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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.

This review summarizes current evidence on the abuse and misuse of the gabapentinoids pregabalin and gabapentin. Pharmacovigilance studies, register-based studies, surveys, clinical toxicology studies, and forensic toxicology studies were identified and scrutinized with the goal to define the problem, identify risk factors, and discuss possible methods to reduce the potential for abuse and misuse. Studies found that gabapentinoids are abused and misused and that individuals with a history of psychiatric disorders or substance use disorder seem to be at high risk. Moreover, some evidence supports the notion that patients with opioid use disorders may be at an increased risk of abusing gabapentinoids. Available evidence also suggests that abuse and misuse are more frequent in users of pregabalin compared with users of gabapentin. Health professionals and prescribers should be aware of the risk for misuse of pregabalin and gabapentin, which eventually could lead to abuse, substance dependence, and intoxications. Prescribing to patients belonging to risk populations such as those with psychiatric disorders or substance use disorder should be avoided if possible and, if prescribed, signs of misuse and abuse should be monitored. Funding Agencies|Linkoping University

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.

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. Funding Agencies: Futurum Region Jönköping County [FUTURUM-394751, FUTURUM-422461, FUTURUM-484411, FUTURUM-519431]; Swedish Stroke Association; Medical Research Council of Southeast Sweden UK Research & Innovation (UKRI) Medical Research Council UK (MRC) [FORSS-475481, FORSS-645491, FORSS-931033]

This article summarises the current evidence on the risk of venous thromboembolism (VTE) with the use of antipsychotics. An increasing number of observational studies indicate an elevated risk of VTE in antipsychotic drug users. Although the use of certain antipsychotics has been associated with VTE, current data can neither conclusively verify differences in occurrence rates of VTE between first- and second-generation antipsychotics or between individual compounds, nor identify which antipsychotic drugs have the lowest risk of VTE. The biological mechanisms involved in the pathogenesis of this adverse drug reaction are still to be clarified but hypotheses such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinaemia and hyperprolactinaemia have been suggested. Risk factors associated with the underlying psychiatric disorder may at least partly explain the increased risk. Physicians should be aware of this potentially serious and even sometimes fatal adverse drug reaction and should consider discontinuing or switching the antipsychotic treatment in patients experiencing a VTE. Even though supporting evidence is limited, prophylactic antithrombotic treatment should be considered in risk situations for VTE.

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.

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. Funding agencies: Medical Research Council of Southeast Sweden (FORSS); Futurum-Academy of Health and Care, Region Jonkoping County

Objective To estimate the reliability and validity of the Cone Evasion Walk test (CEW), a new test assessing the ability to evade obstacles, in people with acute stroke. Methods To estimate the reliability of the CEW, video recordings of 20 people with acute stroke performing the test were assessed by 10 physiotherapists on two occasions, resulting in a total of 400 ratings. Patients performed the CEW (n = 221), functional ambulation classification (FAC; n = 204), Timed Up and Go (TUG; n = 173), TUG cognitive (TUG‐cog; n = 139), Serial 7s attention task from the Montreal Cognitive Assessment (MoCA‐S7; n = 127), and the Star Cancellation Test (SCT; n = 151). These tests and side of lesion (n = 143) were used to examine construct validity. The predictive validity was evaluated in relation to falls during the following 6 months (n = 203). Results The intraclass correlation coefficients for intrarater and interrater reliability were 0.88–0.98. For validity, there were significant correlations between the CEW and FAC (rs = −0.67), TUG (rs = 0.45), MoCA‐S7 (rs = −0.36), and SCT total score (rs = −0.36). There was a significant correlation between the number of cones touched on the left side and the proportion of cancelled stars on the left (rs = −0.23) and right (rs = 0.23) side in the SCT. Among right hemisphere stroke participants (n = 79), significantly more persons hit cones on the left side (n = 25) than the right side (n = 8), whereas among those with a left hemisphere stroke (n = 64) significantly more persons hit cones on the right side (n = 11) than the left (n = 3). Cox regression showed that participants who touched four to eight cones had an increased risk of falls over time (hazard ratio 2.11, 95% CI [1.07, 4.17]) compared with those who touched none. Conclusion The new CEW test was reliable and valid in assessing the ability to evade obstacles while walking and to predict falls in patients with acute stroke.

To investigate whether Roux-en-Y gastric bypass (RYGB) affects oral desogestrel (etonogestrel) pharmacokinetics.Single centre, open label, phase-2 pharmacokinetic study.University hospital of Linköping, Sweden.Fourteen women with planned RYGB surgery were included; nine women aged 18-45 years using 75 micrograms desogestrel completed the study.Steady-state etonogestrel pharmacokinetic (PK) parameters were measured on three occasions for each individual (at 8 ± 6 weeks before surgery, and at 12 ± 2 and 52 ± 2 weeks after surgery). Each patient served as her own control. On each occasion, serum samples were collected during a 24-hour period and etonogestrel concentrations were determined with ultra-performance liquid chromatography/tandem mass spectrometry.Area under the plasma concentration time curve of etonogestrel (AUCAll women had significant postoperative weight loss. There were no significant differences in AUCTo our knowledge, this is the first study to investigate the effects on desogestrel pharmacokinetics after RYGB. This study did not reveal any clinically significant changes in etonogestrel pharmacokinetics, suggesting that oral desogestrel may be used by women after RYGB surgery. The sample size was limited, however, and therefore the results should be interpreted cautiously.The pharmacokinetics of oral desogestrel does not appear to change after gastric bypass surgery.

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. 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. 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). 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.

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.

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 0.5) 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. Copyright © 2013 John Wiley & Sons, Ltd.

A large proportion of potential drug interactions are known from pre-authorization studies, but adverse drug reactions (ADRs) due to interactions (adverse drug interactions) are often first detected through astute observation in clinical practice. Individual case safety reports (ICSRs) are collected from broad patient populations and allow for the identification of groups of similar reports. Systematic screening for adverse drug interactions in ICSRs will require an understanding of which information on these reports can be suggestive of adverse drug interactions.The aim of the study was to identify what reported information may support the identification of drug interaction safety signals in collections of ICSRs.Three previously published safety signals of suspected adverse drug interactions were re-evaluated. To this end, 137 reports related to these signals were retrieved from the WHO Global ICSR Database, VigiBase™, and corresponding original reports were obtained from national pharmacovigilance centres. Criteria from an operational score for causality analysis of drug interactions of clinical cases, the Drug Interaction Probability Scale (DIPS), were applied to each of these reports with the aim of identifying what supportive information tends to be available in ICSRs. For three DIPS elements (plausible time course, resolution of the ADR after terminating the drug inducing the interaction without changes in affected drug therapy (positive dechallenge) and alternative causes of the reaction) we also compared the amount of information in VigiBase™ and in original reports, and in free text and structured data.Commonly fulfilled DIPS elements on reports supporting an adverse drug interaction signal were plausible time course (50 reports; 36%) and positive dechallenge (8 reports; 6%). Alternative causes for the observed adverse reaction were observed in 72 (53%) reports. We found limited differences between VigiBase™ and original reports for the structured data, although a substantial amount of additional information was available in free text in original reports.Information on plausible time courses and resolution of the adverse reaction upon withdrawal of the drug suspected to have induced the interaction may be a useful element in identifying suspected adverse drug interactions from ICSRs. Of these, plausible time course is by far the most commonly reported element in the three signals studied here. Our analysis also demonstrated the importance of sharing and analysing information available in free text where relevant clinical details are often available, such as those mentioned above, along with severity and dosage changes.

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.

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 a ...

BACKGROUND: Tramadol is a weak opioid analgesic, which is generally considered to be safe. However, conflicting data exist on the dependence potential of tramadol. OBJECTIVE: The aim of this study ...

In a systematic screening of the World Health Organization Adverse Drug Reaction database, VigiBase, in July 2008, a measure of association used to detect interactions (Omega) highlighted azithromycin with the individual statins atorvastatin, lovastatin and simvastatin and rhabdomyolysis. The aim was to examine all reports including rhabdomyolysis-azithromycin and statins in VigiBase to assess if the data were suggestive of an interaction.The individual case reports in VigiBase and the original files were reviewed. In order to investigate the reporting over time for rhabdomyolysis with azithromycin and statins to VigiBase, Omega values were generated retrospectively.The reporting over time showed that rhabdomyolysis under concomitant use of azithromycin and statins was reported more often than expected from 2000 and onwards in Vigibase. After exclusion of possible duplicates and follow-up reports, 53 cases from five countries remained. Rhabdomyolysis occurred shortly after initiation of azithromycin in 23% of cases. In 11 patients an interaction had been suggested by the reporter. With the exception of one patient, the statin doses reported were within the recommended daily doses.Case reports in VigiBase are suggestive that interactions between azithromycin and statins resulting in rhabdomyolysis may occur. This analysis showed the potential of the newly developed disproportionality measure, Omega, which can help to identify drug interactions in VigiBase in the future. The results also showed that reviewing spontaneous reports can add information to drug interactions not established previously.

Spontaneously Reported Suspected Adverse Drug Reactions in Association with Complementary and Alternative Medicine Products

There is limited information on the pharmacokinetics ofziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linköping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20 -320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L(-1) mg(-1) d(-1) forZIPand SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively,with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for dose-normalized serum concentrations of ZIP, SMDZ, andSMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIPconcentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.

To determine the association between fatal pulmonary embolism and use of antipsychotic drugs in a Swedish medicolegal autopsy series. Persons aged 18-65 years and subjected to a medicolegal autopsy in 1992-2005 were selected. On the basis of external cause of death, determined by the forensic pathologist, unnatural deaths (including fatal intoxications) were excluded and participants in whom pulmonary embolism was the cause of death were identified. Use of antipsychotics was based on the results of the postmortem analyses and categorized as use of high-potency first-generation antipsychotics, low-potency first-generation antipsychotics, second-generation antipsychotics or no use of antipsychotics. Logistic regression analyses were performed. Use of antipsychotics was verified in 538 of the 14,439 included participants. Pulmonary embolism was recorded as the cause of death in 279 participants and 33 of these used antipsychotics. Use of low-potency first-generation antipsychotics and second-generation antipsychotics was significantly associated with fatal pulmonary embolism (adjusted odds ratio: 2.39; 95% confidence interval: 1.46-3.92 and 6.91; 95% confidence interval: 3.95-12.10, respectively). Out of 26 participants classified as high-potency first-generation antipsychotic drug users, none had pulmonary embolism as the cause of death. Pulmonary embolism was overrepresented among medicolegal autopsy cases identified as users of low-potency first-generation and second-generation antipsychotics.

* Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal. * The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%. * In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown.* Fatal adverse drug reactions account for approximately 3% of all deaths in the general population. * Haemorrhages amount to almost two-thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions. * Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.To determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.Every seventh randomly selected deceased in three counties in South-east Sweden during 1 January 2001-31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug-related fatalities.Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.The medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.

To describe spontaneously reported cases of torsades de pointes (TdP) in Sweden and to investigate if this adverse drug reaction (ADR) was labelled in the summary of product characteristics (SPC) for the drugs implicated.Reported cases of TdP 1991-2006 were identified and evaluated with regard to drug use and other possible risk factor.Among a total of 61 788 ADRs, 88 cases of TdP were identified. In these cases, 27 different suspected drugs were implicated. Cardiac drugs were involved in most reports (74%; 65/88), with sotalol being the most frequently suspected drug (57%, 58/88). In addition to drug treatment two or more established risk factors were present in 85% of the cases (75/88). Heart disease (90%; 79/88) was the most common risk factor followed by age over 65 years (72%; 63/88) and female gender (70%; 62/88). TdP or QT prolongation were labelled in the SPC for 33% (9/27) of the drugs implicated in the 88 cases. However, supporting evidence for an association was found elsewhere in 56% (15/27) for the different drugs implicated in the reports. Although citalopram was the third most common suspected drug in the reports (10%; 9/88), TdP was not listed in the SPC.TdP is a rarely reported ADR. Several risk factors are often present. In two thirds of the drugs implicated in the reports neither TdP nor QT prolongation was labelled in the SPC. Further investigations are needed regarding the association between citalopram and TdP.

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. Funding Agencies|Swedish Research Council; Swedish Cancer Society; Medical Research Council of Southeast Sweden; Novartis

Aims: To determine the prevalence of non-prescribed drug use among subjects suspected of drug impaired driving with a psychoactive prescription drug, and to identify associated factors. Methods: Subjects investigated for drug-impaired driving in Sweden during 2006-2009 with a confirmed intake of diazepam, flunitrazepam, tramadol, zolpidem or zopiclone were identified using the Swedish Forensic Toxicology Database. Information on dispensed prescription drugs was retrieved from the Swedish Prescribed Drug Register. Non-prescribed use was our outcome, defined as a psychoactive prescription drug intake confirmed by toxicological analysis in a subject by whom it was not dispensed in the 12 months preceding the sampling. Prevalence proportions were calculated for each drug and logistic regression was used to identify associated factors. Results: In total, 2225 subjects were included. The median age (range) was 34 (15-80) years and 1864 (83.8%) subjects were male. Non-prescribed use was found in 1513 subjects (58.7%); for flunitrazepam 103 (76.3%), diazepam 1098 (74.1%), tramadol 192 (40.3%), zopiclone 60 (29.7%), and zolpidem 60 (21.2%) subjects, respectively. Younger age and multiple-substance use were associated with non-prescribed use, whereas ongoing treatment with other psychoactive drugs was negatively associated with non prescribed use. Conclusions: Non-prescribed use of psychoactive prescription drugs was common in subjects suspected of drug-impaired driving and was more frequent for benzodiazepines and tramadol compared to zolpidem and zopiclone. The young and multi-substance users were more likely, whereas subjects with ongoing prescribed treatment with other psychoactive drugs were less likely, to use non-prescribed drugs. Funding Agencies|County Council of Ostergotland, Sweden [LIO-131751]; Forensic Science Centre, Sweden [CFV 121218]; Linkoping University, Sweden [LIU 2009-01356]

Tramadol is an extensively used centrally acting analgesic and is considered a safe drug devoid of many serious adverse effects of traditional opioids. However, recently, toxicity and an abuse potential of tramadol have been reported. This study examined fatal unintentional tramadol intoxications among Swedish forensic autopsy cases between 1995 and 2005. All fatal intoxications were selected, in which toxic concentrations of tramadol (1 microg/g femoral blood) had been detected, and where the forensic pathologist considered the intoxication unintentional and the fatal outcome at least partly explained by tramadol. Toxicology analyses, police reports, autopsy protocols and medical records were scrutinized. A total of 17 cases (eleven men and six women) of fatal unintentional tramadol intoxications were identified. For these cases the median age was 44 years (range 18-78 years) and the median tramadol concentration was 2.0 microg/g (range 1.1-12.0 microg/g). Other pharmaceutical substances, illicit drugs or ethanol were detected in addition to tramadol in all of these cases. In fact, intoxication with multiple drugs was considered the cause of death in 10 (59%) cases. However, in seven cases tramadol was the only substance present in toxic concentrations. A history of substance abuse was identified in 14 (82%) subjects and a present tramadol abuse in 8 (47%). These results suggest that fatal intoxications with tramadol may occur unintentionally and that subjects with a history of substance abuse may be at certain risk. Precaution is therefore warranted when prescribing tramadol in such patients.

1. Several studies suggest an association between venous thromboembolism and the use of antipsychotic drugs, especially clozapine, but the biological mechanisms are unknown. It has been suggested that antipsychotic drugs enhance aggregation of platelets and thereby increase the risk of venous thrombosis. The purpose of the present study was to examine the effects of clozapine and its main metabolite, N-desmethyl clozapine, as well as olanzapine, risperidone and haloperidol, on platelet adhesion and aggregation and on plasma coagulation in vitro. 2. Blood was collected from healthy subjects free of medication. Platelet adhesion to different protein surfaces and aggregation were measured in microplates. The coagulation methods of activated partial thromboplastin time (APTT) and prothrombin time were performed in platelet-poor plasma. 3. Clozapine was the only compound that increased platelet adhesion and aggregation and shortened APTT. The effect appeared at therapeutic concentrations and was significant but weak. 4. This weak effect of clozapine on haemostasis may explain, in part, the association of this compound and venous thromboembolism.

To evaluate the frequency, severity and preventability of warfarin-induced cerebral haemorrhages due to warfarin and warfarin-drug interactions in patients living in the county of Ostergötland, Sweden.All patients with a diagnosed cerebral haemorrhage at three hospitals during the period 2000-2002 were identified. Medical records were studied retrospectively to evaluate whether warfarin and warfarin-drug interactions could have caused the cerebral haemorrhage. The proportion of possibly avoidable cases due to drug interactions was estimated.Among 593 patients with cerebral haemorrhage, 59 (10%) were assessed as related to warfarin treatment. This imply an incidence of 1.7/100,000 treatment years. Of the 59 cases, 26 (44%) had a fatal outcome, compared to 136 (25%) among the non-warfarin patients (p0.01). A warfarin-drug interaction could have contributed to the haemorrhage in 24 (41%) of the warfarin patients and in 7 of these (12%) the bleeding complication was considered being possible to avoid.Warfarin-induced cerebral haemorrhages are a major clinical problem with a high fatality rate. Almost half of the cases was related to a warfarin-drug interaction. A significant proportion of warfarin-related cerebral haemorrhages might have been prevented if greater caution had been taken when prescribing drugs known to interact with warfarin.

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. Also funded by Sahlgrenska Academy, (V 2011/437)

Purpose One of the main methods for monitoring the safety of marketed drugs is spontaneously reporting of suspected adverse drug reactions (ADRs). The objective of this study was to describe the pattern of spontaneously reported fatal adverse drug reactions (FADRs) by analysing data from the national spontaneous reporting system in Sweden. Methods In Sweden it is compulsory to report all new or serious suspected ADRs to the Medical Products Agency. The information in these reports is stored in the national database SWEDIS (Swedish Drug Information System). All suspected FADRs reported to SWEDIS between 1 January 1995 and 31 December 2004 were reviewed and analysed. Results During the study period 990 reports of FADRs were found. The main distribution of suspected FADRs was: haemorrhages (n = 603; 60.9%), blood and bone marrow dysfunction (n = 71; 7.2%), sudden death (n = 38; 3.8%) and pulmonary embolism (n = 30; 3.0%). Antithrombotic agents were the drugs most frequently implicated in the FADRs (n = 605; 61.1%). Vitamin K antagonists were reported in 453 cases (45.8%) and acetylsalicylic acid in 82 cases (8.3%). Among the fatalities with blood and bone marrow dysfunction methotrexate was the most frequently reported drug. For sudden death and pulmonary embolism, antipsychotics and oestrogen containing drugs, respectively, were most commonly reported. Conclusions Bleeding complications amounted more than half of all reports of FADRs and vitamin K antagonists were implicated in most of these reports. However, as spontaneous reporting systems are primarily set up for signalling purposes, the data must be interpreted with utmost care. Copyright © 2006 John Wiley & Sons, Ltd.

Background. We wanted to study the incidence of venous thromboembolism (VTE), acquired risk factors of VTE and preventable cases among users of combined oral contraceptives (COCs). Methods. Al ...

Background Although a majority of patients with hypertension require a multidrug therapy, this is rarely considered when measuring adherence from refill data. Moreover, investigating the association between refill non-adherence to antihypertensive therapy (AHT) and elevated blood pressure (BP) has been advocated. Objective Identify factors associated with non-adherence to AHT, considering the multidrug therapy, and investigate the association between non-adherence to AHT and elevated BP. Methods A retrospective cohort study including patients with hypertension, identified from a random sample of 5025 Swedish adults. Two measures of adherence were estimated by the proportion of days covered method (PDC≥80%): (1) Adherence to any antihypertensive medication and, (2) adherence to the full AHT regimen. Multiple logistic regressions were performed to investigate the association between sociodemographic factors (age, sex, education, income), clinical factors (user profile, number of antihypertensive medications, healthcare use, cardiovascular comorbidities) and non-adherence. Moreover, the association between non-adherence (long-term and a month prior to BP measurement) and elevated BP was investigated. Results Non-adherence to any antihypertensive medication was higher among persons < 65 years (Odds Ratio, OR 2.75 [95% CI, 1.18–6.43]) and with the lowest income (OR 2.05 [95% CI, 1.01–4.16]). Non-adherence to the full AHT regimen was higher among new users (OR 2.04 [95% CI, 1.32–3.15]), persons using specialized healthcare (OR 1.63, [95% CI, 1.14–2.32]), and having multiple antihypertensive medications (OR 1.85 [95% CI, 1.25–2.75] and OR 5.22 [95% CI, 3.48–7.83], for 2 and ≥3 antihypertensive medications, respectively). Non-adherence to any antihypertensive medication a month prior to healthcare visit was associated with elevated BP. Conclusion Sociodemographic factors were associated with non-adherence to any antihypertensive medication while clinical factors with non-adherence to the full AHT regimen. These differing findings support considering the use of multiple antihypertensive medications when measuring refill adherence. Monitoring patients' refill adherence prior to healthcare visit may facilitate interpreting elevated BP.

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. Funding Agencies|Department of Pedagogical; County Council Ostergotland [LIO-198671]; Mellon Foundation at the Faculty of Humanities, University of the Witwatersrand, South Africa

OBJECTIVE: This study was carried out in order to investigate the utilization pattern of metamizole to better estimate the quantitative risk of agranulocytosis since a cluster of such cases have be ...

PURPOSE: To assess the occurrence and pattern of adverse drug reactions as a cause for acute hospital admission.METHODS: In 681 randomly selected patients, acutely admitted to a clinic of internal ...

To investigate the effects of zinc (Zn(2+)) concentrations on cultured benign prostatic hyperplasia (BPH) smooth muscle cell (SMC) proliferation.The effects of Zn(2+) were studied in primary cultures of human BPH SMC, stimulated with either 10-μM lysophosphatidic acid (LPA) or LPA in combination with 100-nM testosterone. Deoxyribonucleic acid replication and protein synthesis using [(3)H]-thymidine and [(35)S]-methionine incorporation were measured. Furthermore, studies were performed to evaluate if Zn(2+) could potentiate the inhibitory effect of phosphodiesterase-5 blockers, on BPH SMC proliferation.Zn(2+) generated a bell-shaped concentration response, both regarding deoxyribonucleic acid replication and protein synthesis in cultured BPH SMC. Below a threshold value (approximately 200 μM), a significant mitogenic effect was seen, whereas higher concentrations inhibited SMC proliferation after stimulation with LPA. This effect was even more pronounced after stimulation of LPA in combination with testosterone. Moreover, phosphodiesterase-5 inhibitors, that is, sildenafil blocked LPA-stimulated BPH SMC proliferation. This antiproliferative effect, was significantly potentiated by coincubation with Zn(2+) in an additative manner.The bell-shaped concentration response of Zn(2+) on cultured BPH SMC proliferation suggests that changes in prostate Zn(2+) concentrations, during aging, diet, or inflammatory conditions, may be of importance in the pathogenesis of BPH.

Objective: A few cases of adverse reactions linked to erroneous use of transdermal opioid patches have been reported in the literature. The aim of this study was to describe and characterize medication errors (MEs) associated with use of transdermal fentanyl and buprenorphine. Methods: All events concerning transdermal opioid patches reported between 2004 and 2011 to a regional incident reporting system and assessed as MEs were scrutinized and characterized. MEs were defined as "a failure in the treatment process that leads to, or has the potential to lead to, harm to the patient". Results: In the study 151 MEs were identified. The three most common error types were wrong administration time 67 (44%), wrong dose 34 (23%), and omission of dose 20 (13%). Of all MEs, 118 (78%) occurred in the administration stage of the medication process. Harm was reported in 26 (17%) of the included cases, of which 2 (1%) were regarded as serious harm (nausea/vomiting and respiratory depression). Pain was the most common adverse reaction reported. Conclusions: Of the reported MEs related to transdermal fentanyl and buprenorphine, most occurred during administration. Improved routines to ascertain correct and timely administration and educational interventions to reduce MEs for these drugs are warranted.

Myocarditis has in several case reports been associated with use of clozapine. Eight cases of myocarditis during treatment with clozapine that were submitted to the Swedish Adverse Drug Reaction Advisory Committee and 18 cases that were reported in the literature are summarized. As part of the routine signal detection process on the World Health Organization (WHO) Program on International Drug Monitoring database, which contains more than two million case reports of spontaneously reported suspected adverse drug reactions, a Bayesian confidence propagation neural network (BCPNN) is used. This article also shows the retrospective output of the BCPNN over time for clozapine and myocarditis and discusses its implications. In 19 (79%; duration of treatment not stated for 2 patients) of 24 patients with myocarditis, the symptoms occurred within the first 6 weeks of clozapine treatment. Many patients shared a similar clinical course, with symptoms such as an influenza-like illness, fever, sinus tachycardia, hypotension, chest discomfort, and heart failure. The reaction was fatal in 12 (46%) of these patients. The other patients generally had a prompt recovery. By using the BCPNN technique, a quantitative association between clozapine and myocarditis was demonstrated, and the association might have been high-lighted for clinical review in 1994 had this BCPNN method been in use at the WHO center at the time. Myocarditis seems to be a rare and potentially lethal adverse effect of clozapine. Admittance for observation, interruption of the clozapine treatment, and treatment with corticosteroids should be considered for patients in whom this reaction is suspected.

Approaches to the treatment of the eating disorder bulimia nervosa include both pharmacological and non-pharmacological therapies. Currently, only one drug, fluoxetine, is approved for the treatment of bulimia nervosa. As increased food intake is an important common characteristic of bulimia nervosa and obesity, the same endogenous factors have been suggested to play a role in the pathogenesis of both conditions. Consequently, most research has focused on compounds affecting systems involved in appetite regulation and food intake, assuming that the uncontrolled urge of eating binges can thus be reduced. The patent activity in this field has been dominated by inventions related to 5-HT (serotonin) receptors, neuropeptide Y receptors and corticotrophin releasing factor receptors. In this article, more than 140 patents issued from 1998 to the first half of 2000 are reviewed.