Related Articles

Inhaled corticosteroids in children: effects on bone mineral density and growth.

Lancet Respir Med. 2014 Apr 8;

Authors: Fuhlbrigge AL, Kelly HW

Abstract
Potent, topically active corticosteroids with minimum systemic activity have fewer adverse effects than do systemic corticosteroids, and can control both asthma and allergic rhinitis when given in recommended doses. However, study findings show that children with asthma receiving budesonide and beclometasone dipropionate have decreased linear growth, and that children who receive long-term inhaled corticosteroid therapy for asthma have height deficits 1-2 years after treatment initiation that persist into adulthood. The effects of inhaled corticosteroids on growth seem to be dependent on both dose and duration; the degree of systemic effects is dependent on pharmacokinetic properties (ie, absorption, distribution, and elimination), whereas the effective dose delivered is dependent on the delivery system and potency of the molecule. The effects of corticosteroids on bone mineral density in children seem to be more amenable to intervention; long-term therapy with inhaled corticosteroid therapy is safer than frequent bursts of oral corticosteroids on bone mineral accretion in this regard. Importantly, adequate nutrition (particularly sufficient intake of calcium and vitamin D) should prevent or blunt the effects of corticosteroids on bone mineral density. The potential adverse effects of inhaled corticosteroids need to be weighed against the large and well established benefit of these drugs to control persistent asthma. To minimise any adverse effects, treatment with inhaled corticosteroids should always aim to reach the lowest effective dose that gives the patient good asthma control.

PMID: 24717638 [PubMed - as supplied by publisher]

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Mysteries of α1-antitrypsin deficiency: emerging therapeutic strategies for a challenging disease.

Dis Model Mech. 2014 Apr;7(4):411-9

Authors: Ghouse R, Chu A, Wang Y, Perlmutter DH

Abstract
The classical form of α1-antitrypsin deficiency (ATD) is an autosomal co-dominant disorder that affects ~1 in 3000 live births and is an important genetic cause of lung and liver disease. The protein affected, α1-antitrypsin (AT), is predominantly derived from the liver and has the function of inhibiting neutrophil elastase and several other destructive neutrophil proteinases. The genetic defect is a point mutation that leads to misfolding of the mutant protein, which is referred to as α1-antitrypsin Z (ATZ). Because of its misfolding, ATZ is unable to efficiently traverse the secretory pathway. Accumulation of ATZ in the endoplasmic reticulum of liver cells has a gain-of-function proteotoxic effect on the liver, resulting in fibrosis, cirrhosis and/or hepatocellular carcinoma in some individuals. Moreover, because of reduced secretion, there is a lack of anti-proteinase activity in the lung, which allows neutrophil proteases to destroy the connective tissue matrix and cause chronic obstructive pulmonary disease (COPD) by loss of function. Wide variation in the incidence and severity of liver and lung disease among individuals with ATD has made this disease one of the most challenging of the rare genetic disorders to diagnose and treat. Other than cigarette smoking, which worsens COPD in ATD, genetic and environmental modifiers that determine this phenotypic variability are unknown. A limited number of therapeutic strategies are currently available, and liver transplantation is the only treatment for severe liver disease. Although replacement therapy with purified AT corrects the loss of anti-proteinase function, COPD progresses in a substantial number of individuals with ATD and some undergo lung transplantation. Nevertheless, advances in understanding the variability in clinical phenotype and in developing novel therapeutic concepts is beginning to address the major clinical challenges of this mysterious disorder.

PMID: 24719116 [PubMed - in process]

Asymmetric Dimethylarginine in Chronic Obstructive Pulmonary Disease (ADMA in COPD).

Int J Mol Sci. 2014;15(4):6062-71

Authors: Scott JA, Duongh M, Young AW, Subbarao P, Gauvreau GM, Grasemann H

Abstract
l-Arginine metabolism including the nitric oxide (NO) synthase and arginase pathways is important in the maintenance of airways function. We have previously reported that accumulation of asymmetric dimethylarginine (ADMA) in airways, resulting in changes in l-arginine metabolism, contributes to airways obstruction in asthma and cystic fibrosis. Herein, we assessed l-arginine metabolism in airways of patients with chronic obstructive pulmonary disease (COPD). Lung function testing, measurement of fractional exhaled NO (FeNO) and sputum NO metabolites, as well as quantification of l-arginine metabolites (l-arginine, l-ornithine, l-citrulline, ADMA and symmetric dimethylarginine) using liquid chromatography-mass spectrometry (LC-MS) were performed. Concentrations of l-ornithine, the product of arginase activity, correlated directly with l-arginine and ADMA sputum concentrations. FeNO correlated directly with pre- and post-bronchodilator forced expiratory volume in one second (FEV1). Sputum arginase activity correlated inversely with total NO metabolite (NOx) and nitrite concentrations in sputum, and with pre- and post-bronchodilator FEV1. These findings suggest that ADMA in COPD airways results in a functionally relevant shift of l-arginine breakdown by the NO synthases towards the arginase pathway, which contributes to airway obstruction in these patients.

PMID: 24727374 [PubMed - in process]

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Pediatric lung transplantation: promise being realized.

Curr Opin Pediatr. 2014 Apr 12;

Authors: Conrad C, Cornfield DN

Abstract
PURPOSE OF REVIEW: Lung transplantation for infants and children is an accepted but rarely exercised option for the treatment of end-stage lung disease, with outcomes equivalent to those for adults. However, widespread misconceptions regarding pediatric outcomes often confound timely and appropriate referral to specialty centers. We present the updated information for primary pediatricians to utilize when counseling families with children confronted by progressive end-stage pulmonary or cardiovascular disease.
RECENT FINDINGS: We provide general guidelines to consider for referral, and discuss allocation of organs in children, information regarding standard treatment protocols, and survival outcomes.
SUMMARY: Lung transplantation is a worthwhile treatment option to consider in children with end-stage lung disease. The treatment is complex, but lung transplant provides substantial survival benefit and markedly improved quality of life for children and their families. This timely review provides comprehensive information for pediatricians who are considering options for treatment of children with end-stage lung disease.

PMID: 24732565 [PubMed - as supplied by publisher]