Pharmacokinetics of Rifabutin in Japanese HIV-Infected Patients with or without Antiretroviral Therapy

Objective

Based on drug-drug interaction, dose reduction of rifabutin is recommended when co-administered with HIV protease inhibitors for human immunodeficiency virus (HIV)-associated mycobacterial infection. The aim of this study was to compare the pharmacokinetics of rifabutin administered at 300 mg/day alone to that at 150 mg every other day combined with lopinavir-ritonavir in Japanese patients with HIV/mycobacterium co-infection.

Methods

Plasma concentrations of rifabutin and its biologically active metabolite, 25-O-desacetyl rifabutin were measured in 16 cases with HIV-mycobacterial coinfection. Nine were treated with 300 mg/day rifabutin and 7 with 150 mg rifabutin every other day combined with lopinavir-ritonavir antiretroviral therapy (ART). Samples were collected at a median of 15 days (range, 5–63) of rifabutin use.

Results

The mean C_max and AUC_0–24 of rifabutin in patients on rifabutin 150 mg every other day were 36% and 26% lower than on 300 mg/day rifabutin, while the mean C_max and AUC_0–24 of 25–O-desacetyl rifabutin were 186% and 152% higher, respectively. The plasma concentrations of rifabutin plus its metabolite were similar between the groups within the first 24 hours, but it remained low during subsequent 24 to 48 hours under rifabutin 150 mg alternate day dosing.

Conclusion

Rifabutin dose of 150 mg every other day combined with lopinavir-ritonavir seems to be associated with lower exposure to rifabutin and its metabolite compared with rifabutin 300 mg/day alone in Japanese patients. Further studies are needed to establish the optimal rifabutin dose during ART. The results highlight the importance of monitoring rifabutin plasma concentration during ART.

Trial registration

UMIN-CTR (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=search&action=input&language=E) UMIN000001102     

Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Systematic Review of Cost-Effectiveness Models

Objective

To conduct a systematic review of economic models of newer anticoagulants for stroke prevention in atrial fibrillation (SPAF).

Patients and Methods

We searched Medline, Embase, NHSEED and HTA databases and the Tuft’s Registry from January 1, 2008 through October 10, 2012 to identify economic (Markov or discrete event simulation) models of newer agents for SPAF.

Results

Eighteen models were identified. Each was based on a lone randomized trial/new agent, and these trials were clinically and methodologically heterogeneous. Dabigatran 150 mg, 110 mg and sequentially-dosed were assessed in 9, 8, and 9 models, rivaroxaban in 4 and apixaban in 4. Warfarin was a first-line comparator in 94% of models. Models were conducted from United States (44%), European (39%) and Canadian (17%) perspectives. Models typically assumed patients between 65–73 years old at moderate-risk of stroke initiated anticoagulation for/near a lifetime. All models reported cost/quality-adjusted life-year, 22% reported using a societal perspective, but none included indirect costs. Four models reported an incremental cost-effectiveness ratio (ICER) for a newer anticoagulant (dabigatran 110 mg (n = 4)/150 mg (n = 2); rivaroxaban (n = 1)) vs. warfarin above commonly reported willingness-to-pay thresholds. ICERs vs. warfarin ranged from $3,547–$86,000 for dabigatran 150 mg, $20,713–$150,000 for dabigatran 110 mg, $4,084–$21,466 for sequentially-dosed dabigatran and $23,065–$57,470 for rivaroxaban. Apixaban was found economically-dominant to aspirin, and dominant or cost-effective ($11,400–$25,059) vs. warfarin. Indirect comparisons from 3 models suggested conflicting comparative cost-effectiveness results.

Conclusions

Cost-effectiveness models frequently found newer anticoagulants cost-effective, but the lack of head-to-head trials and the heterogeneous characteristics of underlying trials and modeling methods make it difficult to determine the most cost-effective agent.     

Socioeconomic Inequalities in Non-Communicable Diseases Prevalence in India: Disparities between Self-Reported Diagnoses and Standardized Measures

Background

Whether non-communicable diseases (NCDs) are diseases of poverty or affluence in low-and-middle income countries has been vigorously debated. Most analyses of NCDs have used self-reported data, which is biased by differential access to healthcare services between groups of different socioeconomic status (SES). We sought to compare self-reported diagnoses versus standardised measures of NCD prevalence across SES groups in India.

Methods

We calculated age-adjusted prevalence rates of common NCDs from the Study on Global Ageing and Adult Health, a nationally representative cross-sectional survey. We compared self-reported diagnoses to standardized measures of disease for five NCDs. We calculated wealth-related and education-related disparities in NCD prevalence by calculating concentration index (C), which ranges from −1 to +1 (concentration of disease among lower and higher SES groups, respectively).

Findings

NCD prevalence was higher (range 5.2 to 19.1%) for standardised measures than self-reported diagnoses (range 3.1 to 9.4%). Several NCDs were particularly concentrated among higher SES groups according to self-reported diagnoses (C_srd) but were concentrated either among lower SES groups or showed no strong socioeconomic gradient using standardized measures (C_sm): age-standardised wealth-related C: angina C_srd 0.02 vs. C_sm −0.17; asthma and lung diseases C_srd −0.05 vs. C_sm −0.04 (age-standardised education-related C_srd 0.04 vs. C_sm −0.05); vision problems C_srd 0.07 vs. C_sm −0.05; depression C_srd 0.07 vs. C_sm −0.13. Indicating similar trends of standardized measures detecting more cases among low SES, concentration of hypertension declined among higher SES (C_srd 0.19 vs. C_sm 0.03).

Conclusions

The socio-economic patterning of NCD prevalence differs markedly when assessed by standardized criteria versus self-reported diagnoses. NCDs in India are not necessarily diseases of affluence but also of poverty, indicating likely under-diagnosis and under-reporting of diseases among the poor. Standardized measures should be used, wherever feasible, to estimate the true prevalence of NCDs.     

Kinetics of IL-7 and IL-15 Levels after Allogeneic Peripheral Blood Stem Cell Transplantation following Nonmyeloablative Conditioning

Background

We analysed kinetics of IL-7 and IL-15 levels in 70 patients given peripheral blood stem cells after nonmyeloablative conditioning.

Methods

EDTA-anticoagulated plasma and serum samples were obtained before conditioning and about once per week after transplantation until day 100. Samples were aliquoted and stored at −80°C within 3 hours after collection until measurement of cytokines. IL-7 and IL-15 levels were measured by ELISAs.

Results

Median IL-7 plasma levels remained below 6 pg/L throughout the first 100 days, although IL-7 plasma levels were significantly higher on days 7 (5.1 pg/mL, P = 0.002), 14 (5.2 pg/mL, P<0.001), and 28 (5.1 pg/mL, P = 0.03) (but not thereafter) than before transplantation (median value of 3.8 pg/mL). Median IL-15 serum levels were significantly higher on days 7 (12.5 pg/mL, P<0.001), 14 (10.5 pg/mL, P<0.001), and 28 (6.2 pg/mL, P<0.001) than before transplantation (median value of 2.4 pg/mL). Importantly, IL-7 and IL-15 levels on days 7 or 14 after transplantation did not predict grade II–IV acute GVHD.

Conclusions

These data suggest that IL-7 and IL-15 levels remain relatively low after nonmyeloablative transplantation, and that IL-7 and IL-15 levels early after nonmyeloablative transplantation do not predict for acute GVHD.     

Development and Validation of Intracranial Thrombus Segmentation on CT Angiography in Patients with Acute Ischemic Stroke

Background and Purpose

Thrombus characterization is increasingly considered important in predicting treatment success for patients with acute ischemic stroke. The lack of intensity contrast between thrombus and surrounding tissue in CT images makes manual delineation a difficult and time consuming task. Our aim was to develop an automated method for thrombus measurement on CT angiography and validate it against manual delineation.

Materials and Methods

Automated thrombus segmentation was achieved using image intensity and a vascular shape prior derived from the segmentation of the contralateral artery. In 53 patients with acute ischemic stroke due to proximal intracranial arterial occlusion, automated length and volume measurements were performed. Accuracy was assessed by comparison with inter-observer variation of manual delineations using intraclass correlation coefficients and Bland–Altman analyses.

Results

The automated method successfully segmented the thrombus for all 53 patients. The intraclass correlation of automated and manual length and volume measurements were 0.89 and 0.84. Bland-Altman analyses yielded a bias (limits of agreement) of −0.4 (−8.8, 7.7) mm and 8 (−126, 141) mm³ for length and volume, respectively. This was comparable to the best interobserver agreement, with an intraclass correlation coefficients of 0.90 and 0.85 and a bias (limits of agreement) of −0.1 (−11.2, 10.9) mm and −17 (−216, 185) mm³.

Conclusions

The method facilitates automated thrombus segmentation for accurate length and volume measurements, is relatively fast and requires minimal user input, while being insensitive to high hematocrit levels and vascular calcifications. Furthermore, it has the potential to assess thrombus characteristics of low-density thrombi.     

Population Pharmacodynamic Modeling and Simulation of the Respiratory Effect of Acetazolamide in Decompensated COPD Patients

Background

Chronic obstructive pulmonary disease (COPD) patients may develop metabolic alkalosis during weaning from mechanical ventilation. Acetazolamide is one of the treatments used to reverse metabolic alkalosis.

Methods

619 time-respiratory (minute ventilation, tidal volume and respiratory rate) and 207 time-PaCO₂ observations were obtained from 68 invasively ventilated COPD patients. We modeled respiratory responses to acetazolamide in mechanically ventilated COPD patients and then simulated the effect of increased amounts of the drug.

Results

The effect of acetazolamide on minute ventilation and PaCO₂ levels was analyzed using a nonlinear mixed effect model. The effect of different ventilatory modes was assessed on the model. Only slightly increased minute ventilation without decreased PaCO₂ levels were observed in response to 250 to 500 mg of acetazolamide administered twice daily. Simulations indicated that higher acetazolamide dosage (>1000 mg daily) was required to significantly increase minute ventilation (P<.001 vs pre-acetazolamide administration). Based on our model, 1000 mg per day of acetazolamide would increase minute ventilation by >0.75 L min⁻¹ in 60% of the population. The model also predicts that 45% of patients would have a decrease of PaCO2>5 mmHg with doses of 1000 mg per day.

Conclusions

Simulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide.     

Net Clinical Benefit of Oral Anticoagulants: A Multiple Criteria Decision Analysis

Background

This study quantitatively evaluated the comparative efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, and apizaban) and warfarin for treatment of nonvalvular atrial fibrillation. We also compared these agents under different scenarios, including population with high risk of stroke and for primary vs. secondary stroke prevention.

Methods

We used multiple criteria decision analysis (MCDA) to assess the benefit-risk of these medications. Our MCDA models contained criteria for benefits (prevention of ischemic stroke and systemic embolism) and risks (intracranial and extracranial bleeding). We calculated a performance score for each drug accounting for benefits and risks in comparison to treatment alternatives.

Results

Overall, new agents had higher performance scores than warfarin; in order of performance scores: dabigatran 150 mg (0.529), rivaroxaban (0.462), apixaban (0.426), and warfarin (0.191). For patients at a higher risk of stroke (CHADS₂ score≥3), apixaban had the highest performance score (0.686); performance scores for other drugs were 0.462 for dabigatran 150 mg, 0.392 for dabigatran 110 mg, 0.271 for rivaroxaban, and 0.116 for warfarin. Dabigatran 150 mg had the highest performance score for primary stroke prevention, while dabigatran 110 mg had the highest performance score for secondary prevention.

Conclusions

Our results suggest that new oral anticoagulants might be preferred over warfarin. Selecting appropriate medicines according to the patient’s condition based on information from an integrated benefit-risk assessment of treatment options is crucial to achieve optimal clinical outcomes.     

Adherence to International Follow-Up Guidelines in Type 2 Diabetes: A Longitudinal Cohort Study in Luxembourg

Introduction

Type 2 diabetes is associated with severe micro- and macro-vascular complications. Physicians’ and patients’ adherence to follow-up guidelines permits postponing or reducing these complications. The objectives were to assess the level of adherence to fundamental follow-up guidelines and determine patients’ characteristics associated with this level of adherence in the context of Luxembourg, where no guidelines were implemented.

Study population

The exhaustive residing population treated for type 2 diabetes in Luxembourg during the 2000-2006 period (N = 21,068).

Methods

Seven fundamental criteria were extracted from international guidelines (consultation with the treating physician, HbA1c tests, electrocardiogram, retinal, dental, lipid and renal check-ups). The factors associated with the level of adherence to those criteria were identified using a partial proportional odds model.

Results

In 2006, despite 90% of the patients consulted at least 4 times their treating physician, only 0.6% completed all criteria; 55.0% had no HbA1c test (−8.6 points since 2000) and 31.1% had a renal check-up (+21.6 points). The sex (OR_male: 0.87 [95%CI, 0.83−0.92]), the nationality (OR_NonEU: 0.64 [0.52−0.78]), the type of antidiabetic treatment (OR_oral: 1.48 [1.35−1.63], OR_mixed: 1.35 [1.20−1.52]) and the type of treating physician (OR_G-ID: 0.47 [0.42−0.53]) were the main factors associated with the level of adherence in 2006 (3 or more criteria).

Conclusion

A large percentage of patients were not provided with a systematic annual follow-up between 2000 and 2006. This study highlighted the necessity to promote guidelines in Luxembourg, education for physicians and to launch a national discussion on a disease management program for diabetic patients.     

SLC22A1-ABCB1 Haplotype Profiles Predict Imatinib Pharmacokinetics in Asian Patients with Chronic Myeloid Leukemia

Objective

This study aimed to explore the influence of SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5*3 genetic polymorphisms on imatinib mesylate (IM) pharmacokinetics in Asian patients with chronic myeloid leukemia (CML).

Patients and Methods

Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n = 70 each) and CML patients (n = 38) were enrolled in a prospective pharmacogenetics study. Imatinib trough (C_0h) and clearance (CL) were determined in the patients at steady state. Haplowalk method was applied to infer the haplotypes and generalized linear model (GLM) to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test.

Results

Global haplotype score statistics revealed a SLC22A1 sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T), to be significantly associated with IM clearance (p = 0.013). Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (*10⁻² L/hr/mg): CAC vs AGT: 4.03 vs 3.16, p = 0.017; CAC vs CGC: 4.03 vs 3.15, p = 0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C_0h than patients carrying 0 or 1 copy [CL (*10⁻² L/hr/mg): 2.19 vs 3.29, p = 0.026; C_0h (*10⁻⁶ 1/ml): 4.76 vs 3.17, p = 0.013, respectively]. Further subgroup analysis revealed SLC22A1 and ABCB1 haplotypic combinations to be significantly associated with clearance and C_0h (p = 0.002 and 0.009, respectively).

Conclusion

This exploratory study suggests that SLC22A1-ABCB1 haplotypes may influence IM pharmacokinetics in Asian CML patients.     

Effects of Anabolic Steroids on Chronic Obstructive Pulmonary Disease: A Meta-Analysis of Randomised Controlled Trials

Background

Anabolic steroids are known to improve body composition and muscle strength in healthy people. However, whether anabolic steroids improve the physical condition and function in patients with chronic obstructive pulmonary disease (COPD) remains undetermined. A meta-analysis was conducted to review the current evidence regarding the effects of anabolic steroids on COPD patients.

Methods

A comprehensive literature search of PubMed and EMBASE was performed to identify randomised controlled trials that examine the effects of anabolic steroids on COPD patients. Weighted mean differences (WMDs) with 95% confidence intervals were calculated to determine differences between anabolic steroid administration and control conditions.

Results

Eight eligible studies involving 273 COPD patients were identified in this meta-analysis. Significant improvements were found in body weight (0.956 kg), fat-free mass (1.606 kg), St. George''s Respiratory Questionnaire total score (−6.336) and symptom score (−12.148). The apparent improvements in maximal inspiratory pressure (2.740 cmH₂O) and maximal expiratory pressure (12.679 cmH₂O) were not significant. The effects on handgrip strength, forced expiratory volume in one second (FEV₁), predicted FEV₁ percent, PaO₂, PaCO₂ and six-min walk distance were negative, with WMDs of −0.245 kg, −0.096 L/sec, −1.996% of predicted, −1.648 cmHg, −0.039 cmHg and −16.102 meters, respectively.

Conclusions

Limited evidence available from the published literature suggests that the benefit of anabolic steroids on COPD patients cannot be denied. However, further studies are needed to identify the specific benefits and adverse effects of anabolic steroids on COPD patients and to determine the optimal populations and regimes of anabolic steroids in COPD patients.     

Mineral Metabolism Markers Are Associated with Myocardial Infarction and Hemorrhagic Stroke but Not Ischemic Stroke in Hemodialysis Patients: A Longitudinal Study

Background/Aims

The associations between phosphate, calcium, and intact parathyroid hormone (PTH) levels and composite cardiovascular end points have been studied. This study examined the associations of these markers with myocardial infarction (MI) and stroke separately.

Methods

This is a longitudinal study on 65,849 hemodialysis patients from the Japan Renal Data Registry. Patients with prior events at baseline were excluded. Predictors were phosphate, albumin-corrected calcium, intact PTH, and calcium times phosphate product levels. Outcome was the first episode of MI or stroke during a 1-year observation period. Data were analyzed using multiple logistic regression analyses, adjusted for potential confounders.

Results

There were 1,048, 651, and 2,089 events of incident MI, hemorrhagic, and ischemic stroke, respectively. Incident MI was associated with phosphate levels ≥6.5 mg/dL (odds ratio 1.49; confidence interval 1.23–1.80) compared with phosphate levels of 4.7–5.4 mg/dL and intact PTH levels>500 pg/mL (1.35; 1.03–1.79) compared with intact PTH levels of 151–300 pg/mL. Higher albumin-corrected calcium level was positively associated with MI (p = 0.04 by trend analysis). Hemorrhagic stroke was associated only with intact PTH levels>500 pg/mL (1.54; 1.10–2.17). Incident ischemic stroke had no association with phosphate, calcium, or intact PTH levels. The association of calcium times phosphate product with outcomes was essentially the same pattern as that of phosphate and outcomes.

Conclusions

MI was associated with phosphate, calcium, and intact PTH levels, whereas hemorrhagic stroke was associated only with intact PTH. Ischemic stroke was not associated with any of them. The potential distinct beneficial effect on MI and stroke by managing bone and mineral disease should be investigated in future studies.     

Effect of High- versus Low-Intensity Supervised Aerobic and Resistance Training on Modifiable Cardiovascular Risk Factors in Type 2 Diabetes; The Italian Diabetes and Exercise Study (IDES)

Background

While current recommendations on exercise type and volume have strong experimental bases, there is no clear evidence from large-sized studies indicating whether increasing training intensity provides additional benefits to subjects with type 2 diabetes.

Objective

To compare the effects of moderate-to-high intensity (HI) versus low-to-moderate intensity (LI) training of equal energy cost, i.e. exercise volume, on modifiable cardiovascular risk factors.

Design

Pre-specified sub-analysis of the Italian Diabetes and Exercise Study (IDES), a randomized multicenter prospective trial comparing a supervised exercise intervention with standard care for 12 months (2005–2006).

Setting

Twenty-two outpatient diabetes clinics across Italy.

Patients

Sedentary patients with type 2 diabetes assigned to twice-a-week supervised progressive aerobic and resistance training plus exercise counseling (n = 303).

Interventions

Subjects were randomized by center to LI (n = 142, 136 completed) or HI (n = 161, 152 completed) progressive aerobic and resistance training, i.e. at 55% or 70% of predicted maximal oxygen consumption and at 60% or 80% of predicted 1-Repetition Maximum, respectively, of equal volume.

Main Outcome Measure(s)

Hemoglobin (Hb) A_1c and other cardiovascular risk factors; 10-year coronary heart disease (CHD) risk scores.

Results

Volume of physical activity, both supervised and non-supervised, was similar in LI and HI participants. Compared with LI training, HI training produced only clinically marginal, though statistically significant, improvements in HbA_1c (mean difference −0.17% [95% confidence interval −0.44,0.10], P = 0.03), triglycerides (−0.12 mmol/l [−0.34,0.10], P = 0.02) and total cholesterol (−0.24 mmol/l [−0.46, −0.01], P = 0.04), but not in other risk factors and CHD risk scores. However, intensity was not an independent predictor of reduction of any of these parameters. Adverse event rate was similar in HI and LI subjects.

Conclusions

Data from the large IDES cohort indicate that, in low-fitness individuals such as sedentary subjects with type 2 diabetes, increasing exercise intensity is not harmful, but does not provide additional benefits on cardiovascular risk factors.

Trial Registration

www.ISRCTN.org ISRCTN-04252749.     

Dietary Restriction and Exercise for Diabetic Patients with Chronic Kidney Disease: A Systematic Review

Background

Obesity and sedentary lifestyle are major health problems and key features to develop cardiovascular disease. Data on the effects of lifestyle interventions in diabetics with chronic kidney disease (CKD) have been conflicting.

Study Design

Systematic review.

Population

Diabetes patients with CKD stage 3 to 5.

Search Strategy and Sources

Medline, Embase and Central were searched to identify papers.

Intervention

Effect of a negative energy balance on hard outcomes in diabetics with CKD.

Outcomes

Death, cardiovascular events, glycaemic control, kidney function, metabolic parameters and body composition.

Results

We retained 11 studies. There are insufficient data to evaluate the effect on mortality to promote negative energy balance. None of the studies reported a difference in incidence of Major Adverse Cardiovascular Events. Reduction of energy intake does not alter creatinine clearance but significantly reduces proteinuria (mean difference from −0.66 to −1.77 g/24 h). Interventions with combined exercise and diet resulted in a slower decline of eGFR (−9.2 vs. −20.7 mL/min over two year observation; p<0.001). Aerobic and resistance exercise reduced HbA1c (−0.51 (−0.87 to −0.14); p = 0.007 and −0.38 (−0.72 to −0.22); p = 0.038, respectively). Exercise interventions improve the overall functional status and quality of life in this subgroup. Aerobic exercise reduces BMI (−0.74% (−1.29 to −0.18); p = 0.009) and body weight (−2.2 kg (−3.9 to −0.6); p = 0.008). Resistance exercise reduces trunk fat mass (−0,7±0,1 vs. +0,8 kg ±0,1 kg; p = 0,001−0,005). In none of the studies did the intervention cause an increase in adverse events.

Limitations

All studies used a different intervention type and mixed patient groups.

Conclusions

There is insufficient evidence to evaluate the effect of negative energy balance interventions on mortality in diabetic patients with advanced CKD. Overall, these interventions have beneficial effects on glycaemic control, BMI and body composition, functional status and quality of life, and no harmful effects were observed.     

Efficacy,safety and tolerability of GSK2190915, a 5-lipoxygenase activating protein inhibitor,in adults and adolescents with persistent asthma: a randomised dose-ranging study

Background

GSK2190915 is a high affinity 5-lipoxygenase-activating protein inhibitor being developed for the treatment of asthma. The objective of this study was to evaluate GSK2190915 efficacy, dose–response and safety in subjects with persistent asthma treated with short-acting beta2-agonists (SABAs) only.

Methods

Eight-week multicentre, randomised, double-blind, double-dummy, stratified (by age and smoking status), parallel-group, placebo-controlled study in subjects aged ≥12 years with a forced expiratory volume in 1 second (FEV₁) of 50–85% predicted. Subjects (n = 700) were randomised to receive once-daily (QD) oral GSK2190915 (10–300 mg), twice-daily inhaled fluticasone propionate 100 μg, oral montelukast 10 mg QD or placebo. The primary endpoint was mean change from baseline (randomisation) in trough (morning pre-dose and pre-rescue bronchodilator) FEV₁ at the end of the 8-week treatment period. Secondary endpoints included morning and evening peak expiratory flow, symptom-free days and nights, rescue-free days and nights, day and night-time symptom scores, day and night-time rescue medication use, withdrawals due to lack of efficacy, Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores.

Results

For the primary endpoint, there was no statistically significant difference between any dose of GSK2190915 QD and placebo. However, repeated measures sensitivity analysis demonstrated nominal statistical significance for GSK2190915 30 mg QD compared with placebo (mean difference: 0.115 L [95% confidence interval: 0.00, 0.23], p = 0.044); no nominally statistically significant differences were observed with any of the other doses. For the secondary endpoints, decreases were observed in day-time symptom scores and day-time SABA use for GSK2190915 30 mg QD versus placebo (p ≤ 0.05). No dose–response relationship was observed for the primary and secondary endpoints across the GSK2190915 dose range studied; the 10 mg dose appeared to be sub-optimal. GSK2190915 was associated with a dose-dependent reduction in urinary leukotriene E₄. The profile and incidence of adverse events were similar between treatment groups.

Conclusion

Efficacy was demonstrated for GSK2190915 30 mg compared with placebo in day-time symptom scores and day-time SABA use. No additional improvement on efficacy endpoints was gained by administration of GSK2190915 doses greater than 30 mg. GSK2190915 was well-tolerated. These results may support further studies with GSK2190915 30 mg.

Trial registration

Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01147744","term_id":"NCT01147744"}}NCT01147744.     

Determinants of the Changes in Glycemic Control with Exercise Training in Type 2 Diabetes: A Randomized Trial

Aims

To assess the determinants of exercise training-induced improvements in glucose control (HbA_1C) including changes in serum total adiponectin and FFA concentrations, and skeletal muscle peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein content.

Methods

A sub-cohort (n = 35; 48% men; 74% Caucasian) from the HART-D study undertaking muscle biopsies before and after 9 months of aerobic (AT), resistance (RT), or combination training (ATRT).

Results

Changes in HbA_1C were associated with changes in adiponectin (r = −0.45, P = 0.007). Participants diagnosed with type 2 diabetes for a longer duration had the largest increase in PGC-1α (r = 0.44, P = 0.008). Statistical modeling examining changes in HbA_1C suggested that male sex (P = 0.05), non-Caucasian ethnicity (P = 0.02), duration of type 2 diabetes (r = 0.40; P<0.002) and changes in FFA (r = 0.36; P<0.004), adiponectin (r = −0.26; P<0.03), and PGC-1α (r = −0.28; P = 0.02) explain ∼65% of the variability in the changes in HbA_1C.

Conclusions

Decreases in HbA_1C after 9 months of exercise were associated with shorter duration of diabetes, lowering of serum FFA concentrations, increasing serum adiponectin concentrations and increasing skeletal muscle PGC-1α protein expression.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00458133","term_id":"NCT00458133"}}NCT00458133     

Smokers with CT Detected Emphysema and No Airway Obstruction Have Decreased Plasma Levels of EGF,IL-15, IL-8 and IL-1ra

Rationale

Low-grade inflammation and emphysema have been shown to be associated with an increased risk of lung cancer. However, the systemic inflammatory response in patients with emphysema is still unknown.

Objective

To compare the plasma cytokine profiles in two groups of current or former smokers without airway obstruction: a control group of individuals without computed tomography (CT) detected emphysema vs. a study group of individuals with CT detected emphysema.

Methods

Subjects underwent a chest CT, spirometry, and determination of EGF, IL-15, IL-1ra, IL-8, MCP-1, MIP-1β, TGFα, TNFα, and VEGF levels in plasma. Cytokine levels in each group were compared adjusting for confounding factors.

Results

160 current smokers and former smokers without airway obstruction participated in the study: 80 without emphysema and 80 subjects with emphysema. Adjusted group comparisons revealed significant reductions in EGF (−0.317, p = 0.01), IL-15 (−0.21, p = 0.01), IL-8 (−0.180, p = 0.02) and IL-1ra (−0.220, p = 0.03) in subjects with emphysema and normal spirometry.

Conclusions

Current or former smokers expressing a well-defined disease characteristic such as emphysema, has a specific plasma cytokine profile. This includes a decrease of cytokines mainly implicated in activation of apoptosis or decrease of immunosurveillance. This information should be taken into account when evaluated patients with tobacco respiratory diseases.     

Monitoring Low Molecular Weight Heparins at Therapeutic Levels: Dose-Responses of,and Correlations and Differences between aPTT,Anti-Factor Xa and Thrombin Generation Assays

Background

Low molecular weight heparins (LMWH’s) are used to prevent and treat thrombosis. Tests for monitoring LMWH’s include anti-factor Xa (anti-FXa), activated partial thromboplastin time (aPTT) and thrombin generation. Anti-FXa is the current gold standard despite LMWH’s varying affinities for FXa and thrombin.

Aim

To examine the effects of two different LMWH’s on the results of 4 different aPTT-tests, anti-FXa activity and thrombin generation and to assess the tests’ concordance.

Method

Enoxaparin and tinzaparin were added ex-vivo in concentrations of 0.0, 0.5, 1.0 and 1.5 anti-FXa international units (IU)/mL, to blood from 10 volunteers. aPTT was measured using two whole blood methods (Free oscillation rheometry (FOR) and Hemochron Jr (HCJ)) and an optical plasma method using two different reagents (ActinFSL and PTT-Automat). Anti-FXa activity was quantified using a chromogenic assay. Thrombin generation (Endogenous Thrombin Potential, ETP) was measured on a Ceveron Alpha instrument using the TGA RB and more tissue-factor rich TGA RC reagents.

Results

Methods’ mean aPTT at 1.0 IU/mL LMWH varied between 54s (SD 11) and 69s (SD 14) for enoxaparin and between 101s (SD 21) and 140s (SD 28) for tinzaparin. ActinFSL gave significantly shorter aPTT results. aPTT and anti-FXa generally correlated well. ETP as measured with the TGA RC reagent but not the TGA RB reagent showed an inverse exponential relationship to the concentration of LMWH. The HCJ-aPTT results had the weakest correlation to anti-FXa and thrombin generation (R_s0.62–0.87), whereas the other aPTT methods had similar correlation coefficients (R_s0.80–0.92).

Conclusions

aPTT displays a linear dose-respone to LMWH. There is variation between aPTT assays. Tinzaparin increases aPTT and decreases thrombin generation more than enoxaparin at any given level of anti-FXa activity, casting doubt on anti-FXa’s present gold standard status. Thrombin generation with tissue factor-rich activator is a promising method for monitoring LMWH’s.     

Effect of root length on epicotyl dormancy release in seeds of Paeonia ludlowii,Tibetan peony

Background and Aims

Epicotyl dormancy break in seeds that have deep simple epicotyl morphophysiological dormancy (MPD) requires radicle emergence and even a certain root length in some species. However, the mechanisms by which root length affects epicotyl dormancy break are not clear at present. This study aims to explore the relationship between root length and epicotyl dormancy release in radicle-emerged seeds of Tibetan peony, Paeonia ludlowii, with discussion of the possible mechanisms.

Methods

Radicle-emerged seeds (radicle length 1·5, 3·0, 4·5 and 6·0 cm) were incubated at 5, 10 and 15 °C. During the stratification, some seeds were transferred to 15 °C and monitored for epicotyl–plumule growth. Hormone content was determined by ELISA, and the role of hormones in epicotyl dormancy release was tested by exogenous hormone and embryo culture.

Key Results

Cold stratification did not break the epicotyl dormancy until the root length was ≥6 cm. The indole-3-actic acid (IAA) and GA₃ contents of seeds having 6 cm roots were significantly higher than those of seeds with other root lengths, but the abscisic acid (ABA) content was lowest among radicle-emerged seeds. GA₃ (400 mg L⁻¹) could break epicotyl dormancy of all radicle-emerged seeds, while IAA (200 mg L⁻¹) had little or no effect. When grown on MS medium, radicles of naked embryos grew and cotyledons turned green, but epicotyls did not elongate. Naked embryos developed into seedlings on a mixed medium of MS + 100 mg L⁻¹ GA₃.

Conclusions

A root length of ≥6·0 cm is necessary for epicotyl dormancy release by cold stratification. The underlying reason for root length affecting epicotyl dormancy release is a difference in the GA₃/ABA ratio in the epicotyl within radicle-emerged seeds, which is mainly as a result of a difference in ABA accumulation before cold stratification.     

Frequency and Risk Factors for Under- and Over-Treatment in Stroke Prevention for Patients with Non-Valvular Atrial Fibrillation in General Practice

Objective

To determine adequacy of antithrombotic treatment in patients with non-valvular atrial fibrillation. To determine risk factors for under- and over-treatment.

Design

Retrospective, cross-sectional study of electronic health records from 36 general practitioners in 2008.

Setting

General practice in the Netherlands.

Subjects

Primary care physicians (n = 36) and patients (n = 981) aged 65 years and over.

Main Outcome Measures

Rates of adequate, under and over-treatment, risk factors for under and over-treatment.

Results

Of the 981 included patients with a mean of age 78, 18% received no antithrombotic treatment (under-treatment), 13% received antiplatelet drugs and 69% received oral anticoagulation (OAC). Further, 43% of the included patients were treated adequately, 26% were under-treated, and 31% were over-treated. Patients with a previous ischaemic stroke were at high risk for under-treatment (OR 2.4, CI 1.6–3.5), whereas those with contraindications for OAC were at high risk for over-treatment (OR 37.0, CI 18.1–79.9). Age over 75 (OR 0.2, CI: 0.1–0.3]), diabetes (OR 0.1, CI: 0.1–0.3), heart failure (OR 0.2, CI: 0.1–0.3), hypertension (OR 0.1, CI: 0.1–0.2) and previous ischaemic stroke (OR 0.04, CI: 0.02–0.11) protected against over-treatment.

Conclusions

In general practice, CHADS₂-criteria are being used, but the antithrombotic treatment of patients with atrial fibrillation frequently deviates from guidelines on this topic. Patients with previous stroke are at high risk of not being prescribed OAC. Contraindications for OAC, however, seem to be frequently overlooked.     

Use of Liver Stiffness Measurement for Liver Resection Surgery: Correlation with Indocyanine Green Clearance Testing and Post-Operative Outcome

Background

Liver stiffness measurement (LSM) using transient elastography has recently become available for the assessment of liver fibrosis. Whether LSM can predict the functional liver reserve in patients undergoing liver resection is not certain.

Aim

To correlate liver stiffness measurement (LSM) with indocyanine green (ICG) clearance test and liver biochemistry, and to determine its usefulness in predicting postoperative outcomes in patients undergoing liver resection.

Patients and Methods

Transient elastography and ICG clearance test were performed pre-operatively in 44 patients with hepatocellular carcinoma. The LSM and ICG retention rate at 15 minutes (R15) were correlated with pre-operative factors and post-operative outcomes.

Results

There was significant correlation between ICG R15 and LSM. In patients with LSM ≥11 kPa vs <11 kPa, there was significantly higher ICG R15 (17.1% vs 10.0% respectively, p = 0.025). For patients with ICG R15≥10% compared to those <10%, there was significantly higher LSM (12.0 vs 7.6 kPa respectively, p = 0.015). Twenty-eight patients proceeded to resection. There was a significant correlation between LSM and the peak INR after liver resection (r = 0.426, p = 0.024). There was a significant correlation between ICG R15 and the post-operative peak AST level (r = −0.414, p = 0.029) and peak ALT level (r = −0.568, p = 0.002). The operative time was a significant independent factor associated with post-operative complications and peak INR.

Conclusion

LSM correlated well with ICG R15 in patients undergoing liver resection, and predicted early post-operative complications. Addition of LSM to ICG R15 testing may provide better prognostic information for patients undergoing resection.