Views of pharmacy graduates and pharmacist tutors on evidence-based practice in relation to over-the-counter consultations: a qualitative study

RATIONALE, AIMS AND OBJECTIVES: Health care services offered to the public should be based on the best available evidence. We aimed to explore pharmacy tutors' and trainees' views on the importance of evidence when making decisions about over-the-counter (OTC) medicines and also to investigate whether the tutor influenced the trainee in practice.

METHODS: Following ethical approval and piloting, semi-structured interviews were conducted with pharmacy graduates (trainees) and pharmacist tutors. Transcribed interview data were entered into the NVivo software package (version 10), coded and analysed via thematic analysis.

RESULTS: Twelve trainees (five males, seven females) and 11 tutors (five males, six females) participated. Main themes that emerged were (in)consistency and contradiction, confidence, acculturation, and continuation and perpetuation. Despite having an awareness of the importance and potential benefits, an evidence-based approach did not seem to be routinely or consistently implemented in practice. Confidence in products was largely derived from personal use and patient feedback. A lack of discussion about evidence was justified on the basis of not wanting to lessen patient confidence in requested product(s) or possibly negating the placebo effect. Trainees became acculturated to 'real-life' practice; university teaching and evidence was deemed less relevant than meeting customer expectations. The tutor's actions were mirrored by their trainee resulting in continuation and perpetuation of the same professional attitudes and behaviours.

CONCLUSIONS: Evidence appeared to have limited influence on OTC decision making. The tutor played a key role in the trainee's professional development. More work could be performed to investigate how evidence can be regarded as relevant and something that is consistently implemented in practice.

Effect of lycopene supplementation on insulin-like growth factor-1 and insulin-like growth factor binding protein-3: a double-blind, placebo-controlled trial

Objective: Studies have suggested a link between lycopene and insulin-like growth factor-1 ( IGF-1). The aim of this study was to test the effect of lycopene supplementation on IGF-1 and binding protein-3 ( IGFBP-3) status in healthy male volunteers.

Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomised placebo controlled trial

OBJECTIVE: To test whether simvastatin improves physiological and biological outcomes in patients undergoing esophagectomy.

BACKGROUND: One-lung ventilation during esophagectomy is associated with inflammation, alveolar epithelial and systemic endothelial injury, and the development of acute lung injury (ALI). Statins that modify many of the underlying processes are a potential therapy to prevent ALI.

METHODS: We conducted a randomized double-blind placebo-controlled trial in patients undergoing esophagectomy. Patients received simvastatin 80 mg or placebo enterally for 4 days preoperatively and 7 days postoperatively. The primary end point was pulmonary dead space (Vd/Vt) at 6 hours after esophagectomy or before extubation. Inflammation was assessed by plasma cytokines and intraoperative exhaled breath condensate pH; alveolar type 1 epithelial injury was assessed by plasma receptor for advanced glycation end products and systemic endothelial injury by the urine albumin-creatinine ratio.

RESULTS: Thirty-nine patients were randomized; 8 patients did not undergo surgery and were excluded. Fifteen patients received simvastatin and 16 received placebo. There was no difference in Vd/Vt or other physiological outcomes. Simvastatin resulted in a significant decrease in plasma MCP-1 on day 3 and reduced exhaled breath condensate acidification. Plasma receptor for advanced glycation end products was significantly lower in the simvastatin-treated group, as was the urine albumin-creatinine ratio on day 7 postsurgery. ALI developed in 4 patients in the placebo group and no patients in the simvastatin group although this difference was not statistically significant (P = 0.1).

CONCLUSIONS: In this proof of concept study, pretreatment with simvastatin in esophagectomy decreased biomarkers of inflammation as well as pulmonary epithelial and systemic endothelial injury.

The short-term effect of topical dorzolamide compared with placebo on perimetry testing in normal subjects

Purpose. To study the effect of topical dorzolamide on retinal sensitivity in normal subjects. Methods. 20 normal subjects were prospectively randomized in a two period crossover study. Baseline threshold perimetry (HVF, program 24-2, Statpac analysis) was obtained. The study eye was randomly chosen and then was randomly assigned to receive either dorzolamide 2% or placebo one hour before repeat HVF. After at least two weeks washout the same eye was given the opposite drop one hour prior to repeat HVF. Global indices were compared using a paired T-test. Results. AFTER PLACEBO AFTER DORZOLAMIDE P-VALUE (mean±SD) (mean±SD) MD 0.12±1.4 0.16±1.4 0.82 PSD 1.83±0.6 1.66±0.4 0.04 SF 1.28±0.4 1.24±0.2 0.73 CPSD 1.05±0.9 0.84±0.6 0.35 Conclusion. In this population, topical dorzolamide had little effect on visual function.

The effect of multiple micronutrient supplementation on left ventricular ejection fraction in patients with chronic stable heart failure: a randomized, placebo-controlled trial:A randomized, placebo-controlled trial

Objectives: This study sought to investigate the effect of a multiple micronutrient supplement on left ventricular ejection fraction (LVEF) in patients with heart failure. Background: Observational studies suggest that patients with heart failure have reduced intake and lower concentrations of a number of micronutrients. However, there have been very few intervention studies investigating the effect of micronutrient supplementation in patients with heart failure. Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study involving 74 patients with chronic stable heart failure that compared multiple micronutrient supplementation taken once daily versus placebo for 12 months. The primary endpoint was LVEF assessed by cardiovascular magnetic resonance imaging or 3-dimensional echocardiography. Secondary endpoints were Minnesota Living With Heart Failure Questionnaire score, 6-min walk test distance, blood concentrations of N-terminal prohormone of brain natriuretic peptide, C-reactive protein, tumor necrosis factor alpha, interleukin-6, interleukin-10, and urinary levels of 8-iso-prostaglandin F2 alpha. Results: Blood concentrations of a number of micronutrients increased significantly in the micronutrient supplement group, indicating excellent compliance with the intervention. There was no significant difference in mean LVEF at 12 months between treatment groups after adjusting for baseline (mean difference: 1.6%, 95% confidence interval: -2.6 to 5.8, p = 0.441). There was also no significant difference in any of the secondary endpoints at 12 months between treatment groups. Conclusions: This study provides no evidence to support the routine treatment of patients with chronic stable heart failure with a multiple micronutrient supplement. (Micronutrient Supplementation in Patients With Heart Failure [MINT-HF]; NCT01005303).

Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU):A randomised, double-blind, placebo-controlled trial

Background: Delirium is frequently diagnosed in critically ill patients and is associated with poor clinical outcomes. Haloperidol is the most commonly used drug for delirium despite little evidence of its effectiveness. The aim of this study was to establish whether early treatment with haloperidol would decrease the time that survivors of critical illness spent in delirium or coma. Methods: We did this double-blind, placebo-controlled randomised trial in a general adult intensive care unit (ICU). Critically ill patients (≥18 years) needing mechanical ventilation within 72 h of admission were enrolled. Patients were randomised (by an independent nurse, in 1:1 ratio, with permuted block size of four and six, using a centralised, secure web-based randomisation service) to receive haloperidol 2·5 mg or 0·9% saline placebo intravenously every 8 h, irrespective of coma or delirium status. Study drug was discontinued on ICU discharge, once delirium-free and coma-free for 2 consecutive days, or after a maximum of 14 days of treatment, whichever came first. Delirium was assessed using the confusion assessment method for the ICU (CAM-ICU). The primary outcome was delirium-free and coma-free days, defined as the number of days in the first 14 days after randomisation during which the patient was alive without delirium and not in coma from any cause. Patients who died within the 14 day study period were recorded as having 0 days free of delirium and coma. ICU clinical and research staff and patients were masked to treatment throughout the study. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN83567338. Findings: 142 patients were randomised, 141 were included in the final analysis (71 haloperidol, 70 placebo). Patients in the haloperidol group spent about the same number of days alive, without delirium, and without coma as did patients in the placebo group (median 5 days [IQR 0-10] vs 6 days [0-11] days; p=0·53). The most common adverse events were oversedation (11 patients in the haloperidol group vs six in the placebo group) and QTc prolongation (seven patients in the haloperidol group vs six in the placebo group). No patient had a serious adverse event related to the study drug. Interpretation: These results do not support the hypothesis that haloperidol modifies duration of delirium in critically ill patients. Although haloperidol can be used safely in this population of patients, pending the results of trials in progress, the use of intravenous haloperidol should be reserved for short-term management of acute agitation. Funding: National Institute for Health Research. © 2013 Elsevier Ltd.

The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus.

OBJECTIVE: To determine the effect of dietary supplementation with omega-3 fish oils with or without copper on disease activity in systemic lupus erythematosus (SLE). Fish oil supplementation has a beneficial effect on murine models of SLE, while exogenous copper can decrease the formation of lupus erythematosus cells in rats with a hydralazine-induced collagen disease. METHODS: A double blind, double placebo controlled factorial trial was performed on 52 patients with SLE. Patients were randomly assigned to 4 treatment groups. Physiological doses of omega-3 fish oils and copper readily obtainable by dietary means were used. One group received 3 g MaxEPA and 3 mg copper, another 3 g MaxEPA and placebo copper, another 3 mg copper and placebo fish oil, and the fourth group received both placebo capsules. Serial measurements of disease activity using the revised Systemic Lupus Activity Measure (SLAM-R) and peripheral blood samples for routine hematological, biochemical, and immunological indices were taken at baseline, 6, 12, and 24 weeks. RESULTS: There was a significant decline in SLAM-R score from 6.12 to 4.69 (p <0.05) in those subjects taking fish oil compared to placebo. No significant effect on SLAM-R was observed in subjects taking copper. Laboratory variables were unaffected by either intervention. CONCLUSION: In the management of SLE, dietary supplementation with fish oil may be beneficial in modifying symptomatic disease activity.

Effect of pioglitazone on endothelial function in impaired glucose tolerance

Aim: Flow-mediated dilation (FMD) is a surrogate marker of endothelial function, which has been proposed as a barometer of vascular health. Impaired microvascular response to reactive hyperaemia is thought to be the mechanism behind reduced shear stress and subsequently impaired FMD, which has been associated with cardiovascular events. This study aims to assess the effect of pioglitazone on the vasculature of patients with impaired glucose tolerance (IGT).

Materials and Methods: Forty IGT patients with no cardiovascular disease were compared with 24 healthy age- and sex-matched controls. Endothelial function was assessed using FMD of the brachial artery. Adiponectin (ADN) levels were measured and insulin sensitivity was calculated using homeostasis model assessment of insulin resistance (HOMA-IR). A randomised double-blind placebo-controlled trial of the IGT subjects was then performed, with subjects receiving either pioglitazone 30 mg od or matched placebo for 12 weeks before the measurements were repeated.

Results: The IGT subjects had a significantly impaired FMD compared with the controls (p < 0.001). Diastolic shear stress (DSS) was also significantly reduced in IGT (p = 0.04). High molecular weight (HMW) ADN was significantly lower in the IGT group than in controls (p = 0.03). On analysis of the IGT group after 12 weeks treatment, FMD was significantly increased in the pioglitazone group compared with placebo (p = 0.03) as was endothelium-independent dilation (EID) (p = 0.03). A significant increase in total ADN (p < 0.001), HMW ADN (p < 0.001) and HMW/total ratio (p = 0.001) occurred in the pioglitazone group compared with placebo.

Conclusions: Pioglitazone improved endothelial function in IGT. Treatment with pioglitazone may reduce the risk of cardiovascular disease in this patient group.

Effect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial

BACKGROUND:
In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS.
METHODS:
We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged =16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 µg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO(2)/F(I)O(2)) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86.
FINDINGS:
We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08).
INTERPRETATION:
Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of ß-2 agonist treatment in ventilated patients with this disorder cannot be recommended.

The effect of lutein- and zeaxanthin-rich foods v. supplements on macular pigment level and serological markers of endothelial activation inflammation and oxidation pilot studies in healthy volunteers:pilot studies in healthy volunteers

The aim of the present study was to compare the effect of lutein- and zeaxanthin-rich foods and supplements on macular pigment level (MPL) and serological markers of endothelial activation, inflammation and oxidation in healthy volunteers. We conducted two 8-week intervention studies. Study 1 (n 52) subjects were randomised to receive either carrot juice (a carotene-rich food) or spinach powder (a lutein- and zeaxanthin-rich food) for 8 weeks. Study 2 subjects (n 75) received supplements containing lutein and zeaxanthin, ß-carotene, or placebo for 8 weeks in a randomised, double-blind, placebo-controlled trial. MPL, serum concentrations of lipid-soluble antioxidants, inter-cellular adhesion molecule 1, vascular cell adhesion molecule 1, C-reactive protein and F2-isoprostane levels were assessed at baseline and post-intervention in both studies. In these intervention studies, no effects on MPL or markers of endothelial activation, inflammation or oxidation were observed. However, the change in serum lutein and zeaxanthin was associated or tended to be associated with the change in MPL in those receiving lutein- and zeaxanthin-rich foods (lutein r 0.40, P = 0.05; zeaxanthin r 0.30, P = 0.14) or the lutein and zeaxanthin supplement (lutein r 0.43, P = 0.03; zeaxanthin r 0.22, P = 0.28). In both studies, the change in MPL was associated with baseline MPL (food study r - 0.54, P <0.001; supplement study r - 0.40, P <0.001). We conclude that this 8-week supplementation with lutein and zeaxanthin, whether as foods or as supplements, had no significant effect on MPL or serological markers of endothelial activation, inflammation and oxidation in healthy volunteers, but may improve MPL in the highest serum responders and in those with initially low MPL.

Antioxidants, but not B-group vitamins increase the resistance of low-density lipoprotein to oxidation:a randomized, factorial design, placebo-controlled trial

We have conducted an intervention trial to assess the effects of antioxidants and B-group vitamins on the susceptibility of low-density lipoprotein (LDL) to oxidation. A total of 509 men aged 30-49 from a local workforce were screened for total plasma homocysteine. The 132 selected (homocysteine concentration > or = 8.34 mumol/l) men were randomly assigned, using a factorial design, to one of four groups receiving supplementation with B group vitamins alone (1 mg folic acid, 7.2 mg pyridoxine, 0.02 mg cyanocobalamin), antioxidant vitamins (150 mg ascorbic acid, 67 mg alpha-tocopherol, 9 mg beta-carotene), B vitamins with antioxidant vitamins, or placebo. Intervention was double-blind. A total of 101 men completed the 8-week study. The lag time of LDL isolated ex vivo to oxidation (induced by 2 mumol/l cupric chloride) was increased in the two groups receiving antioxidants whether with (6.88 +/- 1.65 min) or without (8.51 +/- 1.77 min) B-vitamins, compared with placebo (-2.03 +/- 1.50) or B-vitamins alone (-3.34 +/- 1.08) (Mean +/- S.E., P <0.001). Antibodies to malondialdehyde (MDA) modified LDL were also measured, but there were no significant changes in titers of these antibodies in any group of subjects whether receiving antioxidants or not. Contrast analysis showed that there was no interaction between antioxidants and B-group vitamins. This study indicates that while B-group vitamins lower plasma homocysteine they do not have an antioxidant effect. Thus B-group vitamins and antioxidants appear to have separate, independent effects in reducing cardiovascular risk.

Effect of B-group vitamins and antioxidant vitamins on hyperhomocysteinemia:a double-blind, randomized, factorial-design, controlled trial

Mild hyperhomocysteinemia is accepted as a risk factor for premature cardiovascular disease. In a population with a high prevalence of cardiovascular disease, we screened a group of clinically healthy working men aged 30-49 y (n = 509) for plasma homocysteine and 5,10-methylene tetrahydrofolate reductase (MTHFR) genotype status. Those with mildly elevated homocysteine concentrations (> or = 8.34 micromol/L) were selected for intervention. In a randomized, factorial-design, controlled trial we assessed the effects of B-group vitamins and antioxidant vitamin supplementation on homocysteine concentrations. The 132 men were randomly assigned to one of four groups: supplementation with B-group vitamins alone (1 mg folic acid, 7.2 mg pyridoxine, and 0.02 mg cyanocobalamin), antioxidant vitamins alone (150 mg ascorbic acid, 67 mg RRR-alpha-tocopherol, and 9 mg beta-carotene), B-group vitamins with antioxidant vitamins, or placebo. Intervention was double-blind. A total of 101 men completed the 8-wk intervention. When homocysteine concentrations were analyzed by group, significant (P <0.001) decreases (32.0% and 30.0%, respectively) were observed in both groups receiving B-group vitamins either with or without antioxidants. The effect of B-group vitamins alone over 8 wk was a reduction in homocysteine concentrations of 27.9% (95% CI: 22.0%, 33.3%; P <0.001) whereas antioxidants alone produced a nonsignificant increase of 5.1% (95% CI: -2.8%, 13.6%; P = 0.21). There was no evidence of any interaction between the two groups of vitamins. The effect of B-group vitamin supplementation seemed to depend on MTHFR genotype. Supplementation with the B-group vitamins with or without antioxidants reduced homocysteine in the men with mildly elevated concentrations, and hence may be effective in reducing cardiovascular risk.

Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis

The aim of this study was to evaluate the safety and effect on clinical outcomes and biomarkers of inflammation and tissue damage of the neutrophil elastase inhibitor AZD9668 (60 mg twice daily orally for 4 weeks) in cystic fibrosis. This was a randomised, double-blind, placebo-controlled study. Primary outcome measures were sputum neutrophil count, lung function, 24-h sputum weight, BronkoTest® diary card data and health-related quality-of-life (revised cystic fibrosis quality-of-life questionnaire). Secondary end-points included sputum neutrophil elastase activity, inflammatory biomarkers in sputum and blood, urine and plasma desmosine (an elastin degradation marker), AZD9668 levels and safety parameters (adverse events, routine haematology, biochemistry, electrocardiogram and sputum bacteriology). 56 patients were randomised, of which 27 received AZD9668. There was no effect for AZD9668 on sputum neutrophil counts, neutrophil elastase activity, lung function or clinical outcomes, including quality of life. In the AZD9668 group, there was a trend towards reduction in sputum inflammatory biomarkers with statistically significant changes in interleukin-6, RANTES and urinary desmosine. The pattern of adverse events was similar between groups. Consistent reductions in sputum inflammatory biomarkers were seen in the AZD9668 group, and reduction in urinary desmosine suggests that AZD9668 impacts elastin cleavage by neutrophil elastase.

The effect of chronic captopril therapy on adrenergic receptors, plasma noradrenaline and the vascular responses to infused noradrenaline

Adrenergic receptors (alpha 2, beta 2), plasma noradrenaline, heart rate and the pressor responsiveness to infused noradrenaline were examined in ten healthy male volunteers before and after 2 weeks of placebo or captopril therapy in a double blind cross-over study. No significant differences in these measurements were observed between the captopril and placebo treated groups. The study shows that in sodium replete normotensive subjects, long-term angiotensin converting enzyme inhibition does not lead to changes in adrenoceptor density. There is also no alteration in plasma noradrenaline levels nor in the pressor responsiveness to infused noradrenaline. These data suggest that the known interaction between the renin-angiotensin system and the sympathetic nervous system observed in animals is probably of little significance in man.