Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 77
Filtrar
1.
Clin Pharmacol Ther ; 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31220337

RESUMO

Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10-5 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10-9 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified.

2.
PLoS One ; 14(6): e0218115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242253

RESUMO

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

3.
Clin Pharmacol Ther ; 106(5): 1028-1036, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31066027

RESUMO

Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.

4.
Rheumatology (Oxford) ; 58(10): 1767-1776, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30982886

RESUMO

OBJECTIVE: To evaluate whether polypharmacy is associated with treatment response and serious adverse events (SAEs) in patients with RA using data from the British Society for Rheumatology Biologics Register (BSRBR-RA). METHODS: The BSRBR-RA is a prospective observational cohort study of biologic therapy starters and a DMARD comparator arm. A logistic regression model was used to calculate the odds of a EULAR 'good response' after 12 months of biologic therapy by medication count. Cox proportional hazards models were used to identify risk of SAEs. The utility of the models were compared with the Rheumatic Disease Comorbidity Index using Receiver Operator Characteristic and Harrell's C statistic. RESULTS: The analysis included 22 005 patients, of which 83% were initiated on biologics. Each additional medication reduced the odds of a EULAR good response by 8% [odds ratios 0.92 (95% CI 0.91, 0.93) P < 0.001] and 3% in the adjusted model [adjusted odds ratios 0.97 (95% CI 0.95, 0.98) P < 0.001]. The Receiver Operator Characteristic demonstrated significantly greater areas under the curve with the polypharmacy model than the Rheumatic Disease Comorbidity Index. There were 12 547 SAEs reported in 7286 patients. Each additional medication equated to a 13% increased risk of an SAE [hazard ratio 1.13 (95% CI 1.12, 1.13) P < 0.001] and 6% in the adjusted model [adjusted hazard ratio 1.06 (95% CI 1.05, 1.07) P < 0.001]. Predictive values for SAEs were comparable between the polypharmacy and Rheumatic Disease Comorbidity Index model. CONCLUSION: Polypharmacy is a simple but valuable predictor of clinical outcomes in patients with RA. This study supports medication count as a valid measure for use in epidemiologic analyses.

5.
Exp Gerontol ; 120: 62-67, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30831202

RESUMO

Polypharmacy, defined through the number of medications prescribed, has been linked to a range of adverse health outcomes in people with dementia. It is however unclear whether a numerical threshold of concurrently prescribed drugs is a suitable predictor for cognitive decline. We aimed to test associations between polypharmacy and both short-term (six months) and long-term (three years) cognitive trajectories in patients with incident dementia. Using data from a large mental health and dementia care database in South London, a cohort of 12,148 patients (mean age = 80.7 years, 61.1% female, mean MMSE = 18.6) clinically diagnosed with dementia was identified. We determined the number of medications prescribed at dementia diagnosis and defined two exposure groups: polypharmacy (5-9 medication) and excessive polypharmacy (≥10 medications), with 0-4 medications as reference group. All Mini Mental State Examination (MMSE) scores between one year before and three years after dementia diagnosis were ascertained. Effects of polypharmacy on cognitive decline were studied using Generalized Additive Models for Location, Scale and Shape and Linear Mixed Estimation Models. At the time of dementia diagnosis polypharmacy was present in 3503 (28.8%) patients and excessive polypharmacy in 1235 (10.2%) patients. In all three groups MMSE scores initially improved after dementia diagnosis and further decline was detected in the time interval from six months to three years after dementia diagnosis. No significant differences to the control group were found in relation to polypharmacy or excessive polypharmacy, neither in the initial cognitive improvement nor long-term decline. In conclusion, polypharmacy defined by the number of drugs does not appear to predict cognitive decline in a naturalistic cohort of patients with dementia. More sophisticated tools, considering appropriateness of prescribing and the clinical picture, might be better placed to evaluate cognitive outcomes in dementia and to make practice and research recommendations.

6.
BMJ ; 364: l525, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30814048

RESUMO

OBJECTIVE: To evaluate the association between antibiotic treatment for urinary tract infection (UTI) and severe adverse outcomes in elderly patients in primary care. DESIGN: Retrospective population based cohort study. SETTING: Clinical Practice Research Datalink (2007-15) primary care records linked to hospital episode statistics and death records in England. PARTICIPANTS: 157 264 adults aged 65 years or older presenting to a general practitioner with at least one diagnosis of suspected or confirmed lower UTI from November 2007 to May 2015. MAIN OUTCOME MEASURES: Bloodstream infection, hospital admission, and all cause mortality within 60 days after the index UTI diagnosis. RESULTS: Among 312 896 UTI episodes (157 264 unique patients), 7.2% (n=22 534) did not have a record of antibiotics being prescribed and 6.2% (n=19 292) showed a delay in antibiotic prescribing. 1539 episodes of bloodstream infection (0.5%) were recorded within 60 days after the initial UTI. The rate of bloodstream infection was significantly higher among those patients not prescribed an antibiotic (2.9%; n=647) and those recorded as revisiting the general practitioner within seven days of the initial consultation for an antibiotic prescription compared with those given a prescription for an antibiotic at the initial consultation (2.2% v 0.2%; P=0.001). After adjustment for covariates, patients were significantly more likely to experience a bloodstream infection in the deferred antibiotics group (adjusted odds ratio 7.12, 95% confidence interval 6.22 to 8.14) and no antibiotics group (8.08, 7.12 to 9.16) compared with the immediate antibiotics group. The number needed to harm (NNH) for occurrence of bloodstream infection was lower (greater risk) for the no antibiotics group (NNH=37) than for the deferred antibiotics group (NNH=51) compared with the immediate antibiotics group. The rate of hospital admissions was about double among cases with no antibiotics (27.0%) and deferred antibiotics (26.8%) compared with those prescribed immediate antibiotics (14.8%; P=0.001). The risk of all cause mortality was significantly higher with deferred antibiotics and no antibiotics than with immediate antibiotics at any time during the 60 days follow-up (adjusted hazard ratio 1.16, 95% confidence interval 1.06 to 1.27 and 2.18, 2.04 to 2.33, respectively). Men older than 85 years were particularly at risk for both bloodstream infection and 60 day all cause mortality. CONCLUSIONS: In elderly patients with a diagnosis of UTI in primary care, no antibiotics and deferred antibiotics were associated with a significant increase in bloodstream infection and all cause mortality compared with immediate antibiotics. In the context of an increase of Escherichia coli bloodstream infections in England, early initiation of recommended first line antibiotics for UTI in the older population is advocated.


Assuntos
Antibacterianos/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Sepse/mortalidade , Infecções Urinárias/mortalidade , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Inglaterra/epidemiologia , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/mortalidade , Feminino , Humanos , Masculino , Admissão do Paciente/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Estudos Retrospectivos , Sepse/tratamento farmacológico , Sepse/microbiologia , Infecções Urinárias/complicações , Infecções Urinárias/tratamento farmacológico
7.
Gastroenterology ; 156(6): 1707-1716.e2, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30664875

RESUMO

BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 × 10-9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 × 10-6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 × 10-6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.


Assuntos
Afro-Americanos/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Grupo com Ancestrais do Continente Europeu/genética , Hispano-Americanos/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Adulto , Amoxicilina/efeitos adversos , Antibacterianos/efeitos adversos , Estudos de Casos e Controles , Ácido Clavulânico/efeitos adversos , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Antígeno HLA-A2/genética , Cadeias HLA-DRB1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
Clin Pharmacol Ther ; 106(1): 245-253, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30661239

RESUMO

Some patients prescribed flucloxacillin (~ 0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single-nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA-B*57:01 was the major risk factor (allelic odds ratio (OR) = 36.62; P = 2.67 × 10-97 ). HLA-B*57:03 also showed an association (OR = 79.21; P = 1.2 × 10-6 ). Within the HLA-B protein sequence, imputation showed valine97 , common to HLA-B*57:01 and HLA-B*57:03, had the largest effect (OR = 38.1; P = 9.7 × 10-97 ). We found no HLA-B*57 association with DILI due to other isoxazolyl penicillins (n = 6) or amoxicillin (n = 15) and no significant non-HLA signals for any penicillin-related DILI.

9.
Exp Gerontol ; 106: 240-245, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29452289

RESUMO

Polypharmacy has been linked to higher risks of hospitalisation and death in community samples. It is commonly present in people with dementia but these risks have rarely been studied in this population. We aimed to investigate associations between polypharmacy and emergency department attendance, any and unplanned hospitalisation, and mortality in patients with dementia. Using a large mental health care database in South London, linked to hospitalisation and mortality data, we assembled a retrospective cohort of patients diagnosed with dementia. We ascertained number of medications prescribed at the time of dementia diagnosis and conducted multivariate Cox regression analyses. Of 4668 patients with dementia identified, 1128 (24.2%) were prescribed 4-6 medications and 739 (15.8%) ≥7 medications. Compared to those using 0-3 medications, patients with dementia using 4-6 or ≥7 agents had an increased risk of emergency department attendance (hazard ratio 1.20/1.35), hospitalisation (hazard ratio 1.12/1.32), unplanned hospital admission (hazard ratio 1.12/1.25), and death within two years (hazard ratio 1.29/1.39) after controlling for potential confounders. We found evidence of a dose response relationship with each additional drug at baseline increasing the risk of emergency department attendance and mortality by 5% and hospitalisation by 3%. In conclusion, polypharmacy at dementia diagnosis is associated with a higher risk of adverse health outcomes. Future research is required to elucidate which specific agents underlie this relationship and if reduction of inappropriate prescribing is effective in preventing these outcomes in dementia.

10.
Clin Epidemiol ; 10: 31-39, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29296099

RESUMO

Background: Functional and cognitive domains have rarely been evaluated for their prognostic value in general practice databases. The aim of this study was to identify functional and cognitive domains in The Health Improvement Network (THIN) and to evaluate their additional value for the prediction of 1-month and 1-year mortality in elderly people. Materials and methods: A cohort study was conducted using a UK nationwide general practitioner database. A total of 1,193,268 patients aged 65 years or older, of whom 15,300 had dementia, were identified from 2000 to 2012. Information on mobility, dressing and accommodation was recorded frequently enough to be analyzed further in THIN. Cognition data could not be used due to very poor recording of data in THIN. One-year and 1-month mortality was predicted using logistic models containing variables such as age, sex, disease score and functionality status. Results: A significant but moderate improvement in 1-year and 1-month mortality prediction in elderly people was observed by adding accommodation to the variables age, sex and disease score, as the c-statistic (95% confidence interval [CI]) increased from 0.71 (0.70-0.72) to 0.76 (0.75-0.77) and 0.73 (0.71-0.75) to 0.79 (0.77-0.80), respectively. A less notable improvement in the prediction of 1-year and 1-month mortality was observed in people with dementia. Conclusion: Functional domains moderately improved the accuracy of a model including age, sex and comorbidities in predicting 1-year and 1-month mortality risk among community-dwelling older people, but they were much less able to predict mortality in people with dementia. Cognition could not be explored as a predictor of mortality due to insufficient data being recorded.

11.
J Antimicrob Chemother ; 73(2): 287-296, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29149266

RESUMO

Background: Antibiotic use can have negative unintended consequences including disruption of the human microbiota, which is thought to protect against pathogen overgrowth. We conducted a systematic review to assess whether there is an association between exposure to antibiotics and subsequent risk of community-acquired infections. Methods: We searched MEDLINE, EMBASE and Web of Science for studies published before 30 June 2017, examining the association between antibiotic use and subsequent community-acquired infection. Infections caused by Clostridium difficile and fungal organisms were excluded. Studies focusing exclusively on resistant organism infections were also excluded. Results: Eighteen of 22588 retrieved studies met the inclusion criteria. From these, 16 studies reported a statistically significant association between antibiotic exposure and subsequent risk of community-acquired infection. Infections associated with prior antibiotic use included Campylobacter jejuni infection (one study), recurrent furunculosis (one study), invasive Haemophilus influenzae type b infection (one study), infectious mastitis (one study), meningitis (one study), invasive pneumococcal disease (one study), Staphylococcus aureus skin infection (one study), typhoid fever (two studies), recurrent boils and abscesses (one study), upper respiratory tract infection and urinary tract infection (one study) and Salmonella infection (five studies), although in three studies on Salmonella infection the effect was of marginal statistical significance. Conclusions: We found an association between prior antibiotic use and subsequent risk of a diverse range of community-acquired infections. Gastrointestinal and skin and soft tissue infections were most frequently found to be associated with prior antibiotic exposure. Our findings support the hypothesis that antibiotic use may predispose to future infection risk, including infections caused by both antibiotic-resistant and non-resistant organisms.

12.
Clin Pharmacol Ther ; 103(5): 843-853, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28762467

RESUMO

Agranulocytosis is a serious, although rare, adverse reaction to sulfasalazine, which is used to treat inflammatory joint and bowel disease. We performed a genome-wide association study comprising 9,380,034 polymorphisms and 180 HLA alleles in 36 cases of sulfasalazine-induced agranulocytosis and 5,170 population controls. Sulfasalazine-induced agranulocytosis was significantly associated with the HLA region on chromosome 6. The top hit (rs9266634) was located close to HLA-B, odds ratio (OR) 5.36 (95% confidence interval (CI) (2.97, 9.69) P = 2.55 × 10-8 ). We HLA-sequenced a second cohort consisting of 40 cases and 142 treated controls, and confirmed significant associations with HLA-B*08:01, OR = 2.25 (95% CI (1.02, 4.97) P = 0.0439), in particular the HLA-B*08:01 haplotype HLA-DQB1*02:01-DRB1*03:01-B*08:01-C*07:01, OR = 3.79 (95% CI (1.63, 8.80) P = 0.0019), and with HLA-A*31:01, OR = 4.81 (95% CI (1.52, 15.26) P = 0.0077). The number needed to test for HLA-B*08:01 and HLA-A*31:01 to avoid one case was estimated to be 1,500. We suggest that intensified monitoring or alternative treatment should be considered for known carriers of HLA-B*08:01 or HLA-A*31:01.

13.
J Rheumatol ; 44(12): 1786-1793, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28966210

RESUMO

OBJECTIVE: Polypharmacy (PP), the prescribing of multiple drugs for an individual, is rising in prevalence. PP associates with an increased risk of adverse drug reactions (ADR) and hospital admissions. We investigated the relationship between PP, characteristics of rheumatoid arthritis (RA), and the risk of unplanned hospital admissions. METHODS: Patients from a hospital RA cohort were retrospectively analyzed. Information was collected from electronic medical records. Cox proportional hazards were used to compare hospitalization risk according to levels of PP. Admissions were adjudicated to determine whether an ADR was implicated. RESULTS: The study included 1101 patients; the mean number of all medications was 5. PP correlated with increasing age, disease duration, disease activity, and disability. At least 1 unplanned admission occurred for 16% of patients. Patients taking ≥ 10 medications had an adjusted HR for hospitalization of 3.1 (95% CI 2.1-4.5), compared to those taking 0-5 medications. Corticosteroid use associated with a doubling in adjusted risk of admission of 1.7 (95% CI 1.2-2.4). The most common reason for hospitalization was infection (28%). While in half of all admissions an ADR was a possible contributing factor, only 2% of admissions were found to directly result from an ADR. CONCLUSION: PP is common in RA and is a prognostic marker associated with increased risk of acute hospitalizations. Our data suggest that PP may be an indicator of comorbidity burden rather than a contributing cause of a drug-related toxicity. PP should be monitored to minimize inappropriate combination of prescribed medications. PP may be a useful predictor of clinical outcomes in epidemiologic studies.


Assuntos
Corticosteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Hospitalização , Polimedicação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
14.
BMC Fam Pract ; 18(1): 70, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28587644

RESUMO

BACKGROUND: Because of ageing populations, the growth in the number of people with multi-morbidity and greater compliance with disease-specific guidelines, polypharmacy is becoming increasingly common. Although the correct drug treatment in patients with complex medical problems can improve clinical outcomes, quality of life and life expectancy, polypharmacy is also associated with an increased risk of adverse drug events, some severe enough to result in hospital admission and even death. Hence, having systems in place to ensure that medications are started only when there is a suitable indication, ensuring patients are fully aware of the benefits and complications that may arise from their treatment, and reviewing patients regularly to ensure their medication regime remains appropriate, are essential. DISCUSSION: The development and rapid uptake of electronic patient records - particularly in primary care settings where the majority of prescribing takes place - makes monitoring of patients more straightforward than in the past; and allows identification of sub-groups of patients at particularly high risk of adverse drug events and complications. It also facilitates 'deprescribing' the process by which medications are reviewed and stopped if not clinically beneficial. In recent years, we have also seen the development of smartphone 'apps' to improve communication between patients and healthcare professionals, improve people's understanding of their conditions and their treatment, and maintain a record of changes made to patient's medication. In the longer term, developments such as the introduction of artificial intelligence and clinical decision support systems also have the potential to improve prescribing and minimise the risks from polypharmacy. Finally, there is considerable scope to improve the quality of prescribing and reduce risks from poly-pharmacy using non-medical groups such as pharmacists, specialist nurses and physician assistants. Polypharmacy has increased in recent decades and will continue to increase as populations age and the number of people with multiple long-term conditions increases. As with all areas of medicine, the evidence-base in this area continues to evolve. Further trials on the impact on patients with polypharmacy of new interventions such as technology-based solutions and the use of different professional groups are needed to improve the evidence-base in this area.


Assuntos
Polimedicação , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Previsões , Humanos , Reconciliação de Medicamentos , Multimorbidade/tendências , Participação do Paciente , Medição de Risco , Fatores de Risco
15.
Heart ; 103(23): 1867-1873, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28601812

RESUMO

OBJECTIVES: The present study aimed to assess the relationship between inflammatory disorders with cardiometabolic diseases and mortality within a community-based population. METHODS: The UK Biobank data were used to conduct two investigations: a cross-sectional study to estimate cardiometabolic risk and a prospective cohort study to estimate mortality risk. Binary regression analyses were used to model the association between coronary heart disease, stroke, type 2 diabetes, venous thromboembolism and peripheral artery disease diagnoses with seven inflammatory disorders (eg, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, ankylosing spondylitis (AS), systemic vasculitis, Crohn's disease and ulcerative colitis (UC)). Cox proportional hazards was used to estimate all-cause and cardiovascular-related mortality. RESULTS: About 4% (n=19, 082) of the study population (n=5 02 641) were diagnosed with a chronic inflammatory disorder. The most common inflammatory disorder was psoriasis (n=6286), and the least common was SLE (n=654). SLE showed the strongest association with multiple (relative risk (RR) 6.36, 95% CI 4.37 to 9.25) risk of cardiometabolic diseases, followed by the RA (RR 1.70, 95% CI 1.59 to 1.83), UC (RR 1.69, 95% CI 1.51 to 1.89), AS (RR 1.28, 95% CI 1.09 to 1.52), vasculitis (RR 1.64, 95% CI 1.42-1.90) and psoriasis (RR 1.25, 95% 1.16 to 1.35) disorders. The magnitude of the association was higher among participants prescribed non-steroidal anti-inflammatory drugs or corticosteroids drugs, with multiple cardiometabolic risk being greater within SLE (RR 12.35, 95% CI 7.18 to 21.24), followed by UC (RR 3.81, 95% CI 2.69 to 5.38), Crohn's disease (RR 3.07, 95% CI 1.85 to 5.11), RA (RR 3.06, 95% CI 2.44 to 3.85), psoriasis (RR 2.36, 95% CI 1.88 to 2.95), AS (RR 2.25, 95% CI 1.48 to 3.41) and vasculitis (RR 1.89, 95% CI 1.28 to 2.79). Similar pattern was observed with respect to the cumulative cardiometabolic risk. CONCLUSION: Inflammatory disorders are associated with heightened risk of cardiometabolic events, which may vary by anti-inflammatory therapy and duration. All-cause mortality was also higher among specific inflammatory disorders compared with the absence of inflammatory disorders.


Assuntos
Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/mortalidade , Inflamação/mortalidade , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/diagnóstico , Causas de Morte , Doença Crônica , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Reino Unido , Adulto Jovem
16.
CMAJ ; 189(15): E560-E568, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28420680

RESUMO

BACKGROUND: There are conflicting findings from observational studies of the arrhythrogenic potential of azithromycin. Our aim was to quantify the association between azithromycin use and the risk of ventricular arrhythmia. METHODS: We conducted a nested case-control study within a cohort of new antibiotic users identified from a network of 7 population-based health care databases in Denmark, Germany, Italy, the Netherlands and the United Kingdom for the period 1997-2010. Up to 100 controls per case were selected and matched by age, sex and database. Recency of antibiotic use and type of drug (azithromycin was the exposure of interest) at the index date (occurrence of ventricular arrhythmia) were identified. We estimated the odds of ventricular arrhythmia associated with current azithromycin use relative to current amoxicillin use or nonuse of antibiotics (≥ 365 d without antibiotic exposure) using conditional logistic regression, adjusting for confounders. RESULTS: We identified 14 040 688 new antibiotic users who met the inclusion criteria. Ventricular arrhythmia developed in 12 874, of whom 30 were current azithromycin users. The mean age of the cases and controls was 63 years, and two-thirds were male. In the pooled data analyses across databases, azithromycin use was associated with an increased risk of ventricular arrhythmia relative to nonuse of antibiotics (adjusted odds ratio [OR] 1.97, 95% confidence interval [CI] 1.35-2.86). This increased risk disappeared when current amoxicillin use was the comparator (adjusted OR 0.90, 95% CI 0.48-1.71). Database-specific estimates and meta-analysis confirmed results from the pooled data analysis. INTERPRETATION: Current azithromycin use was associated with an increased risk of ventricular arrhythmia when compared with nonuse of antibiotics, but not when compared with current amoxicillin use. The decreased risk with an active comparator suggests significant confounding by indication.


Assuntos
Antibacterianos/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Azitromicina/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Amoxicilina/efeitos adversos , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
17.
Gastroenterology ; 152(5): 1078-1089, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28043905

RESUMO

BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Cromossomos Humanos Par 2/genética , Antígenos HLA-A/genética , Alelos , Antidepressivos/efeitos adversos , Antifúngicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Fenofibrato/efeitos adversos , Genes MHC Classe I/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipolipemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Naftalenos/efeitos adversos , Razão de Chances , Fenótipo , Inibidores da Agregação de Plaquetas/efeitos adversos , Polimorfismo de Nucleotídeo Único , Sertralina/efeitos adversos , Terbinafina , Ticlopidina/efeitos adversos
18.
CNS Drugs ; 30(11): 1097-1109, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27423216

RESUMO

BACKGROUND: Antipsychotic (AP) drugs are commonly used to manage the behavioural symptoms of dementia. Nevertheless, international (i.e. the European Medicines Agency in Europe) and national (i.e. the Medicines and Healthcare products Regulatory Agency in the UK and the Italian Drug Agency) regulatory agencies issued safety warnings against AP use in dementia in 2004 and 2009. OBJECTIVE: The aim of this study is to investigate the short- and long-term impact of safety warnings on the use of APs in UK and Italian persons with dementia using two nationwide databases: The Health Improvement Network (THIN) from the UK and the Health Search Database-Cegedim-Strategic Data-Longitudinal Patient Database (HSD-CSD-LPD) from Italy. METHODS: We calculated the overall quarterly prevalence of AP use by class and by individual drug in persons with dementia aged ≥65 years and used generalized linear models to explore the effect of the safety warnings. RESULTS: We identified 58,497 and 10,857 individuals aged ≥65 years with dementia from the THIN and HSD-CSD-LPD databases, respectively, over the period 2000-2012. After the 2004 warnings, the use of atypical APs decreased, whereas the use of conventional APs increased, in Italy and the UK until 2009. However, the trend for APs individually showed that the use of risperidone/olanzapine decreased, whereas the use of quetiapine increased in both countries. After the 2009 warnings (until 2012), the use of atypical and conventional APs decreased in the UK (from 11 to 9 and 5 to 3 %, respectively), but such use increased in Italy (from 11 to 18 and 9 to 14 %, respectively). CONCLUSION: The 2004 warnings led to a reduction in the use of olanzapine and risperidone and increased the use of quetiapine/conventional APs in both countries. From 2009, the use of APs decreased in persons with dementia in the UK but not in Italy. Possible reasons for the difference in AP use between the two countries include a more proactive approach towards reducing the use of APs in the UK than in Italy.


Assuntos
Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Demência/tratamento farmacológico , Idoso , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Bases de Dados Factuais , Prescrições de Medicamentos , Feminino , Humanos , Itália , Masculino , Olanzapina , Padrões de Prática Médica , Estudos Retrospectivos , Risperidona/efeitos adversos , Risperidona/uso terapêutico , Reino Unido
19.
Lancet Diabetes Endocrinol ; 4(6): 507-16, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27157822

RESUMO

BACKGROUND: Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Genome-wide association studies (GWASs) in ethnic Chinese people in Taiwan and Hong Kong have shown an association between agranulocytosis induced by antithyroid drugs and the HLA alleles HLA-B*38:02 and HLA-DRB1*08:03. We aimed to identify genetic variants associated with antithyroid drug-induced agranulocytosis in a white European population. METHODS: We did a GWAS in 234 European adults with any non-chemotherapy drug-induced agranulocytosis (absolute neutrophil count ≤0·5 × 10(9)/L [≤500/µL]) and 5170 population controls. 39 of the 234 patients had agranulocytosis that was induced by antithyroid drugs (thiamazole [methimazole], carbimazole, or propylthiouracil). After imputation and HLA allele prediction, 9 380 034 single nucleotide polymorphisms (SNPs) and 180 HLA alleles were tested for association. The genome-wide significance threshold was p<5 × 10(-8). FINDINGS: Agranulocytosis induced by non-chemotherapy drugs in general was significantly associated with the HLA region on chromosome 6, with odds ratios (ORs) of 3·24 (95% CI 2·31-4·55, p=1·20 × 10(-11)) for HLA-B*27:05 and 3·57 (2·61-4·90, p=2·32 × 10(-15)) for the top SNP (rs114291795). Drug-specific analysis showed that the association with HLA-B*27:05 was largely driven by cases induced by antithyroid drugs. In a multiple logistic regression model, the OR for HLA-B*27:05 was 7·30 (3·81-13·96) when antithyroid drug-induced agranulocytosis was compared with population controls (p=1·91 × 10(-9)) and 16·91 (3·44-83·17) when compared with a small group of hyperthyroid controls (p=5·04 × 10(-4)). Three SNPs were strongly associated with antithyroid drug-induced agranulocytosis: rs652888 (OR 4·73, 95% CI 3·00-7·44, p=1·92 × 10(-11)) and rs199564443 (17·42, 7·38-41·12, p=7·04 × 10(-11)), which were independent of HLA-B*27:05, and rs1071816 (5·27, 3·06-9·10, p=2·35 × 10(-9)) which was in moderate linkage disequilibrium with HLA-B*27:05. In heterozygous carriers of all three SNPs, the predicted probability of antithyroid drug-induced agranulocytosis was about 30% (OR 753, 95% CI 105-6812). To avoid one case of agranulocytosis, based on the possible risk reduction if all three SNPs are genotyped and carriers are treated or monitored differently from non-carriers, roughly 238 patients would need to be genotyped. INTERPRETATION: In white European people, antithyroid drug-induced agranulocytosis was associated with HLA-B*27:05 and with other SNPs on chromosome 6. In the future, carriers of these variants could be placed under intensified monitoring or offered alternative treatment for hyperthyroidism. FUNDING: Swedish Research Council, Swedish Heart and Lung Foundation, Clinical Research Support at Uppsala University, German Federal Institute for Drugs and Medical Devices, Carlos III Spanish Health Institute, European Regional Development Fund, UK National Institute for Health Research, The Selander's Foundation, Thuréus Foundation, European Commission, and Science for Life Laboratory.


Assuntos
Agranulocitose/genética , Antitireóideos/efeitos adversos , Antígeno HLA-B27/genética , Adulto , Idoso , Agranulocitose/induzido quimicamente , Estudos de Casos e Controles , Cromossomos Humanos Par 6 , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
20.
Br J Clin Pharmacol ; 82(2): 487-97, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27061849

RESUMO

INTRODUCTION: Antipsychotic drugs (APDs) are used to treat several mental illnesses. Some APDs have long been known to be associated with QT prolongation, potentially leading to torsades de pointes (TdP) and sudden cardiac death (SCD). In 2005, thioridazine was withdrawn because of the risk of SCD, bringing further attention to the arrhythmogenic potential of APDs. AIM: The aim of the current study was to evaluate the use of APDs in five European countries during the years 1996-2010. METHODS: A cohort study was conducted using prescription/dispensing data from seven healthcare databases [the AARHUS University Hospital Database (Denmark), the German Pharmacoepidemiological Research Database (GePaRD) (Germany), Health Search Database/Thales (HSD) and Emilia Romagna Regional Database (ERD) (Italy), PHARMO Database Network and Integrated Primary Care Information (IPCI) (the Netherlands) and The Health Improvement Network (THIN) (the UK), covering a population of 27 million individuals. The annual prescription rate of APDs was measured overall and for individual medications. APDs were classified as torsadogenic according to the Arizona-CERT list. All analyses were stratified by age, gender and calendar year. RESULTS: A total of 559 276 person-years (PYs) of exposure to APDs was captured. The crude annual prescription rate of APD use ranged from 3.0/1000 PYs in ERD to 7.7/1000 PYs in AARHUS. Among APDs with established torsadogenic potential, thioridazine was the most frequently used medication in the UK. Haloperidol was commonly prescribed in Italy and the Netherlands. The use of APDs with torsadogenic potential was much higher in elderly patients. CONCLUSIONS: Substantial use of APDs with torsadogenic potential has been reported in Europe in recent years, in spite of increasing concerns about their arrhythmogenic potential. This use was even greater in elderly patients, who are at higher risk of SCD.


Assuntos
Antipsicóticos/efeitos adversos , Morte Súbita Cardíaca/etiologia , Síndrome do QT Longo/induzido quimicamente , Torsades de Pointes/induzido quimicamente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/administração & dosagem , Criança , Pré-Escolar , Estudos de Coortes , Morte Súbita Cardíaca/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Lactente , Síndrome do QT Longo/epidemiologia , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica/estatística & dados numéricos , Padrões de Prática Médica/tendências , Fatores de Risco , Torsades de Pointes/epidemiologia , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA