Efficient discovery of anti-inflammatory small-molecule combinations using evolutionary computing

The control of biochemical fluxes is distributed, and to perturb complex intracellular networks effectively it is often necessary to modulate several steps simultaneously. However, the number of possible permutations leads to a combinatorial explosion in the number of experiments that would have to be performed in a complete analysis. We used a multiobjective evolutionary algorithm to optimize reagent combinations from a dynamic chemical library of 33 compounds with established or predicted targets in the regulatory network controlling IL-1β expression. The evolutionary algorithm converged on excellent solutions within 11 generations, during which we studied just 550 combinations out of the potential search space of ~9 billion. The top five reagents with the greatest contribution to combinatorial effects throughout the evolutionary algorithm were then optimized pairwise. A p38 MAPK inhibitor together with either an inhibitor of IκB kinase or a chelator of poorly liganded iron yielded synergistic inhibition of macrophage IL-1β expression. Evolutionary searches provide a powerful and general approach to the discovery of new combinations of pharmacological agents with therapeutic indices potentially greater than those of single drugs

Comorbidity and health-related quality of life in patients with severe chronic obstructive pulmonary disease attending Swedish secondary care units

Josefin Sundh,1 Gunnar Johansson,2 Kjell Larsson,3 Anders Lindén,3 Claes-Göran Löfdahl,4 Christer Janson,5 Thomas Sandström6 1Department of Respiratory Medicine, Örebro University, Örebro, Sweden; 2Department of Public Health and Caring Science, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 3Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 4Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 5Department of Medical Sciences: Respiratory Medicine and Allergology, Uppsala University, Uppsala, Sweden; 6Department of Public Health and Clinical Medicine, Division of Medicine/Respiratory Medicine, Umeå University, Umeå, Sweden Introduction: Our understanding of how comorbid diseases influence health-related quality of life (HRQL) in patients with chronic obstructive pulmonary disease (COPD) is limited and in need of improvement. The aim of this study was to examine the associations between comorbidities and HRQL as measured by the instruments EuroQol-5 dimension (EQ-5D) and the COPD Assessment Test (CAT). Methods: Information on patient characteristics, chronic bronchitis, cardiovascular disease, diabetes, renal impairment, musculoskeletal symptoms, osteoporosis, depression, and EQ-5D and CAT questionnaire results was collected from 373 patients with Forced Expiratory Volume in one second (FEV1) <50% of predicted value from 27 secondary care respiratory units in Sweden. Correlation analyses and multiple linear regression models were performed using EQ-5D index, EQ-5D visual analog scale (VAS), and CAT scores as response variables. Results: Having more comorbid conditions was associated with a worse HRQL as assessed by all instruments. Chronic bronchitis was significantly associated with a worse HRQL as assessed by EQ-5D index (adjusted regression coefficient [95% confidence interval] –0.07 [–0.13 to –0.02]), EQ-5D VAS (–5.17 [–9.42 to –0.92]), and CAT (3.78 [2.35 to 5.20]). Musculoskeletal symptoms were significantly associated with worse EQ-5D index (–0.08 [–0.14 to –0.02]), osteoporosis with worse EQ-5D VAS (–4.65 [–9.27 to –0.03]), and depression with worse EQ-5D index (–0.10 [–0.17 to –0.04]). In stratification analyses, the associations of musculoskeletal symptoms, osteoporosis, and depression with HRQL were limited to female patients. Conclusion: The instruments EQ-5D and CAT complement each other and emerge as useful for assessing HRQL in patients with COPD. Chronic bronchitis, musculoskeletal symptoms, osteoporosis, and depression were associated with worse HRQL. We conclude that comorbid conditions, in particular chronic bronchitis, depression, osteoporosis, and musculoskeletal symptoms, should be taken into account in the clinical management of patients with severe COPD. Keywords: chronic bronchitis, EQ-5D, CAT, osteoporosis, depression, musculoskeletal symptom

The phenotype of concurrent chronic bronchitis and frequent exacerbations in patients with severe COPD attending Swedish secondary care units

Josefin Sundh,1 Gunnar Johansson,2 Kjell Larsson,3 Anders Lindén,3 Claes-Göran Löfdahl,4 Thomas Sandström,5 Christer Janson6 1Department of Respiratory Medicine, Örebro University, Örebro, Sweden; 2Department of Public Health and Caring Science, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 3Unit for Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 4Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 5Department of Public Health and Clinical Medicine, Division of Medicine/Respiratory Medicine, Umeå University, Umeå, Sweden; 6Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden Background: Chronic bronchitis and previous exacerbations are both well-known risk factors for new exacerbations, impaired health-related quality of life, and increased mortality in COPD. The aim of the study was to characterize the phenotype of concurrent chronic bronchitis and frequent exacerbation in severe COPD. Methods: Information on patient characteristics, comorbidity, and exacerbations from the previous year (total number and number requiring hospitalization) was collected from 373 patients with stage III and IV COPD attending 27 secondary care respiratory units in Sweden. Logistic regression used chronic bronchitis and frequent exacerbations (≥2 exacerbations or ≥1 hospitalized exacerbations in the previous year) as response variables. Stratification and interaction analyses examined effect modification by sex. Results: Chronic bronchitis was associated with current smoking (adjusted odds ratio [OR] [95% CI], 2.75 [1.54–4.91]; P=0.001), frequent exacerbations (OR [95% CI], 1.93 [1.24–3.01]; P=0.004), and musculoskeletal symptoms (OR [95% CI], 1.74 [1.05–2.86]; P=0.031), while frequent exacerbations were associated with lung function (forced expiratory volume in 1 second as a percentage of predicted value [FEV1% pred]) (OR [95% CI] 0.96 [0.94–0.98]; P=0.001) and chronic bronchitis (OR [95% CI] 1.73 [1.11–2.68]; P=0.015). The phenotype with both chronic bronchitis and frequent exacerbations was associated with FEV1% pred (OR [95% CI] 0.95 [0.92–0.98]; P=0.002) and musculoskeletal symptoms (OR [95% CI] 2.55 [1.31–4.99]; P=0.006). The association of smoking with the phenotype of chronic bronchitis and exacerbations was stronger in women than in men (interaction, P=0.040). Conclusion: Musculoskeletal symptoms and low lung function are associated with the phenotype of combined chronic bronchitis and frequent exacerbations in severe COPD. In women, current smoking is of specific importance for this phenotype. This should be considered in clinical COPD care. Keywords: lung function, smoking, chronic obstructive lung disease, musculoskeletal symptom