Side effects of genome structural changes.

The first extensive catalog of structural human variation was recently released. It showed that large stretches of genomic DNA that vary considerably in copy number were extremely abundant. Thus it is conceivable that they play a major role in functional variation. Consistently, genomic insertions and deletions were shown to contribute to phenotypic differences by modifying not only the expression levels of genes within the aneuploid segments but also of normal copy-number neighboring genes. In this report, we review the possible mechanisms behind this latter effect.

Increased clozapine plasma concentrations and side effects induced by smoking cessation in 2 CYP1A2 genotyped patients.

Clozapine, an atypical antipsychotic, depends mainly on cytochrome P4501A2 (CYP1A2) for its metabolic clearance. CYP1A2 is inducible by smoking, and lower plasma concentrations of clozapine are measured in smokers than in nonsmokers. Case reports have been published on the effects of discontinuing smoking in patients receiving clozapine, which might lead to elevated plasma concentrations and severe side effects. We present 2 cases on the consequences of smoking cessation in patients receiving this drug. In the first patient, smoking cessation resulted, within 2 weeks, in severe sedation and fatigue, with an approximately 3-fold increase of plasma clozapine concentrations. In the second patient, a very high plasma concentration of clozapine (3004 ng/mL) was measured 6 days following a 16-day stay in a general hospital, during which smoking was prohibited. In the latter patient, the replacement of omeprazole, a strong CYP1A2 inducer, by pantoprazole, a weaker CYP1A2 inducer, could have contributed, in addition to smoking cessation, to the observed strong increase of plasma clozapine concentrations. Genotyping of the 2 patients revealed that they were carriers of the AA genotype for the -164C>A polymorphism (CYP1A2*1F) in intron 1 of CYP1A2 gene, which has previously been shown to confer a high inducibility of CYP1A2 by smoking. Thus, at the initiation of clozapine treatment, smoking patients should be informed that, if they decide to stop smoking, they are encouraged to do so but must inform their prescriber beforehand. Also, because of the increased use of no-smoking policies in many hospitals, studies examining the consequences of such policies on the pharmacokinetics/pharmacodynamics of drugs metabolized by CYP1A2, taking into account different CYP1A2 genotypes, are needed.

IRP Poster - Side-effects in Software Transactional Memory

Poster for IRP project 'Side-effects in Software Transactional Memory: Extending Deuce with TwilightSTM'

Provision of information about drug side-effects to patients

To make informed decisions about taking medicinal drugs, people need accurate information about side-effects. A European Union guideline now recommends use of qualitative descriptions for five bands of risk, ranging from very rare (affecting < 0·01% of the population), to very common (>10%). We did four studies of more than 750 people, whom we asked to estimate the probability of having a side-effect on the basis of qualitative and quantitative descriptions. Our results showed that qualitative descriptions led to gross overestimation of risk. Until further work is done on how patients taking the drugs interpret these terms, the terms should not be used in drug information leaflets.

Communicating information about medication side effects: effects on satisfaction, perceived risk to health, and intention to comply

Previous research has shown that people's evaluations of explanations about medication and their intention to comply with the prescription are detrimentally affected by the inclusion of information about adverse side effects of the medication. The present study (Experiment 1) examined which particular aspects of information about side effects (their number, likelihood of occurrence, or severity) are likely to have the greatest effect on people's satisfaction, perception of risk, and intention to comply, as well as how the information about side effects interacts with information about the severity of the illness for which the medication was prescribed. Across all measures, it was found that manipulations of side effect severity had the greatest impact on people's judgements, followed by manipulations of side effect likelihood and then number. Experiments 2 and 3 examined how the severity of the diagnosed illness and information about negative side effects interact with two other factors suggested by Social Cognition models of health behaviour to affect people's intention to comply: namely, perceived benefit of taking the prescribed drug, and the perceived level of control over preventing or alleviating the side effects. It was found that providing people with a statement about the positive benefit of taking the medication had relatively little effect on judgements, whereas informing them about how to reduce the chances of experiencing the side effects had an overall beneficial effect on ratings.

Is 15 per cent very common? Informing people about the risks of medication side effects

Objectives - To assess the general public's interpretation of the verbal descriptors for side effect frequency recommended for use in medicine information leaflets by a European Union (EU) guideline, and to examine the extent to which differences in interpretation affect people's perception of risk and their judgments of intention to comply with the prescribed treatment. Method - Two studies used a controlled empirical methodology in which people were presented with a hypothetical, but realistic, scenario about visiting their general practitioner and being prescribed medication. They were given an explanation that focused on the side effects of the medicine, together with information about the probability of occurrence using either numerical percentages or the corresponding EU verbal descriptors. Interpretation of the descriptors was assessed. In study 2, participants were also required to make various judgments, including risk to health and intention to comply. Key findings - In both studies, use of the EU recommended descriptors led to significant overestimations of the likelihood of particular side effects occurring. Study 2 further showed that the "overestimation" resulted in significantly increased ratings of perceived severity of side effects and risk to health, as well as significantly reduced ratings of intention to comply, compared with those for people who received the probability information in numerical form. Conclusion - While it is recognised that the current findings require replication in a clinical setting, the European and national authorities should suspend the use of the EU recommended terms until further research is available to allow the use of an evidence-based approach.

Evaluating explanations about drug prescriptions: effects of varying the nature of information about side effects and its relative position in explanations

This study evaluates computer-generated written explanations about drug prescriptions that are based on an analysis of both patient and doctor informational needs. Three experiments examine the effects of varying the type of information given about the possible side effects of the medication, and the order of information within the explanation. Experiment 1 investigated the effects of these two factors on people's ratings of how good they consider the explanations to be and of their perceived likelihood of taking the medication, as well as on their memory for the information in the explanation. Experiment 2 further examined the effects of varying information about side effects by separating out the contribution of number and severity of side effects. It was found that participants in this study did not “like” explanations that described severe side effects, and also judged that they would be less likely to take the medication if given such explanations. Experiment 3 therefore investigated whether information about severe side effects could be presented in such a way as to increase judgements of how good explanations are thought to be, as well as the perceived likelihood of adherence. The results showed some benefits of providing additional explanatory information.

Comparison of two methods of presenting risk information to patients about the side effects of medicines

Objective: To determine whether the use of verbal descriptors suggested by the European Union (EU) such as "common" (1-10% frequency) and "rare" (0.01-0.1%) effectively conveys the level of risk of side effects to people taking a medicine. Design: Randomised controlled study with unconcealed allocation. Participants: 120 adults taking simvastatin or atorvastatin after cardiac surgery or myocardial infarction. Setting: Cardiac rehabilitation clinics at two hospitals in Leeds, UK. Intervention: A written statement about one of the side effects of the medicine (either constipation or pancreatitis). Within each side effect condition half the patients were given the information in verbal form and half in numerical form (for constipation, "common" or 2.5%; for pancreatitis, "rare" or 0.04%). Main outcome measure: The estimated likelihood of the side effect occurring. Other outcome measures related to the perceived severity of the side effect, its risk to health, and its effect on decisions about whether to take the medicine. Results: The mean likelihood estimate given for the constipation side effect was 34.2% in the verbal group and 8.1% in the numerical group; for pancreatitis it was 18% in the verbal group and 2.1% in the numerical group. The verbal descriptors were associated with more negative perceptions of the medicine than their equivalent numerical descriptors. Conclusions: Patients want and need understandable information about medicines and their risks and benefits. This is essential if they are to become partners in medicine taking. The use of verbal descriptors to improve the level of information about side effect risk leads to overestimation of the level of harm and may lead patients to make inappropriate decisions about whether or not they take the medicine.

Expressing medicine side effects: assessing the effectiveness of absolute risk, relative risk, and number needed to harm, and the provision of baseline risk information

Objective: To assess the effectiveness of absolute risk, relative risk, and number needed to harm formats for medicine side effects, with and without the provision of baseline risk information. Methods: A two factor, risk increase format (relative, absolute and NNH) x baseline (present/absent) between participants design was used. A sample of 268 women was given a scenario about increase in side effect risk with third generation oral contraceptives, and were required to answer written questions to assess their understanding, satisfaction, and likelihood of continuing to take the drug. Results: Provision of baseline information significantly improved risk estimates and increased satisfaction, although the estimates were still considerably higher than the actual risk. No differences between presentation formats were observed when baseline information was presented. Without baseline information, absolute risk led to the most accurate performance. Conclusion: The findings support the importance of informing people about baseline level of risk when describing risk increases. In contrast, they offer no support for using number needed to harm. Practice implications: Health professionals should provide baseline risk information when presenting information about risk increases or decreases. More research is needed before numbers needed to harm (or treat) should be given to members of the general populations. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Communicating risk of medication side effects: an empirical evaluation of EU recommended terminology

Two experiments compared people's interpretation of verbal and numerical descriptions of the risk of medication side effects occurring. The verbal descriptors were selected from those recommended for use by the European Union (very common, common, uncommon, rare, very rare). Both experiments used a controlled empirical methodology, in which nearly 500 members of the general population were presented with a fictitious (but realistic) scenario about visiting the doctor and being prescribed medication, together with information about the medicine's side effects and their probability of occurrence. Experiment 1 found that, in all three age groups tested (18 - 40, 41 - 60 and over 60), participants given a verbal descriptor (very common) estimated side effect risk to be considerably higher than those given a comparable numerical description. Furthermore, the differences in interpretation were reflected in their judgements of side effect severity, risk to health, and intention to comply. Experiment 2 confirmed these findings using two different verbal descriptors (common and rare) and in scenarios which described either relatively severe or relatively mild side effects. Strikingly, only 7 out of 180 participants in this study gave a probability estimate which fell within the EU assigned numerical range. Thus, large scale use of the descriptors could have serious negative consequences for individual and public health. We therefore recommend that the EU and National authorities suspend their recommendations regarding these descriptors until a more substantial evidence base is available to support their appropriate use.

Interpreting information about medication side effects: differences in risk perception and intention to comply when medicines are prescribed for adults or young children

This study investigates whether, and how, people's perception of risk and intended health behaviours are affected by whether a medicine is prescribed for themselves or for a young child. The question is relevant to the issue of whether it is beneficial to produce medicines information that is tailored to particular subgroups of the population, such as parents of young children. In the experiment, participants read scenarios which referred either to themselves or their (imagined) 1-year-old child, and were required to make a number of risk judgements. The results showed that both parents and non-parents were less satisfied, perceived side effects to be more severe and more likely to occur, risk to health to be higher, and said that they would be less likely to take (or give) the medicine when the recipient was the child. On the basis of the findings, it is suggested that it may well be beneficial to tailor materials to broader classes of patient type.

Memory for medication side effects in younger and older adults: the role of subjective and objective importance

Older adults often experience memory impairments, but can sometimes use selective processing and schematic support to remember important information. The current experiments investigate to what degree younger and healthy older adults remember medication side effects that were subjectively or objectively important to remember. Participants studied a list of common side effects, and rated how negative these effects were if they were to experience them, and were then given a free recall test. In Experiment 1, the severity of the side effects ranged from mild (e.g., itching) to severe (e.g., stroke), and in Experiment 2, certain side effects were indicated as critical to remember (i.e., “contact your doctor if you experience this”). There were no age differences in terms of free recall of the side effects, and older adults remembered more severe side effects relative to mild effects. However, older adults were less likely to recognize critical side effects on a later recognition test, relative to younger adults. The findings suggest that older adults can selectively remember medication side effects, but have difficulty identifying familiar but potentially critical side effects, and this has implications for monitoring medication use in older age.