Asthma and Therapeutics: Recombinant Therapies in Asthma

Numerous recombinant therapies are being investigated for the treatment of asthma. This report reviews the current status of several of these novel agents. Anti-immunoglobulin (Ig)E (omalizumab, Xolair) markedly inhibits all aspects of the allergen challenge in subjects who have reduction of free serum IgE to undetectable levels. Several clinical studies in atopic asthma have demonstrated benefit by improved symptoms and lung function and a reduction in corticosteroid requirements. Early use in atopic asthmatics may be even more effective. Several approaches target interleukin (IL)-4. Soluble IL-4 receptor has been shown to effectively replace inhaled corticosteroid; further studies are under way. Recombinant anti-IL-5 and recombinant IL-12 inhibit blood and sputum eosinophils and allergen-induced eosinophilia without any effect on airway responsiveness, allergen-induced airway responses, or allergen-induced airway hyperresponsiveness. Efalizumab, a recombinant antibody that inhibits lymphocyte trafficking, is effective in psoriasis. A bronchoprovocation study showed a reduction in allergen-induced late asthmatic response and allergen-induced eosinophilia, which suggests that it should be effective in clinical asthma. These exciting novel therapies provide not only promise of new therapies for asthma but also valuable tools for investigation of asthma mechanisms

Globular Cluster Systems in Giant Ellipticals: the Mass/Metallicity Relation

Hubble Space Telescope ACS/WFC data in (B,I) are used to investigate the globular cluster populations around 6 gE galaxies ~40 Mpc distant. The total comprises a sample of ~8000 high-probability globular clusters. PSF-convolved King-model profiles are used to measure their individual total magnitudes, colors, and effective radii. The classic bimodal form of the GC color-magnitude distribution shows up unambiguously in all the galaxies, allowing an accurate definition of the mean colors along each of the two sequences as a function of magnitude (the mass/metallicity relation or MMR). The blue, metal-poor cluster sequence shows a clearly defined but nonlinear MMR, changing smoothly from a near-vertical sequence at low luminosity to an increasingly redward slope at higher luminosity, while the red, metal-rich sequence is nearly vertical at all luminosities. All the observed features of the present data agree with the interpretation that the MMR is created primarily by GC self-enrichment, along the lines of the quantitative model of Bailin and Harris (2009): The "threshold" mass at which this effect should become noticeable is near 1 million Solar masses, which is closely consistent with the transition region that is seen in the data. Correlation of the median half-light radii of the GCs with other parameters shows that the metal-poor clusters are consistently 17% larger than those of the metal-rich clusters, at all galactocentric distances and luminosities. At the same time, cluster size scales with halo location as r_h ~ R_gc^0.11, indicating that both metallicity and the external tidal environment play roles in determining the scale size of a given cluster. Lastly, both the red and blue GC components show metallicity gradients with galactocentric distance, following Z ~ R_gc^-0.1.Comment: In press for Astrophysical Journal. Complete preprint with higher quality figures is available at http://physwww.mcmaster.ca/%7Eharris/Publications.htm

Role of Leukotriene Receptor Antagonists in the Treatment of Exercise-Induced Bronchoconstriction: A Review

Asthma is a very common disorder that still causes significant morbidity and mortality. A high percentage of individuals with asthma also experience exercise-induced bronchoconstriction (EIB). This article reviews the current literature and updates the reader on the safety, efficacy, and clinical applications of leukotriene modifiers in the treatment of EIB

The Role of Primary Care in Asthma Control and Severity: Asthma and Primary Care in Alberta

Background: Asthma is a common chronic inflammatory disease of the airways affecting 3 millionCanadians. Primary Care Providers (PCPs) are integral to care coordination, enhanced through thedevelopment of a strong patient-PCP relationship with Continuity of Care (COC). A recent CIHI studynoted that 40% of Albertans do not have a COC model for primary care.Objectives: We aim to evaluate how primary care for adults with asthma impacts different measures ofcontrol.Methods: Prospective population-based recruitment of adults through various community venuesacross Alberta. Those who had self-reported asthma and were willing to participate completed a surveywhich included demographics, comorbidities, medication use (including biologics, allergy medications,steroids), Asthma Control Questionnaire (ACQ-5), Asthma Control Test (ACT), Quality of Life (QoL)measured through the mini-Asthma Quality of Life Questionnaire (mini-AQLQ) and health care utilization(including Emergency Department (ED) visits, hospitalizations and ICU stays for asthma).Results: Of the 1685 individuals approached, 61 (3.6%) reported having asthma, of which 47 lived inAlberta. Most (41, 87%) had a PCP, with 30 (64%) visiting their PCP at least twice a year. Uncontrolledasthma was noted in 21 (45%) with either the ACQ-5 or ACT. The mini-AQLQ indicated 5 (11%) withreduced QoL. Mean lifetime hospitalizations, lifetime Emergency Department (ED) visits, and ICU staysrelated to asthma were 1.52, 4.55 and 0.25 respectively. Further, mean hospitalizations and ED visits inthe past 12 months related to asthma were 0.05 and 0.30 respectively.Conclusions: Asthma control was poor in 21 (45%) surveyed individuals, suggesting sub-optimal asthmamanagement in Alberta. Knowledge of Primary Care Networks (PCNs) was low, while ED and hospitalusage was high

Overreliance on Bronchodilators as a Risk Factor for Life-Threatening Asthma

OBJECTIVE: To assess the potential impact on the risk of life-threatening asthma of current recommendations in pharmacotherapy, which emphasize the early use of steroids and the avoidance of beta-agonist overuse

Normal Expiratory Flow Rate and Lung Volumes in Patients with Combined Emphysema and Interstitial Lung Disease: A Case Series and Literature Review

Pulmonary function tests in patients with idiopathic pulmonary fibrosis characteristically show a restrictive pattern including small lung volumes and increased expiratory flow rates resulting from a reduction in pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. When the diseases coexist, pulmonary volumes are compensated, and a smaller than expected reduction or even normal lung volumes can be found. The present report describes 10 patients with progressive breathlessness, three of whom experienced severe limitation in their quality of life. All patients showed lung interstitial involvement and emphysema on computed tomography scan of the chest. The 10 patients showed normal spirometry and lung volumes with severe compromise of gas exchange. Normal lung volumes do not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters

Effects of Asm-024, A Modulator of Acetylcholine Receptor Function, On Airway Responsiveness and Allergen-Induced Responses in Patients with Mild Asthma

OBJECTIVES: To evaluate the safety, tolerability and clinical activity of ASM-024, a new cholinergic compound with dual nicotinic and muscarinic activity, in mild allergic asthma

Pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism

To study the impact of the 79A > C polymorphism in the cytidine deaminase (CDA) gene on the pharmacokinetics of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) in non-small-cell lung cancer (NSCLC) patients. Patients (n = 20) received gemcitabine 1,125 mg/m(2) as a 30 min i.v. infusion as part of treatment for NSCLC. Plasma samples were collected during 0-6 h after gemcitabine administration. Gemcitabine and dFdU were quantified by high performance liquid chromatography with ultraviolet detection. The CDA 79A > C genotype was determined with PCR and DNA sequencing. Gemcitabine was rapidly cleared from plasma and undetectable after 3 h. The allele frequency of the 79A > C polymorphism was 0.40. Diplotypes were distributed as A/A n = 8, A/C n = 8 ,and C/C n = 4. No significant differences were found between the different CDA genotypes and gemcitabine or dFdU AUC, clearance, or half-life. The 79A > C polymorphism in the CDA gene does not have a major consistent and signficant impact on gemcitabine pharmacokinetics