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Introduction: Pharmacovigilance includes analysis of large databases of information on drugs and events using algorithms that detect disproportional frequencies of associations. In order to test such algorithms, attempts have been made to provide canonical reference lists of so-called 'positive controls' and 'negative controls'. Reference sets with even modest levels of misclassification may result in under- or overstatement of the performance of algorithms.Aim: We sought to determine the extent to which 'negative control' drug-event pairs in the Observational Medical Outcomes Partnership (OMOP) database are misclassifiedMethods: We searched the medical literature for evidence of associations between drugs and events listed by OMOP as negative controls.Results: The criteria used in OMOP to classify positive and negative controls are asymmetric; drug-event associations published only as case series or case reports are classified as positive controls if they are cited in Drug-Induced Diseases by Tisdale and Miller, but as negative controls if case series or case reports exist but are not cited in Tisdale and Miller. Of 233 drug-event pairs classified in the 2013 version of OMOP as negative controls, 21 failed to meet pre-specified OMOP adjudication criteria; in another 19 cases we found case reports, case series, or observational evidence that the drug and event are associated. Overall, OMOP misclassified, or may have misclassified, 40 (17 %) of all 'negative controls.'Conclusions: Results from studies of the performance of signal-detection algorithms based on the OMOP gold standard should be viewed with circumspection, because imperfect gold standards may lead to under/overstatement of absolute and relative signal detection algorithm performance. Improvements to OMOP would include omitting misclassified drug-event pairs, assigning more specific event labels, and using more extensive sources of information. [ABSTRACT FROM AUTHOR]

Aims Hyponatraemia is one of the major adverse effects of thiazide and thiazide-like diuretics and the leading cause of drug-induced hyponatraemia requiring hospital admission. We sought to review and analyze all published cases of this important condition. Methods Ovid Medline, Embase, Web of Science and PubMed electronic databases were searched to identify all relevant articles published before October 2013. A proportions meta-analysis was undertaken. Results One hundred and two articles were identified of which 49 were single patient case reports. Meta-analysis showed that mean age was 75 (95% CI 73, 77) years, 79% were women (95% CI 74, 82) and mean body mass index was 25 (95% CI 20, 30) kg m−2. Presentation with thiazide-induced hyponatraemia occurred a mean of 19 (95% CI 8, 30) days after starting treatment, with mean trough serum sodium concentration of 116 (95% CI 113, 120) m m and serum potassium of 3.3 (95% CI 3.0, 3.5) m m. Mean urinary sodium concentration was 64 m m (95% CI 47, 81). The most frequently reported drugs were hydrochlorothiazide, indapamide and bendroflumethiazide. Conclusions Patients with thiazide-induced hyponatraemia were characterized by advanced age, female gender, inappropriate saliuresis and mild hypokalaemia. Low BMI was not found to be a significant risk factor, despite previous suggestions. The time from thiazide initiation to presentation with hyponatraemia suggests that the recommended practice of performing a single investigation of serum biochemistry 7-14 days after thiazide initiation may be insufficient or suboptimal. Further larger and more systematic studies of thiazide-induced hyponatraemia are required. [ABSTRACT FROM AUTHOR]

Background: Life-threatening adverse drug reactions (ADRs) such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) continue to affect patients' lives long after the event. Survivors and their relatives rely heavily on Internet sources for support and advice, but narratives of their experiences posted on patient websites have not been explored previously.Objectives: The aim of the study was to illuminate patient experience by analysing Internet narratives of drug-induced SJS and TEN and considering the reasons for postings on patient websites, and the concerns they reflect. We also aimed to compare these experiences with a previous study of survivors of SJS and TEN conducted by face-to-face interview.Methods: We searched for unsolicited personal narratives or descriptions of drug-induced SJS and TEN posted on the Internet between February 2009 and June 2010, and analysed them using a thematic qualitative approach.Results: We analysed 208 Internet descriptions. Motivation for posting on the Internet included a desire to share experiences and to seek advice from others. Patients and their relatives expressed concern that the ADR may be hereditary, worries about effects on fertility and a fear of recurrence. They also wished to increase awareness of the potential harms from medicines and to inform others of the suspected cause of the ADR.Conclusion: Individuals experiencing SJS or TEN had many unanswered questions and concerns long after the event. Our findings could guide health professionals in the management of survivors of the ADR, and in communicating more effectively with patients and their relatives. Internet forum postings of patient experiences of ADRs provide insight into patient concerns and supplement findings from detailed face-to-face interviews. [ABSTRACT FROM AUTHOR]

For any therapeutic intervention in an individual, there is a balance between the potential benefits and the possible harms. The extent to which the benefits are desirable in a given condition depends on the efficacy of the intervention, the chance of obtaining it and the seriousness and intensity of the condition. The extent to which the harms are undesirable depends on the nature of the hazard that can lead to harm, the chance that the harm will occur and its seriousness and intensity. Rational therapeutic decisions require clinicians to consider competing courses of action, with potential benefits of different desirability and potential harms of different undesirability. They also have a duty to explain to the patient, for the contemplated interventions, both the possible benefits and the potential harms that the patient may consider significant. In an individual patient, it is necessary to consider (a) the probabilities of benefit from both intervention and non-intervention and (b) the probabilities of harm from both intervention and non-intervention. However, there are several potential problems. Here, we consider how failure to distinguish maximum benefits from probable benefits, or hazards (potential harms) from probable harms, and failure to consider all the competing probabilities may lead to imperfect therapeutic decisions. We also briefly discuss methods to assess the benefit to harm balance., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Opioid deaths have increased in England and Wales. Coroners' Prevention of Future Deaths reports (PFDs) provide important insights that may enable safer use and avert harms, yet reports implicating opioids have not been synthesized. We aimed to identify opioid-related PFDs and explore coroners' concerns to prevent future deaths., Methods: In this systematic case series, we screened 3897 coronial PFDs dated between 01 July 2013 and 23 February 2022, obtained by web scraping the UK's Courts and Tribunals Judiciary website. PFDs were included when an opioid was implicated in the death. Included PFDs were descriptively analysed, and content analysis was used to assess concerns reported by coroners., Results: Opioids were involved in 219 deaths reported in PFDs (5·6% of PFDs), equating to 4418 years of life lost (median 33 years/person). Morphine (29%), methadone (23%) and diamorphine (16%) were the most common implicated opioids. Coroners most frequently raised concerns regarding systems and protocols (52%) or safety issues (15%). These concerns were most often addressed to National Health Service (NHS) organizations (51%), but response rates were low overall (47%)., Conclusions: Opioids could be used more safely if coroners' concerns in PFDs were addressed by national organizations such as NHS bodies, government agencies and policymakers, as well as individual prescribing clinicians., (© The Author(s) 2023. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Health systems encourage switching from originators to biosimilars as biosimilars are more cost-effective. The speed and completeness of biosimilar adoption is a measure of efficiency. We describe the approach to biosimilar adoption at a single hospital Trust and compare its efficiency against the English average. We additionally follow up patients who reverted to a previously used biologic, having switched to a biosimilar, to establish whether they benefitted from re-establishing prior treatment. The approach we describe resulted in a faster and more complete switch to biosimilars, which saved an additional £380 000 on drug costs in 2021/2022. Of patients who reverted to their original biologic, 87% improved short-term, and a time on treatment analysis showed the benefit was retained long term. Our approach to biosimilar adoption outperformed the English average and permits patients to revert to their original biosimilar post-switch if appropriate., (© 2023 British Pharmacological Society.)

Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations. In the first part of this review we proposed an operational definition that incorporates the processes by which products are manufactured, the causes of shortages and stock-outs (local shortages), and the contributory factors. Here we discuss causes and possible solutions. Drug shortages have complex causes, and a single cause cannot always be identified. Reasons include lack or shortage of raw materials, manufacturing difficulties, regulatory and political actions, voluntary recalls, just-in-time inventory systems, halts in production for financial or other business reasons, low demand (eg, orphan products, reduced usage), mergers, market shifts (eg, diversion to home markets) and unexpected increases in demand (eg, improved diagnosis, new trial information, epidemics and pandemics, inappropriate use, off-label use). Potential solutions are as diverse as the potential causes. Prevention is hard, because shortages are not easily predicted. Everyone in the supply chain is involved in anticipating and managing shortages, with responsibilities for preventing them or at least trying to mitigate their effects. This includes manufacturers and suppliers, particularly of generic formulations, pharmacists, prescribers, patients and governments. Solutions can therefore be linked to the causes and classified according to where the responsibility for implementing them lies., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Drug shortages are repeatedly in the news. The earliest drug shortages were reported during the First World War, but the numbers of shortages have increased in recent years. In the first part of this two-part review, we discuss definitions of drug shortages and so-called stockouts, which are localized shortages, and the harms that they can cause. Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations, but we lack an adequate definition. The problems are too complicated to be encompassed in a brief intensional dictionary-style definition, and that is reflected in the many different attempts at definition that have been proposed. We therefore propose an extensional operational definition that incorporates the processes by which products are manufactured, the causes of shortages and the contributory factors. A definition of this sort allows one to identify the main causes of a particular drug shortage and therefore the remedies that might prevent, mitigate or manage it. In the second part of the review we discuss the causes and solutions in more detail. Adverse drug reactions and medication errors attributable to shortages occur but are not often reported. Adverse reactions to substitute medicines are possible, and errors can occur because of unfamiliarity or unnecessary treatment with replacement medicines. Other harmful outcomes include withdrawal reactions, undertreatment, treatment delays and cancellations, failure of alternatives and disruption of clinical trials., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Pharmacogenomic testing has the potential to target medicines more effectively towards those who will benefit and avoid use in individuals at risk of harm. Health economies are actively considering how pharmacogenomic tests can be integrated into health care systems to improve use of medicines. However, one of the barriers to effective implementation is evaluation of the evidence including clinical usefulness, cost-effectiveness, and operational requirements. We sought to develop a framework that could aid the implementation of pharmacogenomic testing. We take the view from the National Health Service (NHS) in England., Methods: We used a literature review using EMBASE and Medline databases to identify prospective studies of pharmacogenomic testing, focusing on clinical outcomes and implementation of pharmacogenomics. Using this search, we identified key themes relating to the implementation of pharmacogenomic tests. We used a clinical advisory group with expertise in pharmacology, pharmacogenomics, formulary evaluation, and policy implementation to review data from our literature review and the interpretation of these data. With the clinical advisory group, we prioritized themes and developed a framework to evaluate proposals to implement pharmacogenomics tests., Results: Themes that emerged from review of the literature and subsequent discussion were distilled into a 10-point checklist that is proposed as a tool to aid evidence-based implementation of pharmacogenomic testing into routine clinical care within the NHS., Conclusion: Our 10-point checklist outlines a standardized approach that could be used to evaluate proposals to implement pharmacogenomic tests. We propose a national approach, taking the view of the NHS in England. Using this approach could centralize commissioning of appropriate pharmacogenomic tests, reduce inequity and duplication using regional approaches, and provide a robust and evidence-based framework for adoption. Such an approach could also be applied to other health systems., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Insulin poisoning, as opposed to hypoglycaemia induced by therapeutic doses of insulin, is rare, and guidelines on management differ. We have reviewed the evidence on treatment of insulin poisoning., Methods: We searched PubMed, EMBASE and J-Stage with no restrictions of date or language for controlled studies on treatment of insulin poisoning, collected published cases of insulin poisoning from 1923, and used data from the UK National Poisons Information Service., Results: We identified no controlled trials of treatment in insulin poisoning and few relevant experimental studies. Case reports described 315 admissions (301 patients) with insulin poisoning between 1923 and 2022. The insulin with the longest duration of action was long-acting in 83 cases, medium-acting in 116, short-acting in 36 and a rapid-acting analogue in 16. Decontamination by surgical excision of the injection site was reported in six cases. To restore and maintain euglycaemia, almost all cases were treated with glucose, infused for a median 51 hours, interquartile range 16-96 h in 179 cases; 14 patients received glucagon and nine octreotide; adrenaline was tried occasionally. Both corticosteroids and mannitol were occasionally given to mitigate hypoglycaemic brain damage. There were 29 deaths reported, 22/156 (86% survival) up to 1999 and 7/159 (96% survival) between 2000 and 2022 (p = 0.003)., Conclusions: There is no randomized controlled trial to guide treatment of insulin poisoning. Treatment with glucose infusion, sometimes supplemented with glucagon, is almost always effective in restoring euglycaemia, but optimum treatments to maintain euglycaemia and restore cerebral function remain uncertain., (© 2023 Diabetes UK.)

The initial purposes of regulation of medicines in England, and latterly in the United Kingdom, were principally to raise government revenue, to discourage murder by poisoning and to regulate the activities of pharmacists. It was only much later that regulators sought to ensure that medicines were of good quality, reasonably safe, and at least somewhat effective, and to curtail misuse of drugs. Here we survey the history of the regulation of medicines and poisons in England from the perspective of clinicians with an interest in therapeutics., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Competing Interests: Competing interests: JKA has published articles and edited textbooks on adverse drug reactions and interactions, for which he has sometimes received royalties, and has often given medicolegal advice, including appearances as an expert witness in coroners’ courts, for which he has received fees. He is an associate editor of BMJ Evidence-Based Medicine and was a coauthor of the editorial that introduced the Coroners’ Concerns to Prevent Harms Series in the journal. GCR was financially supported by the National Institute for Health Research School for Primary Care Research, the Naji Foundation, and the Rotary Foundation to study for a doctor of philosophy (2017-2020), but no longer has any financial conflicts of interest; she is an associate editor of BMJ Evidence-Based Medicine, was lead author of the editorial that introduced the Coroners’ Concerns to Prevent Harms Series, and is developing (https://preventabledeathstracker.net/) a programme of research on preventable deaths.

Introduction: The UK Medicines and Healthcare products Regulatory Agency (MHRA) has published frequent summaries of spontaneous reports of suspected adverse drug reactions (ADRs) (Yellow Cards) to vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The EudraVigilance database has provided similar data for the European Economic Area., Objective: Our objective was to characterize the evolution over time of spontaneous reports of suspected ADRs to coronavirus disease 2019 (COVID-19) vaccines and to observe the effect of a publicized reaction (cerebral venous and sinus thrombosis [CVST]) on reporting rates., Methods: We used publicly available data on reports of suspected ADRs and doses of vaccine administered, published by the MHRA, EudraVigilance, and the European Centre for Disease Prevention and Control to calculate reporting rates., Results: Approximately 4814 Yellow Card reports (23 fatal) per million doses of ChAdOx1 nCoV-19 (AstraZeneca) and 2890 (13 fatal) per million doses of tozinameran (Pfizer/BioNTech) have been lodged. Between 15 March and 31 October 2021, cumulative European reports of CVST rose from 0 to 443 (183 with thrombocytopenia, 72 fatal) with ChAdOx1 nCoV-19 and from 2 to 315 (9 with thrombocytopenia, 28 fatal) with tozinameran. European cases of retinal vein occlusion and thrombosis rose from 0 to 168 with ChAdOx1 nCoV-19 and from 1 to 220 with tozinameran; four of the ChAdOx1 nCoV-19 cases were associated with thrombocytopenia., Conclusion: Reports of fatal adverse reactions to coronavirus vaccines are very rare. Reports of CVST have been made in relation to both vaccines. Most were submitted after the reaction had been publicized. Thrombocytopenia occurred in a minority of cases. Reports linked both vaccines to cases of retinal vein thrombosis, just four cases with thrombocytopenia. This suggests two different mechanisms of thrombosis associated with the vaccines., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Enzyme-inducing antibacterial drugs can impair the efficacy of hormonal contraceptives. Suspicion that other antibiotics might do likewise led to advice that extra contraceptive precautions should be taken during a course of antibiotics. However, current advice is that the purported interaction does not occur, based on small studies observing few pregnancies, assuming that all women are susceptible, and without measuring unbound hormone concentrations., Objective: To test the null hypothesis that antibiotics do not impair the effectiveness of oral contraceptives., Design: A database review of Yellow Card reports to the UK's Medicines and Healthcare products Regulatory Agency., Data: Spontaneous reports of suspected adverse drug reactions in people taking antibacterial drugs (n=74 623), enzyme-inducing medicines (n=32 872), or control medicines (n=65 578)., Main Outcome Measures: Reports of the primary outcome-unintended pregnancies; reports of cardiac arrhythmias and headaches (control events); reports of congenital abnormalities (positive control events); and reports of diarrhoea (a possible confounding factor)., Results: Compared with control medicines, unintended pregnancies were seven times more commonly reported with antibiotics and 13 times more commonly reported with enzyme inducers (the positive controls). Congenital abnormalities were reported seven times more often with enzyme inducers but were not more common with antibiotics. Diarrhoea was not a confounding factor., Conclusion: This study provides a signal that antibacterial drugs may reduce the efficacy of hormonal contraceptives. Women taking hormonal contraceptives should be warned that antibiotics may impair their effectiveness. Extra precautions can be taken during a course of antibiotics; an unintended pregnancy is a life-changing event., Competing Interests: Competing interests: JKA and REF have both written widely about adverse drug reactions and interactions and have from time to time received fees for legal reports, payments for articles, and royalties on books that they have written on the subject., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: We competed with each other in selecting the harms to include.

Competing Interests: Competing interest statement: Competing interests The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none. Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests

Introduction: Harms from medical devices are important, but have been much less well studied than adverse drug reactions. Information provided to device users is of variable quality., Objective: Our aim was to define "medical device fault" and "adverse effect of a medical device"; to establish whether medical device faults arise in design, manufacture, or use; and to consider ways of mitigating the adverse effects of medical devices., Methods: We analysed 100 consecutive faults reported by the US Food and Drug Administration (FDA) and 50 faults reported by the UK Medicines and Healthcare products Regulatory Agency (MHRA), and classified faults according to the point at which they occurred., Results: Nearly 70% of reported faults related to devices that entered the body. Over 70% arose at the design stage, a quarter of the faults were associated with manufacture, and less than 5% were primarily caused by faulty use., Conclusion: We defined a medical device fault as an unintended failure in the design, manufacture, or use of a medical device that leads to, or has the potential to lead to, harm to the patient, and an adverse effect of a medical device as an unintended and appreciably harmful effect, caused by a medical device, which demonstrates a hazard of the device and may warrant preventive measures, or a change in the mode of use, or withdrawal of the device. Most faults that generate warnings arise from problems at the design stage, some arise at the manufacturing stage, and a few in usage. Careful assessment of the design of safety-critical devices in the light of previous problems may help to prevent repetition of errors. It would be helpful if, in addition to user manuals, manufacturers were required to produce Summaries of Device Characteristics (SDCs, "labels") that contained a systematically presented set of information about a product.

Introduction: Coroners inquire into sudden, unexpected, or unnatural deaths. We have previously established 99 cases (100 deaths) in England and Wales in which medicines or part of the medication process or both were mentioned in coroners' 'Regulation 28 Reports to Prevent Future Deaths' (coroners' reports)., Objective: We wished to see what responses were made by National Health Service (NHS) organizations and others to these 99 coroners' reports., Methods: Where possible, we identified the party or parties to whom these reports were addressed (names were occasionally redacted). We then sought responses, either from the UK judiciary website or by making requests to the addressee directly or, for NHS and government entities, under the Freedom of Information Act 2000. Responses were analysed by theme to indicate the steps taken to prevent future deaths., Results: We were able to analyse one or more responses to 69/99 cases from 106 organizations. We analysed 201 separate actions proposed or taken to address the 160 concerns expressed by coroners. Staff education or training was the most common form of action taken (44/201). Some organisations made changes in process (24/201) or policy (17/201), and some felt existing policies were sufficient to address some concerns (22/201)., Conclusions: Coroners' concerns are often of national importance but are not currently shared nationally. Only a minority of responses to coroners' reports concerning medicines are in the public domain. Processes for auditing responses and assessing their effectiveness are opaque. Few of the responses appear to provide robust and generally applicable ways to prevent future deaths.

The terms 'licensed', 'unlicensed', and 'off-label', often used in relation to marketing and prescribing medicinal products, may confuse UK prescribers. To market a medicinal product in the UK requires a Marketing Authorization ('product licence') for specified indications under specified conditions, regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The Marketing Authorization includes the product's agreed terms of use (the 'label'), described in the Summary of Product Characteristics (SmPC). Prescribing a licensed product outside those terms is called 'off-label' prescribing. Products for which no-one holds a UK Marketing Authorization are unlicensed. Prescribers can prescribe authorized products according to the conditions described in the SmPC ('on-label') or outside those conditions ('off-label'). They can also prescribe unauthorized products, even if they are unlicensed in the UK, if they are licensed elsewhere or if they have been manufactured in the UK by a licensed manufacturer as a 'special'. The complexities of this system can be understood by considering the status of the manufacturer of the product, the company that markets it (which may or may not be the same), the product itself, and its modes of use, and by emphasizing the word 'authorized'. If a Marketing Authorization is granted to the supplier of a product, it will specify the authorized modes of use; the product will be prescribable as authorized (i.e. 'on-label') or in other modes of use, which will all be off-label. Unlicensed products with no authorized modes of use can be regarded as 'unauthorized products'. All 'specials' can be regarded as authorized products lacking authorized modes of use., (© 2017 The British Pharmacological Society.)

We have traced the historical link between the Law of Mass Action and clinical pharmacology. The Law evolved from the work of the French chemist Claude Louis Berthollet, was first formulated by Cato Guldberg and Peter Waage in 1864 and later clarified by the Dutch chemist Jacobus van 't Hoff in 1877. It has profoundly influenced our qualitative and quantitative understanding of a number of physiological and pharmacological phenomena. According to the Law of Mass Action, the velocity of a chemical reaction depends on the concentrations of the reactants. At equilibrium the concentrations of the chemicals involved bear a constant relation to each other, described by the equilibrium constant, K. The Law of Mass Action is relevant to various physiological and pharmacological concepts, including concentration-effect curves, dose-response curves, and ligand-receptor binding curves, all of which are important in describing the pharmacological actions of medications, the Langmuir adsorption isotherm, which describes the binding of medications to proteins, activation curves for transmembrane ion transport, enzyme inhibition and the Henderson-Hasselbalch equation, which describes the relation between pH, as a measure of acidity and the concentrations of the contributory acids and bases. Guldberg and Waage recognized the importance of dynamic equilibrium, while others failed to do so. Their ideas, over 150 years old, are embedded in and still relevant to clinical pharmacology. Here we explain the ideas and in a subsequent paper show how they are relevant to understanding adverse drug reactions., (© 2015 The British Pharmacological Society.)

Background: Adverse drug reactions are sometimes described as being 'non-dose-related' because no relationship has been found between increasing doses and either the intensity of the response or the proportion of individuals in whom the response occurs; furthermore, hypersensitivity reactions are often regarded as being non-dose-related, even if different doses have not been studied. However, the law of mass action implies that all pharmacological effects are concentration related and should increase in intensity with increasing dose. We set out to explain this paradox., Methods: We searched for published adverse drug reactions that have been described as non-dose-related and analysed them., Results: We identified four categories of explanations that resolve the paradox: (i) the reaction is not real; it may have occurred by chance or there may be methodological problems, such as bias or confounding factors; (ii) the dose-response curve for the adverse effect reaches a maximum at doses lower than were studied (i.e. a hypersusceptibility reaction); this underpins the use of test doses to predict the possibility of an adverse reaction at therapeutic doses; (iii) susceptibility to the adverse reaction differs widely among individuals; and (iv) imprecision or inaccuracy in the measurement of either dose or effect obscures dose responsiveness. This last explanation encompasses: (a) reactions related to cumulative dose; (b) dissociation between dose and concentration through saturable pharmacokinetics; and (c) variability in the measurement of the effect., Conclusions and Implications: If an adverse drug reaction appears to be non-dose-related, the reasons should be sought, having these mechanisms in mind., (© 2015 The British Pharmacological Society.)

Background: A computerized physician order entry (CPOE) system with embedded clinical decision support can reduce medication errors in hospitals, but might increase the time taken to generate orders., Aims: We aimed to quantify the effects of temporal (month, day of week, hour of shift) and other factors (grade of doctor, prior experience with the system, alert characteristics, and shift type) on the time taken to generate a prescription order., Setting: A large university teaching hospital using a locally developed CPOE system with an extensive audit database., Design: We retrospectively analyzed prescription orders from the audit database between August 2011 and July 2012., Results: The geometric mean time taken to generate a prescription order within the CPOE system was 11.75 s (95% CI 11.72 to 11.78). Time to prescribe was most affected by the display of high-level (24.59 s (24.43 to 24.76); p<0.001) or previously unseen (18.87 s (18.78 to 18.96); p<0.001) alerts. Prescribers took significantly less time at weekends (11.29 s (11.23 to 11.35)) than on weekdays (11.88 s (11.84 to 11.91); p<0.001), in the first (11.25 s (11.16 to 11.34); p<0.001) and final (11.56 s (11.47 to 11.66); p<0.001) hour of their shifts, and after the first month of using the system., Conclusions: The display of alerts, prescribing experience, system familiarity, and environment all affect the time taken to generate a prescription order. Our study reinforces the need for appropriate alerts to be presented to individuals at an appropriate place in the workflow, in order to improve prescribing efficiency., (© The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.comFor numbered affiliations see end of article.)

Purpose: Inconsistencies and omissions in drug-drug interaction (DDI) management guidelines may lead to harm and suboptimal therapy. The purpose of this study was to define a checklist for DDI management guidelines to help developers produce high-quality guidelines that will support healthcare providers in clinical practice., Methods: We carried out a two-round Delphi process with an international panel of healthcare providers, most of whom are pharmacists involved in providing DDI information, in order to select those items that should be addressed in DDI management guidelines (including grading systems that could be used)., Results: Twenty-three panellists reached consensus on 19 items in two main domains. These were consolidated into a checklist of 15 elements for standardized reporting in management guidelines. For each element a description is provided to specify what information should be documented in that specific element., Conclusions: It was possible to reach a broad consensus on which relevant items should be included in a checklist for the development of DDI management guidelines.

We report a patient with Crohn's disease and end-stage renal failure, which resulted in severe vitamin D deficiency and hyperparathyroidism. This resulted in the development of calciphylaxis, which initially manifested as pulmonary vasculature calcification; however, the diagnosis was not clear until the classic skin lesions had developed. Calciphylaxis is a rare condition, which is increasing in incidence, and a high index of suspicion is essential for early diagnosis and treatment. This condition is associated with a high degree of morbidity and mortality and, indeed, our patient died within 7 days of diagnosis.