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1.
Eur J Hum Genet ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238909

RESUMO

Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.

2.
Hypertension ; : HYPERTENSIONAHA11914308, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32200679

RESUMO

GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ'5538. In male wild-type mice, intravenous AZ'5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ'5538 had no effect on blood pressure or renal hemodynamics in Gpr81-/- mice. Gpr81 mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ'5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in Gpr81-/- mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.

3.
J Hypertens ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32141970

RESUMO

OBJECTIVE: Nonadherence to medication is present in at least 50% of patients with apparent treatment-resistant hypertension. We examined the factors associated with nonadherence as detected by a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based urine antihypertensive drug assay. METHODS: All urine antihypertensive test results, carried out for uncontrolled hypertension (BP persistently >140/90 mmHg) between January 2015 and December 2016 at a single toxicology laboratory were analysed. Drugs detected were compared with the antihypertensive drugs prescribed. Patients were classified as adherent (all drugs detected), partially nonadherent (at least one prescribed drug detected) or completely nonadherent (no drugs detected). Demographic and clinical parameters were compared between the adherent and nonadherent groups. Binary logistic regression analysis was performed to determine association between nonadherence and demographic and clinical factors. RESULTS: Data on 300 patients from nine hypertension centres across the United Kingdom were analysed. The median age was 59 years, 47% women, 71% Caucasian, median clinic BP was 176/95 mmHg and the median number of antihypertensive drugs prescribed was four. One hundred and sixty-six (55%) were nonadherent to prescribed medication with 20% of these being completely nonadherent. Nonadherence to antihypertensive medication was independently associated with younger age, female sex, number of antihypertensive drugs prescribed, total number of all medications prescribed (total pill burden) and prescription of a calcium channel blocker. CONCLUSION: This LC-MS/MS urine analysis-based study suggests the majority of patients with apparent treatment-resistant hypertension are nonadherent to prescribed treatment. Factors that are associated with nonadherence, particularly pill burden, should be taken into account while treating these patients.

4.
Diabetes Obes Metab ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32157772

RESUMO

AIM: To compare the effects of a glucagon-like peptide-1 receptor agonist and a dipeptidyl peptidase-4 inhibitor on magnetic resonance imaging-derived measures of cardiovascular function. MATERIALS AND METHODS: In a prospective, randomized, open-label, blinded endpoint trial liraglutide (1.8 mg) and sitagliptin (100 mg) were compared in asymptomatic, non-insulin treated young (aged 18-50 years) adults with obesity and type 2 diabetes. The primary outcome was difference in circumferential peak early diastolic strain rate change (PEDSR), a biomarker of cardiac diastolic dysfunction 26 weeks after randomization. Secondary outcomes included other indices of cardiac structure and function, HbA1c and body weight. RESULTS: Seventy-six participants were randomized (54% female, mean ± SD age 44 ± 6 years, diabetes duration 4.4 years, body mass index 35.3 ± 6.1 kg m-2 ), of whom 65% had ≥1 cardiovascular risk factor. Sixty-one participants had primary outcome data available. There were no statistically significant between-group differences (intention-to-treat; mean [95% confidence interval]) in PEDSR change (-0.01 [-0.07, +0.06] s-1 ), left ventricular ejection fraction (-1.98 [-4.90, +0.94]%), left ventricular mass (+1.14 [-5.23, +7.50] g) or aortic distensibility (-0.35 [-0.98, +0.28] mmHg-1 × 10-3 ) after 26 weeks. Reductions in HbA1c (-4.57 [-9.10, -0.37] mmol mol-1 ) and body weight (-3.88 [-5.74, -2.01] kg) were greater with liraglutide. CONCLUSION: There were no differences in cardiovascular structure or function after short-term use of liraglutide and sitagliptin in younger adults with obesity and type 2 diabetes. Longer studies in patients with more severe cardiac dysfunction may be necessary before definitive conclusions can be made about putative pleiotropic properties of incretin-based therapies.

6.
BMJ Open ; 10(2): e034137, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32060156

RESUMO

INTRODUCTION: In the UK and Ireland, severe and complex obesity is managed in specialist weight management services (SWMS), which provide multicomponent lifestyle interventions to support weight loss, and use of medication if available. Liraglutide 3 mg (LIRA 3 mg) is an effective weight-loss medication, but weight loss in individual patients is variable, and its efficacy has not been assessed in SWMS. This study aims to investigate whether a targeted prescribing pathway for LIRA 3 mg with multiple prespecified stopping rules could help people with severe obesity and established complications achieve ≥15% weight loss in order to determine whether this could be considered a clinically effective and cost-effective strategy for managing severe and complex obesity in SWMS. METHODS AND ANALYSIS: In this 2-year, multicentre, open-label, real-world randomised controlled trial, 384 adults with severe and complex obesity (defined as body mass index ≥35 kg/m2 plus either prediabetes, type 2 diabetes, hypertension or sleep apnoea) will be randomised via a 2:1 ratio to receive either standard SWMS care (n=128) or standard SWMS care plus a targeted prescribing pathway for LIRA 3 mg with prespecified stopping rules at 16, 32 and 52 weeks (n=256).The primary outcome is to compare the proportion of participants achieving a weight loss of ≥15% at 52 weeks with a targeted prescribing pathway versus standard care. Secondary outcomes include a comparison of (1) the weight loss maintenance at 104 weeks and (2) the budget impact and cost effectiveness between the two groups in a real-world setting. ETHICS AND DISSEMINATION: The Health Research Authority and the Medicines and Healthcare products Regulatory Authority in UK, the Health Products Regulatory Authority in Ireland, the North West Deanery Research Ethics Committee (UK) and the St Vincent's University Hospital European Research Ethics Committee (Ireland) have approved the study. The findings of the study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov-Identifier: NCT03036800.European Clinical Trials Database-Identifier: EudraCT Number 2017-002998-20.

7.
Acta Paediatr ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31899550

RESUMO

AIM: To review multiorgan involvement and management in children with Down syndrome (DS). METHODS: A literature review of articles from 1980 to 2019 using the MEDLINE interface of PubMed was performed using the following search terms- [Down syndrome] or [Trisomy 21] AND [Cardiology] or [Respiratory] or [neurodevelopment] or [epilepsy] or [musculoskeletal] or [immune system] or [haematological] or [endocrine] or [gastrointestinal] or [ophthalmological] or [Ear Nose Throat] or [dermatology] or [renal]. RESULTS: Congenital heart disease particularly septal defects occur in over 60% of infants with DS and 5%-34% of infants develop persistent pulmonary hypertension of the newborn irrespective of a diagnosis of congenital heart disease. Early recognition and management of aspiration, obstructive sleep apnoea and recurrent lower respiratory tract infections (LRTI) could reduce risk of developing pulmonary hypertension in later childhood. Children with DS have an increased risk of autistic spectrum disorder, attention deficit disorder and epilepsy particularly infantile spasms, which are associated with poor neurodevelopmental outcomes. Congenital anomalies of the gastrointestinal and renal system as well as autoimmune diseases, coeliac disease, arthropathy, thyroid dysfunction fold diabetes mellitus and dermatological conditions are more common. Hearing and visual anomalies are also well recognised association with DS (Table 1). CONCLUSION: Children with DS are at an increased risk of multiorgan comorbidities. Organ-specific health surveillance may provide holistic care for the children and families with DS throughout childhood.

8.
J Diabetes Sci Technol ; 14(1): 55-64, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31596145

RESUMO

BACKGROUND: Accurately predicting the risk of diabetic foot ulceration (DFU) could dramatically reduce the enormous burden of chronic wound management and amputation. Yet, the current prognostic models are unable to precisely predict DFU events. Typically, efforts have focused on individual factors like temperature, pressure, or shear rather than the overall foot microclimate. METHODS: A systematic review was conducted by searching PubMed reports with no restrictions on start date covering the literature published until February 20, 2019 using relevant keywords, including temperature, pressure, shear, and relative humidity. We review the use of these variables as predictors of DFU, highlighting gaps in our current understanding and suggesting which specific features should be combined to develop a real-time microclimate prognostic model. RESULTS: The current prognostic models rely either solely on contralateral temperature, pressure, or shear measurement; these parameters, however, rarely reach 50% specificity in relation to DFU. There is also considerable variation in methodological investigation, anatomical sensor configuration, and resting time prior to temperature measurements (5-20 minutes). Few studies have considered relative humidity and mean skin resistance. CONCLUSION: Very limited evidence supports the use of single clinical parameters in predicting the risk of DFU. We suggest that the microclimate as a whole should be considered to predict DFU more effectively and suggest nine specific features which appear to be implicated for further investigation. Technology supports real-time in-shoe data collection and wireless transmission, providing a potentially rich source of data to better predict the risk of DFU.

9.
Br J Pharmacol ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31721165

RESUMO

PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects of NO/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.

10.
Lancet Diabetes Endocrinol ; 7(12): 925-937, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31748169

RESUMO

BACKGROUND: The multicentre, international ADDITION-Europe study investigated the effect of promoting intensive treatment of multiple risk factors among people with screen-detected type 2 diabetes over 5 years. Here we report the results of a post-hoc 10-year follow-up analysis of ADDITION-Europe to establish whether differences in treatment and cardiovascular risk factors have been maintained and to assess effects on cardiovascular outcomes. METHODS: As previously described, general practices from four centres (Denmark, Cambridge [UK], Leicester [UK], and the Netherlands) were randomly assigned by computer-generated list to provide screening followed by routine care of diabetes, or screening followed by intensive multifactorial treatment. Population-based stepwise screening programmes among people aged 40-69 years (50-69 years in the Netherlands), between April, 2001, and December, 2006, identified patients with type 2 diabetes. Allocation was concealed from patients. Following the 5-year follow-up, no attempts were made to maintain differences in treatment between study groups. In this report, we did a post-hoc analysis of cardiovascular and renal outcomes over 10 years following randomisation, including a 5 years post-intervention follow-up. As in the original trial, the primary endpoint was a composite of first cardiovascular event, including cardiovascular mortality, cardiovascular morbidity (non-fatal myocardial infarction and non-fatal stroke), revascularisation, and non-traumatic amputation, up to Dec 31, 2014. Analyses were based on the intention-to-treat principle. ADDITION-Europe is registered with ClinicalTrials.gov, NCT00237549. FINDINGS: 343 general practices were randomly assigned to routine diabetes care (n=176) or intensive multifactorial treatment (n=167). 317 of these general practices (157 in the routine care group, 161 in the intensive treatment group) included eligible patients between April, 2001, and December, 2006. Of the 3233 individuals with screen-detected diabetes, 3057 agreed to participate (1379 in the routine care group, 1678 in the intensive treatment group), but at the 10-year follow-up 14 were lost to follow-up and 12 withdrew, leaving 3031 to enter 10-year follow-up analysis. Mean duration of follow-up was 9·61 years (SD 2·99). Sustained reductions over 10 years following diagnosis were apparent for bodyweight, HbA1c, blood pressure, and cholesterol in both study groups, but between-group differences identified at 1 and 5 years were attenuated at the 10-year follow-up. By 10 years, 443 participants had a first cardiovascular event and 465 died. There was no significant difference between groups in the incidence of the primary composite outcome (16·1 per 1000 person-years in the routine care group vs 14·3 per 1000 person-years in the intensive treatment group; hazard ratio [HR] 0·87, 95% CI 0·73-1·04; p=0·14) or all-cause mortality (15·6 vs 14·3 per 1000 person-years; HR 0·90, 0·76-1·07). INTERPRETATION: Sustained reductions in glycaemia and related cardiovascular risk factors over 10 years among people with screen-detected diabetes managed in primary care are achievable. The differences in prescribed treatment and cardiovascular risk factors in the 5 years following diagnosis were not maintained at 10 years, and the difference in cardiovascular events and mortality remained non-significant. FUNDING: National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Novo Nordisk, Novo Nordisk Foundation, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, UK National Health Service, Merck, Julius Center for Health Sciences and Primary Care, UK Department of Health, and Nuts-OHRA.

11.
Elife ; 82019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31657718

RESUMO

Experience and changes in neuronal activity can alter CNS myelination, but the signalling pathways responsible remain poorly understood. Here we define a pathway in which endothelin, signalling through the G protein-coupled receptor endothelin receptor B and PKC epsilon, regulates the number of myelin sheaths formed by individual oligodendrocytes in mouse and zebrafish. We show that this phenotype is also observed in the prefrontal cortex of mice following social isolation, and is associated with reduced expression of vascular endothelin. Additionally, we show that increasing endothelin signalling rescues this myelination defect caused by social isolation. Together, these results indicate that the vasculature responds to changes in neuronal activity associated with experience by regulating endothelin levels, which in turn affect the myelinating capacity of oligodendrocytes. This pathway may be employed to couple the metabolic support function of myelin to activity-dependent demand and also represents a novel mechanism for adaptive myelination.

12.
J Pain Res ; 12: 2651-2662, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564957

RESUMO

Chronic pain of uncertain etiology often presents a challenge to both patients and their health care providers. It is a complex condition influenced by structural and physiological changes in the peripheral and central nervous systems, and it directly influences, and is modulated by, psychological well-being and personality style, mood, sleep, activity level and social circumstances. Consequently, in order to effectively treat the pain, all of these need to be evaluated and addressed. An effective management strategy takes a multidisciplinary biopsychosocial approach, with review of all current medications and identification and careful withdrawal of those that may actually be contributing to ongoing pain. The management approach is primarily nonpharmacological, with carefully considered addition of medication, beginning with pain-modulating treatments, if necessary. In this article, we present a primary care approach to the assessment and management of a patient with chronic pain where the cause cannot be identified.

13.
Diabetes Res Clin Pract ; 157: 107836, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31479704

RESUMO

The place of Sulphonylurea based insulin secretagogues in the management of Type 2 diabetes appears as controversial today as it was fifty years ago. Newer therapies are associated with less hypoglycaemia and weight gain than Sulphonylureas but currently cost more and lack assurances which come with long-term exposure. Emergence of recent CVOT data for SGLT-2 inhibitors and GLP-1 receptor agonists is likely to influence therapeutic choices and guidance is now supportive of their earlier use in cases at high risk of cardiovascular disease. Meta-analyses of Sulphonylurea trials have failed to indicate a consistent effect (positive or negative) on cardiovascular disease or mortality, although are limited by the relative scarcity of studies directly reporting these outcomes. The CAROLINA trial is reassuring in demonstrating cardiovascular safety for the Sulphonylurea Glimepiride when compared directly with the DPP-4 inhibitor Linagliptin, suggesting either of these agents would be relatively safe second line options after Metformin in the majority of patients. This review provides a balanced assessment of available Sulphonylurea treatments in the context of current cardiovascular outcome trial data (CVOT) data and hopefully assists informed decision making about the place of these drugs in contemporary glucose lowering practice.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Adulto , Idoso , Doenças Cardiovasculares , Humanos , Hipoglicemiantes/farmacologia , Pessoa de Meia-Idade , Compostos de Sulfonilureia/farmacologia
14.
Pharmacoepidemiol Drug Saf ; 28(10): 1369-1376, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31385428

RESUMO

PURPOSE: To validate an algorithm for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) episodes derived in an electronic health record (EHR) database, against AECOPD episodes collected in a randomized clinical trial using an electronic case report form (eCRF). METHODS: We analyzed two data sources from the Salford Lung Study in COPD: trial eCRF and the Salford Integrated Record, a linked primary-secondary routine care EHR database of all patients in Salford. For trial participants, AECOPD episodes reported in eCRF were compared with algorithmically derived moderate/severe AECOPD episodes identified in EHR. Episode characteristics (frequency, duration), sensitivity, and positive predictive value (PPV) were calculated. A match between eCRF and EHR episodes was defined as at least 1-day overlap. RESULTS: In the primary effectiveness analysis population (n = 2269), 3791 EHR episodes (mean [SD] length: 15.1 [3.59] days; range: 14-54) and 4403 moderate/severe AECOPD eCRF episodes (mean length: 13.8 [16.20] days; range: 1-372) were identified. eCRF episodes exceeding 28 days were usually broken up into shorter episodes in the EHR. Sensitivity was 63.6% and PPV 71.1%, where concordance was defined as at least 1-day overlap. CONCLUSIONS: The EHR algorithm performance was acceptable, indicating that EHR-derived AECOPD episodes may provide an efficient, valid method of data collection. Comparing EHR-derived AECOPD episodes with those collected by eCRF resulted in slightly fewer episodes, and eCRF episodes of extreme lengths were poorly captured in EHR. Analysis of routinely collected EHR data may be reasonable when relative, rather than absolute, rates of AECOPD are relevant for stakeholders' decision making.

15.
Clin Appl Thromb Hemost ; 25: 1076029619864663, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31402687

RESUMO

Venous thromboembolism (VTE) represents a major health-care problem. Understanding patient satisfaction with VTE care is an important health-care goal. A national online survey was administered to adults who had experienced a recent VTE event. The survey assessed patient satisfaction by: (1) satisfaction with VTE care provider; (2) likelihood to recommend VTE provider; and (3) satisfaction with communication between VTE care providers. Each question was correlated with patient demographics, patient care harms (ie, misdiagnosis, wrong treatment), patient beliefs concerning outcomes, and type of anticoagulant therapy. Respondents (907) were 52.4 ± 14.4 years, predominantly Caucasian, mostly women, and generally had health insurance. Most respondents were satisfied with VTE care providers, likely to recommend their VTE provider, and satisfied with communication between providers. Dissatisfaction was strongly associated with treatment mistakes, a wrong diagnosis or treatment, or delayed treatment. A national sample of VTE patients were generally satisfied with VTE care experiences. The VTE care dissatisfaction was strongly associated with perceived mistakes in VTE care. Interventions aimed at reducing, acknowledging, and communicating errors could be studied to improve VTE care satisfaction.


Assuntos
Assistência ao Paciente/normas , Satisfação do Paciente , Tromboembolia Venosa/terapia , Adulto , Idoso , Comunicação , Feminino , Humanos , Masculino , Erros Médicos , Pessoa de Meia-Idade , Inquéritos e Questionários
17.
EClinicalMedicine ; 11: 11-17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31317129

RESUMO

Background: Acetylcysteine (NAC) is effective at preventing liver injury after paracetamol overdose. The Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning (SNAP) Study demonstrated that a 12 h NAC regimen was associated with fewer adverse drug reactions compared with the standard 21 h regimen. Here, we describe the clinical effectiveness of the SNAP NAC regimen. Methods: The SNAP regimen, consisting of intravenous NAC 100 mg/kg over 2 h then 200 mg/kg over 10 h, was introduced to treat all paracetamol overdose patients at the Royal Infirmary of Edinburgh, the Royal Victoria Infirmary, Newcastle and St Thomas' Hospital, London. Patient data were prospectively and systematically collected before and after the change in treatment (total patients N = 3340, 21 h N = 1488, SNAP N = 1852). Health record linkage was used to determine patient outcome after hospital discharge. Findings: There was no difference in liver injury or liver synthetic dysfunction between regimens. Hepatotoxicity (peak ALT > 1000 U/L) occurred in 64 (4.3%) and 67 (3.6%) patients, respectively, in the 21 h and SNAP groups (absolute difference - 0.7%, 95% CI - 2.1 to 0.6). Multivariable logistic regression did not identify treatment regimen as an outcome-associated factor. No patients were readmitted to hospital with, or died from, liver failure within 30 days of discharge. Anti-histamine treatment (for NAC anaphylactoid drug reactions) was prescribed for 163 (11.0%) patients with the 21 h regimen and 37 (2.0%) patients with the SNAP regimen (absolute difference 9.0% (95% CI 7.3 to 10.7)). Interpretation: In clinical use the SNAP regimen has similar efficacy as standard therapy for preventing liver injury and produces fewer adverse reactions.

18.
Heart ; 105(19): 1452-1453, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31296590
19.
Hypertension ; 74(2): 323-330, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177906

RESUMO

Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Antagonistas do Receptor de Endotelina A/uso terapêutico , Nifedipino/administração & dosagem , Pró-Proteína Convertase 9/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Análise de Variância , Doenças Cardiovasculares/etiologia , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Resultado do Tratamento
20.
Br J Clin Pharmacol ; 85(9): 1907-1924, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31206748

RESUMO

Weighing up sources of evidence is a key skill for clinical decision-makers. Randomised controlled trials (RCTs) and observational studies each have advantages and disadvantages, and in both cases perceived weaknesses can be improved through modifications of design and analysis. In the field of pharmacoepidemiology, RCTs are the best way to determine whether an intervention modifies an outcome being studied, largely because randomisation reduces bias and confounding. Observational studies are useful to investigate whether benefits/harms of a treatment are seen in day-to-day clinical practice in a wider group of patients. Although observational studies, even in a small cohort, can provide very useful clinical evidence, they may also be misleading (as shown by subsequent RCTs), in part because of allocation bias. There is an unmet need for clinicians to become well versed in appraising the study design and statistical analysis of observational pharmacoepidemiology (OP) studies, rather like the medical training already offered for RCT evaluation. This is because OP studies are likely to become more common with the computerisation of healthcare records and increasingly contribute to the evidence base available for clinical decision-making. However, when the results of an RCT conflict with the results of an OP study, the findings of the RCT should be preferred, especially if its findings have been repeated elsewhere. Conversely, OP studies that align with the findings of RCTs can provide rich and useful information to complement that generated by RCTs.

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