Chronic obstructive pulmonary disease (COPD) represents one of the major causes of mortality and morbidity worldwide. The pathogenesis of COPD is complex and multi-factorial, and is mediated by both pulmonary and systemic factors.
Patients with COPD suffer frequent exacerbations that require medical intervention. © 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.
Release of acetylcholine from parasympathetic nerves in the airways activates postjunctional muscarinic receptors present on smooth muscle, submucosal glands and blood vessels. This triggers bronchoconstriction, muscle hypertrophy, mucus secretion, and vasodilatation, respectively. The release of acetylcholine from parasympathetic nerves in lungs is induced by a variety of stimuli and downregulated by the inhibitory activity of neuronal M2 muscarinic receptors via a feedback mechanism.
Increased parasympathetic nerve activity occurs in a variety of airway diseases in childhood, including viral-induced wheeze and asthma. Common to these conditions are reversible airway obstruction, mucus hypersecretion, vasodilation and enhanced vascular permeability. In animal models of airway hyperreactivity similar findings of increased acetylcholine release resulting in enhanced supply of this neurotransmitter to the postjunctional smooth muscles, submucosal glands and airway vessels, were demonstrated. While the number and function of postjunctional muscarinic receptors in the airways are unchanged in such airway disorders, inhibitory activity on the parasympathetic nerves appears to be impaired. Specifically, M2 muscarinic receptor dysfunction has been demonstrated in models of bronchial hyperreactivity induced by a variety of triggers, including viruses, atmospheric pollutants and allergens.
The mechanisms leading to impairment of neuronal M2 muscarinic receptor function and their putative relevance to the pathogenesis and the treatment of airway disease in childhood are described.
Finally, the available data on the activity of ipratropium bromide, a short-acting anticholinergic drug, in the most common pediatric airway disease are reported and the possible therapeutic efficacy of tiotropium bromide, a more recently introduced long-acting, selective anticholinergic compound, is discussed.
The corticosteroid mometasone and the long-acting β(2)-selective adrenoreceptor agonist formoterol have been combined in a single pressurized metered-dose inhaler for use in patients aged ≥12 years with asthma.
In a 26-week well designed trial in patients with persistent asthma uncontrolled on medium-dose inhaled corticosteroids (ICS), mometasone/formoterol 200 μg/10 μg twice daily (bid) was more effective than placebo or the same nominal dosage of formoterol alone in reducing the incidence of asthma deteriorations, as well as in improving lung function, asthma control, asthma symptoms and asthma-related quality-of-life outcomes. The combination was also more effective than the same nominal dosage of mometasone alone in improving lung function and asthma control.
Similarly, in a 12-week well designed trial in patients with persistent asthma uncontrolled on high-dose ICS, mometasone/formoterol 400 μg/10 μg bid was more effective than the same nominal dosage of mometasone alone in improving lung function, asthma control and asthma symptoms. Treatment with a lower dosage of the combination (200 μg/10 μg bid) yielded similar results and, moreover, significantly reduced the incidence of asthma deteriorations compared with mometasone alone.
Mometasone/formoterol was generally well tolerated in clinical trials of 12-52 weeks' duration. The adverse event profile of the combination was consistent with that of its individual components; no new or unexpected safety signals were detected.
Alveolar nitric oxide (CA(NO) ) is a potential biomarker of small airway inflammation. We investigated effects on CA(NO) of the addition of coarse and fine particle inhaled corticosteroids to standard therapy in severe asthma.
Methods: Severe asthmatics taking ≥1600µg/day budesonide or equivalent performed a randomised open-label crossover study. Subjects with FEV(1) <80%, gas trapping and CA(NO) ≥2ppb entered a 6week dose-ramp run-in of Fluticasone/Salmeterol(FPSM) 250/50µg BID for 3weeks, then 500/50µg BID for 3weeks. Patients then received additional HFA-BDP 200µg BID or FP 250µg BID for 3wks in a cross-over. Participants then received prednisolone(PRED) 25mg/day for 1week. Nitric oxide, lung function, mannitol challenge, systemic inflammatory markers and urinary cortisol were measured.
Results: 15 completed per protocol: mean(SD) age, 51(12)yr; FEV(1,) 58(13)% predicted; residual volume, 193(100)% predicted; mannitol(PD10) , 177(2.8)mcg. There was no significant difference between FPSM and add-on therapy for CA(NO) . FPSM/BDP and FPSM/PRED suppressed Jaw(NO) and FE(NO) compared to FPSM alone, but there was no significant difference between FPSM/BDP and FPSM/FP. ECP, e-selectin and ICAM-1 were suppressed by FPSM/PRED compared to FPSM and FPSM/FP but not FPSM/BDP. Plasma cortisol was significantly suppressed by FPSM/PRED.
Conclusion: In severe asthma, CA(NO) is insensitive to changes in dose and delivery of inhaled corticosteroids and is not suppressed by systemic corticosteroids. Additional inhaled HFA-BDP reducted FE(NO) and Jaw(NO) without adrenal suppression. There was a trend to reduction in FE(NO) and Jaw(NO) with additional FP but this did not reach statistical significance. Prednisolone reduced FE(NO) and Jaw(NO) with suppression of systemic inflammatory markers and urinary cortisol. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.