Combined mediator blockade or topical steroid for treating the unified allergic airway

BACKGROUND: Asthma and allergic rhinitis are manifestations of a single unified allergic airway, for which the best treatment is uncertain. OBJECTIVE: To compare the anti-inflammatory efficacy in the unified allergic airway of combined oral mediator antagonism and combined topical steroid. METHODS: Subjects with asthma and perennial allergic rhinitis entered a randomized double blind crossover study comparing montelukast 10 mg and cetirizine 10 mg to extra-fine inhaled beclomethasone 400 mcg/day and intranasal beclomethasone 200 mcg/day, each taken once daily for 2 months, after 2-week placebo washouts. Measurements were made after each washout and randomized treatment, comprising: methacholine PC20, exhaled and nasal nitric oxide, blood eosinophils and eosinophilic cationic protein, symptoms, lung and nasal function tests. RESULTS: Seventeen patients completed per protocol. For PC20 and exhaled nitric oxide, only combined topical steroid produced improvements (P < 0.005) from placebo baseline. Combined steroid was superior by a 0.93 (95% CI 0.14-0.93, P < 0.05) doubling dilution difference for PC20 and a 0.99 (95% CI 0.9-15.1, P < 0.01) doubling difference for exhaled nitric oxide. Both treatments attenuated eosinophils and eosinophilic cationic protein, and reduced nasal symptoms (P < 0.05). Only steroid improved nasal nitric oxide (P=0.05) and asthma symptoms (P < 0.05). Neither treatment affected lung or nasal function tests. CONCLUSION: Combined topical steroid and combined mediator antagonism both attenuated systemic inflammation in the unified allergic airway, but only the former reduced bronchial and nasal inflammatory markers. The relevance of this to exacerbations and airway remodelling needs to be defined.     

Differential anti-inflammatory effects of large and small particle size inhaled corticosteroids in asthma

BACKGROUND: Extra-fine particle formulations of hydrofluoroalkane-134a beclometasone dipropionate (HFA-BDP) exhibit clinical effects comparable with conventional particle formulations of chlorofluorocarbon beclometasone dipropionate (CFC-BDP) at half the dose. There is little data comparing their effects on inflammation. We have evaluated the effects of HFA-BDP and CFC-BDP on pulmonary and systemic markers of asthmatic inflammation. METHODS: A double-blind randomized crossover trial was undertaken comparing the anti-inflammatory effects of HFA-BDP (100 and 400 microg/day) and CFC-BDP (200 and 800 microg/day). Treatment with montelukast was evaluated as add-on to the higher dose of BDP. RESULTS: Compared with baseline after withdrawal of usual asthma therapy, 100 microg of HFA-BDP significantly attenuated serum eosinophilic cationic protein levels (0.61-fold change, 95% CI 0.49-0.77; a 39% reduction, P < 0.001), but 200 microg of CFC-BDP did not (0.87-fold change, 95% CI 0.63-1.23; P = 1). A dose of 800 microg of CFC-BDP and 400 microg of HFA-BDP led to reductions in exhaled nitric oxide (0.57-fold change, 95% CI 0.44-0.73; a 43% reduction, P < 0.001 and 0.65-fold change, 95% CI 0.47-0.91; a 35% reduction, P = 0.008, respectively); and peripheral eosinophils (-74 cells/microl, 95% CI -146 to -2; P = 0.020 and -77 cells/microl, 95% CI -140 to -14; P = 0.012, respectively). Montelukast further reduced exhaled nitric oxide (0.81-fold change, 95% CI 0.66-0.98; P = 0.028) with 400 microg HFA-BDP and eosinophils (-44 cells/microl, 95% CI -80 to -8; P = 0.012) with 800 microg CFC-BDP, but not vice versa. CONCLUSION: Chlorofluorocarbon beclometasone dipropionate and HFA-BDP have differential effects on pulmonary and systemic inflammation, which dictate the additive effects of montelukast.     

Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection

Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography–tandem mass spectrometry. Plasma and PBMC levels of the active drugs (LPV, TFV, and 3TC) were sustained for 5 weeks; PBMC exposures to LPV, ritonavir, and 3TC were 12-, 16-, 42-fold higher than those in plasma. Apparent T_1/2z of LPV, TFV, and 3TC were 219.1, 63.1, and 136.3 h in plasma; 1045.7, 105.9, and 127.7 h in PBMCs. At day 8, LPV, TFV, and 3TC levels in LNMCs were 4.1-, 5.0-, and 1.9-fold higher than in those in PBMCs and much higher than in plasma. Therefore, 1 dose of a 4-drug nanosuspension exhibited persistent drug levels in LNMCs, PBMCs, and plasma for 5 weeks. With interspecies scaling and dose adjustment, this 4-in-1 HIV drug-combination could be a long-acting treatment with the potential to target residual virus in tissues and improve patient adherence.     

A Census of Midsize to Large Supermarkets in Toronto: A Cross-Sectional Analysis of the Consumer Nutrition Environment

Objective

Assess the consumer nutrition environment in midsize to large supermarkets by supermarket type and area-level socioeconomic variables.

Left subclavian artery stenting: an option for the treatment of the coronary-subclavian steal syndrome

Introduction

The subclavian steal syndrome is characterized by the vertebral artery flow inversion, due to a stenotic lesion in the origin of the subclavian artery. The Coronary-subclavian Steal Syndrome is a variation of the Subclavian Steal Syndrome and is characterized by inversion of flow in the Internal Thracic artery that has been used as conduct in a myocardial revascularization. Its diagnosis must be suspected in patients with difference in pulse and arterial pressure in the upper limbs, that present with angina pectoris and that have done a myocardial revascularization. Its treatment must be a surgical bypass or a transluminal angioplasty.

Objective

The objective is to show the left subclavian artery stenting as a safe and effective method to treat the coronary-subclavian steal syndrome.

Methods

Historical prospective, non-randomized trial, through revision of the hospital records of the patients treated with the stenting of the left subclavian artery, from January 2006 to September 2012.

Results

In the mentioned period, 4.291 miocardial revascularizations were performed with the use of the left mammary artery, and 16 patients were identified to have the Coronary-subclavian steal syndrome. All of them were submitted to endovascular treatment. The success rate was 100%; two patients experienced minor complications; none of them presented with major complications. Eleven of the 16 patients had ultrassonographic documentation of patent stent for at least one year; two patients lost follow up and other two died.

Conclusion

The stenting of the left subclavian artery is a good option for the treatment of the Coronary-subclavian Steal Syndrome, with high level of technical and clinical success.     

Emerging role of long acting muscarinic antagonists for asthma

Acetlycholine is involved in the control of airway smooth muscle constriction and in recruitment of inflammatory cells via neuronal and paracrine effects on muscarinic type 3 receptors. Long acting muscarinic antagonists (LAMA) are well established in guidelines for COPD but are not currently licensed for use in asthma. There are emerging data from key clinical trials to show that LAMA may confer bronchodilator effects and improved control when used in addition to inhaled corticosteroid (ICS) alone or in conjunction with long acting β-adrenoceptor agonists (LABA). Further studies in persistent asthmatic patients are required to evaluate ICS sparing effects of LAMA looking particularly at airway hyper-responsiveness and surrogate inflammatory markers, in addition to evaluation of possible synergy between LAMA and LABA when given together. Future possible development of combination inhalers comprising ICS/LAMA or ICS/LAMA/LABA will require long term studies looking at asthma control and exacerbations in both adult and paediatric patients.     

(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors

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Transcription in yeast: separation and properties of multiple FNA polymerases

Four peaks of DNA-directed RNA polymerase activity are resolved by salt gradient elution of a sonicated yeast cell extract on DEAE-Sephadex. The enzymes, which are named IA, IB, II, and III in order of elution, all appear to come from cell nuclei. Only enzyme II is sensitive to alpha-amanitin. All enzymes are more active with Mn(++) than with Mg(++) as divalent ion. Enzymes IB and II have salt optima in the range 0.05-0.10 M (NH(4))(2)SO(4), whereas enzyme III is maximally active at 0.20-0.25 M (NH(4))(2)SO(4). With optimal salt concentration and saturating DNA, the template preference ratio, activity on native calfthymus DNA divided by activity on denatured calf-thymus DNA, is 2.2 for IB, 0.4 for II, and 3.5 for III. None of the yeast polymerases was inhibited by rifamycin SV. Rifamycin AF/013 effectively inhibited polymerases IB, II, and III.