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26.  Association between statin therapy and outcomes in critically ill patients: a nested cohort study 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1472-6904-11-12
PMCID: PMC3199769  PMID: 21819615
27.  An evaluation of ciprofloxacin pharmacokinetics in critically ill patients undergoing continuous veno-venous haemodiafiltration 
Background
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.
Methods
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.
Results
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.
Conclusions
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
doi:10.1186/1472-6904-11-11
PMCID: PMC3161942  PMID: 21816053
28.  The effects of polyunsaturated fatty acids in alcohol dependence treatment - a double-blind, placebo-controlled pilot study 
Background
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.
Methods
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.
Results
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.
Conclusions
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
NCT01211769
doi:10.1186/1472-6904-11-10
PMCID: PMC3162484  PMID: 21787433
29.  Comparative in vitro study of the antimicrobial activities of different commercial antibiotic products of vancomycin 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-11-9
PMCID: PMC3158544  PMID: 21777438
30.  Comparison of renal effects of ibuprofen versus indomethacin during treatment of patent ductus arteriosus in contiguous historical cohorts 
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1186/1472-6904-11-8
PMCID: PMC3150255  PMID: 21718490
31.  No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study 
Background
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.
Methods
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.
Results
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.
Conclusions
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
doi:10.1186/1472-6904-11-7
PMCID: PMC3127977  PMID: 21631929
32.  The future of pharmaceutical care in France: a survey of final-year pharmacy students' opinions 
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-11-6
PMCID: PMC3115856  PMID: 21612642
33.  Drug safety of rosiglitazone and pioglitazone in France: a study using the French PharmacoVigilance database 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-11-5
PMCID: PMC3119167  PMID: 21609444
34.  Use, tolerability and compliance of spironolactone in the treatment of heart failure 
Background
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.
Methods
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).
Results
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).
Conclusion
Use of spironolactone is associated with an incidence of adverse events, which may have an impact on treatment compliance.
doi:10.1186/1472-6904-11-4
PMCID: PMC3121672  PMID: 21599961
35.  Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies 
Background
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.
Methods
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.
Results
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.
Conclusions
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).
doi:10.1186/1472-6904-11-3
PMCID: PMC3070638  PMID: 21414193
36.  Constipation and diarrhoea - common adverse drug reactions? A cross sectional study in the general population 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-11-2
PMCID: PMC3049147  PMID: 21332973
37.  Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer 
Background
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.
Methods
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.
Results
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.
Conclusions
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
doi:10.1186/1472-6904-11-1
PMCID: PMC3045896  PMID: 21291562
38.  Increasing polypharmacy - an individual-based study of the Swedish population 2005-2008 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-10-16
PMCID: PMC3014875  PMID: 21122160
39.  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 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-10-15
PMCID: PMC2974660  PMID: 20964869
40.  Comparison of the pharmacokinetics, safety and tolerability of two concentrations of a new liquid recombinant human growth hormone formulation versus the freeze-dried formulation 
Background
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.
Methods
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).
Results
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.
Conclusion
Both concentrations of a new liquid multi-dose formulation are bioequivalent to the FD reference formulation and all are well tolerated.
Trial registration number
NCT01034735.
doi:10.1186/1472-6904-10-14
PMCID: PMC2987775  PMID: 20961422
41.  Pharmacokinetic comparability of Prolastin®-C to Prolastin® in alpha1-antitrypsin deficiency: a randomized study 
Background
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.
Methods
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.
Results
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.
Conclusion
Prolastin-C demonstrated pharmacokinetic equivalence and a comparable safety profile to Prolastin.
Trial Registration
ClinicalTrials.gov Identifier: NCT00295061
doi:10.1186/1472-6904-10-13
PMCID: PMC2958874  PMID: 20920295
42.  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 
Background
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.
Methods
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).
Results
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).
Conclusions
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
doi:10.1186/1472-6904-10-12
PMCID: PMC2955588  PMID: 20920236
43.  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 
Background
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.
Methods
We conducted a cross-sectional survey among adult people living with HIV/AIDS (PLWHA) through a structured questionnaire.
Results
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.
Conclusion
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.
doi:10.1186/1472-6904-10-11
PMCID: PMC2949664  PMID: 20849595
44.  The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-10-10
PMCID: PMC2906415  PMID: 20602760
45.  Traumeel S® for pain relief following hallux valgus surgery: a randomized controlled trial 
Background
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.
Method
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.
Results
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).
Conclusions
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
doi:10.1186/1472-6904-10-9
PMCID: PMC2873239  PMID: 20380750
46.  Assessing Safety Culture in Pharmacies: The psychometric validation of the Safety Attitudes Questionnaire (SAQ) in a national sample of community pharmacies in Sweden 
Background
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
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-10-8
PMCID: PMC2868807  PMID: 20380741
47.  Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis - An open clinical trial- 
Background
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.
Methods
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.
Results
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.
Conclusions
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
doi:10.1186/1472-6904-10-7
PMCID: PMC2873929  PMID: 20346179
48.  Use of analgesics in intentional drug overdose presentations to hospital before and after the withdrawal of distalgesic from the Irish market 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-10-6
PMCID: PMC2858125  PMID: 20298551
49.  EVITA: a tool for the early EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6904-10-5
PMCID: PMC2858124  PMID: 20233429
50.  Characteristics of primary health care units with focus on drug information from the pharmaceutical industry and adherence to prescribing objectives: a cross-sectional study 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1472-6904-10-4
PMCID: PMC2831842  PMID: 20156362

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