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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  Comparative in vitro study of the antimicrobial activities of different commercial antibiotic products for intravenous administration 
Background
The antimicrobial resistance is a global problem, probably due to the indiscriminate and irrational use of antibiotics, prescriptions for incorrect medicines or incorrect determinations of dose, route and/or duration. Another consideration is the uncertainty of patients receiving antibiotics about whether the quality of a generic medicine is equal to, greater than or less than its equivalent brand-name drug. The antibiotics behaviors must be evaluated in vitro and in vivo in order to confirm their suitability for therapeutic use.
Methods
The antimicrobial activities of Meropenem and Piperacillin/Tazobactam were studied by microbiological assays to determine their potencies (content), minimal inhibitory concentrations (MICs), critical concentrations and capacity to produce spontaneous drug-resistant mutants.
Results
With respect to potency (content) all the products fulfill USP requirements, so they should all be considered pharmaceutical equivalents. The MIC values of the samples evaluated (trade marks and generics) were the same for each strain tested, indicating that all products behaved similarly. The critical concentration values were very similar for all samples, and the ratios between the critical concentration of the standard and those of each sample were similar to the ratios of their specific antibiotic contents. Overall, therefore, the results showed no significant differences among samples. Finally, the production of spontaneous mutants did not differ significantly among the samples evaluated.
Conclusions
All the samples are pharmaceutical equivalents and the products can be used in antimicrobial therapy.
doi:10.1186/1472-6904-10-3
PMCID: PMC2830186  PMID: 20113478
15.  Reporting randomised clinical trials of analgesics after traumatic or orthopaedic surgery is inadequate: a systematic review 
Background
Several randomised clinical trials (RCTs) of analgesics in postoperative pain after traumatic or orthopaedic surgery (TOS) have been published, but no studies have assessed the quality of these reports. We aimed to examine the quality of reporting RCTs on analgesics for postoperative pain after TOS.
Methods
Reports of RCTs assessing analgesics in postoperative pain after TOS were systematically searched from electronic databases. The quality of reports was assessed using the CONSORT checklist (scoring range from 0 to 22). The quality was considered poor when scoring was 12 or lesser. The publication year and the impact factor of journals were recorded.
Results
A total of 92 reports of RCTs were identified and 69 (75%) scored 12 or lesser in CONSORT checklist (range 5-17). The mean (SD) CONSORT score of all reports was 10.6 (2.7). Missing CONSORT items included primary and secondary outcome measures (11%), the specific objectives and hypothesis definition (12%), the sample size calculation (12%), the dates defining the periods of recruitment (12%), the discussion of external validity of findings (14%), the allocation sequence generation (24%), and the interpretation of potential bias or imprecision of results (25%). There was a little improvement in CONSORT scores over time (r = 0.62; p < 0.001) and with impact factor of journals (r = 0.30; p < 0.001).
Conclusion
Quality of reporting RCTs on analgesics after TOS is poor. Reporting of those RCTs should be improved according to methodological standard checklists in the next years.
doi:10.1186/1472-6904-10-2
PMCID: PMC2822812  PMID: 20067642
16.  Quantitative relationship between the octanol/water partition coefficient and the diffusion limitation of the exchange between adipose and blood 
Background
The goal of physiologically based pharmacokinetics (PBPK) is to predict drug kinetics from an understanding of the organ/blood exchange. The standard approach is to assume that the organ is "flow limited" which means that the venous blood leaving the organ equilibrates with the well-stirred tissue compartment. Although this assumption is valid for most solutes, it has been shown to be incorrect for several very highly fat soluble compounds which appear to be "diffusion limited". This paper describes the physical basis of this adipose diffusion limitation and its quantitative dependence on the blood/water (Kbld-wat) and octanol/water (Kow) partition coefficient.
Methods
Experimental measurements of the time dependent rat blood and adipose concentration following either intravenous or oral input were used to estimate the "apparent" adipose perfusion rate (FA) assuming that the tissue is flow limited. It is shown that the ratio of FA to the anatomic perfusion rate (F) provides a measure of the diffusion limitation. A quantitative relationship between this diffusion limitation and Kbld-wat and Kow is derived. This analysis was applied to previously published data, including the Oberg et. al. measurements of the rat plasma and adipose tissue concentration following an oral dose of a mixture of 13 different polychlorinated biphenyls.
Results
Solutes become diffusion limited at values of log Kow greater than about 5.6, with the adipose-blood exchange rate reduced by a factor of about 30 for a solute with a log Kow of 7.36. Quantitatively, a plot of FA/F versus Kow is well described assuming an adipose permeability-surface area product (PS) of 750/min. This PS corresponds to a 0.14 micron aqueous layer separating the well-stirred blood from the adipose lipid. This is approximately equal to the thickness of the rat adipose capillary endothelium.
Conclusions
These results can be used to quantitate the adipose-blood diffusion limitation as a function of Kow. This is especially important for the highly fat soluble persistent organic chemicals (e.g. polychlorinated biphenyls, dioxins) whose pharmacokinetics are primarily determined by the adipose-blood exchange kinetics.
doi:10.1186/1472-6904-10-1
PMCID: PMC2845558  PMID: 20055995

Results 1-16 (16)