Steven Lane

Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia.

Some chronic myeloid leukemia (CML) patients do not respond to imatinib, whereas others lose an initial response. To identify potential imatinib failures, we investigated the expression of imatinib uptake transporter (human organic cation transporter 1; hOCT1) and efflux transporters (ATP‐binding cassette transporters ABCB1, ABCG2, and ABCC1) using real‐time quantitative reverse transcription‐polymerase chain reaction in 70 CML patients. Patients with high pretreatment hOCT1 expression had superior complete cytogenetic response (CCR) rates (P=0.008), progression‐free and overall survival (P=0.01 and 0.004). Pretreatment ABCB1, ABCG2, and ABCC1 levels did not correlate with treatment outcome. Regression analysis demonstrated that pretreatment hOCT1 expression was the most powerful predictor of CCR achievement at 6 months (P=0.002). Imatinib uptake into a CML cell line with high hOCT1 expression was greater than into those with modest or low expression (P=0.002). The expression of hOCT1, but not efflux transporters, is important in determining the clinical response to imatinib.

Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses

Objectives To determine the incremental net health benefits of dabigatran etexilate 110 mg and 150 mg twice daily and warfarin in patients with non-valvular atrial fibrillation and to estimate the cost effectiveness of dabigatran in the United Kingdom. Design Quantitative benefit-harm and economic analyses using a discrete event simulation model to extrapolate the findings of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study to a lifetime horizon. Setting UK National Health Service. Population Cohorts of 50 000 simulated patients at moderate to high risk of stroke with a mean baseline CHADS2 (Congestive heart failure, Hypertension, Age≥75 years, Diabetes mellitus, previous Stroke/transient ischaemic attack) score of 2.1. Main outcome measures Quality adjusted life years (QALYs) gained and incremental cost per QALY of dabigatran compared with warfarin. Results Compared with warfarin, low dose and high dose dabigatran were associated with positive incremental net benefits of 0.094 (95% central range −0.083 to 0.267) and 0.146 (−0.029 to 0.322) QALYs. Positive incremental net benefits resulted for high dose dabigatran in 94% of simulations versus warfarin and in 76% of those versus low dose dabigatran. In the economic analysis, high dose dabigatran dominated the low dose, had an incremental cost effectiveness ratio of £23 082 (€26 700;

Clinical expression of leflunomide-induced pneumonitis

35 800) per QALY gained versus warfarin, and was more cost effective in patients with a baseline CHADS2 score of 3 or above. However, at centres that achieved good control of international normalised ratio, such as those in the UK, dabigatran 150 mg was not cost effective, at £42 386 per QALY gained. Conclusions This analysis supports regulatory decisions that dabigatran offers a positive benefit to harm ratio when compared with warfarin. However, no subgroup for which dabigatran 110 mg offered any clinical or economic advantage over 150 mg was identified. High dose dabigatran will be cost effective only forpatients at increased risk of stroke or for whom international normalised ratio is likely to be less well controlled.

Hyperglycaemia as a predictor of outcome during non-invasive ventilation in decompensated COPD

OBJECTIVES To review all the current evidence of LEF-induced pneumonitis (LEIP) which will help rheumatologists recognize suspected cases of LEIP and to influence clinical guidelines. METHODS Thirty-two reported cases of LEIP (13 males and 19 females) were identified from a literature search and classified using Searles and McKendrys classification criteria. Their clinical characteristics were reviewed. RESULTS All patients had a history of either exposure to MTX or interstitial lung disease (ILD) or both and all patients had RA. Most patients (82%) had LEIP within the first 20 weeks of initiation of LEF. All patients who had a loading dose LEF and most patients with ILD developed LEIP early (within 12 weeks of exposure). Case mortality was 19%. Two patients had previous MTX-induced pneumonitis (MTX-P) prior to initiation of LEF; both died from LEIP. There was a high mortality in the following groups of patients: diffuse alveolar damage (DAD) on histological examination, pre-existing ILD and ground glass shadowing on high resolution computerised tomography (HRCT). Treatment with cholestyramine did not appear to alter clinical outcome. CONCLUSIONS LEIP usually occurs within the first 20 weeks of initiation of LEF. Clinical features of patients who died were pre-existing ILD, ground glass shadowing on HRCT and DAD on histological examination, and these could be poor prognostic indicators. Patients need to be made aware of this rare complication. LEF should not be used in patients with previous MTX-P and should be used with caution in patients with ILD.

The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors

Rationale: Hyperglycaemia predicts a poor outcome in Intensive Care Unit (ICU) patients. Whether this is true for respiratory failure necessitating non-invasive ventilation (NIV) is not known. Objectives: To determine whether hyperglycaemia within 24 h of admission independently predicts outcome of NIV during acute decompensated ventilatory failure complicating chronic obstructive pulmonary disease (COPD) exacerbations. Methods: Patients with COPD presenting with acute hypercapnic respiratory failure at University Hospital Aintree between June 2006 and September 2007 and receiving NIV within 24 h of admission were studied prospectively. Random blood glucose levels were measured before NIV administration. Results: 88 patients (mean baseline pH 7.25, PaCO2 10.20 kPa, and PaO2 8.19 kPa) met the inclusion criteria, with NIV normalising arterial pH off therapy in 79 (90%). After multivariate logistic regression, the following predicted outcome: baseline respiratory rate (OR 0.91; 95% CI 0.84 to 0.99), random glucose ⩾7 mmol/l (OR 0.07; 95% CI 0.007 to 0.63) and admission APACHE II (Acute Physiology and Chronic Health Evaluation II) score (OR 0.75; 95% CI 0.62 to 0.90). The combination of baseline respiratory rate (RR) <30 breaths/min and random glucose <7 mmol/l increased prediction of NIV success to 97%, whilst use of all three factors was 100% predictive. Conclusions: In acute decompensated ventilatory failure complicating COPD, hyperglycaemia upon presentation was associated with a poor outcome. Baseline RR and hyperglycaemia are as good at predicting clinical outcomes as the APACHE II score. Combining these variables increases predictive accuracy, providing a simple method of early risk stratification.

Circulating Histones Are Major Mediators of Cardiac Injury in Patients With Sepsis.

BACKGROUND Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet. AIMS To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy. METHODS Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability. RESULTS Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2). CONCLUSIONS Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms.

Adverse antiepileptic drug effects in new-onset seizures A case-control study

Objective:To investigate the impact of circulating histones on cardiac injury and dysfunction in a murine model and patients with sepsis. Design:Prospective, observational clinical study with in vivo and ex vivo translational laboratory investigations. Setting:General ICU and university research laboratory. Subjects:Sixty-five septic patients and 27 healthy volunteers. Twelve-week-old male C57BL/6N mice. Interventions:Serial blood samples from 65 patients with sepsis were analyzed, and left ventricular function was assessed by echocardiography. Patients’ sera were incubated with cultured cardiomyocytes in the presence or absence of antihistone antibody, and cellular viability was assessed. Murine sepsis was initiated by intraperitoneal Escherichia coli injection (108 colony-forming unit/mouse) in 12-week-old male C57BL/6N mice, and the effect of antihistone antibody (10 mg/kg) was studied. Murine blood samples were collected serially, and left ventricular function was assessed by intraventricular catheters and electrocardiography. Measurements and Main Results:Circulating histones and cardiac troponins in human and murine plasma were quantified. In 65 patients with sepsis, circulating histones were significantly elevated compared with healthy controls (n = 27) and linearly correlated with cardiac troponin T levels (rs = 0.650; p < 0.001), noradrenaline doses required to achieve hemodynamic stability (rs = 0.608; p < 0.001), Sequential Organ Failure Assessment scores (p = 0.028), and mortality (p = 0.008). In a subset of 36 septic patients without prior cardiac disease, high histone levels were significantly associated with new-onset left ventricular dysfunction (p = 0.001) and arrhythmias (p = 0.01). Left ventricular dysfunction only predicted adverse outcomes when combined with elevated histones or cardiac troponin levels. Furthermore, patients’ sera directly induced histone-specific cardiomyocyte death ex vivo, which was abrogated by antihistone antibodies. In vivo studies on septic mice confirmed the cause-effect relationship between circulating histones and the development of cardiac injury, arrhythmias, and left ventricular dysfunction. Conclusion:Circulating histones are novel and important mediators of septic cardiomyopathy, which can potentially be utilized for prognostic and therapeutic purposes.

Household Tobacco Smoke and Admission Weight Predict Severe Bronchiolitis in Infants Independent of Deprivation: Prospective Cohort Study

Objective: Adverse effects (AEs) are a major concern when starting antiepileptic drug (AED) treatment. This study quantified the extent to which AE reporting in people with new-onset seizures started on AEDs is attributable to the medication per se, and investigated variables contributing to AE reporting. Methods: We pooled data from 2 large prospective studies, the Multicenter Study of Early Epilepsy and Single Seizures and the Northern Manhattan Study of incident unprovoked seizures, and compared adverse event profile (AEP) total and factor scores between adult cases prescribed AEDs for new-onset seizures and untreated controls, adjusting for several demographic and clinical variables. Differences in AEP scores were also tested across different AED monotherapies and controls, and between cases and controls grouped by number of seizures. Results: A total of 212 cases and 206 controls were identified. Most cases (94.2%) were taking low AED doses. AEP scores did not differ significantly between the 2 groups. Depression, female gender, symptomatic etiology, younger seizure onset age, ≥2 seizures, and history of febrile seizures were associated with higher AEP scores. There were no significant differences in AEP scores across different monotherapies and controls. AEP scores increased in both cases and controls with increasing number of seizures, the increment being more pronounced in cases. Conclusions: When AED treatment is started at low doses following new-onset seizures, AE reporting does not differ from untreated individuals. Targeting specific factors affecting AE reporting could lead to improved tolerability of epilepsy treatment.

Does the position of restraint of disturbed psychiatric patients have any association with staff and patient injuries

Objectives To examine demographic, environmental and clinical factors associated with severe bronchiolitis in infants admitted to hospital and quantify the independent effects of these factors. Design Prospective cohort study. Setting Alder Hey Childrens Hospital, Liverpool, United Kingdom. Participants 378 infants admitted to hospital with a diagnosis of bronchiolitis, of whom 299 (79%) were antigen positive to respiratory syncytial virus (RSV). Outcome Severity of disease during admission, defined as “no need for supplemental oxygen” (reference group), “any need for supplemental oxygen” and “any need for mechanical ventilation”. Results Univariate analysis found male sex (p = 0.035) and tobacco smoking by a household member (p<0.001) were associated with need for both supplemental oxygen and mechanical ventilation. Premature birth, low gestation, low birth weight, low admission weight and low corrected age on admission were also associated with need for mechanical ventilation (all p≤0.002). Deprivation scores (IMD 2004) were significantly higher in households where a member smoked compared to non-smoking households (p<0.001). The odds of smoking predicted by deprivation were 7 times higher (95%CI (3.59, 14.03)), when comparing the least and most deprived quintiles of the study population. Family history of atopic disease and deprivation score were not associated with severe disease. Multivariate multinomial logistic regression which initially included all covariates, found household tobacco smoking (adjusted OR = 2.45, 95%CI (1.60, 3.74) predicted need for oxygen supplementation. Household tobacco smoking (adjusted OR = 5.49, (2.78, 10.83)) and weight (kg) on admission (adjusted OR = 0.51, (0.40, 0.65)) were both significant predictors in the final model for mechanical ventilation. The same associations and similar size of effects were found when only children with proven RSV infection were included in analysis. Conclusions Low admission weight and householder tobacco smoking increased the risk of severe bronchiolitis in infants admitted to hospital. These effects were independent of a standard deprivation measure. NIHR Study Ref. DHCS/G121/10.

Cost-effectiveness of pharmacogenetics-guided warfarin therapy vs. alternative anticoagulation in atrial fibrillation.

The aim of this study was to examine the risk of injury among patients and staff following involvement in a restraint episode in relation to restraint position (standing, supine or prone) and other aspects of the pre-incident behaviour including perceived causation. Mixed effects logistic regression was used to estimate the relative odds of injury to staff or patient in a series of 680 restraint episodes involving 260 patients in an adult mental health service in England between 1999 and 2001. There was no statistically significant association between patient injury and restraint position in this sample, but a prone restraint position was weakly associated with staff injury. Staff injury was most likely when an actual assault had occurred prior to the incident. Patient injury was more likely when the patient had self-harmed, had been abusing substances and had used a weapon prior to the incident, and less likely when the patient was showing signs of frustration with their environment. The use of prone restraint may be weakly associated with an increased risk of injury to staff. However, other aspects of the incident are stronger predictors and should be considered when planning training for front line staff.