Id Category Title Body Created Modified Actions
49    Evidence-based medicine Evidence-based medicine (EBM) and clinical pharmacy 126 Statistical versus clinical signifi cance 128 Odds ratios and relative risk 130 Binary and continuous data 132 L’Abbé plots 133 Mean difference and standardized mean difference 134 Assessing the quality of randomized studies 136 Critical appraisal of systematic reviews 138 Critical assessment of papers 140 Guidelines 143 Number needed to treat (NNT) 144 Confi dence intervals 147 ----------------------- Page 147----------------------- 126 CHAPTER 7 Evidence-based medicine Evidence-based medicine (EBM) and clinical pharmacy EBM has become standard practice during recent years, although it is probably more widely practised in primary care in the UK. The following defi nition of EBM can be adapted for clinical pharmacy. Defi nition of EBM EBM is the conscientious, explicit and judicious use of current best 1 evidence in making decisions about the care of individual patients. The authors of the defi nition go on to state that the practice of EBM requires the integration of individual clinical expertise with the best avail- able external clinical evidence from systematic research. The second defi nition comes from the McMaster University website: EBM is an approach to healthcare that promotes the collection, interpretation and integration of valid, important and applicable patient-reported, clinician-observed and research-derived evidence. The best available evidence, moderated by patient circumstances and 2 preferences, is applied to improve the quality of clinical judgements. Evidence-based clinical pharmacy Borrowing the Sackett defi nition, a defi nition might be as follows: Evidence-based clinical pharmacy is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients . This entirely fi ts with the concept of pharmaceutical care (see b p.244) and challenges clinical pharmacists not only to keep abreast of develop- ments in their chosen specialty, but also to apply clinical developments to patient circumstances and preferences. 3 One of Bandolier’s maxims is that EBM is essentially ‘tools not rules’. Pharmacists need to remember this when applying current best evidence to patient care. Strengths of evidence A hierarchy of evidence (Table 7.1 ) is helpful in avoiding types of studies that are inherently biased. A number of grading systems are currently available which are useful in terms of identifying the level of evidence available and as a tool for categorizing recommendations made in clinical guidelines, for example. For updated information on this topic, see the 4 GRADE website. Some evidence tables regard large randomized trials as level I evidence. Evidence from levels IV and V should not be overlooked if it is all that is available. Conversely, recommendations should not be made on level V evidence if level I or II evidence is available. 1 Sackett DL et al . (1996). British medical Journal 312 : 71–2. 2 McMaster University. . 3 . 4 . ----------------------- Page 148----------------------- EVIDENCE-BASED MEDICINE (EBM) AND CLINICAL PHARMACY 127 Table 7.1 Type and strength of effi cacy evidence I Strong evidence from at least one systematic review of multiple well-designed randomized controlled trials II Strong evidence from at least one properly designed randomized controlled trial of appropriate size III Evidence from well-designed trials without randomization, single group, cohort, time series, or matched case-controlled studies IV Evidence from well-designed non-experimental studies from more than one centre or research group V Opinions of respected authorities, based on clinical evidence, descriptive studies, or reports of expert committees Further reading Useful resource for pharmacy is available on the Bandolier website bandolier/booth/booths/pharmacy.html. ----------------------- Page 149----------------------- 128 CHAPTER 7 Evidence-based medicine Statistical versus clinical signifi cance Simply because a study fi nding is statistically signifi cant, does not mean that the fi nding is important. Large trials or large meta-analyses have the potential to fi nd very small statistically signifi cant differences between groups. An important consideration when interpreting signifi cant fi ndings is assessment of how clinically signifi cant the fi nding is. ‘ Clinical signifi cance ’ refers to a value judgement people must make when determining the meaningfulness of the magnitude of an intervention effect. For example, if an expensive medication was found to signifi cantly d systolic blood pressure (SBP) by an average of 2mmHg, it would be important to consider the clinical merit of the intervention. Would there be any important health benefi ts to a patient of a d in SBP of just 2mmHg? Would it be worth investing in an expensive intervention if it delivered such a meagre d in SBP? Are there any cheaper medications available that produce greater d in BP? Well-conducted rigorous randomized controlled trials should recruit enough participants to detect a difference between groups which is determined as clinically signifi cant before the study. ----------------------- Page 150----------------------- This page intentionally left blank ----------------------- Page 151----------------------- 130 CHAPTER 7 Evidence-based medicine Odds ratios and relative risk What is an odds ratio? The number needed to treat (NNT) is a very useful way of describing the benefi ts (or harms) of treatments, both in individual trials and in systematic reviews. Few papers report results using this easily interpretable measure. However, NNT calculations come second to working out whether an effect of treatment in one group of patients is different from that found in the control groups. Many studies, particularly systematic reviews, report their results as odds ratios or as a d in odds ratios, and some trials do the same. Odds ratios are also commonly used in epidemiological studies to describe the probable harm an exposure might cause. Calculating the odds The odds of an event occurring are calculated as the number of events divided by the number of non-events. For example, 24 pharmacists are on call in a major city. Six pharmacists are called. The odds of being called are 6 divided by 18 (the number who were not called) or 0.33. An odds ratio is calculated by dividing the odds in the treated or exposed group by the odds in the control group. In general, epidemiological studies try to identify factors that cause harm — those with odds ratios > 1. For example, if we look at case–control studies investigating the potential harm of giving high doses of calcium-channel blockers to treat hypertension. Clinical trials typically look for treatments that d event rates, and that have odds ratios <1. In these cases, a percentage d in the odds ratio is often quoted instead of the odds ratio. For example, the ISIS-4 trial reported a 7 % d in the odds of mortality with captopril treatment, rather than reporting an odds ratio of 0.93. Relative risks Few people have a natural ability to interpret event rates that are reported in terms of odds ratios. Understanding risks and relative risks seems to be easier to grasp. The risk (or probability) of being called in the example already described in ‘Calculating the odds’ is 6 divided by 24 (the total number on call) or 0.25 (25 % ). The relative risk is also known as the ‘risk ratio’, and if reporting positive outcomes, such as improvement, it can be called ‘relative benefi t’. Risks and odds In many situations in medicine, we can get a long way in interpreting odds ratios by pretending that they are relative risks. When events are rare, risks and odds are very similar. For example, in the ISIS-4 study 2231 out of 29 022 patients in the control group died within 35 days: a risk of 0.077 (2231/29 022) or an odds of 0.083 (2231/(29 022–2231)). This is an absolute difference of 6 in 1000 or a relative error of ~ 7 % .This close approximation holds true when we talk about odds ratios and relative risks, provided that the events are rare. ----------------------- Page 152----------------------- ODDS RATIOS AND RELATIVE RISK 131 Why use an odds ratio rather than relative risk? If odds ratios are diffi cult to interpret, why don’t we always use relative risks instead? There are several reasons for continuing with odds ratios, most of which relate to the superior mathematical properties of odds ratios. Odds ratios can always take values between zero and infi nity, which is not the case for relative risks. The range that relative risk can take depends on the baseline event rate. This could obviously cause problems if we were performing a meta- analysis of relative risks in trials with greatly different event rates. Odds ratios also possess a symmetrical property: if you reverse the outcomes in the analysis and look at good outcomes rather than bad outcomes, the relationships have reciprocal odds ratios. Again, this is not true for relative risks. Odds ratios are always used in case–control studies where disease prevalence is not known: the apparent prevalence depends solely on the ratio of sampling cases to controls, which is totally artifi cial. To use an effect measure that is altered by prevalence in these circumstances would obviously be wrong, so odds ratios are the ideal choice. This, in fact, provides the historical link with their use in meta-analyses: the statistical methods that are routinely used are based on methods fi rst published in the 1950s for the analysis of stratifi ed case–control studies. Meta-analytical methods that combine relative risks and absolute risk reductions are now available, but more caution is required in their application, especially when there are large variations in baseline event rates. A fourth point of convenience occurs if it is necessary to make adjustments for confounding factors using multiple regression. When measuring event rates, the correct approach is to use logistic regression models that work in terms of odds and report effects as odds ratios. All of which makes odds ratios likely to be in use for some time — so it is important to understand how to use them. Of course, it is also important to consider the statistical signifi cance of an effect in addition to its size: as with relative risks, it is easy to spot statistically signifi cant odds ratios by noting whether their 95 % confi dence intervals do not include 1, which is analogous to a <1 in 20 chance (or a probability of <0.05 or gambling odds of better than 19:1) that the reported effect is solely due to chance. Formula to calculate an odds ratio odds on treatment Odds ratio = odds on control Where odds ratio = 1, this implies no difference in effect Formula to calculate a relative risk risk on treatment Risk ratio = risk on control Where risk ratio = 1, this implies no difference in effect ----------------------- Page 153----------------------- 132 CHAPTER 7 Evidence-based medicine Binary and continuous data Broadly, statistical tests can be grouped into those used to compare binary (also called ‘dichotomous’) outcome data and those used to compare continuous outcome data. Binary outcomes are those that can only take two possible values, such as dead or alive, pain or no pain, and smoker or non-smoker. Statistical tests on binary data, such as relative risks, compare the rate of an event between the groups; it also makes the calculation of NNT possible. Continuous outcomes are derived from data that can take any value on a scale. Some examples of continuous data include height, BP, time, or the score in a test. Statistical tests on continuous data (e.g. t tests) compare the difference between means of each group (see b p.134). ----------------------- Page 154----------------------- L’ABBÉ PLOTS 133 L’Abbé plots L’Abbé plots are named after a paper by Kristen L’Abbé and colleagues and are an extremely valuable contribution to understanding systematic reviews. The authors suggest a simple graphical representation of the information from trials. Each point on a L’Abbé scatter plot represents one trial in the review. They are a simple and effective way to present a series of results, without complex statistics. The proportion of patients achieving the outcome with the experimental intervention is plotted against the event rate in the control group. Even if a review does not show the data in this way, it is relatively simple to determine this if the information is available. For treatment, trials in which the experimental intervention was better than the control are in the upper-left section of the plot, between the y -axis and the line of equality. If the experimental intervention was no better than the control, the point falls on the line of equality, and if the control was better than the experimental intervention, the point is in the lower-right section of the plot, between the x- axis and the line of equality (Fig. 7.1 ). For prophylaxis, this pattern is reversed. Because prophylaxis d the number of bad events (e.g. death after myocardial infarction following the use of aspirin), we expect a smaller proportion of patients harmed by treatment than in the control group. So if the experimental intervention is better than the control, the trial results should be between the x- axis and the line of equality. y 100 y t i l a u Treatment q e f o d better e e 75 n i v t L o n than r e p m control m e i t a n e 50 o r i t t r h o t p i o w Control better r P 25 than treatment 0 x 0 25 50 75 100 Proportion improved with control Fig. 7.1 L’Abbé plot for treatment. ----------------------- Page 155----------------------- 134 CHAPTER 7 Evidence-based medicine Mean difference and standardized mean difference Analyses of continuous data often show the difference between the means of the groups being compared. In a meta-analysis, this can involve either comparing the mean difference of trials in two groups directly if the unit of measurement of the outcome is the same (e.g. if height is the outcome of interest and all trials measure height in centimetres) or standardizing the outcome measure and comparing the difference between the standard- ized means if different assessment scales are used to measure subjective conditions, such as mood, depression, or pain. In a meta-analysis of continuous data, if an experimental intervention has an identical effect as a control (or comparison), the mean difference or standardized mean difference is zero. Therefore if the lower limit of a confi dence interval around a mean difference or standardized mean difference is > 0, the mean of the experimental intervention group is signifi cantly greater than that of the control group. Similarly, if the upper limit of the confi dence interval is <0, the mean of the experimental intervention is signifi cantly lower than that of the control. However, if the confi dence interval incorporates the value 0, there is no signifi cant difference between the means of the groups being compared. Consider the output from a Cochrane review which compared the effect of very low calorie diets (VLCDs) with other interventions for weight loss in patients with type 2 diabetes mellitus (Fig. 7.2 ). In this case, weight loss is measured in kilograms so there is no need for standardization. As can be seen, the meta-analysis of the two trials indicated that the mean difference in weight between the management with a VLCD and other interventions is –2.95kg. This suggests that patients with type 2 diabetes mellitus on a VLCD are, on average, 2.95kg lighter than patients with type 2 diabetes mellitus on the comparison interventions. However, the range of the 95 % confi dence intervals includes 0, which indicates that the difference in weight loss between the two groups is not statistically signifi cant. ----------------------- Page 156----------------------- M E A Review: Long-term non-pharmacological weight loss interventions for adults with type 2 diabetes mellitus N Comparison: 01 VLCD vs different intervention (1–10: fixed models. 11–20: random models, rho = 0.75) D I F F Outcome: 01 weight loss (kg) E R E N Study Treatment Control Weighted mean difference (fixed) Weight Weighted mean difference (fixed) C E N Mean (SD) N Mean (SD) 95% CI (%) 95% CI A N Wing, 1991a 17 –8.60 (9.20) 16 –6.80 (6.90) 39.5 –1.80 [–7.33, 3.73] D S T A Wing, 1994 48 –14.20 (10.30) 45 –10.50 (11.60) 60.5 –3.70 [–8.17, 0.77] N Total (95% CI) 65 61 100.0 –2.95 [–6.42, 0.53] D A 2 R D Test for heterogeneity chi-square = 0.27 df = 1p = 0.60 1 = 0.0% I Test for overall effect z = 1.66 p = 0.1 Z E D M E –10.0 –5.0 0 5.0 10.0 A N Favours treatment Favours control D I Fig. 7.2 Meta-analysis of a VLCD versus other interventions for weight loss in patients with type 2 diabetes mellitus. F F E R E N C E 1 3 5 ----------------------- Page 157----------------------- 136 CHAPTER 7 Evidence-based medicine Assessing the quality of randomized studies Assessment tools for randomized studies are widely available and all have problems because they do not cover all the issues that could be consid- ered to be important. This simple method picks up on the main issues of randomization, blinding, and patient withdrawal from studies (Table 7.2 ). The maximum quality score is 5 if all the criteria are fulfi lled. In addition, a more general appraisal tool is presented (Table 7.3 ). It picks up details from the scoring system described in Table 7.2 . 1 Table 7.2 Simple assessment tool for a randomized trial Is the study randomized? Score Yes 1 Is the randomization appropriate? Yes — e.g. random number tables 1 No — e.g. alternate patients, date of birth, or hospital number –1 Was the study double blind? Yes 1 Was blinding correctly carried out? Yes — e.g. double dummy 1 No — e.g. treatments did not look identical –1 Were withdrawals and drop-outs described? Yes 1 1 Jadad A et al. (1996). Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials. 17: 1–12. ----------------------- Page 158----------------------- ASSESSING THE QUALITY OF RANDOMIZED STUDIES 137 Table 7.3 General appraisal tool for a randomized trial Was the method of randomization appropriate (e.g. computer generated)? Was the study described as ‘double-blind’? And was the method of blinding adequate (e.g. double dummy, or identical tablets)? Was the trial sensitive, i.e. able to detect a difference between treatment groups (e.g. use of a placebo, or additional active groups)? Were baseline values for each treatment group adequate for trialists to measure a change following treatment? Were the groups similar at the start of the trial? Similar patients? Diagnostic criteria clearly stated? Similar baseline measures? Was the size of the trial adequate? How many patients were there in each group? Were outcomes clearly defi ned and measured appropriately? Were they clinically meaningful? Were they primary/surrogate outcomes? Were the outcome data presented clearly? If multiple tests were conducted, were single positive results inappropriately presented? 1 Quality score Randomization Double-blinding Withdrawals/ Total score drop-outs ----------------------- Page 159----------------------- 138 CHAPTER 7 Evidence-based medicine Critical appraisal of systematic reviews Systematic reviews are considered to be the best level of evidence if they are well conducted and evaluate a number of randomized trials. They can be particularly useful when seeking to answer clinical questions. However, they are only reliable if the process of the review has followed rigorous scientifi c principles. Authors should explicitly state the topic being reviewed and have made a reasonable attempt to identify all the relevant studies. The 10 questions listed in Table 7.4 help in that assessment. If the paper fails either of the fi rst two questions, it is not worth proceeding further. 1 Table 7.4 Ten questions to make sense of a review For each question answer : Yes, No, or Don’t Know A. Are the results of the review valid? 1 . Did the review address a clearly focused issue (e.g. the population, intervention, and/or outcomes)? 2 . Did the authors look for the appropriate sort of papers? Check that the authors looked for randomized controlled trials or had clear reasons for including other types of studies. Is it worth continuing? 3 . Do you think the relevant important studies were included? Look for search methods, use reference list, unpublished studies and non-English language articles. 4 . Did the authors do enough to assess the quality of the studies included? This would routinely be in the form of an assessment tool for randomized controlled trials. 5 . If the results of studies were combined, was it reasonable to do so? B. What are the results? 6 . What is the overall result of the review? Is there a clear numerical expression? 7 . How precise are the results? What were the confi dence intervals? C. Will the results help my local situation? 8 . Can the results be applied locally? 9 . Were all important outcomes considered? 10. Are the benefi ts worth the harms and costs? 1 Oxman AD et al . (1994). Users guide to the medical literature. VI: How to use an overview. Journal of the American Medical Association 272 : 1367–71. ----------------------- Page 160----------------------- This page intentionally left blank ----------------------- Page 161----------------------- 140 CHAPTER 7 Evidence-based medicine Critical assessment of papers When reading a clinical trial paper, it is too easy to read the abstract quickly and skim through the main text. Taking the time to critically eval- uate the paper might seem daunting and too time-consuming. In many situations a quick read through is all that is needed. However, if the infor- mation gleaned from the paper is going to be used to decide on treat- ment options or might be used to support a formulary application, a more thoughtful approach is required. The information in this section specifi cally relates to critically evaluating a clinical trial paper, but the same process, adapted to the content, can be used for other types of clinical paper. It is not necessary to be a statistician or an expert in trial design to critically evaluate a paper. Much of the evaluation is common sense. A full critical evaluation should take all the following points into account, but even simply bearing them in mind will help you get more out of any paper you read. • Title — does this accurately refl ect the content of the paper? Ideally, the title should state the question under investigation, rather than potentially biasing readers by declaring the results. Cryptic titles are a popular way of attracting readers’ attention, but if it is too obscure, could it be because that the authors don’t really know what they are writing about? Before progressing, consider how useful this trial is in the clinical setting. If it is too esoteric, it might not be worth reading any further! • Authors — should be from professions/institutions appropriate to the subject studied. Be cautious with papers authored by pharmaceutical industry employees, but don’t dismiss these out of hand. Too many authors might mean that the work is scrappy. Multicentre studies should list the key authors and acknowledge other participants at the end of the paper. Is a statistician listed as an author or acknowledged? This should provide reassurance that the statistics are correct. • Journal — don’t assume that because a paper is published in a main- stream journal it is a good paper. However, be more cautious about papers from obscure journals. • The introduction — should give relevant background information, building logically to the study topic. If the introduction is waffl y or irrelevant, ask yourself if the authors really know what they are writing about. • Method — a well-written method should give suffi cient information for another person to reproduce the study. The information given should include the following. • Type of study (e.g. randomized controlled trial, cohort, or case study). • Numbers involved, ideally including details of powering. • Patient selection and randomization — details of patient demo-graphics should be given and the baseline characteristics of each group should be roughly the same (and should be acknowledged if not). • Inclusion/exclusion criteria — consider whether these are appropriate. If there are too many exclusion criteria, the study might not be relevant to the clinical setting. ----------------------- Page 162----------------------- CRITICAL ASSESSMENT OF PAPERS 141 • Outcome measurements — by now, the question that the authors are trying to answer should be clear. The factors used to measure the outcome should be appropriate and, if possible, directly related to the question. Be cautious of surrogate markers. In many clinical settings, it might be unethical, too invasive, or take too long to use the target outcome. However, check that the surrogate marker closely refl ects the target outcome as a whole and not just one aspect of it. • An appropriate comparator drug should be used at its standard dose. Any new drug should be tested against standard therapy. If a drug is compared with placebo or an outdated or rarely used drug, ask yourself why. With the exception of the study treatment, all other interventions should be the same. • A randomized controlled trial should ideally be double-blinded (i.e. neither the study participants nor the investigators know which subjects are receiving the study drug and which subjects are receiving the comparator). Sometimes this is not feasible or ethical, but there might be bias if the trial is open-label (both subjects and investigator know who is receiving which treatment) or single-blind (the investigator but not the participants know who is receiving each treatment). • Be cautious with crossover trials — if the disease studied could improve with time without treatment (especially if it is self-limiting or seasonal), a crossover trial is inappropriate. An adequate ‘washout’ period between treatments is essential. • The details of statistical tests should be given — the tests should be appropriate to the type of data presented. Beware of trials that use numerous statistical tests. Why are so many tests needed? Is it that there is nothing to prove? Further discussion of statistical tests is beyond the scope of this topic. Consult relevant textbooks for further information. • Results — should answer the question originally asked and be easy to comprehend. • Graphs and tables should be relevant and clear. Too many graphs and tables suggest that the authors are having diffi culty proving their point! Watch labelling of axes on graphs. Sometimes labelling is skewed (e.g. does not start at zero) to give more impressive results. • If means are quoted, the variance and/or median should also be quoted. This helps determine whether the mean is a true ‘average’ or whether extreme values have skewed the results. • The results might be statistically signifi cant, but are they clinically signifi cant? Results presented as odds ratios, relative risks, or NNT are generally easier to apply to a clinical setting. • The discussion — should logically build from the results to answer the original question, one way or another. If the authors make statements such as ‘further study is required . . . ’, ask yourself why. Is this because the original study design was unsuitable? Any doubts or inconsistencies should be dealt with satisfactorily, not just explained away. ----------------------- Page 163----------------------- 142 CHAPTER 7 Evidence-based medicine • The conclusion — should be appropriate to the data presented and give a defi nite fi nal answer. If the conclusion is woolly, was there any point in the study in the fi rst place or were the authors just ‘paper chasing’? • The bibliography — should be up to date and relevant. Beware of too many references from obscure journals. You should be able to satisfactorily follow up statements made in the rest of the paper by reference to the original papers quoted. • Acknowledgements — look for any specialists not in the author list, which might provide reassurance if you had any doubts about the authors’ expertise in any angle of the study. Watch out for funding or sponsorship from parties with a vested interest in the outcome of the study (notably the pharmaceutical industry!). However, don’t dismiss studies sponsored by the pharmaceutical industry out of hand. Much good work is supported by the pharmaceutical industry. Further reading Sackett DL et al. ( 2005 ). Evidence-based Medicine . Churchill Livingstone . Jones C ( 2002 ). Evidence-based medicine. 1: Research methods . Pharmaceutical Journal 268 : 875 – 7 . ----------------------- Page 164----------------------- GUIDELINES 143 Guidelines Guideline development is a common way of either seeking to introduce new practices or attempting to stop some current practices. Guidelines can be time consuming and costly to develop. There is evidence that they 1 can be effective if carefully prepared and peer reviewed. Shekelle et al . proposed the following key steps that need to be followed. • Identify and refi ne the subject area. • Create a guideline development group. • Based on systematic reviews: • assess the evidence about the clinical question or condition • translate the evidence into a recommendation within the guideline. • Ensure that the guideline is externally reviewed. 2 A useful checklist for guidelines is provided by Shaneyfelt et al . This review of some 270 guidelines lists some 25 points to consider when preparing a guideline. These include stating the purpose of the guideline, using an expiry date, and grading the recommendations according to the strength of the evidence. 1 Shekelle PG et al . (1999). Developing clinical guidelines. Western Journal of Medicine 170 : 348–51. 2 Shaneyfelt TM et al (1999). Are guidelines following guidelines? Journal of the Amereican Medical Association 281 : 1900–5. ----------------------- Page 165----------------------- 144 CHAPTER 7 Evidence-based medicine Number needed to treat (NNT) The NNT is a measure of clinical signifi cance and changes view from ‘Does a treatment work?’ to ‘How well does a treatment work?’. This concept is widely used and useful not only in its own right, but also to enable direct comparisons of treatments. The league table of treatments from the Oxford Pain Research Unit (Fig. 7.3 ) illustrates the value of such an approach. Ideally, we would want an NNT of 1. Although there are treatments that meet this criterion (e.g. anaesthetic agents) in practice NNTs are > 1 for the reasons discussed here. The NNT is defi ned as follows: the number of people who must be treated for one patient to benefi t. The NNT is expressed in terms of a specifi c clinical outcome and should be shown with confi dence intervals. Calculating the NNT for active treatments The NNT calculation is based from the understanding of risk ratios (Fig. 7.4 ). Although the NNT is the reciprocal of the absolute risk reduction, it is not necessary to understand this concept to calculate the NNT. A worked example is included so that the process is transparent. The equation is quite simple, and it is easy to calculate the NNT in published trials using a pocket calculator. The NNT was initially used to describe prophylactic interventions. The NNT for prophylaxis is given by the following equation: 1/(proportion of patients benefi ting from the control intervention minus the proportion of patients benefi ting from the experimental intervention). The NNT for active treatment is given by the following equation: 1/(proportion of patients benefi ting from the experimental intervention minus the proportion of patients benefi ting from the control intervention). From the equation in Fig. 7.4 it should be apparent that any response in the control arm leads to NNT > 1. People often ask what a good NNT is; it depends whether the NNT is for treatment (ideally in the range 2–4) or prophylaxis (the NNT is generally larger). Issues such as toxicity have an infl uence, including the cost. For example, a cheap and safe interven- tion that prevents a serious disease but has an NNT of 100 might well be acceptable. ----------------------- Page 166----------------------- NUMBER NEEDED TO TREAT (NNT) 145 Total number in comparison Ibuprofen, 800 mg 76 Ibuprofen, 600 mg 222 Ibuprofen, 400 mg 2898 Ibuprofen, 200 mg 726 Ibuprofen, 100 mg 186 Diclofenac, 100 mg 308 Diclofenac, 50 mg 636 Diclofenac, 25 mg 100 Naproxen, 440 mg 257 Naproxen, 550 mg 169 Naproxen, 220/250 mg 183 Paracetamol, 1000 mg/codeine, 60 mg 127 Aspirin, 1200 mg 279 Paracetamol, 600 mg or 650 mg/codeine, 60 mg 816 Aspirin, 1000 mg 716 Aspirin, 600 mg/650 mg 5061 Dextropropoxyphene HCI, 65 mg/paracetamol, 650 mg 963 Paracetamol, 1000 mg 2283 Paracetamol, 600 mg/650 mg 1167 Paracetamol, 300 mg/Codeine, 30 mg 442 Paracetamol, 500 mg 649 Pethidine, 100 mg (intramuscular) 300 Morphine, 10 mg (intramuscular) 946 Dextropropoxyphene HCI, 65 mg 440 Dihydrocodeine, 30 mg 194 Codeine, 60 mg 13.5 Tramadol, 150 mg 561 Tramadol, 100 mg 882 Tramadol, 75 mg 563 Tramadol, 50 mg 770 2 4 6 8 10 12 14 15 18 NNT with 95% confidence intervals Fig. 7.3 League table of NNT to produce 50 % pain relief for 4–6h compared with placebo in patients with pain of moderate or severe intensity. Controls Active treatment Number of patients Ncon Nact Improved = clinical end point Impcon Impact 1 NNT = Impact Impcon N N act con Fig. 7.4 Number needed to treat (NNT). ----------------------- Page 167----------------------- 146 CHAPTER 7 Evidence-based medicine Using the NNT to express harm The number needed to harm (NNH) can also be helpful, in addition to the NNT. The NNH is calculated using a similar formula derived from data for adverse events rather than desired effect (Fig. 7.5 ). Controls Active treatment Number of patients Ncon Nact AE-number with the adverse AEcon AEact 1 NNH = AE AE act con N N act con Fig. 7.5 Number needed to harm (NNH). ----------------------- Page 168----------------------- CONFIDENCE INTERVALS 147 Confi dence intervals Most pharmacists are aware of p values in terms of an answer being sig- nifi cant (in a statistical sense) or not. However, the use of p is increasingly redundant, and new methods of reporting signifi cance have emerged. The most common method is the confi dence interval, which enables us to estimate the margin of error. For example, if we measured BP in 100 adults, we could derive a mean result. If we then took a further 100 adults and repeated the experiment, we would arrive at a similar, but not identical, fi gure. The confi dence interval, expressed as a percentage, enables calculation of the margin of error and tells us how good our mean is. Generally, the fi gure is set at 95 % , so we can be confi dent that the true mean lies somewhere between the upper and lower estimates (Fig. 7.6 ). Expressed a different way, there is only a 5 % chance of the result being outside the calculated limits. The statistics involved are derived from a range of 1.96 standard deviations above and below the point estimated. For a 99 % confi dence interval, a fi gure of 2.58 standard deviations is used. Calculating confi dence intervals Although the formulae are available in standard statistics works, there are a number of confi dence interval calculators on the web that require the use of the calculated point estimate and the number of samples to derive the confi dence interval at a given percentage. 2.5% 2.5% 95% Mean Lower limit Upper limit Fig. 7.6 Illustration of the data incorporated within a 95 % confi dence interval. ----------------------- Page 169----------------------- This page intentionally left blank ----------------------- Page 170----------------------- Chapter 8 149 Herbal medicines Herbal drugs 150 General information about commonly used herbal medications 154 Chinese herbal medicine 157 Herbal interactions 158 Perioperative considerations for herbal drugs 160 ----------------------- Page 171----------------------- 150 CHAPTER 8 Herbal medicines Herbal drugs The effi cacy and safety of herbal drugs present a number of issues to pharmacists. Herbal drugs are more often complex mixtures of active constituents that vary in quality for a number of reasons, such as envi- ronmental and genetic factors. Furthermore, the constituents responsible for the claimed therapeutic effects are frequently unknown or only partly explained. The position is further complicated by the traditional practice of using combinations of herbal drugs, and it is not uncommon to have as many as fi ve or more herbal drugs in one product. There is potential risk from impurities/adulterations of herbal medicine mixed with toxic plant extracts because of misidentifi cation or intentional addition of allopathic drugs. The European pharmacopoeia includes 120 monographs on herbal drugs. Control of the starting materials is essential to ensure the reproduc- ible quality of herbal medicinal products. Herbal drugs must be accurately identifi ed by macroscopic and microscopic comparison with authentic material. Herbal drugs are referred to by their binomial Latin names of genus and species; only permitted synonyms should be used. Different batches of the same herbal ingredient can differ in quality because of a number of factors. • Inter- or intra-species variation. • Environmental factors. • Time of harvesting. • Plant part used — active constituents usually vary between plant parts, and it is not uncommon for a herbal drug to be adulterated with parts of the plant that are not normally used. • Storage conditions and processing treatments can greatly affect the quality of an herbal ingredient. • Instances of herbal remedies adulterated with other plant material and conventional medicines. • Extraction/drying methods. Identity tests establish the botanical identity of a herbal drug. • Chemical (e.g. colour or precipitation) and chromatographic tests are used for identifi cation of the ingredients. • Assay — a herbal drug with known active principles should have an assay established to set the criterion for the minimum acceptable percentage of active substance(s). Legislation of herbal drugs Although herbal drugs have been used as traditional remedies for centu- ries and are perceived by many to be without major safety problems, the UK has a series of controls to limit general availability. Hazardous plants, such as digitalis, rauwolfi a, and nux vomica, are specifi cally controlled under the Medicines Act as prescription-only medicines (POMs). Certain herbal ingredients are controlled under the Medicines (Retail Sale and Supply of Herbal Remedies) Order, 1977, SI 2130. This Order (part I) specifi es 25 plants that cannot be supplied except by a pharmacy, ----------------------- Pag  2016-10-22 05:54:49  2016-10-22 05:54:49  View Edit Delete
50    There are no legal restrictions on the clinical conditions that supple- mentary prescribers can treat, and there is no specifi c formulary or list of medicines for supplementary prescribing. The independent and sup- plementary prescribers decide when supplementary prescribing is appro- priate and when the clinical management plan is drawn up (Fig. 14.1 ). The medicines to be prescribed by the supplementary prescriber must be pre- scribed by an independent prescriber at NHS expense and referred to in the patient’s clinical management plan. Some of the areas where sup- plementary prescribing might be of most benefi t include the treatment of long-term medical conditions, such as asthma, coronary heart disease, or patients requiring anticoagulation. Supplementary prescribers are able to prescribe the following • All general sales list (GSL), pharmacy medicines, appliances and devices, foods, and other borderline substances approved by the advisory committee on borderline substances. • All POMs. • Controlled drugs. • Medicines for use outside their licensed indications (i.e. ‘off-label’ prescribing), ‘black-triangle’ drugs, and drugs marked ‘less suitable for prescribing’ in the BNF . • Unlicensed drugs that are part of a clinical trial which has a clinical trial authorization. Benefi ts of supplementary prescribing include the following: • Quicker access to medicines for patients. • i effi ciency. • d in doctor’s workload. • Improved use of skill mix. The supplementary prescriber should not be required to enter into a pre- scribing partnership that entails them prescribing any medicine that they do not feel competent to prescribe. It is recommended that supplemen- tary prescribers prescribe generically if possible, except where this would not be clinically appropriate or if there is no approved generic name. Further reading Department of Health . Supplementary Prescribing M Medicinespharmacyandindustry/Prescriptions/TheNon-MedicalPrescribingProgramme/ Supplementaryprescribing/index.htm ----------------------- Page 291----------------------- 270 CHAPTER 14 Medicines management Hospital name and department Clinical management plan Name of patient: Patient medication sensitivities/allergies: Patient identification (e.g. ID number or, date of birth): Independent prescriber(s): Name and profession Supplementary prescriber(s): Name and profession Condition(s) to be treated: Might be specific indications or broader terms and might also include treating side effects of specified drugs/classes of drug (e.g. treatment of HIV and related opportunistic infections/complications or treatment of side effects of antiretrovirals and other drugs used in treatment of HIV). Aim of treatment: Medicines that could be prescribed by supplementary prescriber: Preparation Drug names and preparations Can also be drug classes (e.g. antiretrovirals) Indication—does not have to be very specific Dose schedule—does not have to be very specific (e.g. could say ‘as BNF’) Specific indications for referral back to the independent prescriber: Guidelines or protocols supporting the clinical management plan: Frequency of review and monitoring by: Supplementary prescriber Supplementary prescriber and independent prescriber Process for reporting ADRs: Shared record to be used by independent prescriber and supplementary prescriber: Agreed by independent prescriber(s): (signature and name) Agreed by supplementary prescriber(s): (signature and name) Date agreed with patient/carer: Fig. 14.1 Example of a clinical management plan for supplementary prescribers. ----------------------- Page 292----------------------- This page intentionally left blank ----------------------- Page 293----------------------- 272 CHAPTER 14 Medicines management Independent prescribing Pharmacists in the UK can train to become independent prescribers when they are registered pharmacists, have at least 2 years experience practising as a clinical pharmacist, and have completed an independent prescribing education and training programme, which includes a period of supervised practice. Independent prescribing is detailed here. For supplementary pre- scribing see b p.268. The Department of Health defi nes independent prescribing as ‘ prescribing by a practitioner (e.g. doctor, dentist, nurse, pharmacist) responsible and accountable for the assessment of patients with undiagnosed or diagnosed conditions and for decisions about the clinical management required, including 1 prescribing ’. The practitioner is required to assess the patient, interpret the assessment, and make a decision on the appropriate therapy including safety and a process for monitoring. Independent prescribing usually takes place as part of a multidisciplinary team using a single healthcare record, and the practitioner is accountable for their prescribing. Patients need to be informed that a non-medical practitioner is prescribing their medicine and give their consent. The pharmacist prescriber must ensure that their prescriptions are checked and dispensed by another pharmacist, in accordance with local clinical governance procedures that are in place for all prescribers. Pharmacists are able to prescribe any licensed or unlicensed medicine for any medical condition for which they are competent and experienced to prescribe independently. At the time of publication the exceptions to this are that pharmacists are unable to prescribe controlled drugs independently. Pharmacists are able to prescribe licensed medicines for unlicensed indications, i.e. ‘off label’, independently if it is accepted clinical practice and supported by a local policy. Pharmacist prescribing must be in accordance with the RPSGB's Medicines, Ethics and Practice —A Guide for Pharmacists . Pharmacists are required to demonstrate Continuing Professional Development (CPD) in their area of prescribing practice. The RPSGB have published a clinical governance framework for pharmacist 2 3 prescribers and a Pharmacist Prescriber Pack. Organizations should have a ‘non-medical prescribing policy’ in place to support pharmacist independent prescribing. Some specialist organizations also have guidance on pharmacist independent prescribing in a specialist area — e.g. the British Oncology Pharmacy Association (BOPA) Guidance for the Development 1 Department of Health (2006). Improving Patients’ Access to Medicines: A Guide to Implementing Nurse and Pharmacist Independent Prescribing within the NHS in England . London: Department of Health. 2 Royal Pharmaceutical Society of Great Britain (2007). Clinical Governance Framework for Pharmacist Precribers and Organisations Commissioning or Participating in Pharmacist Prescribing (GB wide). 3 Royal Pharmaceutical Society of Great Britain. Pharmacist Prescriber Pack. ----------------------- Page 294----------------------- INDEPENDENT PRESCRIBING 273 of Pharmacist Non-Medical Prescribing and Review of Patients Receiving 1 . Anticancer Medicines . Benefi ts The benefi ts of pharmacist independent prescribing are to improve patient care without compromising patient safety, make it easier for patients to get the medicines they require, increase patient choice, make better use of healthcare professional skills, and contribute to more fl exible team- working in the NHS. 1 Faculty of Cancer Pharmacy and the British Oncology Pharmacy Association (2009). Guidance for the Development of Pharmacist Non Medical Prescribing and Review of Patients Receiving Anti-cancer Medicines . M Review_Best_Practice_Guidelines_FINAL.pdf ----------------------- Page 295----------------------- 274 CHAPTER 14 Medicines management Community (FP10) prescription use in hospitals Hospital out-patient departments can use community (FP10) prescriptions, according to local policy. In the UK, these are prescriptions that can be written by hospital doctors and dispensed by a community pharmacy, d workload of busy pharmacy departments. Who is it appropriate to use them for? • Patients who are mobile and can easily get to a community pharmacy. • Patients requiring an item that cannot be easily obtained by the hospital pharmacy. • Patients who don’t have time or would rather not wait in the hospital pharmacy. • Patients on hospital transport who are unable to wait in the hospital pharmacy. Who is it inappropriate to use them for? • Patients requiring expensive items, unless they are part of a shared-care arrangement. • Patients on clinical trials. • Patients on drugs that are only available from hospitals. • Patients requiring items that can be purchased without a prescription. • Patients on complex therapy who may need counselling, but might miss out if they don’t attend the hospital pharmacy. Things to remember • These prescriptions incur a dispensing fee for each item prescribed. • Prescriptions are removed from the hospital and dispensed by community pharmacists and, as such, could be vulnerable to loss or tampering. • The pharmacist who dispenses the prescription might not be familiar with prescribing habits or handwriting. • It is very diffi cult for the dispensing pharmacist to contact the doctor in the event of error, omission, or illegible prescribing. • The hospital is charged the commercial costs, in addition to the dispensing fees for the items prescribed. The resulting cost can be more expensive than if it were dispensed from the hospital pharmacy. • The hospital is reimbursed for any prescription charge, so for cheaper items, they can be cheaper or issued without charge using an FP10 prescription. • Drugs supplied are exempt from value added tax (VAT); hence it might be cost-effective to prescribe some drugs on FP10 prescriptions. ----------------------- Page 296----------------------- This page intentionally left blank ----------------------- Page 297----------------------- 276 CHAPTER 14 Medicines management Electronic prescribing Electronic prescribing systems are available commercially and are fully implemented by some hospitals and institutions, often linked to a patient management system. The NHS is aiming for all prescribing in secondary care within the UK to be undertaken electronically. Some systems ensure a paper-free environment because an electronic prescription is used for patient care, electronic signatures are used for drug administration, and electronic transfer is used for ordering drugs from the pharmacy. Fully implemented electronic systems can mean that all patient records are electronic. Electronic prescribing systems are often intelligent and fl ag areas of drug interaction, incorrect dosing, other prescribing errors, additional information required for safe drug administration, and formulary issues. These systems require input and maintenance by pharmacy and information technology teams. High-risk areas, such as chemotherapy prescribing, should be implemented as a high priority. Most cancer hospitals and networks have implemented or are working towards implementing electronic prescribing systems for oral and injectable chemotherapy to minimize the risks associated with the prescribing and administration of these drugs for adult and paediatric patients. Pharmacy staff using an electronic prescribing system require training in its use before working with the system. These systems have various levels of security, depending on the role of the professional in the use of the system. It is essential that there is good security for any electronic prescribing system, with frequent back-ups, and a system must be in place in case of system failure. Standard operating procedures should be in place for all aspects of the system. Benefi ts • Safer use of medicines. • d in medication errors. • Improved quality and safety of prescribing. • Improved safety of prescribing medication to patients with drug allergies. • Prescriptions are legible. • Accessibility of information between primary and secondary care. • Improved patient compliance with protocols. • Management of formulary compliance. • Supports decision-making when prescribing. • Implementation of policy decisions. • Improved use of staff time. • Pharmacy can make early identifi cation of new scripts for screening and supply. • Audit trail of transactions. • Drug-usage reports for individual patients. • Aids clinical audit. ----------------------- Page 298----------------------- ELECTRONIC PRESCRIBING 277 Further reading Smith J ( 2004 ). Building a Safer NHS for Patients: Improving Medication Safety . London : Department of Health . Donyai P et al . ( 2008 ). The effects of electronic prescribing on the quality of prescribing . British Journal of Clinical Pharmacology 65 : 230 – 7 . ----------------------- Page 299----------------------- 278 CHAPTER 14 Medicines management Incident reporting • Each hospital or institution should have a policy in place for reporting incidents. An incident reporting policy often covers all incidents, including adverse events, hazards, and near misses of an adverse event or hazard. Such a policy applies to all hospital staff. An induction programme to a hospital usually covers details of any local policy. • An incident reporting program identifi es, assesses, and manages risks that could compromise or threaten the quality of patient services or staff working in a safe environment, as part of the overall management of risk. It is a confi dential process, and all staff should complete the appropriate documentation if they are involved in, or aware of, an incident. • An ‘incident’ is usually defi ned as an event or circumstance that could have, or did, lead to unintended or unexpected harm, loss, or damage. Incidents might involve actual or potential injury, damage, loss, fi re, theft, violence, abuse, accidents, ill health, and infection. • It is necessary for incidents to be reported to ensure that the hospital can analyse the data for trends, causes, and costs. Action plans can then be developed to minimize future similar incidents. Reporting of incidents is also a mechanism for staff to have input into change of practice and procedures. Incident reporting follows a ‘no-blame’ culture. • Medication incidents must be reported through this mechanism to ensure that there can be a review of trends, a root-cause analysis, arrangements for improvement, and a follow-up audit. This is a requirement of medicines management in hospitals. • The types of incident that a pharmacist can report include medication errors and failure of systems or processes that affect patient care. • In addition to reporting an incident, a pharmacist must also deal with an incident by communicating with the relevant members of staff involved (see b p.72). Further reading Department of Health ( 2003 ). A Vision for Pharmacy in the new NHS . London : Department of Health . National Patient Safety Agency . National Reporting and Learning Service . M http://www.nrls.npsa. ----------------------- Page 300----------------------- MEDICAL REPRESENTATIVES 279 Medical representatives • Medical representatives provide information to healthcare practitioners, but their prime function is to promote and sell their products and services. • Medical representatives should provide their services according to the Association of the British Pharmaceutical Industry (ABPI) code of practice (or similar). If the code of practice is breached, medical representatives can be reported to the director of the Prescription Medicines Code of Practice Authority (PMCPA). • Most hospitals have a policy for dealing with medical representatives — check the local policy. • Some hospitals do not allow medical representatives to leave samples. Check the policy for the local hospital before accepting trial samples from medical representatives. • It is GCP for medical representatives to make an appointment before meeting with a member of staff. Some hospital policies restrict the grades of staff that are allowed to meet with medical representatives. • Medical representatives are not allowed to promote unlicensed indications for their products or products that have not yet been licensed. However, they are allowed to answer specifi c questions on unlicensed use (see b p.262). • Hospital drug prices are confi dential to the hospital and under no circumstance must they be revealed to a medical representative. • Most hospitals limit the level of hospitality provided by representatives. For example, it is reasonable for representatives to provide food for a working lunch, but not expensive meals at a restaurant. Further reading Guidance Notes for Health Professionals, Understanding the ABPI Code of Practice for the Pharmaceutical Industry and Controls on the Promotion of Prescription Medicines in the UK . M ----------------------- Page 301----------------------- 280 CHAPTER 14 Medicines management Overseas visitors • The term ‘overseas visitor’ is used for patients who have fallen ill unexpectedly while visiting the UK and who, consequently, require standard NHS emergency care. • People who do not normally live in the UK are not automatically entitled to use the NHS free of charge. • Patients who are eligible for full NHS treatment include the following. • Anyone legally living in the UK for  12 months. • Permanent residents. • Students in the UK for > 6 months. • Refugees or asylum seekers who have made an application to remain in the UK and are waiting for a decision on their immigration status. • People detained by the immigration authorities. • People from countries with a reciprocal agreement — e.g. European Union residents. • Patients who are not eligible for full NHS treatment include the following. • Students on courses in the UK for <6 months. • Refugees or asylum seekers who have not yet submitted applications to the Home Offi ce. • Those who have had an asylum application turned down and exhausted the appeals process. • Illegal immigrants. • The NHS hospital is legally responsible for establishing whether patients are not normally resident in the UK. • If patients are not eligible for free NHS care, the hospital must charge the patient for the costs of the NHS care. • When the patient is charged depends on the urgency of the treatment needed. • For immediately necessary treatment, treatment must not be delayed or withheld while the patient’s chargeable status is being established. • For urgent and non-urgent treatment, patients should pay a deposit equivalent to the estimated full cost of treatment in advance. • Any surplus can be returned to the patient on completion of the treatment. • Treatment that is available to overseas patients free of charge is as follows. • A&E visits. However, treatment in other departments following an A&E visit (e.g. X-ray) is charged. • Emergency or immediately necessary treatment. • Treatment of sexually transmitted diseases (except HIV). • Treatment of diseases that are a threat to public health (e.g. tuberculosis (TB)) and acute treatment of all infectious diseases. • Family planning. • Compulsory psychiatric treatment. • If an overseas visitor chooses to be treated privately, they are classed as an ‘international private patient’. These patients are treated as private patients (see b p.282). ----------------------- Page 302----------------------- OVERSEAS VISITORS 281 Further reading Department of Health ( 2007 ). Implementing the Overseas Visitors Hospital Charging Regulations . London : Department of Health . Department of Health . Overseas Visitors . M Publications/ PublicationsPolicyAndGuidance/DH_4080313 Department of Health ( 2010 ) Overseas Visitors . M Entitlementsandcharges/OverseasVisitors/index.htm Pollard AJ , Savulescu J ( 2004 ). Eligibility of overseas visitors and people of uncertain residential status for NHS treatment . British Medical Journal 329 : 346 – 9 . ----------------------- Page 303----------------------- 282 CHAPTER 14 Medicines management Private patients In the UK, patients can choose to have treatment either from the NHS or privately. Private patients usually have private health insurance, which covers some, or all, of the costs of private treatment. Patients can be treated privately either in a private hospital or in NHS hospitals. Private patients treated in NHS hospitals are discussed in this section. • NHS hospitals either have specifi c wards for private patients or private patients are treated on the same ward as NHS patients, often in a side room. • Patients who are treated privately either have private health insurance or are paying themselves. • Before the patient receives treatment, the private health insurance company must confi rm what they will cover, according to the patient’s insurance policy. • Patients’ drugs must be charged accurately to the private health insurance companies to ensure that the NHS generates income from using NHS facilities to treat these patients. • If a patient is having private treatment, this should be annotated in some way on the patient notes or identifi cation labels. • Any prescription for a private patient must be annotated as ‘private patient’ to ensure that the pharmacy department can charge appropriately for the drugs. • Private patients do not have to pay NHS prescriptions charges. • Charging and systems can vary for in-patients and out-patients. • An on-cost is usually added to the drug price when charging for private patients‘ drugs. • Clinical pharmacists’ input into patient care for drug review and counselling might be appropriate. • Check what systems are in place for private patients’ drugs in your hospital. • Patients can choose to change from being a private patient to an NHS patient between consultations. In 2009, the Department of Health issued guidance for patients to enable them to remain NHS patients, but to pay for additional private care, such 1 as drugs, not available in or funded by the NHS. The NHS continues to provide the care the patient is entitled to in the NHS, and the private care has to be delivered separately from the NHS care. Hospitals should have specifi c policies in place for patients requesting additional private care in accordance with this guidance. 1 Department of Health (2009) Guidance on NHS patients who wish to pay for additional private care . M PublicationsPolicyAndGuidance/ DH_096428 ----------------------- Page 304----------------------- PROFESSIONAL SUPERVISION SKILLS 283 Professional supervision skills • Start with goals or an action plan for the member of staff you are supervising. • These should be SMART — i.e. Specifi c, Measurable, Achievable, Relevant,and Timescale. • Effective goals have fi ve parts: — intentions — outcomes — methods and resources — midpoints and deadlines — action plans. • Prioritize the workload with your staff. • Set timelines. • Time management — ensure that time is managed effectively. • Listen effectively to your member of staff. • Review and monitor action plans and progress at regular intervals. • Support and coach, as necessary. • Be available to discuss ways forward with the member of staff. • Communicate the ‘bigger picture’, so that staff understand why tasks are being undertaken. • Be honest. Tips on day-to-day supervision • Some of the professional supervision skills should be used on a daily basis to help with day-to-day supervision. • Be aware of the workload to be covered that day and the staff available to undertake the work. • If necessary, prioritize the day’s work with the staff. • Be available to trouble-shoot. • Support the staff with the urgent and important work, if necessary. ----------------------- Page 305----------------------- 284 CHAPTER 14 Medicines management National Service Frameworks (NSFs) NSFs are national standards for specifi ed clinical areas to ensure equality of NHS services throughout the UK. NSFs were developed by the Department of Health, with the help of external reference groups. These groups are made up of health professionals, service users and carers, health service managers, partner agencies, and other advocates. Usually, one new framework is developed each year. National Service Frameworks: • establish national standards and promote specifi c service models • identify key interventions for a defi ned service or care group • put in place strategies to support implementation • establish ways to ensure progress within an agreed timescale • are a measure to i quality and d variations in service within the NHS • drive the delivery of the NHS modernization agenda. Some examples of NSFs developed to date include the following: • coronary heart disease • cancer • paediatric intensive care • mental health • older people • diabetes • long-term conditions (e.g. neurological) • renal services • children. Opportunities for pharmacy Some NSFs specifi cally mention pharmacy or medicine-related issues. • Become familiar with the framework standards, and consider how to contribute to the achievement of the standards. • A pharmacist should be involved with the local implementation team responsible for the development and delivery of a service plan and identifying what has to be done to implement the NSF. • Decide on the services that can be initiated and the relevant links to the NSF standards. • Identify links to the local delivery plan and other local priorities. • Participate with an existing or developing service where possible. • Identify the opportunities for pharmacy. • Consult with other stakeholders who can infl uence the development of a proposed service. • Identify training needs to provide a new service. • Identify the outcomes proposed — are they realistic and measurable? • Develop a business case which refers to the NSF, local priorities, and needs, and includes integration into local services. Further reading Stanley J ( 2004 ). Benchmarking the role of pharmacists in implementing NSFs . Pharmacy Management 20 : 2 – 5 . ----------------------- Page 306----------------------- This page intentionally left blank ----------------------- Page 307----------------------- 286 CHAPTER 14 Medicines management Appraisal An appraisal meeting provides a formal opportunity for managers and staff to meet and discuss job performance, achievements against objectives previously set, future work objectives and priorities, career aspirations, and training and development needs. This process should ensure that staff are clear about what they are trying to achieve and why, and managers are clear on the progress being made by everyone in their department. Defi nitions • Appraisal is a dynamic ongoing process of performance management through objectives and staff development. • Performance management is a system to align the work of individuals as closely as possible to the work of the organization. The appraisal process • Appraisal supports effective performance and personal development. • Appraisals should take place annually, according to the local hospital policy. • The line manager usually conducts the appraisal. • Both the appraiser and the appraisee should prepare for the annual appraisal meeting. It is good practice to have at least 2wks notice to enable an individual to have time to prepare. • In preparation for the annual appraisal, the appraisee should list their strengths and weaknesses, achievements, and performance highs and lows for the previous 12 months. There may be specifi c appraisal paperwork that needs completing by both the appraiser and the appraisee prior to the appraisal, according to local policy. • The annual appraisal should be conducted to ensure an open two-way discussion, and usually lasts for ~2h. • During the appraisal, the following areas are usually covered. • Introduction and purpose of an appraisal. • Review of the objectives set at the last appraisal, a discussion of which ones are met, and resolving diffi culties with those that have not been met. • Review of an individual’s work over the past year. • Outline and agree future objectives. • Review of individuals current knowledge and skills. • Prioritization of areas requiring development to improve effectiveness at work. • Agree a personal development plan for the next year. • Discussion of how an individual’s objectives fi t within the team and organization’s objectives. • Discussion on how the organization/line manager can help the appraisee achieve their objectives. • Constructive feedback on performance. • Recognition of an individual’s performance. • Discussion of any of the appraisee’s concerns. • Review of job description and plans to update it accordingly. ----------------------- Page 308----------------------- APPRAISAL 287 • A paper record of the appraisal, which is signed by the appraisee and the appraiser, should be kept. Review of performance should be continuous, and any concerns should be raised throughout the year and not left to the annual appraisal. Further reading Naisby A (ed) ( 2002 ). Appraisal and Performance Management . London : Spiro Press . Chartered Institute of Personnel and Development ( 2010 ). Performance Appraisal . M http://www. ----------------------- Page 309----------------------- 288 CHAPTER 14 Medicines management Confi dentiality Pharmacists and pharmacy staff are expected to maintain the confi denti- ality of any patient or customer they have contact with during the course of their professional duties. Information that should remain confi dential includes the following: • patient’s identity and address • diagnosis • details of prescribed and non-prescribed medicines. Pharmacists must also ensure that any written or electronic patient infor- mation is stored and disposed of securely and that electronic systems are password protected. To avoid unintentional disclosure, it is important to develop good habits when dealing with patient information. • Discussing a patient with colleagues is often necessary for patient care or training purposes, but be cautious about revealing names or other patient identifi ers. • Do not discuss patients in public areas — e.g. the lifts or the front of the shop. • If talking about your work to family or friends, only talk about patients in very general terms. • Ensure that written information (e.g. patient handover lists and prescriptions) is not left lying where other patients or the public can see it. • If discussing medication with a patient, try to do this in a reasonably private area. If hospital in-patients have visitors, ask if the patient would like you to return when they have gone. • Ensure that computers have passwords and always log off at the end of a session. Disclosure of information In certain situations, pharmacists might have to disclose confi dential infor- mation. The UK pharmacy code of ethics allows this in the following cir- cumstances. • With patient consent or parent/guardian/carer consent for a child or adult not competent to give consent themselves. Information about adolescent patients should not normally be revealed without their consent. • If required by law or statute. • If necessary to prevent serious injury or damage to the health of the patient, a third party or the public health. ----------------------- Page 310----------------------- CONFIDENTIALITY 289 The RPSGB has published a fact sheet on confi dentiality, which includes 1 guidance on disclosure of information. In addition, advice on disclosure of information if necessary to protect children and vulnerable adults can be 2 found on the Pharmaceutical Journal website. Confi dentiality when a friend, relative, or colleague is a patient Pharmacists and pharmacy staff can be put in a diffi cult position in this situation, especially if others know that the patient is in their care. Well- meaning questions about the patient’s welfare might be diffi cult to deal with without causing offence. • Explain to the patient what level of involvement you have in their care and that you would have access to their medical notes. Ask whether they would prefer that another pharmacist deals with their care (although this might not always be feasible). • If at all possible, discuss the situation with the patient and ask them what information they are willing for you to reveal to other friends, family, or colleagues. • If the patient is unwilling for you to reveal any information, or if you are unable to discuss this with the patient, any enquiries should be dealt with by politely explaining that you cannot provide information about the patient. Bear in mind, however, that simply making this statement potentially discloses the fact that the individual is known to you as a patient. • Try to avoid compromising your integrity by denying all knowledge of the patient, but in some situations this might be necessary. • Inform the medical team that the patient is known to you socially. • Personal information known to you because of your relationship to the patient should not be revealed to medical or nursing colleagues without the patient’s consent. • The patient might use your relationship to ask you to provide medical information that you would not normally reveal. Provide only the same information as you would to any other patient. • If a colleague is a patient, be especially sensitive to any aspect of care that could breach confi dentiality. As appropriate, you might need to consider the following. • Avoid writing your colleague’s name on ward order sheets. • Use an agreed alias for labelling of medicines. • Label, dispense, and deliver medicines yourself. • Keep any written records separate from those to which other pharmacy staff have access. 1 RPSGB. M 2 M ----------------------- Page 311----------------------- 290 CHAPTER 14 Medicines management Gene therapy The development of genetically modifi ed viruses and advances in cloning and sequencing the human genome have offered the opportunity to treat a wide variety of diseases using ‘gene therapy’. The term ‘gene therapy’ applies to any clinical therapeutic procedure in which genes are intention- ally introduced into human cells. Gene therapy clinical trials have been undertaken in cystic fi brosis, cancer, cardiac disease, HIV, and inherited genetic disorders. Preparation of gene therapy products is a pharmaceu- tical preparation process that should be carried out under the control of a pharmacist in suitable facilities to minimize the risk of microbiological contamination and medication errors. Gene therapy can be divided into two main categories: gene replacement and gene addition. Gene replacement tends to be used for monogenic diseases, in which a single ‘faulty’ gene can be replaced with a normal gene. For example, an abnormal cystic fi brosis transmembrane conductance regulator (CFTR) gene can be replaced in cystic fi brosis. Currently, the majority of gene therapy clinical trials use a gene- addition strategy for cancer, whereby a gene or genes can be ‘added’ to a cell to provide a new function, e.g. addition of tumour suppressor genes to cancer cells. For gene therapy to be successful, a therapeutic gene must be delivered to the nucleus of a target cell, where it can be expressed as a therapeutic protein. Genes are delivered to target cells by vectors in a process called ‘gene transfer’. The greatest challenge to gene therapy is fi nding a vector that can transfer therapeutic genes to target cells specifi cally and effi ciently. Gene transfer vectors can be broadly divided into non-viral and viral systems. Non-viral vectors, such as liposomes, have limited effi ciency. Genetically modifi ed viruses have proved to be the most effi cient way of delivering DNA. Viruses are merely genetic information protected by a protein coat. They have a unique ability to enter (infect) a cell, delivering viral genes to the nucleus using the host cell machinery to express those viral genes. A variety of viruses have been used as vectors, including retroviruses, herpes viruses, and adenoviruses. Many viral vectors have been genetically modifi ed so that they cannot form new viral particles and so are termed ‘replication-defi cient’ or ‘replication-defective’. Replication- defi cient viruses have had the viral genes required for replication and the pathogenic host response removed. This prevents the virus replicating and the potential for the therapeutic virus to reverse back to a pathogenic virus. The deleted genes are replaced by a therapeutic gene, thus allowing the delivery and expression of the therapeutic gene without subsequent spread of the virus to surrounding cells. Future gene therapy vectors will be able to replicate under genetically specifi ed conditions. ----------------------- Page 312----------------------- GENE THERAPY 291 There are potential infectious hazards with gene therapy, including possible transmission of the vector to hospital personnel. Therefore gene therapy products should be manipulated in pharmacy aseptic units, because of the uncertain effects of specifi c genes on normal human cells, potential for operator sensitization on repeated exposure, and the potentially infective nature of some products. Consideration has to be given to protecting both the product and the staff handling these agents. Some gene therapy agents might require handling in negative-pressure isolators in separate specifi c aseptic facilities. A risk assessment should be made for each product, with input from the lead investigator or trust biological safety offi cer, because they should have a good understanding of molecular biology and virology. Further reading Stoner N ( 2009 ). Gene therapy applications . Clinical Pharmacist 1 : 270 – 4 . Watson M , Stoner N ( 2007 ). Safe handling of gene medicines . European Journal of Hospital Pharmacy Practice 13 : 24 – 6 . Vulto AG et al . ( 2007 ). European Association of Hospital Pharmacists (EAHP) guidance on the pharmacy handling of gene medicines . European Journal of Hospital Pharmacy Practice 13 : 29 – 39 . Stoner NS et al . ( 2006 ). Appendix 6 — Gene therapy . In Beaney AM Quality Assurance of Aseptic Preparation Services ( 4th edn). London : Pharmaceutical Press . Brooks G (ed) ( 2002 ). Gene Therapy: The Use of DNA as a Drug . London : Pharmaceutical Press . M Gene therapy advisory committee (GTAC) . htm?ssSourceSiteId=en UK Health and Safety Executive ( 2000 ). A Guide to the Genetically Modifi ed Organisms (Contained Use) Regulations . London : HSE Books . Searle PF et al . ( 2002 ). Cancer gene therapy: from science to clinical trials . Drug Delivery Systems and Sciences 2 : 5 – 13 . Simpson J , Stoner NS ( 2003 ). Implications of gene therapy to pharmacists . Pharmaceutical Journal 271 : 127 – 30 . Stoner NS et al . ( 2003 ). Health and safety considerations for the administration of gene therapy within the clinical setting . Journal of Oncology Pharmacy Practice 9 : 29 – 35 . ----------------------- Page 313----------------------- 292 CHAPTER 14 Medicines management Pharmacogenetics Pharmacogenetics is defi ned as the study of human genetic variation, which causes different responses to drugs. The differences in response can be both in the therapeutic effect and in ADRs. For example, genetic make-up may determine variations in liver enzymes that are produced, which in turn affect drug metabolizm. One of the cytochrome P450 liver enzymes, CYP2D6, metabolizes drugs (e.g. B -blockers, antidepressants, and opioids) in the liver so that they can be eliminated. The level of this enzyme in the liver is genetically determined. Patients are classifi ed as ‘slow metabolizers’ if they have low levels of CYP2D6 in the liver, which means that the drug is eliminated from the body more slowly, resulting in additional toxicity. ‘Fast metabolizers’ have a high level of CYP2D6 in the liver and therefore metabolize the drug more quickly, resulting in a possible reduced therapeutic effect. In practice, ‘slow metabolizers’ may require a lower dose of drug than ‘fast metabolizers’ for the same effect. An example of a drug metabolized through this mechanism is warfarin: 40 % of the variability in warfarin levels is accounted for by the CYP2C9 enzyme. Another example of genetic infl uence on drug response is via receptors. If drugs bind to specifi c receptors to generate a response and the number of receptors present is genetically determined, the response to the drug will vary according to the patient’s genetics. This has enabled drug development to be much more targeted, so that only patients with specifi c characteristics receive the appropriate drugs. For example, breast cancer patients who have the HER2 receptor present on their breast cancer cells will be the only group of breast cancer patients who respond to trastuzumab. This highlights that in cancer patients, the presence or absence of some genes will determine the patient’s response to some anti-cancer drugs. Genetic testing of individuals is usually done from a saliva or blood sample. There will be issues regarding the quality of the tests, their initiation, communication to the patient, and the implication of the test to treatment. The general public would need to be more widely educated about pharmacogenetics and its implications. Tests would need to be rigorously evaluated. Currently there are some home test kits available, but the sale of these is not regulated. This means that some of the test kits available have no guarantee of being validated or of producing accurate results. There are ethical issues that need to be considered in genotyping individuals. (The genotype is the genetic make-up of a cell or individual. Genotyping is the process of determining an individual’s genotype using biological assays to fi nd out the genetic make-up of an individual.) This could lead to discrimination of individuals who carry specifi c genes and affect the allocation of resources. For example, there is concern that some individuals may not be able to obtain insurance policies if their genetic test results are considered negatively. There is also concern about the privacy and confi dentiality of genetic information, where it should be stored, and who would have access to it. Drug companies may only research drugs for diseases that are straightforward to treat, rather than those that could be used for rarer diseases. In addition, pharmacogenetic testing may predict ----------------------- Page 314----------------------- PHARMACOGENETICS 293 for future risks of disease or raise implications for other family members, which adds to the ethical issues of informing patients and their families. Pharmacogenetics will enable more cost-effective and targeted prescribing that will optimize the use of drugs, avoiding the prescribing of drugs that will be ineffective, and reduce the medical and fi nancial impact of adverse drug reactions. This means that in the future patients will be prescribed drugs specifi c to their conditions, taking into account genetic factors when deciding on dosage regimens. However, targeted drugs may be more expensive. In addition, there may be a loss of any benefi t of, for example, racemic mixtures. ----------------------- Page 315----------------------- 294 CHAPTER 14 Medicines management Standards of business conduct for clinical pharmacists Declaration of interests has become an integral part of professional life, and pharmacists are not exempt from showing that they are independent and unbiased. In addition, clinical pharmacists have access to valuable con- fi dential data and can infl uence purchasing decisions that can have a major effect on a particular company’s products. Therefore it is important that pharmacists are aware of relevant guidelines. In the UK, Department of Health guidelines have been produced on these issues and it is prudent to have a local policy designed using this or similar guidance. The Department of Health guidelines cover the standards of conduct expected of all NHS staff, where their private interests could confl ict with their public duties, and the steps that NHS employers should take to safeguard themselves and the NHS against confl ict of interest. Details can be found in the Code of Conduct for NHS Managers 2002; 1 Some key which is available on the Department of Health website. relevant issues are as follows. • Avoid confl ict of interest between private and NHS interests. It is a well-established principle that public sector bodies, which include the NHS, must be impartial and honest in the conduct of their business, and that their employees should remain above suspicion. • NHS staff are expected to ensure that the interest of patients is paramount at all times, to be impartial and honest in the conduct of their offi cial business, and to use the public funds entrusted to them to the best advantage of the service, always ensuring value for money. • It is also the responsibility of staff to ensure that they do not abuse their offi cial position for personal gain or to benefi t their family or friends. • Modest hospitality, provided that it is normal and reasonable in the circumstances (e.g. lunches in the course of working visits), are acceptable, although it should be similar to the scale of hospitality that the NHS, as an employer, would probably offer. Anything else should be declined. • Casual gifts can be offered by contractors or others (e.g. at Christmas time). Such gifts should nevertheless be politely, but fi rmly, declined. Articles of low intrinsic value, such as diaries or calendars, or small tokens of gratitude from patients or their relatives, need not necessarily be refused. • NHS employers need to be aware of all cases in which an employee or their close relative or associate has a signifi cant fi nancial interest in a business. 1 M (accessed October 2011). ----------------------- Page 316----------------------- STANDARDS OF BUSINESS CONDUCT FOR CLINICAL PHARMACISTS 295 • Individual staff must not seek or accept preferential rates or benefi ts in kind for private transactions carried out with companies with which they have had, or might have had, offi cial dealings on behalf of their NHS employer. • All staff who are in contact with suppliers and contractors, in particular those who are authorized to sign purchase orders or place contracts for goods, are expected to adhere to professional standards of the kind set out in the ethical code of the Institute of Purchasing and 1 Supply (IPS). • Fair and open competition between prospective contractors or suppliers for NHS contracts is a requirement of NHS standing orders and of EC directives on public purchasing for works and supplies. • NHS employers should ensure that no special favour is shown to current or former employees in awarding contracts to private or other businesses run by them. • NHS employees are advised not to engage in outside employment that could confl ict with their NHS work or be detrimental to it. • Acceptance by staff of commercial sponsorship for attendance at relevant conferences and courses is acceptable, but only if the employee seeks permission in advance and the employer is satisfi ed that acceptance will not compromise purchasing decisions in any way. • Pharmaceutical companies, for example, might offer to sponsor, wholly or partially, a post for an employing authority. NHS employers should not enter into such arrangements, unless it has been made abundantly clear to the company concerned that the sponsorship will have no effect on purchasing decisions within the authority. • Staff should be particularly careful of using, or making public, internal information of a ‘commercial in confi dence’ nature, if its use would prejudice the principle of a purchasing system based on fair competition. • Finally, many employers maintain a record of interests and pharmacists should cooperate with such practices. 1 Chartered Institute of Purchasing & Supply. M ----------------------- Page 317----------------------- 296 CHAPTER 14 Medicines management Waste management of medicines Pharmaceutical waste refers to the disposal of unwanted medicines, out- of- date or obsolete stock, sharps, and waste arising from diagnostic testing. The current regulations are detailed in the Hazardous Waste Regulations 2005, and further guidance specifi cally for community pharmacies are detailed in the Department of Health document Environment and Sustainability Health Technical Memorandum 07-06: Disposal of Pharmaceutical Waste in Community Pharmacies . The legislation relevant to pharmaceutical waste  2016-10-22 05:55:50  2016-10-22 05:55:50  View Edit Delete
51  gfhfghfgh  fghfghfgh  2016-10-27 10:24:27  2016-10-27 10:24:27  View Edit Delete
52  334  3434  2016-11-21 04:46:09  2016-11-21 04:46:09  View Edit Delete
53  ads  dsadas  2016-12-09 22:36:11  2016-12-09 22:36:11  View Edit Delete
54  Some Elementary Advice To Effectively Defeat Panic  Say Goodbye To Panic Attack With These Tips Did you know that people with higher than normal intelligence are prone to panic attacks? If you experience these attacks, hopefully this knowledge along with the other helpful tips in this article will assist you with finding peace of mind in trying to deal with your situation. <a href=></a>  2017-01-18 11:55:18  2017-01-18 11:55:18  View Edit Delete
55  Sleep Apnea Symptoms Can Be Controlled With These   Like many other ailments, people are not properly informed about the reality of sleep apnea, especially if they have never dealt with it before. Many people begin to develop this issue later in life and are unaware of how to reduce problems with it- that is where this article comes in with useful tips! For people who are using a CPAP machine, you need to take notes to give to your doctor. If you experience any symptoms, like snoring, that were eliminated when you started using the CPAP machine and they come back, you need to let your doctor know. Only your doctor can properly assess any problems. If you are over weight, going on a diet can reduce your sleep apnea, or in rare cases, eliminate it completely. Maintaining a healthy weight can help you breathe easier, so losing weight and maintaining a healthy weight when you have trouble breathing is an obvious step in treating your sleep apnea. Do not take sleeping pills if you suffer from sleep apnea. These pills are not recommended if you suffer from this condition because they relax the muscles of your throat. Skipping them can actually help you get a better night of sleep because your apnea symptoms are not aggravated. Getting a CPAP machine is probably the best option for your sleep apnea. These machines will keep your airways open and help you breathe. You should talk to your doctor about CPAP machines and figure out which model would be the most adapted. This machine should work if you use it properly. Clear up your nasal passage before heading to bed. If you suffer from sleep apnea and have problems with a "stuffed up" nose, using a nasal spray or device can help clear your nasal airway. This is not a permanent solution, but one you can use when your apnea symptoms are the worst. If you have been diagnosed with sleep apnea, it is important to avoid drinking alcohol. Alcoholic beverages will relax the muscles in your throat, which makes it more likely that they will block your airway during your sleep. At the very least, avoid any alcoholic beverages in the evening before you get ready for bed. If you have been diagnosed with sleep apnea, it is important to avoid drinking alcohol. Alcoholic beverages will relax the muscles in your throat, which makes it more likely that they will block your airway during your sleep. At the very least, avoid any alcoholic beverages in the evening before you get ready for bed. If you are a trucker who has sleep apnea, take precautions to stay safe on the road. First of all, get yourself properly diagnosed and treated. If your doctor prescribes a CPAP, use it. They are small and easily portable and can run on battery power if necessary. Try to stay fit and get regular sleep to keep your condition under control. As the above article has demonstrated, you have many different treatment methods available to you when it comes to sleep apnea. Everyone is different, and it's important to find out which treatment option will fit your specific situation best. If you use these tips, you will get better sleep at night. Sleep apnea doesn't have to run your life; you can take control back today. <a href=></a>  2017-02-24 00:16:50  2017-02-24 00:16:50  View Edit Delete
56  tim  tim  2017-03-07 09:44:47  2017-03-07 09:44:47  View Edit Delete
57      2017-03-22 04:24:08  2017-03-22 04:24:08  View Edit Delete
58  2012    2017-03-29 00:05:36  2017-03-29 00:05:36  View Edit Delete
59  nfpfsWuuBHQTBhPhzR  EoeckT check link  2017-04-04 05:24:26  2017-04-04 05:24:26  View Edit Delete
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63  zvMlTnwlOFz  BRAtaL comment6, poema_gomera_iliada_chitat_polnostiu, 469, foto_lamy_skachat, 8622, kontaktor_modulnyi_km632-40_1no_1nz_tdm, 07406, raspisanie_chuguev_losevo, twuaxf, kniga_brachnyi_dogovor_dzhennifer_probst_skachat_besplatno, 68835, windows_azure_active_directory_powershell, %(, raspisanie_aktobe_almaty_24, :OOO, skachat_audioknigu_sudba_barabanshchika, gjmo, ne_doveriaite_koshkam_epub_skachat, scot, gta_4_mod_na_chelovek_pauk_skachat, 8298, torrent_super_mario_galaxy_2_iso, %-[[, pdruchnik_khmia_8_klas_skachat, :PP, blank_kompanii_na_angliiskom, :-]], raspisanie_filmov_na_sts, %-OO, vsichki_kodove_za_gta_san_andreas, knmyo, gta_v_beta_keygen_password_txt, =D, patch_contraceptif_evra_et_grossesse, 472, mi_pervoi_oktavy_gitara, =], mxf_file_reader, rdij, chomikuj_m_jak_mio_1148, dnecpz, fail_ofis_2007, 181851, skachat_commview_for_wifi, 4286, skachat_dekameron_pdf, %-PPP, skachat_muzyku_eis_of_beis, %-D, chuzhoi_raion_4_sezon_skachat_torrentom, %OO, taktivin_otzyvy, %O, whatsapp_for_windows_phone_6, 753, wix_file_source_example, 868631, mod_en_minecraft, yhd, mod_bulatnaia_stal_dlia_medieval-2_total_war, %[[[, skachat_firefox_na_android_23, 445932, gta_robotboy, 4574, skachat_knigi_fb2zip_besplatno, dzoyq, mod_oblivion_xbox_360, 26240, skachat_vebinar, fga, how_to_repair_windows_xp_using_recovery_console, :-PPP, chitat_knigu_illiuziia_vybora, zcs, adobe_photoshop_cs5_windows_81_free_download, 288, skachat_knigi_iulii_shilovoi_v_formate_pdf, lebl, rasshirennyi_modpak_ot_protanki, pdg, gm_ignition_switch_recall_models_affected, gvdnve, skachat_igru_ognem_i_mechom_2_total_var_s_torrenta, dhrp, logic_pro_x_download_windows, 50939, skachat_pesniu_bi-2_ee_glaza_besplatno, 00787, skachat_vintazh_kogda_riadom_ty, %-]]],   2017-04-05 02:35:24  2017-04-05 02:35:24  View Edit Delete
64  erIvoAalkGdoqzoMI  comment5, visual_basic_2008_for_windows_7_32_bit_free_download, 2867, windows_7_password_manager_software, 40265, x_files_season_3_torrent_kickass, 8-PP, tf_abbreviation_modeling, >:-DD, zubnaia_feia_kniga_vikipediia, 28185, skachat_besplatno_novuiu_muzyku_2013, vyg, grafik_raboty_m_video, 718907, tm_model, rdnlw, good_omens_audio_fic, uvwvl, qr_file, :[[, patch_fifa_15_upl, =-(((, kniga_shilovoi_nakazanie_krasotoi, 8221, mod_gpu_fan, %PP, kriak_multilizer_pdf_translator, suu, mod_priboi_story_2, 27581, nuzhnyi_moi_fail, fug, firmware_update_philips_smart_tv, slh, vislovliuvannia_pro_rol_knigi_u_zhitt_liudini, %(((, katalog_stroitelnykh_materialov_kemerovo, 368474, skachat_igru_far_cry_2_na_android_besplatno, 5224, painkiller_patch_161_download, 7157, skachat_tiuner_dlia_gitary_na_pk, 6307, cubase_7_patch__crack_activator, >:-], epub_una_vacante_imprevista, %-[, skachat_flesh_2_sezon_s_torrenta, %[[[, pdf_xchange_viewer_free_download_crack, qcjgp, base_sas_procedures_guide_92, %-PPP, app_mod_whatsapp_plus, 727, windows_7_usb_drivers_problem, 0873, luchshaia_kniga_po_google_analytics, =-]]], exo_growl_2nd_mv_free_download, fzfmgv, audiokniga_kniazhna_meri, 574, quickbooks_windows_to_mac_transfer, 8-[[[, se_img_filer_p_ipad, hpns, baza_v_klash_of_klans_4_tkh, >:D, kitaiskie_bukvy_gta_5, %], mod_kritika_2911, 16236, klubniak_ot_windows_7_skachat, ruq, superpi_1m_download, 4910, obnovlenie_iazykovykh_paketov_windows_8, %(, spetsnaz_kgb_kniga, qwevc, download_spin_tires_mods_free, 704936, alt_j_album_download_rar, kxsrm, skachat_pianino_na_android, sjarpm,   2017-04-05 03:29:23  2017-04-05 03:29:23  View Edit Delete
65  wfyWbCAFzTlTs  comment5, windows_7_password_manager_software, 1999, file_taxes_1040ez_online, ovdod, video_tsinfo_file, ppvfy, windows_mobile_61_update_lg_incite, 723, obrazets_rospisi_na_pasport, 323, ne_mogu_udalit_fail_iz_korziny_mac, 60840, gta_eflc_mods_how_to_install, kao, execute_batch_file_ms_dos, =-[[, skachat_chit_nodus_na_mainkraft_164, :[[, chitat_onlain_dzhek_london_belyi_klyk, 8(, vse_legendy_gta_san_andreas, >:))), file_in_csv, %PPP, do_vstrechi_s_toboi_kniga_skachat_epub, 772595, susy_boyfriend_skachat_besplatno, 297181, obrazets_mezhevogo_plana_zemelnogo_uchastka, 992279, epub_voor_android, 97727, samba_36_windows_server_2012, %-)), windows_phone_8_rukovodstvo_polzovatelia_pdf, %DDD, skachat_s_torrenta_sniper_elite_v2_2012_pc, >:-O, windows_7_rog_edition, 62998, mod_dnssdc_no_services_found_to_register_centos, cthm, xlivedll_gta_4_windows_8_indir, :[, uliss_chitat_otzyvy, nuzc, slushat_audioknigi_iuliana_semenova, zah, windows_7_iis_administration_console, 688368, torrent_jack_reacher_espaol_dvdrip, 81099, patchi_dlia_pb, 306, wm_windowposchanged_vs_wm_size, zgrxrl, sherlok_kholms_kniga_na_angliiskom_kupit, svmfey, get_file_path_mac_terminal, oml, skachat_pekha_i_leps_ona_ne_tvoia, %D, chitat_onlain_povesti_belkina_metel, :-))), qradar_patch_still_in_progress, 989, update_lg_smart_tv_firmware_from_usb, =-[[[, baza_i_top_cnd_tsena, >:]]], play_mkv_windows_media_center, >:[, noragami_op_download, 453574, hackintosh_yosemite_windows_7_dual_boot, ivrbj, kodi_do_gta_san_andreas_tank, kuk, windows_product_key_file_location, frrdj, ffk_tv_aktobe_ordabasy, 4183, skachat_kak_dostat_soseda_4pda, zmsntx, dayz_standalone_patch_048_download, 30867, kniga_angliiskogo_iazyka_4_klass, 143,   2017-04-05 03:57:16  2017-04-05 03:57:16  View Edit Delete
66  HpgyFabNboZUMqZFFy  comment3, webcam_software_windows_7_free, 817, pochemu_v_gta_5_propadaiut_mashiny, :]], windows_8_msdn_iso_direct_link, 140242, modbus_poll_701_crack, 0229, windows_phone_8_store_user_credentials, >:OOO, chicken_qabalah_epub, 31945, spirkin_filosofiia_pdf_skachat, =]], iaichki_a_lialialia_skachat_pesniu, :), chto_oznachaet_mod_10, derb, skachat_fs_14_russkaia_versiia_na_android, zgmmdo, sholokhov_sudba_cheloveka_tekst_skachat, 698573, windows_agent_skachat_besplatno, gexh, skyrim_mod_xp32_maximum_skeleton_extended, 4478, r_copy_files_to_folder, 68686, raspisanie_avtobusov_v_baranovichakh_2014, fag, cubase_7_patch__crack_activator, :D, raspisanie_vshe_politologiia_magistratura, :))), update_acrobat_reader, lmr, filez_ab, >:-OO, bts_multiplexing_mode, 8(, windows_xp_autologon_registry, 8[[[, rbzh_pl_82_skachat_besplatno, yqvqz, kniga_i_ekho_letit_po_goram_chitat_onlain, %[, windows_xp_dlia_slabykh_pk, 21670, failoobmennik_dump_ru, chg, freeware_mdf_file_viewer, 608, iis_modules_error, 413, skachat_shrek_2_the_game, >:-]]], como_imprimir_ebooks_kindle, hkod, bamse_och_tjuvstaden_dvd_torrent, dskeb, sb3_mods_megapack, >:-OO, quickbooks_windows_to_mac_transfer, >:-)), knigi_po_php_2013_skachat_besplatno, >:-[[[, chto_delat_v_gta_5_kogda_proshel_igru, ukf, esafarli_mne_tebia_obeshchali_skachat_knigu, %-]]], mod_pizza, gclkrp, kniga_splin_teksty_pesen, yig, pdruchnik_z_bolog_7_klas_musnko_skachati, zjtf, download_spin_tires_mods_free, 1946, ma_thoi_den_tap_5_tusachmobi, :-)), skachat_knigu_alan_garner_allan_piz_iazyk_razgovora, 031, fei_skachat_torrentom_avi, =-OO,   2017-04-05 04:00:34  2017-04-05 04:00:34  View Edit Delete
67  OASVaKAVGIGrfCHjP  comment6, skachat_besplatno_kurs-samouchitel_razgovornogo_angliiskogo_btc, :-OO, patch_the_forest_002, 841900, ia_kniga_soiuz, 22665, pochta_mailru_faily, 8(((, cs_go_cracked_servers, %-(((, shnyr_pegas_lev_i_kentavr_skachat, uytwsd, windows_live_skachat_besplatno_russkaia_versiia, lgc, patch_football_manager_2013, bnwyby, ne_mogu_udalit_fail_iz_korziny_mac, clk, windows_wiki_versions, %-DD, il_2_sturmovik_1946_vietnam_mod, 6479, kak_skachivat_foto_s_aifona_na_mak, 85565, candy_crush_saga_mod_apk_download, vgvk, windows_not_genuine_cmd_solution, >:-[, kniga_my_s_istekshim_srokom_godnosti_chitat, hcz, kak_prochitat_pdf_na_iphone, tlr, kayla_itsines_pdf_download_diet, hwzaz, skachat_alone_in_the_dark_illumination, bxows, rukovodstvo_po_ustanovke_i_nastroike_windows_7, tukla, windows_7_slic_21_keys, 48634, skachat_vindovs_7_kdf, >:[[[, mody_dlia_heroes_3_era, 156062, ne_modnaia_devushka, 08128, windows_psexec_examples, nrq, ne_yo_non_fiction_album_download_free, irchkr, raspisanie_matchei_ch_m_po_khokkeiu_2014, 88628, krasnaia_kniga_dlia_detei_v_kartinkakh, obb, stanok_dlia_pristrelki_oruzhiia_chertezh, kul, chitat_livejournal_v_kazakhstane, slvn, samouchitel_raboty_v_word_2003_skachat_besplatno, >:-((, skachat_foto_tibetskogo_mastifa, >:-[[[, patch_velcro_militaire, 076, g_patch_domain-containing_protein_11, oyk, uolt_uitmen_listia_travy_na_angliiskom, 163, kak_prochitat_chuzhie_soobshcheniia_na_aifone, %O, sravnenie_interfeisov_windows_i_linux, 576298, skachat_knigi_na_ipad_v_formate_epub_besplatno, 7079, opredelenie_fail_server, 45231, patch_mortal_kombat_x, =-D, modnaia_obuv_muzhskaia_2017, msviie, raspisanie_prigorodnykh_poezdov_dnepropetrovsk_dneprodzerzhinsk, mslfs, skyrim_nif_file_viewer, xsm, om_band_back_patch, %))), obnovlenie_iazykovykh_paketov_windows_8, :-((, windows_phone_81_set_quiet_hours, %PP, skachat_filmy_mp4_na_telefon_bez_registratsii, :(, atb_humanity_skachat, >:-]],   2017-04-05 04:18:23  2017-04-05 04:18:23  View Edit Delete
68  CwTeBRdqsRTNekqH  comment5, pixel_z_skachat_igru, rypzl, raspisanie_multfilmov_v_kinoteatrakh_kazani, qsbv, audiokniga_ottsy_i_deti_skachat, 072, knigi_pro_zombi_apokalipsis_chitat_onlain, :), file-max_limit_22703_reached, =-[[[, pub_file_converter_to_pdf_free, 6462, ip_switcher_windows_7, =-D, wav_file_metadata_format, 472, verbe_la_modul_conjunctiv_timpul_prezent, >:PPP, lara_fabian_je_t_aime_skachat_besplatno, %[[, fail_etc_hosts_skachat, 8881, sholokhov_sudba_cheloveka_tekst_skachat, %[, mjpeg_codec_windows_xp, fpcpz, co_znaczy_patcher, iqyrx, windows_8_youtube_downloader_free, %OO, jak_zmna_hesla_administratora_windows_7, 709762, baixar_mod_mwm_slrr, rcybm, windows_live_messenger_hotmail_download_free, 724, fail_eksplorer_za_android, >:PP, 3com_3c905c-tx_windows_7_drivers, 8PPP, new_york_fashion_designer_game, 189968, kniga_zhizni_smotret_onlain_besplatno_v_khoroshem_kachestve_na_russkom_iazyke, ybtjne, krem_loreal_trio_aktiv_pitanie_i_uvlazhnenie_tsena, fji, nova_3_mod_money, =-))), how_to_read_epub_files_in_chrome, =-D, php_imagemagick_check_if_file_is_image, :)), kak_prochitat_fail_db3, :-)), opredelenie_fail_server, lxntr, obnovlenie_zvukovykh_draiverov_windows_xp, >:-[, gta_ps4_cheats, >:D, detskie_knigi_na_angliiskom_iazyke_dlia_nachinaiushchikh_chitat_onlain, 50002, zagruzit_fail_na_server_c, qojr, gde_skachat_fotoshop_cs6_na_russkom_besplatno_forum, :PP, primer_teksta_blagodarnosti, 005596, lvf_file_media_player_free_download, 8), skachat_vkontakte_video_onlain, 99133, skachat_programmu_excel_besplatno_i_bez_registratsii, >:P, gta_iv_models_file_download, ycfc, alber_kamiu_chuma_skorocheno_chitat, rpbu, audiokniga_angliiskii_onlain, zxvhcv, windows_7_rutor_2014, 84898, skachat_adobe_photoshop_cs5_s_kliuchom, vbbman, cd_key_windows_xp_sp3_vlk, %-(((,   2017-04-05 04:27:06  2017-04-05 04:27:06  View Edit Delete

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