Drug information sources in professional work-a questionnaire study on physicians' usage and preferences (the drug information study).

PURPOSE: This study aimed to explore physicians' use of drug information in professional work, with special focus on those working in primary care, and also in relation to personal characteristics of physicians. METHODS: A web-based questionnaire was distributed by e-mail to physicians in five regions in Sweden. The questions concerned drug-related queries at issue when searching for information, sources used, and factors of importance for the choice of source, as well as responder characteristics. RESULTS: A total of 3254 (85%) out of 3814 responding physicians stated that they searched for drug information every week. For physicians working in primary health care, the corresponding number was 585 (96%). The most common drug-related issues searched for by 76% of physicians every week concerned pharmacotherapeutic aspects (e.g., dosing), followed by adverse drug reactions (63%). For 3349 (88%) physicians, credibility was the most important factor for the choice of sources of drug information, followed by easy access online (n = 3127, 82%). Further analyses among physicians in primary care showed that some personal characteristics, like seniority, sex, and country of education, as well as research experience, were associated with usage and preferences of drug information sources. CONCLUSIONS: This study confirms that physicians often use drug information sources in professional work, in particular those who work in primary health care. Credibility and easy access are key factors for usage. Among physicians in primary care, personal factors influenced the choice of drug information sources.

Clinical relevance of alerts from a decision support system, PHARAO, for drug safety assessment in the older adults.

BACKGROUND: PHARAO is a decision support system developed to evaluate the risk for a set of either common or serious side-effects resulting from a combination of pharmacodynamic effects from a patient's medications. The objective of this study was to investigate the validity of the risk scores for the common side-effects generated by PHARAO in older patients. METHODS: Side-effects included were sedation, constipation, orthostatic symptoms, anticholinergic and serotonergic effects. The alerts generated by PHARAO were tested in 745 persons ≥65 years old. Dispensed prescriptions retrieved from the Swedish prescribed drug register were used to generate the pharmacological risk scores of patients' medications. Symptoms possibly related to side-effects were extracted from medical records data. RESULTS: The PHARAO system generated 776 alerts, most often for the risk of anticholinergic symptoms. The total specificity estimates of the PHARAO system were 0.95, 0.89 and 0.78 for high, intermediate and low risk alerts, respectively. The corresponding sensitivity estimates were between 0.12 and 0.37. The negative predictive value was 0.90 and the positive predictive value ranged between 0.20-0.25. CONCLUSIONS: The PHARAO system had a high specificity and negative predictive value to detect symptoms possibly associated with the of patients' medications, while the sensitivity and positive predictive value were low. The PHARAO system has the potential to minimise the risk of over-alerts in combination with a drug-drug interaction alert system, but should be used in connection with a medical evaluation of the patient.

Use of non-benzodiazepine hypnotics is associated with falls in nursing home residents: a longitudinal cohort study.

BACKGROUND: Falls and related injuries are common among older people, and several drug classes are considered to increase fall risk. AIMS: This study aimed to investigate the association between the use of certain drug classes and falls in older nursing home residents in Sweden, and relate these to different age groups. METHODS: Information on falls that occurred in the previous year and regular use of possible fall risk drugs including non-benzodiazepine hypnotics (zopiclone and zolpidem) was collected from 331 nursing home residents during 2008-2011. Over the following 6 months, the occurrence of serious falls, requiring a physician visit or hospital care, was registered. Association between serious falls and drug use was compared between an older (≥ 85 years) and a younger group. RESULTS: An increased fall risk (Downton Fall Risk Index ≥ 3) was found in 93% of the study subjects (aged 65-101 years). Baseline data indicated an association between falls that occurred in the previous year and regular use of non-benzodiazepine hypnotics (p = 0.005), but not with the other studied drug classes. During the following 6 months, an association between use of non-benzodiazepine hypnotics and serious falls in the older group (p = 0.017, odds ratio 4.311) was found. No association was found between the other studied drug classes and serious falls. DISCUSSION: These results indicate an association between falls and the use of non-benzodiazepine hypnotics, compounds that previously have been considered generally well-tolerated in older people. CONCLUSIONS: Caution is advocated when using non-benzodiazepine hypnotics regularly in older people living in nursing homes.

Comparing Methods for Estimating Direct Costs of Adverse Drug Events.

OBJECTIVES: To estimate how direct health care costs resulting from adverse drug events (ADEs) and cost distribution are affected by methodological decisions regarding identification of ADEs, assigning relevant resource use to ADEs, and estimating costs for the assigned resources. METHODS: ADEs were identified from medical records and diagnostic codes for a random sample of 4970 Swedish adults during a 3-month study period in 2008 and were assessed for causality. Results were compared for five cost evaluation methods, including different methods for identifying ADEs, assigning resource use to ADEs, and for estimating costs for the assigned resources (resource use method, proportion of registered cost method, unit cost method, diagnostic code method, and main diagnosis method). Different levels of causality for ADEs and ADEs' contribution to health care resource use were considered. RESULTS: Using the five methods, the maximum estimated overall direct health care costs resulting from ADEs ranged from Sk10,000 (Sk = Swedish krona; ~€1,500 in 2016 values) using the diagnostic code method to more than Sk3,000,000 (~€414,000) using the unit cost method in our study population. The most conservative definitions for ADEs' contribution to health care resource use and the causality of ADEs resulted in average costs per patient ranging from Sk0 using the diagnostic code method to Sk4066 (~€500) using the unit cost method. CONCLUSIONS: The estimated costs resulting from ADEs varied considerably depending on the methodological choices. The results indicate that costs for ADEs need to be identified through medical record review and by using detailed unit cost data.

In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia.

BACKGROUND: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. METHODS: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. RESULTS: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. CONCLUSIONS: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

Potentially inappropriate prescribing and adverse drug reactions in the elderly: a population-based study.

PURPOSE: Potentially inappropriate prescriptions (PIPs) criteria are widely used for evaluating the quality of prescribing in elderly. However, there is limited evidence on their association with adverse drug reactions (ADRs) across healthcare settings. The study aimed to determine the prevalence of PIPs, defined by the Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria, in the Swedish elderly general population and to investigate the association between PIPs and occurrence of ADRs. METHOD: Persons ≥65 years old were identified from a random sample of 5025 adults drawn from the Swedish Total Population Register. A retrospective cohort study was conducted among 813 elderly with healthcare encounters in primary and specialised healthcare settings during a 3-month period in 2008. PIPs were identified from the Swedish Prescribed Drug Register, medical records and health administrative data. ADRs were independently identified by expert reviewers in a stepwise manner using the Howard criteria. Multivariable logistic regression examined the association between PIPs and ADRs. RESULTS: Overall, 374 (46.0 %) persons had ≥1 PIPs and 159 (19.5 %) experienced ≥1 ADRs during the study period. In total, 29.8 % of all ADRs was considered caused by PIPs. Persons prescribed with PIPs had more than twofold increased odds of experiencing ADRs (OR 2.47; 95 % CI 1.65-3.69). PIPs were considered the cause of 60 % of ADRs affecting the vascular system, 50 % of ADRs affecting the nervous system and 62.5 % of ADRs resulting in falls. CONCLUSION: PIPs are common among the Swedish elderly and are associated with increased odds of experiencing ADRs. Thus, interventions to decrease PIPs may contribute to preventing ADRs, in particular ADRs associated with nervous and vascular disorders and falls.

The impact of a changed legislation on reporting of adverse drug reactions in Sweden, with focus on nurses' reporting.

PURPOSE: In March 2007, a legislative amendment was issued in Sweden compelling nurses to report all suspected adverse drug reactions (ADRs) to the national pharmacovigilance system. The aims of this study were to describe the status of ADR reporting, before and after the implementation of the legislative changes, and to describe the general characteristics of suspected ADRs reported by nurses. METHODS: The Swedish pharmacovigilance system during the study period constituted six regional centres responsible for the handling of all spontaneous ADR reports within their region. In this study, we identified all individual ADR reports from 2005 and 2010, analysed in depth the ADR reports from two regional centres and collated information about the reporter and the nature of the reported ADR. RESULTS: From the two regional centres, a total of 898 and 1074 reports were submitted in 2005 and 2010 respectively. Nurses submitted 31% (275 reports) of the reports in 2005 and 24% (260 reports) in 2010. Nurses' reporting of serious ADRs was 3% (seven reports) in 2005 and 7% (17 reports) in 2010 with reporting of unlabelled ADRs at 4% (11 reports) in 2005 and 17% (45 reports) in 2010. Most of the serious and/or unlabelled reactions were related to vaccine administration (14 reports in 2005 and 36 reports in 2010). CONCLUSIONS: The overall ADR reporting by nurses did not appear to increase after the change in reporting legislation. The proportion of serious and/or unlabelled ADRs reported by nurses did however appear to increase during the same period. Taken together, our data suggests that further pro-active measures should be considered in order to involve nurses in the reporting of suspected ADRs.

On the pedagogy of pharmacological communication: a study of final semester health science students.

BACKGROUND: There is a need to improve design in educational programmes for the health sciences in general and in pharmacology specifically. The objective of this study was to investigate and problematize pharmacological communication in educational programmes for the health sciences. METHODS: An interview study was carried out where final semester students from programmes for the medical, nursing and specialist nursing in primary health care professions were asked to discuss the pharmacological aspects of two written case descriptions of the kind they would meet in their everyday work. The study focused on the communication they envisaged taking place on the concerns the patients were voicing, in terms of two features: how communication would take place and what would be the content of the communication. A phenomenographic research approach was used. RESULTS: The results are presented as outcome spaces, sets of categories that describe the variation of ways in which the students voiced their understanding of communication in the two case descriptions and showed the qualitatively distinct ways in which the features of communication were experienced. CONCLUSIONS: The results offer a base of understanding the students' perspectives on communication that they will take with them into their professional lives. We indicate that there is room for strengthening communication skills in the field of pharmacology, integrating them into programmes of education, by more widely implementing a problem-based, a case-oriented or role-playing pedagogy where final year students work across specialisations and there is a deliberate effort to evoke and assess advanced conceptions and skills.

The understanding of core pharmacological concepts among health care students in their final semester.

BACKGROUND: The overall aim of the study was to explore health care students´ understanding of core concepts in pharmacology. METHOD: An interview study was conducted among twelve students in their final semester of the medical program (n = 4), the nursing program (n = 4), and the specialist nursing program in primary health care (n = 4) from two Swedish universities. The participants were individually presented with two pharmacological clinically relevant written patient cases, which they were to analyze and propose a solution to. Participants were allowed to use the Swedish national drug formulary. Immediately thereafter the students were interviewed about their assessments. The interviews were audio-recorded and transcribed verbatim. A thematic analysis was used to identify units of meaning in each interview. The units were organized into three clusters: pharmacodynamics, pharmacokinetics, and drug interactions. Subsequent procedure consisted of scoring the quality of students´ understanding of core concepts. Non-parametric statistics were employed. RESULTS: The study participants were in general able to define pharmacological concepts, but showed less ability to discuss the meaning of the concepts in depth and to implement these in a clinical context. The participants found it easier to grasp concepts related to pharmacodynamics than pharmacokinetics and drug interactions. CONCLUSION: These results indicate that education aiming to prepare future health care professionals for understanding of more complex pharmacological reasoning and decision-making needs to be more focused and effective.

Prevalence, nature and potential preventability of adverse drug events - a population-based medical record study of 4970 adults.

AIMS: To estimate the 3 month prevalence of adverse drug events (ADEs), categories of ADEs and preventable ADEs, and the preventability of ADEs among adults in Sweden. Further, to identify drug classes and organ systems associated with ADEs and estimate their seriousness. METHODS: A random sample of 5025 adults in a Swedish county council in 2008 was drawn from the Total Population Register. All their medical records in 29 inpatient care departments in three hospitals, 110 specialized outpatient clinics and 51 primary care units were reviewed retrospectively in a stepwise manner, and complemented with register data on dispensed drugs. ADEs, including adverse drug reactions (ADRs), sub-therapeutic effects of drug therapy (STEs), drug dependence and abuse, drug intoxications from overdose, and morbidities due to drug-related untreated indication, were detected during a 3 month study period, and assessed for preventability. RESULTS: Among 4970 included individuals, the prevalence of ADEs was 12.0% (95% confidence interval (CI) 11.1, 12.9%), and preventable ADEs 5.6% (95% CI 5.0, 6.2%). ADRs (6.9%; 95% CI 6.2, 7.6%) and STEs (6.4%; 95% CI 5.8, 7.1%) were more prevalent than the other ADEs. Of the ADEs, 38.8% (95% CI 35.8-41.9%) was preventable, varying by ADE category and seriousness. ADEs were frequently associated with nervous system and cardiovascular drugs, but the associated drugs and affected organs varied by ADE category. CONCLUSIONS: The considerable burden of ADEs and preventable ADEs from commonly used drugs across care settings warrants large-scale efforts to redesign safer, higher quality healthcare systems. The heterogeneous nature of the ADE categories should be considered in research and clinical practice for preventing, detecting and mitigating ADEs.

ABCB1 gene polymorphisms are associated with suicide in forensic autopsies.

BACKGROUND: Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics. OBJECTIVE: The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199G>A, 1236C>T, 2677G>T/A, and 3435C>T in deaths by suicide. PATIENTS AND METHODS: A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases. RESULTS: There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases. CONCLUSION: Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.

Refill adherence and self-reported adverse drug reactions and sub-therapeutic effects: a population-based study.

PURPOSE: To assess refill adherence to dispensed oral long-term medications among the adult population and to investigate whether the percentages of self-reported adverse drug reactions (ADRs) and sub-therapeutic effects (STEs) differed for medications with adequate refill adherence, oversupply, and undersupply. METHOD: Survey responses on self-reported ADRs and STEs were linked to the Swedish Prescribed Drug Register in a cross-sectional population-based study. Refill adherence to antihypertensive, lipid-lowering, and oral anti-diabetic medications was measured using the continuous measure of medication acquisition (CMA). The percentages of self-reported ADRs and STEs were compared between medications with adequate refill adherence (CMA 0.8-1.2), oversupply (CMA > 1.2), and undersupply (CMA < 0.8). RESULTS: The study included 1827 persons, and the refill adherence was measured for 3014 antihypertensive, 839 lipid lowering, and 253 oral anti-diabetic medications. Overall, 65.7% of the medications had adequate refill adherence, 21.9% oversupply, and 12.4% undersupply. The percentages of self-reported ADRs and STEs were respectively 2.6%, 2.7%, and 2.1% (p > 0.5) for ADRs and 1.1%, 1.6%, and 1.5% (p > 0.5) for STEs. CONCLUSIONS: Adequate refill adherence was found in two thirds of the medication therapies. ADRs and STEs were unexpectedly equally commonly reported for medications with adequate refill adherence, oversupply, and undersupply. These results suggest that a better understanding of patients' refill behaviors and their perceived medication adverse outcomes is needed and should be considered in improving medication management. The impact of individual and healthcare factors that may influence the association between refill adherence and reported medication adverse outcomes should be investigated in future studies.

Modelling drug-related morbidity in Sweden using an expert panel of physicians.

PURPOSE: In modelling studies using pharmacists' opinions, drug-related morbidity (DRM) and preventable DRM have been more common than in observational studies, and the resulting costs are extensive. Modelling studies' estimates may vary depending on informants' profession. The purpose of this modelling study was to estimate the proportion of patients with DRM and preventable DRM and the cost of illness (COI) of DRM in Sweden based on physicians' expert opinions. METHOD: A conceptual model of DRM was modified from previous studies. Using a modified Delphi technique, a panel of physicians (n = 19) estimated the probabilities of DRM, preventable DRM, and clinical outcomes of DRM separately for outpatients and inpatients. DRM included new medical problems (adverse drug reactions, drug dependence, and intoxications by overdose) and therapeutic failure (insufficient effects of medicines, and morbidity due to untreated indication). A COI analysis included the direct costs of DRM. RESULTS: Physicians estimated that 51 ± 22% [mean ± standard deviation (SD)] of outpatients experience DRM and 12 ± 8% preventable DRM. Of inpatients, 54 ± 17% was estimated to experience DRM and 16 ± 7% preventable DRM. Of outpatients with DRM, 24 ± 11% was estimated to experience preventable DRM, whereas this proportion for inpatients was 31 ± 15%. The estimated COI was 376 euros per outpatient and 838 euros per inpatient. CONCLUSIONS: Swedish physicians estimated that every other outpatient and inpatient experiences DRM, which is often preventable and costly. As physicians' estimates on the proportion of patients with DRM were higher than in observational studies in restricted subpopulations, DRM may be more common in the general population than observational studies suggest.

A prospective analysis of the preventability of adverse drug reactions reported in Sweden.

PURPOSE: Adverse drug reactions (ADRs) are a major patient safety issue, and a substantial proportion of ADRs are, in fact, preventable. The aim of this study was to describe the proportion and pattern of preventable ADRs in spontaneously reported suspected ADRs and to study the feasibility of using data from an ADR reporting system for this purpose. METHODS: All reports of ADRs, except those in which a vaccine was the suspected drug, submitted to the regional pharmacovigilance center of southeastern Sweden between 2008 and 2009 were analyzed. Causality between the suspected ADR and the medication was assessed using the World Health Organization (WHO) criteria, and preventability was assessed using Hallas criteria. RESULTS: During the study period, 1,290 ADRs were received and 1,255 were classified as having at least a possible causality between a reaction and a drug. Of these, 172 (14%) ADRs were considered preventable, 35 (20%) were classified as definitely preventable, and 137 (80%) as possibly preventable. Of all preventable ADRs, 96 (56%) were related to prescribing, 35 (20%) to administration, and 41 (24%) to clinical and laboratory monitoring of treatment. Warfarin, oxycodone, and ioversol were the most common drugs with preventable ADRs. CONCLUSIONS: This study found that a substantial part of reported ADRs are preventable. Most of these are related to drug prescription, suggesting that interventions aiming to reduce preventable ADRs should focus on this process. Moreover, systems for ADR reporting may be useful in the mission of reducing the unsafe use of drugs.

Exploring possible risk factors for time to first fall and 6-month fall incidence in persons with acute stroke.

Objectives: The aim was to explore how the time to the first fall and 6-month fall incidence relates to rapidly and easily collected data in persons with acute stroke. Methods: Out of consecutively admitted patients with stroke at three stroke units, 284 with at least one follow-up were included in this prospective cohort study. During 6 months following discharge, participants reported falls using a diary and monthly phone calls. Data about participants' characteristics, functions, and activities were collected during hospital stay and analyzed in relation to time to first fall by Cox regression and fall incidence by negative binomial regression. Results: Use of ⩾9 medications, paresis in arms, paresis in legs (National Institutes of Health Stroke Scale), impaired protective reactions in sitting (Postural Reactions Test), and limitations in self-care (Barthel Index) were decisive risk factors for time to first fall. Limitations in mobility (Step Test, 30-s Chair Stand Test) were decisive risk factors for high fall incidence (p < 0.0005). Conclusion: Several easily collected participant characteristics, functions, and activities were identified as risk factors for falls. The findings emphasize the width of assessments that can be used for the identification of individuals at risk for falls and that the risk factors vary in different strata of the population. These results are important when developing multivariate risk models. The risk factors differed in part when analyzing the time to the first fall and 6-month fall incidence.

Effects of cocoa extract and dark chocolate on angiotensin-converting enzyme and nitric oxide in human endothelial cells and healthy volunteers--a nutrigenomics perspective.

Evidence suggests that cocoa from the bean of Theobroma cacao L. has beneficial effects on cardiovascular disease. The aim of this study was to investigate if cocoa extract and dark chocolate influence angiotensin-converting enzyme (ACE) and nitric oxide (NO) in human endothelial cells (in vitro) and in healthy volunteers (in vivo). ACE activity was analyzed with a commercial radioenzymatic assay and measured in human endothelial cells from umbilical veins (HUVEC) after 10 minutes of incubation with cocoa extract. NO was measured after 24 hours of incubation. ACE activity and NO were measured at baseline and after 30, 60, and 180 minutes in 16 healthy volunteers after a single intake of 75 g of dark chocolate containing 72% cocoa. Significant inhibition of ACE activity (P < 0.01) and significant increase of NO (P < 0.001) were seen in HUVEC. In the study subjects, a significant inhibition of ACE activity (mean 18%) 3 hours after intake of dark chocolate was seen, but no significant change in NO was seen. According to ACE genotype, significant inhibition of ACE activity was seen after 3 hours in individuals with genotype insertion/insertion and deletion/deletion (mean 21% and 28%, respectively). Data suggest that intake of dark chocolate containing high amount of cocoa inhibits ACE activity in vitro and in vivo.

Impact of information letters on the reporting rate of adverse drug reactions and the quality of the reports: a randomized controlled study.

BACKGROUND: Spontaneous reporting of adverse drug reactions (ADRs) is an important method for pharmacovigilance, but under-reporting and poor quality of reports are major limitations. The aim of this study was to evaluate if repeated one-page ADR information letters affect (i) the reporting rate of ADRs and (ii) the quality of the ADR reports. METHODS: All 151 primary healthcare units in the Region Västra Götaland, Sweden, were randomly allocated (1:1) to an intervention (n = 77) or a control group (n = 74). The intervention consisted of one-page ADR information letters administered at three occasions during 2008 to all physicians and nurses in the intervention units. The number of ADR reports received from the 151 units was registered, as was the quality of the reports, which was defined as high if the ADR was to be reported according to Swedish regulations, that is, if the ADR was (i) serious, (ii) unexpected, and/or (iii) related to the use of new drugs and not labelled as common in the Summary of Product Characteristics. A questionnaire was administered to evaluate if the ADR information letter had reached the intended recipient. RESULTS: Before the intervention, no significant differences in reporting rate or number of high quality reports could be detected between the randomization groups. In 2008, 79 reports were sent from 37 intervention units and 52 reports from 30 control units (mean number of reports per unit ± standard deviation: 1.0 ± 2.5 vs. 0.7 ± 1.2, P = 0.34). The number of high quality reports was higher in intervention units than in control units (37 vs. 15 reports, 0.5 ± 0.9 vs. 0.2 ± 0.6, P = 0.048). According to the returned questionnaires (n = 1,292, response rate 57%), more persons in the intervention than in the control group had received (29% vs. 19%, P < 0.0001) and read (31% vs. 26%, P < 0.0001) an ADR information letter. CONCLUSIONS: This study suggests that repeated ADR information letters to physicians and nurses do not increase the ADR reporting rate, but may increase the number of high quality reports.

Worth changing? Clinical effects of switching treatment in neovascular age-related macular degeneration from intravitreal ranibizumab and aflibercept to bevacizumab in a region in southern Sweden.

PURPOSE: To examine the clinical effects of switching intravitreal drug treatment from the approved vascular endothelial growth factor inhibitors, ranibizumab and aflibercept, to off label use of bevacizumab in patients with wet age-related macular degeneration. METHODS: This retrospective study scrutinized medical records of patients with wet age-related macular degeneration who switched therapy to bevacizumab due to a policy decision. Best corrected visual acuity, central retinal thickness, and number of injections before and 1 year after the switch was compared. The non-inferiority margin of best corrected visual acuity was five Early Treatment Diabetic Retinopathy Study letters. RESULTS: A switch from ranibizumab was evaluable in 93 eyes and from aflibercept in 19 eyes. Neither of the groups had a significant non-inferior visual acuity 16 month after the switch. Mean best corrected visual acuity in Early Treatment Diabetic Retinopathy Study letters was 63.8 (95% confidence interval: 61.3-66.4) before and 62.2 (95% confidence interval: 59.3-65.1) after in the ranibizumab group and 68.2 (95% confidence interval: 63.3-73.1) before and 67.7 (95% confidence interval: 62.8-72.6) after in the aflibercept group. Mean central retinal thickness in micrometers decreased from 254 (95% confidence interval: 247-261) to 250 (95% confidence interval: 225-275) in the ranibizumab group and from 265 (95% confidence interval: 255-276) to 262 (95% confidence interval: 251-273) in the aflibercept group. The treatment was changed again after the switch in 18% of the patients in the ranibizumab group and 19% in the aflibercept group and these subjects were excluded from the analyses. CONCLUSION: In patients with neovascular age-related macular degeneration, a switch from ranibizumab or aflibercept to bevacizumab seems possible without a significant decrease in visual acuity in most patients.

Preventable drug related mortality in a Swedish population.

PURPOSE: Several studies indicate that the medical burden of fatal adverse drug reactions (FADRs) is significant, but the preventability of FADRs in the general population is largely unknown. The aim of this study was to determine the proportion of preventable FADRs and preventable fatal drug poisonings (FDPs) in a Swedish population. METHODS: Previously, a population-based sample of 1574 deceased subjects was scrutinised for FADRs and FDPs using relevant case records, including death certificates, medical charts and medico-legal files. Forty-nine cases (3%) of FADRs and nine cases (0.6%) of FDPs were identified in 57 subjects. In this study, the preventability of all these identified FADRs and FDPs was evaluated by clinical experts in a stepwise manner, applying a set of predefined and well established preventability criteria. Only cases for which consensus was achieved were included in the study. RESULTS: Of 49 FADRs, 14% (seven fatalities) was considered definitely or possibly preventable and four of these were due to the presence of a contraindication for the drug. All nine FDPs were considered possibly preventable. As one subject had a combination of an FADR and an FDP, a total of 15 persons (26%) were considered having a definitely or possibly preventable FADR or FDP, corresponding to 0.95% of all deceased subjects in Sweden. CONCLUSIONS: The results of this study indicate that approximately one fourth of FADRs and FDPs could be prevented. Therefore, an increased awareness of the possibility to reduce the risk of fatal events due to pharmaceutical drugs is warranted.

Effects of green tea, black tea and Rooibos tea on angiotensin-converting enzyme and nitric oxide in healthy volunteers.

OBJECTIVE: Tea has been reported to reduce cardiovascular mortality, but the underlying mechanisms are largely unknown. The aim of the current project was to investigate the effect of green tea (Japanese Sencha), black tea (Indian Assam B.O.P.) and Rooibos tea (South Africa) on angiotensin-converting enzyme (ACE) and nitric oxide (NO). DESIGN: Seventeen healthy volunteers received a single oral dose of 400 ml green tea, black tea or Rooibos tea in a randomized, three-phase, crossover study. ACE activity and NO concentration were measured (at 0, 30, 60 and 180 min) in all phases. ACE activity was analysed by means of a commercial radioenzymatic assay. Nitrite was analysed as a marker of NO concentration. In addition, ACE genotype was determined using a PCR method. RESULTS: Oral intake of a single dose of Rooibos tea significantly inhibited ACE activity after 30 min (P < 0.01) and after 60 min (P < 0.05). A significant inhibition of ACE activity was seen with green tea for the ACE II genotype 30 min after intake of the tea (P < 0.05) and for the ACE ID genotype 60 min after intake (P < 0.05). A significant inhibition of ACE activity was also seen with Rooibos tea for the ACE II genotype 60 min after intake (P < 0.05). No significant effect on NO concentration was seen. CONCLUSIONS: These results suggest that green tea and Rooibos tea may have cardiovascular effects through inhibition of ACE activity.