Serious adverse events reported for antiobesity medicines: postmarketing experiences from the EU adverse event reporting system EudraVigilance.

BACKGROUND: Use of antiobesity medicines has been linked with serious cardiac and psychiatric adverse events (AEs). Spontaneous reports can provide information about serious, rare and unknown AEs occurring after the time of marketing. In Europe, information about AEs reported for antiobesity medicines can be accessed in the EudraVigilance (EV) database. Therefore, we aimed to identify and characterise AEs associated with the use of antiobesity medicines in Europe. METHODS: AE reports submitted for antiobesity medicines (Anatomical Therapeutic Chemical (ATC) group A08A) from 2007 to 2014 and located in the EV database were analysed. AE data were categorised with respect to time, age and sex of patient/consumer, type of reporter, category and seriousness of reported AEs and medicines. Consumer AE reports were compared with reports from other types of reporters with respect to age and sex of consumer, seriousness, system organ class and medicine. The unit of analysis was one AE and one AE report, respectively. RESULTS: We located 4941 AE reports corresponding to 13 957 AEs for antiobesity medicines in the EV database. More than 90% of all AE cases were serious, including 159 deaths. The majority of AE cases were reported for female adults. The majority of serious AEs was reported for orlistat (37%) and rimonabant (22%). The largest share of serious AEs was of the type 'cardiac disorders' (19%) and 'psychiatric disorders' (18%). Consumer AEs reporting differed from other sources with respect to share and seriousness of AEs, type of AEs (system organ class) and medicines (ATC level 5). CONCLUSIONS: Many serious AEs were found for antiobesity medicines in EV, and consumers contributed with a relatively high share of reports. Although several products have been withdrawn from the market and new medicines are being marketed, the utilisation of antiobesity medicines is widespread, and therefore systematic monitoring of the safety of these medicines is necessary.

Socio-economic status and adherence to tuberculosis treatment: a case-control study in a district of Nepal.

SETTING: A western hill district in Nepal, where tuberculosis (TB) treatment under DOTS was offered by the regional tuberculosis centre, two primary health centres, eight health posts, three sub-health posts and one ward of sub-metropolitan Pokhara. OBJECTIVE: To analyse the contribution of socioeconomic status to non-adherence to DOTS. DESIGN: Case-control study. Data were collected by questionnaire-based face-to-face interviews. The study sample consisted of 50 cases and 100 controls. The participation rate was 80% for cases (non-adherents) and 95% for controls. RESULTS: Logistic regression analysis showed that the risk of non-adherence to TB treatment was significantly associated with unemployment (odds ratio [OR] 9.2), low status occupation (OR 4.4), low annual income (OR 5.4), and cost of travel to the TB treatment facility (OR 3.0). Factors significant in the bivariate analyses--living conditions, literacy and difficulty in financing treatment--were not found to be significantly associated with non-adherence when adjusted for other risk factors in the multivariate regression model. CONCLUSION: Low socio-economic status and particularly lack of money are important risk factors for non-adherence to TB treatment in a poor country such as Nepal.

Use of six main drug therapeutic groups across educational groups: self-reported survey and prescription records.

OBJECTIVES: To assess whether the use of six main therapeutic groups was congruent with the occurrence of related diseases across educational groups. METHODS: Two data sources were analysed: (i) Interview data from The Danish Health and Morbidity Survey 2000 on a representative sample of the Danish population ages 16 years and above (n = 16,690); (ii) Prescription records linked to a health survey on a representative sample of the population of Funen County 2000-2001 (n = 3,422). The use of six therapeutic main groups (ATC groups A, B, C, M, N and R) and related diseases in educational groups was analysed by indirect standardization. Age and gender standardized prevalence ratios (SPRs) and 95% confidence intervals were calculated on the basis of the total study population. RESULTS: In general, respondents in the two least educated groups used medicines more frequently and a higher proportion of them reported the related disease than could be expected from indirect standardization. The opposite picture appeared for respondents in the two highest educational groups (SPR < 100). The overall patterns were similar for the six medicine groups, although some of the SPRs were not significant. CONCLUSION: The results show the uneven distribution of disease in the general population. The distribution of medicine use generally followed this pattern, which means that those in the greatest medical need used the most medicine. Hence, individual co-payment for medicine did not seem to be a barrier to access to medicine in any of the educational groups.

Effect of environmental and physiological factors on the antibacterial activity of Curvularia haloperoxidase system against Escherichia coli.

AIMS: The aim of this study was to investigate the influence of environmental and physiological factors on the susceptibility of Escherichia coli to the Curvularia haloperoxidase system. METHODS AND RESULTS: The Curvularia haloperoxidase system is a novel enzyme system that produces reactive oxygen species which have an antimicrobial effect. Escherichia coli MG1655 was exposed to the Curvularia haloperoxidase system under different temperatures and NaCl concentrations and after exposure to different stress factors. Temperature clearly affected enzymatic activity with increasing antibacterial effect at increasing temperature. The presence of NaCl interfered with the enzyme system and in the presence of 1% NaCl, no antibacterial effect could be observed at pH 7. Cells grown at pH 8.0 were in one experiment more resistant than cells grown at pH 6.5, whereas cells grown in the presence of 2% NaCl were more susceptible to the Curvularia haloperoxidase system. CONCLUSIONS: Environmental and physiological factors can affect the antibacterial activity of the Curvularia haloperoxidase system. SIGNIFICANCE AND IMPACT OF THE STUDY: The study demonstrates a systematic approach in assessing the effect of environmental and physiological factors on microbial susceptibility to biocides. Such information is crucial for prediction of application as well as potential side-effects.

The provision of pharmaceutical care in Denmark: a cross-sectional survey.

BACKGROUND: Pharmaceutical care was a concept initially defined in the early 1990s. It had its roots within clinical pharmacy, in the USA. In Denmark, pharmaceutical care has been part of the professional standards of practice for community pharmacy since 1995. OBJECTIVE: The objective of the present study was to investigate the provision of pharmaceutical care in community practice in Denmark. A focus of the study was the estimation of the frequency of medicine-related problem identification and the process of problem management in the Danish pharmacies. METHODS: A cross-sectional questionnaire-based survey of all Danish community pharmacies was conducted (n = 288). The variables included: detection and identification of medicine-related problems, goal-setting for solving medicine-related problems, and documentation of efforts to solve these. The response rate was 75.7%. A non-respondent analysis was performed. RESULTS: On average three medicine-related problems per pharmacy were found within the working week prior to the survey. For two-thirds of those cases the type of problem involved was identified. For the other third, goals had been set to resolve the problem. Minimal documentation of these activities was reported. The primary collaborators in problem management were general practitioners and patients. CONCLUSION: Pharmaceutical care, in its fullest sense, as defined in policy documents in Denmark, was not evident in practice. While some aspects of pharmaceutical care were being performed, almost no documentation of efforts was taking place in community pharmacy.

Ethical dilemmas in antibiotic prescribing: analysis of everyday practice.

OBJECTIVE: To explore general practitioners' (GP's) views on their obligations with respect to diagnosing infections and prescribing antibiotics. METHODS: The GP's reflections and prioritization were studied by means of interviews and observations. We analysed how their prioritization complied with an ethical guidance that ranked patient autonomy and welfare highest, then competence obligations and obligations to society, followed by fraternal obligations. RESULTS: Balancing of pros and cons was prominent in our informants' decision making but often resulted in decisions that deviated from the ethical guidance. The ranking varied much between the GPs. The highest priorities in the GPs' practice were related to the patient's everyday life (sometimes autonomy, sometimes beneficence in a broad sense), doctor-patient relationship (communication competence), the patient's perceived importance on the job market (society) and relationship with colleagues (fraternal). Perceived lack of resources and uncertainty with respect to both diagnostic and treatment decisions frequently influenced decision making.

Treatment of upper respiratory tract infections--a comparative study of dispensing and non-dispensing doctors.

BACKGROUND: The reported results are part of an overall evaluation of drug management by dispensing (DDs) and non-dispensing doctors (NDDs). This study focuses on appropriate prescription. Other studies assess good pharmacy practice. Whereas rationality of prescription has been studied based on simple indicators, appropriate prescription in relation to diagnoses and symptoms has not been assessed. OBJECTIVE: To analyse prescriptions by DDs and NDDs for patients diagnosed with upper respiratory tract infection. METHODS: Cohort study of 28 private sector DDs and 28 NDDs, using retrospective registry data from a mean of 14.5 and 16.0 patient records per practice, respectively. OUTCOME MEASURES: Drug choice, frequency of the drugs being used, use of antibiotics and dosages for respiratory infections where antibiotics are/are not justified. RESULTS: DDs were associated with a greater number of drugs per encounter (P < = 0.001), a greater number of injections (P = < 0.002), more use of analgesic drugs (P = < 0.001), cough and cold preparations (P < 0.001) and psycholeptics (P = < 0.03). The choice of antibiotics for upper respiratory tract infection (URTI) was assessed as rational, although different for the two practices, but both practices over-prescribe antibiotics frequently. Dispensing doctors frequently prescribe sub-curative dosages and fewer curative dosages (P = < 0.001), compared with NDDs. CONCLUSION: Irrational prescription for URTI is widespread by both dispensing doctors and to a lesser extent, by NDDs. Symptomatic treatments with 'a drug for each symptom' was common, particularly by the DDs. There was also over-prescription of antibiotics and use of sub-therapetitic dosages. This poly-pharmacy, poses a safety risk, a risk of development of resistance and, unnecessarily costly treatment.

Experiences of long-term tranquillizer use: a psychodynamic perspective.

The aim of the article is to analyse narrative descriptions and experiences of long-term tranquillizer use. The analysis is based on a Danish in-depth study of 50 informants with a self-diagnosed dependency on tranquillizers. The theoretical analysis is dependent on psychodynamic reasoning. Further, the psychodynamic perspective is integrated within a multi-dimensional model that considers biological, cognitive, identity, gender and social learning factors. The analysis reveals the possibility of achieving a detailed understanding of the dynamic processes involved in the development of long-term tranquillizer use. Important themes frequently mentioned in the clients' descriptions are traumatic childhood experiences, identity problems, life crises in adulthood and difficulties in stopping taking psychotropic drugs.

Telephone prescribing of antibiotics. General practitioners' views and reflections.

BACKGROUND: In this era of increasing problems with resistance, rational prescribing of antibiotics is extremely important. Therefore, rationales for prescribing require analyses. The objective of this study was to explore general practitioners' (GPs') reasons for prescribing antibiotics by telephone. METHODS: Qualitative analysis of semistructured interviews with and observations of GPs in Iceland enquiring about the rationale for prescribing antibiotics was used. Ten GPs were interviewed for 45 min to 2 h each including three who were observed between 3 and 10 h. RESULTS: The GPs generally indicated a restrictive attitude to telephone prescribing, although they all gave examples of their prescribing by telephone. The prescribing was mostly but not always based on some kind of diagnosis. The factors influencing diagnosis and prescribing were largely non-clinical: knowledge of the patients as persons, including their complaint threshold, confidence in their descriptions, the GPs' communication strategies and the travelling distance between patients and GPs. The clinical factors were the patients' description of signs and symptoms and knowledge of their history. Prescriptions not based on diagnosis were 'therapeutic trial' or GP-approved self-medication. Sometimes, the GPs requested to see a patient even though the diagnosis was based on history, signs and symptoms. CONCLUSIONS: Multiple factors affected the decision-making process when antibiotics were prescribed by telephone, most of which were non-clinical. The diagnosis, if there was one, was generally presumptive. GPs' general attitudes correlated well with current knowledge but were contrasted by the reality of their daily work conditions.

Production of a panel of recombinant gliadins for the characterisation of T cell reactivity in coeliac disease.

BACKGROUND/AIMS: Coeliac disease is a chronic intestinal disorder most probably caused by an abnormal immune reaction to wheat gliadin. The identification of the HLA-DQ2 and HLA-DQ8 as the molecules responsible for the HLA association in coeliac disease strongly implicates a role for CD4 T cells in disease pathogenesis. Indeed, CD4 T cells specific for gliadin have been isolated from the small intestine of patients with coeliac disease. However, identification of T cell epitopes within gliadin has been hampered by the heterogeneous nature of the gliadin antigen. To aid the characterisation of gliadin T cell epitopes, multiple recombinant gliadins have been produced from a commercial Nordic wheat cultivar. METHODS: The alpha-gliadin and gamma-gliadin genes were amplified by polymerase chain reaction from cDNA and genomic DNA, cloned into a pET expression vector, and sequenced. Genes encoding mature gliadins were expressed in Escherichia coli and tested for recognition by T cells. RESULTS: In total, 16 alpha-gliadin genes with complete open reading frames were sequenced. These genes encoded 11 distinct gliadin proteins, only one of which was found in the Swiss-Prot database. Expression of these gliadin genes produced a panel of recombinant alpha-gliadin proteins of purity suitable for use as an antigen for T cell stimulation. CONCLUSION: This study provides an insight into the complexity of the gliadin antigen present in a wheat strain and has defined a panel of pure gliadin antigens that should prove invaluable for the future mapping of epitopes recognised by intestinal T cells in coeliac disease.

Quality assessment of drug sales data: the case of antibacterials in Iceland.

BACKGROUND: Two sets of drug sales data, published by the Icelandic Ministry of Health, did not match for antibacterials in 1989. The search for causes turned out to be a project in itself. OBJECTIVE: To analyze quality problems in the sales data on antibacterials and describe a method for systematic quality assessment of drug sales data. METHODS: Documentary analysis based on the following sources: 1) Nordic Statistics on Medicines, 1975-95; 2) Drug Use (Notkun Iyfja), 1975-93; 3) Icelandic Drug Market, 1975-94; 4) Unpublished data from the Icelandic Ministry of Health. The following framework was developed to evaluate the quality of drug sales data: 1. Completeness of registration; 2. Accuracy and degree of completeness of data; 3. Size and coverage of the data source; 4. Data format; 5. Data accessibility, availability and cost. RESULTS: Four discrepancies were found, two due to changes in DDD, and two larger ones stemming from errors in calculating DDD, resulting in an overestimation of the contribution of the respective products to the total DDD/1000 inhabitants/day. Errors were detected in available sales data at least back to 1980, resulting in sales being overestimated by up to 13%. The reasons for the discrepancies were found mostly under point 2 in the framework. CONCLUSION: The errors uncovered by this study indicate a possible low quality of drug statistics which might lead to wrong conclusions about the level and development of sales of drugs. As a tool, the framework might be used for quality assessment of drug sales data.

Selective flow injection analysis of ultra-trace amounts of Cr(VI), preconcentration of it by solvent extraction, and determination by electrothermal atomic absorption spectrometry (ETAAS).

A rapid, robust, sensitive and selective time-based flow injection (FI) on-line solvent extraction system interfaced with electrothermal atomic absorption spectrometry (ETAAS) is described for analyzing ultra-trace amounts of Cr(VI). The sample is initially mixed on-line with isobutyl methyl ketone (IBMK). The Cr(VI) is complexed by reaction with ammonium pyrrolidine dithiocarbamate (APDC), and the non-charged Cr(VI)-PDC chelate formed is extracted into IBMK in a knotted reactor made from PTFE tubing. The organic extractant is separated from the aqueous phase by a gravity phase separator with a small conical cavity and delivered into a collector tube, from which 55 mul organic concentrate is subsequently introduced via an air flow into the graphite tube of the ETAAS instrument. The operations of the FI-system and the ETAAS detector are synchronously coupled. A significant advantage of the approach is that matrix constituents, such as high salt contents, effectively are eliminated. The extraction procedure was optimized by a simplex approach. A central composite design was subsequently employed to verify the estimated operational optimum. An 18-fold enhancement in sensitivity of Cr(VI) was achieved after preconcentration for 99 s at a sample flow rate of 5.5 ml min(-1), as compared to direct introduction of 55 mul of sample, yielding a detection limit (3sigma) of 3.3 ng l(-1). The sampling frequency was 24.2 samples h(-1). The proposed method was successfully evaluated by analyzing a NIST Cr(VI)-reference material, synthetic seawater and waste waters, and waste water samples from an incineration plant and a desulphurization plant, respectively.

The quality of immunization data from routine primary health care reports: a case from Nepal.

Reported high immunization coverage achieved in Nepal over the last ten years is expected to reduce child mortality in the country. The present study, carried out in hill district in mid-west Nepal, aimed to assess the quality of immunization data in Nepal. The number of children who received different vaccines during one year was obtained from three sources: 1) the Immunization REgister of three Primary Health Care Service Outlets (PHCSOs) where each immunized child is recorded; 2) monthly PHC Reports, which are based on the Immunization Register; 3) monthly DHO Reports, which are based on the above PHC Reports (the DHO reports are the source of official statistics). The number of children in the PHC Reports was higher than the number in the Immunization REgisters for all vaccines. The number of immunizations in the DHO Reports was higher than the number in the PHC Reports for BCG, DPT, and measles; the number was lower for poliomyelitis. The overall number of immunizations was higher in the DHO Reports than in the Immunization Registers, by 31% for BCG, 44% for DPT, 155% for polio, and 71% for measles. We conclude that the official report overestimates the immunization coverage in the district. The immunization programme, therefore, might not result in the expected reduction of morbidity and mortality despite the investment in the programme and reported high coverage.

The effect of hyperbaric oxygen on irradiated oral tissues: transmucosal oxygen tension measurements.

PURPOSE: This study measured the effect of hyperbaric oxygen (HBO) treatment on transmucosal oxygen tension in irradiated human oral mucosa. PATIENTS AND METHODS: Ten patients received 30 dives of HBO as part of their treatment for mandibular osteoradionecrosis. A noninvasive, nonheated oxygen electrode was used to measure the tissue surface transmucosal oxygen tension directly on the attached gingiva. Measurements were done before, during, and after HBO treatment. The normal level of gingival surface transmucosal oxygen tension was measured in five healthy volunteers. RESULTS: During HBO treatment, the transmucosal oxygen tension increased significantly after five dives of HBO (P < .05). After 30 dives, the increases were from a mean of 50% to a mean of 86% of the transmucosal oxygen tension of normal healthy gingiva. CONCLUSION: An increase in the transmucosal oxygen tension is based on neo-angiogenesis. Patients with subischemic tissues, such as the study population with postirradiation mucosal and osseous necrosis, therefore may benefit from treatment with HBO.

Principles and applications of flow injection analysis in biosensors.

In practical applications biosensors are often forced to operate under less than optimal conditions. Because of their construction, and the physical processes and chemical reactions involved in their operation, compromise conditions are frequently required to synchronize all events taking place. Therefore, and in order to implement functions such as periodic calibration, conditioning and possible regeneration of the biosensor, and, very importantly, to yield the freedom to select the optimum detection means, it is advantageous to use these devices in a flow-through mode, particularly by employing the flow injection (FI) approach. The capacity of FI, as offering itself as a complementary facility to augment the performance of biosensors, and in many cases as an attractive alternative, is demonstrated by reference to selected examples, comprising assays based on enzymatic procedures with optical and thermal detection procedures, and via description of a recently introduced technique for immunoassays, termed flow injection renewable surface immunoassays, which promises to entail powerful potentials and to yield compatible or better economy of operation than existing approaches.

Determination of ultra-trace amounts of arsenic(III) by flow-injection hydride generation atomic absorption spectrometry with on-line preconcentration by coprecipitation with lanthanum hydroxide or hafnium hydroxide.

A time-based flow-injection (FI) procedure for the determination of ultra-trace amounts of inorganic arsenic(III) is described, which combines hydride generation atomic absorption spectrometry (HG-AAS) with on-line preconcentration of the analyte by inorganic coprecipitation-dissolution in a filterless knotted Microline reactor. The sample and coprecipitating agent are mixed on-line and merged with an ammonium buffer solution, which promotes a controllable and quantitative collection of the generated hydroxide on the inner walls of the knotted reactor incorporated into the FI-HG-AAS system. Subsequently the precipitate is eluted with 1 mol 1(-1) hydrochloric acid, allowing ensuing determination of the analyte via hydride generation. The preconcentration of As(III) was tested by coprecipitation with two different inorganic coprecipitating agents namely La(III) and Hf(IV). It was shown that As(III) is more effectively collected by lanthanum hydroxide than by hafnium hydroxide, the sensitivity achieved by the former being approximately 25% better. With optimal experimental conditions and with a sample consumption of 6.7 ml per assay, an enrichment factor of 32 was obtained at a sample frequency of 33 samples h(-1). The limit of detection (3sigma) was 0.003 microg 1(-1) and the precision (relative standard deviation) was 1.0% (n = 11) at the 0.1 microg 1(-1) level.

Multistep determination of enzyme activity by flow injection and sequential injection analysis. Assay of amyloglucosidase.

A multi-point assay for determination of the activity of amyloglucosidase (AMG) by FIA and SIA is described. The assay is based on two consecutive reactions that are mutually incompatible. Both the FIA and SIA procedures allow these two reactions to be completely separated, whereby each of the processes can be individually optimized with respect to operational parameters. Special emphasis is placed on comparing the performance and applicability of the two procedures for this type of assay.

Flow injection analysis: A complementary or alternative concept to biosensors.

In practical applications biosensors are often forced to operate under less than optimal conditions. Because of their construction, and the physical processes and chemical reactions involved in their operation, compromise conditions are frequently required to synchronize all events taking place. In this communication it is shown Flow Injection Analysis offers itself as a complementary facility to augment the performance of biosensors, and in many cases as an attractive alternative. Based on the argument that instead of striving to force different reactions to work under compromise conditions, it is much better to separate them, optimize them individually and let them interact with each other in harmony, selected flow-injection applications are discussed. Initially, comments are made on operating sensors in the FIA mode, while the following sections deal with selected examples of enzymatic assays, aimed either at measuring substrate concentrations, including the use of enzyme amplification schemes, or determining enzyme activities.