Maker, Gloria, or any other track. Then download the prepared Paul Colman ringtones to your gadget, and enjoy Australian music by Paul Colman every time your phone rings. If you like Australian or maybe Australien and Christian Rock music, then you will probably like Tree 63, Matthew West, or Paul Colman Trio as well. For all who want a free Paul Colman ringtone, we also recommend listening to Pop, Worship, and praise. Here you can gain your tune both in the MP3 and m4a formats, compatible with both mobile phones and iPhones. Just select a track, and choose free Paul Colman ringtones download option.
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Real Housewives of Beverly Hills
Brooks Ayers Tweets Quote About Being Careful of Gossipy People
Rumors continue to circulate that Brooks Ayers and Real Housewives of Orange County star Vicki Gunvalson have rekindled their romance, despite their turbulent appearance together recently on the show's Season 8 reunion. So has Brooks just tweeted a hint about their relationship?
On September 11, Brooks tweeted this somewhat cryptic message:
September 12, 2013
Hmm. So what exactly are we to make of this? We're wondering if this is Brooks way of commenting on the criticism he got at the reunion, particularly from Vicki's daughter, Briana. Much of the Reunion Part 3 focused on the Housewives finding out about a recorded phone conversation in which Brooks tells Ryan Culberson that he wants to beat Vicki and that Ryan should do the same to Briana.
In fact, Brooks's tweet seems to perhaps be a confirmation that he and Vicki are back together, as if he is telling people to stop gossiping about them and mind their own business. Or maybe the message is completely unrelated to Vicki. Who knows?
But there's no doubt that his Twitter followers think that the message relates to what he dealt with on the Housewives reunion. When one person felt that his tweet means he's playing the victim card, Brooks responded:
@TerriEileenCran Not at all!. I have never played the victim card. Always owned up to my mistakes. Always two sides to every story!— Brooks Ayers (@BrooksAyers) September 12, 2013
So we suppose we still don't know for sure if Brooks and Vicki are back together. Let's just hope Brooks tweets something a little less cryptic about their relationship in the near future.
Source: Brooks's Twitter


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I'm toying with the idea of trying out the Mountain Tamer Quad chain-ring set-up:
Curious if anyone has tried it and if so what front derailleur you used. I've got to replace my front derailleur (munched it mountain biking) and have a couple of Sun Tour friction shifters kicking around...
This is for my touring rig ('88 GT Timberline) that I am looking at taking through some very hilly country later this month, but I also use the bike as my daily commuter where I do some long descents and am mostly in my big (currently 53 tooth) chain-ring throughout the 7 mile (each way) commute. I'd like to retain the high-end speed capability but add a super low end (20T) to handle hill climbs while loaded for touring - hence the interest in the Quad.


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All information is intended for your general knowledge only and is not a substitute for medical advice or treatment for specific medical conditions. You should seek prompt medical care in the case of an emergency and for any specific health issues. Use of this online service is subject to the terms and conditions. External Web site links provided on this site are meant for convenience and for informational purposes only; they do not constitute an endorsement. ActiveHealth may use your personal information to communicate with you about your account, our services or products, or to respond to your requests. Health education content within this website includes information provided by Healthwise Incorporated and ActiveHealth Management. This website is funded by ActiveHealth Management and does not accept advertising from third parties. For information on government-sponsored health programs, please visit the Centers for Medicare and Medicaid Services and the Medicare Rights Center.


text: I purchased a Garmin Edge 500 about 6 months ago and have to say it has kept me motivated to ride and train. I've now decided to add HR monitoring to my training so I ordered a Garmin HR Monroe chest strap. My question is will I be able to just connect or do I need to purchase some additional components? Thanks for any advise.


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Monday, March 14: herb baked chicken, potatoes with carrots, peas, butterscotch pudding, and cornbread.
Tuesday, March 15: baked pork chop, buttered corn, green beans, mandarin oranges, and whole wheat roll.
Wednesday, March 16: Swiss steak, wild rice with apricots, buttered carrots, strawberries/banana, and whole wheat roll.
Thursday, March 17: closed.
Friday, March 18: salmon croquettes, rigatoni and tomatoes, buttered broccoli, banana pudding, and whole wheat roll.
All meals are served with skim milk.
Sherman Chapel AME Zion
Rev. Roland Puryear will host A.M.E. Zion Church Kentucky Conference: Bardstown District on March 10, 11, 12 at Sherman Chapel located on South Proctor Knott Avenue, Lebanon. Sessions will begin at 10 a.m. each day. Rev. Roland Puryear is host and pastor, Rev. James C. Tutt is presiding elder, and Bishp Darryl Sturnes is presiding prelate.
Copyright © 2016
The Lebanon Enterprise is your source for local news, sports, events, and information in Marion County and Lebanon, KY, and the surrounding area.


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1. Champselysees, Paris, France
The Avenue des Champs-Elyseesis the most fashionable and broadest avenue in Paris and is one of the most famous streetsin the world. Along the upper section from the lively Rond-point are stores,offices, movie theaters, luxury shops and sidewalk cafes. It is a great placefor shopping.
2.Moscow Metro
The Moscow Metro was one of the USSR's most e,Moscow ,Russia The Moscow Metro was one of the USSR's most extravagant architectural projects. It's the world's largest one of the subway.Subwaystation buildings with different shapes. With their reflective marble walls, high ceilings and grandiose chandeliers, many Moscow Metro stations have been likened to an "artificial underground sun". It's amazing.
3. Vabbinfaru Island , Maldive
Tthe island is known for its tranquility and romance . Time is like a motionless. It Let your heart to calm down to relaxyourself. Overview Cast away on a secluded coral atoll in the paradisiacal Maldives archipelago, you experience a sense of magic, romance and tranquility at Banyan Tree Maldives Vabbinfaru that's second to none.
4. Parthenon Temple,Athens, Greece.
Parthenon is the most important and characteristic monument of the ancient Greek civilization and still remains its international symbol. It was dedicated to Athena Parthenos, the patron goddess of Athens.
5. Lake Louise,British Columbia,Canada
It's almost impossible, upon first seeing Lake Louise, not to gasp. The beautiful, milky blue lake rests at the foot of Victoria Glacier, which rises majestically and behind it, capped by snow and ice year-round....


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Wednesday, October 31, 2007
Another ATC
I've noticed that the ATCs are usually pretty "artsy." Mine are just little mini cards. Oh well, they're still just so dang cute and fun to make!
Supplies (all Stampin' Up!):
Stamps: Best Blossom (retired), Print Pattern, Itty Bitty Backgrounds
Ink: Always Artichoke, Elegant Eggplant, Very Vanilla
Paper: Whisper White, Always Artichoke, Elegant Eggplant
Accessories: celery grosgrain, rhinestone brads - ice circles, white gel pen
Posted by Amy Sheffer at 10/31/2007 10:06:00 AM
Labels: ATCs
4 comments:
artsy shmartsy - this is beau-ti-ful! i love that color comboReplyDelete
I love purple and green together. I especially like your added dimension...white "dots" on diamond bg, ribbon, jeweled brad, and the flower petals!ReplyDelete
Wow! so beautiful! I love the bling centre!ReplyDelete
beautiful ATC's amy!ReplyDelete
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A re-dedication and a blessing happened for a Central City institution that gives youngsters in need a hand up.
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Larry Osborne, senior pastor at North Coast Church, Vista, California, was the speaker at the February 17 event in the Special Events Center on the main FPU campus. His title was "Ministry in a Hyperchange World: Staying Focused When Everything is a Blur."
In his opening session, Osborne looked at a study of MBA graduates companies "fast-tracked" for major success. The study listed 12 reasons why some didn't live up to their potential, but Osborne boiled it down to two.
- Poor relationship skills. "In other words, they don't play well with others in the sandbox," he said.
- The inability to adapt. "They were poor at what I like to call mid-course corrections," he said.
Relating and adapting are Scriptural skills, according to Osborne, but they are not enough. The most important skill is to do God's will in love. "A very simple recipe that very few people, and unfortunately very few churches, can get out of the oven," he said.
North Coast has been named one of the 10 Most Influential Churches in America for pioneering video venues, leading the multi-site movement, sermon-based small groups, missonal community service and shared leadership. Osborne, who is also president of the North Coast Training Network, has written books including Sticky Teams, Keeping Your Leadership Team and Staff on the Same Page—winner of Christianity Today's Golden Canon 2010 Leadership Book Award—Sticky Church, Ten Dumb Things Smart Christians Believe, A Contrarian's Guide to Knowing God, Spirituality for the Rest of Us and The Unity Factor.
Other Ministry Forum sponsors were Chick-fil-A, Spirit 88.9 radio, Growing Healthy Churches, Link Care Center, Dumont Printing and Mailing, Christian Business Men's Connection, The Pacific District Conference of Mennonite Brethren Churches, Fresno/Madera Youth for Christ, Uncle Harry's Bagels, Producers Dairy, Wawona Foods and The Mennonite Brethren Foundation.
Many people have requested to have access to the Ivan and Beth Paz video. You can watch the video below, or download it here. Or, if you're interested in the audio files, here you go! Session 1 Session 2 Session 3
- Categories:
- University


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What sort of character would you call "Mary-Sue" ?
View Single Post
April 25th, 2007 (8:45 AM).
All Your Base Are Belong To Us
Join Date: May 2006
Location: France
Posts: 69
First of all, I'm not asking "What's a Mary-Sue ?". I know what it means : perfect or/and very clichéd character.
I recently read the beginning of a trainer fic in which a character was called Mary-Sue. It surprised me at first, and then I wondered : can a sane author call his/her character Mary-Sue (or Gary-Stu) ?
And then : If you, as an author, gave a character the name Mary-Sue or Gary-Stu, what would be the character like ?
(I hope this topic hasn't already been done... sorry if it has).
Sorry for my poor English and lack of vocabulary.
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Editors' Note: The download button opens the iTunes App Store, where you may continue the download process. You must have iTunes installed with an active iTunes account in order to download and install the software. This download may not be available in some countries.
Publisher's Description+
What's new in this version:
- New symbol for Assembly point- New color picker with 6 standard colors. - A bug that made the app to crash is now solved


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Boris Doris
Where It's At:
The Wherehouse, a 5,000-square-foot, beautifully renovated old cooperage with bars, dance floors and party rooms, and the adjacent Hot Water, are hot. Last week, the first of Scott RobbeŌĆÖs summer music and party series called ŌĆ£Sound and VisionŌĆØ was launched with FUNK, spotlighting ChicagoŌĆÖs master of funk DJ Plez (Michael Pleasants) and the retro FUNK sound by Milwaukee native Andy Noble of the Noble Brothers.
The psychedelic ŌĆ£video wallpaperŌĆØ projected on the wall was spectacular. ŌĆ£Cocktail specials for the New DepressionŌĆØ were served by dynamic dancing bartenders Adam Garringer and Mitchell Olszewski. The latter also designed the hotwatermilwaukee.com site. Fancy hula-hooping put another exciting spin on the revelry. Anna Stone, head of Hoop Vive, performed with students Rita Burlingame and mother/daughter duo Kristi and Lindsey Tarantino.
Stopping by were Mike Ralph and Ken Wolf, regulars at the WherehouseŌĆÖs ballroom and swing dancing nights, while Susan Winecki and Kathy Carter were first-time Wherehouse partiers.
Bar owner Paul Mueller and GM Adam Smith circulated, as did RobbeŌĆÖs assistant Jonathan Bare, who also kept an eye on the door. In his former life, Robbe, now Film WisconsinŌĆÖs executive director, managed NYCŌĆÖs Tunnel Nightclub and produced shows at the Limelight. His next not-to-be-missed ŌĆ£Sound and VisionŌĆØ is coming up June 11. For the Cause: Battling CrohnŌĆÖs disease hasnŌĆÖt slowed down UW-Milwaukee grad Marie Barabas. SheŌĆÖs working at the Medical College of Wisconsin and starting graduate school this fall to pursue a doctorate. Barabas has pledged to raise $6,000 for the CrohnŌĆÖs & Colitis Foundation of America and just held a fun fund-raiser at Don KrauseŌĆÖs Art Bar. Delicious Transfer pizza was shared; Allen Russell and James Redding from Union Pulse performed; and BarabasŌĆÖ artist friendsŌĆöglass-blower Patrick Bennette, painter Nicki Gerstner, MIAD grad Jessica Manske and jewelry designer Melinda HeilmanŌĆödonated a portion of their eveningŌĆÖs sales.
Among the attendees were UWM grad student Matthew Youngblut and his brother, Nick; Karen Olson; volunteer Amber Campbell; Tyrone Luckett; and Chicagoan Ryan Nagel. The lucky raffle winners included Patrick Kerstein, earning burrito bucks from Chipotle; Eric Mattson, capturing a Lakefront Brewery six-pack; and Holly Gerstner, taking the $100 grand prize. BarabasŌĆÖ next fundraiser will be June 6 at Live on North with a fashion show featuring HammŌĆÖs Universal Fashions, hopping music by DJ Machi and free Pizza Shuttle pizza.
Raising the Bar: Attorney Craig Mastantuono has been hosting annual fund-raisers for the Boys & Girls Clubs at his law office on Marshall Street for the past eight years. His most recent soiree attracted a beneficent bunch of more than 75, who tossed a collective $10,000 into the pot. The proceeds are earmarked for the Ethan Allen School in Wales, aiming to help prevent juvenile delinquency.
Mayor Tom Barrett stopped by the party before running off to deliver MATCŌĆÖs commencement address. The room overflowed with legal types, including Judges Bill Pocan, Karen Christenson and Glenn Yamahiro, as well as the newly appointed Stephanie Rothstein; plus attorneys Rebecca Coffee, Nancy Corbin, Benjamin Wagner, Jeremy Levinson, Joe Peltz and Yvonne Vegas. State Rep. Pedro Colon mingled.
Among the non-legalese were Jim Clark, CEO of the Boys & Girls Clubs, and their programs VP Denisha Tate; and Channel 12ŌĆÖs Colleen Henry and her husband, Steve Kohn. Assistant U.S. Attorney James Santelle, a finalist for the U.S. Attorney for WisconsinŌĆÖs Eastern District, made the rounds.
River Art: For the 12th time, RiverSculpture is adorning MilwaukeeŌĆÖs RiverWalk. This year, Marsha Sehler, the force behind the project, found jewelry designer and artist John Ready, who subsequently created an imaginative collection of ŌĆ£River GemsŌĆØ to adorn the bridges, bridge houses and balconies along the reconstituted waterway.
Using ŌĆ£re-purposed objects,ŌĆØ everything from pots and pans to polished bowling balls, the ŌĆ£jewelryŌĆØ draws attention to the beautiful architectural elements along the river, according to Sehler.
Check out the fanciful displays at the 20th annual RiverSplash! this weekend. Artful Digs: The DeLind Gallery celebrated the grand opening of its beautiful new digs, now at the south entrance of George Watts & Son. Owner Bill DeLind is thrilled with the smaller footprint, but one that has almost equal linear feet of wall space as his previous digs. Supporters dropped in throughout the evening: Richard Yahr and Cherryl Erlandson; hair designer Dean DiPlaris, now at Le Court Salons on Jackson after more than two decades at the PfisterŌĆÖs Janice Salon; Chris Bauer, back from Florida; attorney Alyce Katayama; the Greater Milwaukee FoundationŌĆÖs Doris Heiser and her husband, attorney Ed Heiser; Fred and Kay Austermann; etiquette diva Margery Sinclair; art consultant Catherine Davidson; consultant Tim Murphy; and Cindy Molloy, owner of MolloyŌĆÖs. DeLind employees Michael Goforth, Pam Brown and Tina Bertoni ensured that the event ran smoothly.
If you have any tips for Boris and Doris, contact them at firstname.lastname@example.com. Their next column will appear in the June 18 issue of the Shepherd.


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The wallpaper is an image file that replaces the Ninemsn background on the page and allows advertisers to brand the Ninemsn page with their messaging. The network wallpaper can be setup to be either clickable or non-clickable.
a. The wallpaper must be Ninemsn served and image asset should be provided to Ninemsn
b. The background colour may be set to either black or white and will be visible when users have a high monitor resolution
c. Please ensure that the wallpaper contains a 1030px wide non visible space in the middle
d. It is recommended that all key messaging appears in first 150px outside the website content area. This is to ensure high visibility to users across multiple screen resolutions.
e. All concepts/storyboards must be submitted 10 working days before the campaign to ensure that the concept complies with the Ninemsn brand/design specifications.


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This cam controls the heater control that changes it from hot to cold. So the heater control switch is not connected to anything. I am not sure what that parts name is so no one can seem to help me order another one. Can anyone help me with this???
by jhyakima in Yakima, WA on April 14, 2012


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It burns! IT BUUUUUURNS!!!!Continue reading
Category Archives: actual conversations
We are definitely, positively, absolutely LOST.Continue reading
It's all going to be okay.Continue reading
There's one on every bus. The person who didn't take their meds this morning, the person your mama warned you about, the person who shouldn't be allowed in public without a nanny or a caregiver or a lion tamer. That … Continue reading
Me: My basil died. The World: Who the hell is Basil? What did you do to him? Are the police involved?! Me: No, asshole. My BASIL. The herb. My basil plant died. The World: We're…sorry for your loss? Me: I … Continue reading
I survive on logic and reason. And nothing lately has made any sense, been logical, or reasonable.Continue reading
"If you had listened to me in the first place, none of this would have ever happened."Continue reading


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Amgen Gets a Lift in Deal With Takeda
Biotech giant Amgen Inc., AMGN 1.36 % hurt by plunging sales of its flagship anemia drug, offloaded some financial risk by striking a licensing deal worth as much as $1.19 billion plus royalties with Japanese drug maker Takeda Pharmaceutical Co. TKPYY -1.39 %
The deal gives Takeda marketing rights -- in Japan and in Asia -- to 13 products in Amgen's development pipeline.
Amgen has been beset by safety concerns and regulatory rulings that have undercut its anemia drug Aranesp. The deal means that Takeda is picking up some of the near-term research expenses for a share of potential long-term profits on experimental drugs to treat cancer, inflammation and pain.
Under terms of the deal, Takeda also will buy Amgen's Japanese subsidiary Amgen KK, which has 160 employees, for an undisclosed sum. Takeda will not end up with any stake in Amgen Inc. itself, according to Amgen spokesman David Polk.
Amgen Chief Executive Kevin Sharer characterized the deal as capitalizing on the strength of the Thousand Oaks, Calif., company's pipeline, rather than signaling any weakness in its prospects. Amgen stock, which has lost roughly a third of its value over the past year, fell 18 cents to $47.18 yesterday in 4 p.m. Nasdaq Stock Market composite trading.
"We've got more molecules than we can develop," Mr. Sharer said yesterday. "Even spending 22% of our revenues [on R&D] isn't enough to develop everything in Asia, North America and Europe."
Michael Aberman, a securities analyst with Credit Suisse in New York, said the Takeda pact "gives me confidence" in Amgen's management of expenses and profit goals. However, he said management should go further and seek a buyer for the company to maximize the value of potential future products, such as an osteoporosis drug that would be prescribed by primary-care doctors -- a market in which Amgen has little sales experience.
However, Mr. Sharer said he won't undertake any move that compromises Amgen's independence. "Quite the reverse," he said. "We're not signaling any change in strategic intent. It's just a reasonable investment choice" that lets Amgen focus on markets it knows best in Europe and the U.S.
Talks began last summer as Amgen shared its lab notebooks and data with candidate partners in Japan. Takeda emerged as "the most authoritative and capable" ally to drive development in Japan, where regulatory and clinical-trial conduct differs from comparable procedures in the U.S. and Europe.
The deal excludes the most promising product in Amgen's pipeline, the bone-building drug denosumab, or D-mab. Amgen already had agreed to share some Japanese marketing rights for D-mab with another partner, Daiichi Sankyo. DSNKY 0.19 %
The new pact grants Takeda exclusive rights to develop and commercialize 13 other products in Japan. Takeda's payments to Amgen includes $200 million up front and as much as $340 million to help defray expected world-wide development costs over the next several years, plus $362 million of success-based milestone payments and double-digit royalties on sales in Japan.
The deal includes a global partnership for AMG 706, a novel small-molecule drug that tamps down vessel growth that feeds tumors. For this compound, Takeda will pay Amgen an additional $100 million up front, $175 million more upon meeting certain research milestones and double-digit royalties on any sales in Japan. Outside Japan, the companies would evenly split any future profit on this compound.
Takeda's purchase of Amgen KK is expected to close in March.
Securities analysts took the deal in stride.
"I wouldn't read that much into this deal," said Eric Schmidt of Cowen and Co. "It is relatively modest in terms of financials ... and products," he said, adding that "Few ascribe much value for any of the products in this transaction."
"I don't think Takeda will end up buying Amgen," Mr. Schmidt said, dismissing any prospect of a merger. "The deal should improve operating performance for the next few years." Amgen said the deal won't affect its 2008 earnings guidance of $4 to $4.30 a share, excluding stock options.
A year ago, Amgen traded near $70 a share until the impact of anemia-drug safety concerns -- including a heightened risk of cardiovascular problems and progression of certain cancers -- eroded the company's stock price by roughly a third. Next month, Amgen returns to Washington to face the oncology-drugs advisory committee of the Food and Drug Administration, as the agency tries to determine the extent of anemia-drug risks and limits to safe use.
Write to Marilyn Chase at firstname.lastname@example.com


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Friday, August 15, 2014
0 Comments | Copyright: IANS
Producer Guneet Monga, known for backing content-driven films such as "Gangs Of Wasseypur" and "The Lunchbox", has been named among the 'Most Powerful Women in Indian Business' by a magazine.
Having produced over 20 feature films and 75 short movies, Monga was felicitated alongside corporate and industry big-wigs like Nishi Vasudeva, Pallavi Shroff and Ekta Kapoor among others here.
"I am extremely honoured and grateful to receive this award. It is truly humbling to stand amongst inspiring women icons who have leaned in and made a huge difference in businesses across industries," she said in a statement.
This recognition comes just months after her being voted in the list of powerful women in media and entertainment by international publications such as The Hollywood Reporter and Variety.
Monga has collaborated with Anurag Kashyap to spearhead notable films like "Gangs of Wasseypur", "Shaitan" and "That Girl in Yellow Boots", while under her production house Sikhya Entertainment, she has co-produced movies like "The Lunchbox", "Peddlers", "Shahid" and the soon-to-be released projects "Monsoon Shootout" and "Vakratunda Mahakaaya".
Her films have represented Indian cinema at various film festivals abroad and have garnered international audiences.
Recently, she finished the production of another of her upcoming films, a musical titled "Zubaan" directed by Mozez Singh.
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Lab Girl by Hope Jahren
A frank, illuminating and incandescent memoir by a trailblazing scientist that will make you look at the natural world in a whole new light.
Buy here
The Last Painting of Sara de Vos by Dominic Smith
A literary novel of breathtaking scope, ambition and achievement.
A fourteen day desert journey into the heart of your writing or creative expression with Jan Cornall.
26 Jan - 8 Feb, 2017Book here


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Some Fall color, Colorado, 19th September, Aspen
Started Oct 4, 2012 | Discussions thread
Shop cameras & lenses ▾
bills_pix • Contributing Member • Posts: 541
Re: Some Fall color, Colorado, 19th September, Aspen
Looks like you got some great color at Maroon Bells. Nice shots.
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Published by Midway, Developed by Midway
Genres: Sports
US release date: - | EU release date: -
TNA iMPACT has no review on Wii's World.
TNA>WWE said:
TNA is the best on TV. Spike TV 9PM on Thursday Nights. Tune in for high flying action.
Link said:
TNA>WWE, TNA is the best wrestling show ever and it is obviously will be great on the Wii.
No.1 hardy fan said:
Bret Hart got screwed! F@%$ Vince!
Ekaj185 said:
I can't watch this show, I don't have the channel. Greenday watches Spike TV. Greenday is the best band EVER!
Vince Mcmahon said:
Well, guess what No. 1 hardy fan. I got two words for ya. YYYYYYOOOOOOUUUUURRRRRRR FIRED!
chanus said:
Isn't j hardy on raw now.
oli said:
Tna is the shizneh! Russo is king!
Boogeyman said:
I'm the boogeyman! And I'm comin to getcha!
Gonzo said:
Na, I'm waiting for WWE.
Gonzo said:
Isn't the Boogeyman in WWE now? He was a few months ago, I don't know about now.
DarkVic said:
I would like to see a WWE game on the Wii. Not really a TNA fan, but seeing as this is the only wrestling game that is for the Wii at the moment, I will most likely get it.
hardy-fan2 said:
WWE is better then TNA by a long shot. Vince Mcmahon I don't know when you posted your comment, but now he's dead.
Gonzo said:
Word, WWE is way better!
Luigi said:
What the! At least TNA is real. WWE is fake. They plan everything.
Ian C said:
My dad thinks Vince is alive.
Rick said:
TNA is NOT real. ALL (well, 99.9%) storylines are scripted (kayfabe). This includes the WWE. Only stuff like UFC is real! Duh.
Leon Kennedy said:
Is great KHALI appearing in this game?
Dablackluigi said:
TNA is so horrible now. They used to be great with their original talent, but now they suck. The X-division and their tag teams was better than anything the WWE showed in years. TNA has now ruined itself by hiring and hyping WWE leftover wrestlers and giving their original talent the scraps.
Gza said:
TNA is real? When did this happen? All professional wrestling is scripted, or choreographed. Oh, and DarkVic/Gonzo, I'm not sure when you guys posted. But there are already 2 announced WWE Wii Games, one of which has been out for months. Leon Kennedy- Khali is a part of WWE, so. No, he won't be appearing on iMPACT! :D But yeah, anyway, I prefer watching WWE, but I think TNA's got a more talented Roster and can't wait to play as Rhino again.
Nintendo President Satoru Iwata Passes Away at 55
Rest In Peace
Nintendo has detailed the return of its World Championship
Do you have what it takes?
Disney Infinity 3.0 Edition Officially Revealed
The Force is strong with this one...
Rumor: Disney Infinity 3.0 Leaked Early
Straight from a Galaxy Far, Far Away...
Mario Kart 8 DLC Pack 2...OH YEAAAAH!
Nintendo should do this more.
The Nintendo GameCube: An Interesting Legacy
Will The Wii U Have a Similar Fate?
Project Ukulele - Possible Hint at Characters
Could it be?
Free to Play Pokemon Shuffle now available on 3DS eShop
Nintendo offers another micro-transaction based title
Gold Mario Amiibo is a Wal-Mart Exclusive
Get ready to shell out your coins
Area Effect Announces Izle for Wii U
Part action, part adventure, all cel-shaded
Planes: Fire & Rescue
Released on November 6th, 2014
The Voice: I Want You
Released on October 21st, 2014
Skylanders Trap Team
Released on October 5th, 2014
Wipeout: Create & Crash
Angry Birds Star Wars
Released on October 29th, 2013
yoshi said:
jrncn bbmrban ... Controller compatibility chart
yoshi said:
i have a wii ... Controller compatibility chart
Tigerbaby said:
I love resident of 4 ... Resident Evil Revelations 2 is Skipping Nintendo Systems
Andrew Gray said:
Hey Jeremy, just recently started the game myself. Would you mind sending me your gathering hall/hunter info later? If ... Monster Hunter 4 Ultimate review
johnfell said:
sghujd ... iWin supporting Virtual Console
Wii's World is not officially affiliated with Nintendo! (but they wish we were).


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