Do airway clearance mechanisms influence the local and systemic effects of inhaled corticosteroids?

The role of airway clearance in inhaled drug therapy is complex. Disease-induced bronchoconstriction results in a central drug-deposition pattern where mucociliary clearance is most efficient. When drug-induced bronchodilation is achieved, deposition and uptake becomes more peripheral, and because there is less mucociliary clearance in the periphery, this will lead to an unintentional increase in lung exposure and enhance the risk of systemic side effects. In addition, mucociliary clearance is pathologically reduced in both asthma and chronic obstructive pulmonary disease. Among inhaled corticosteroids, rate of dissolution and lung uptake differs considerably. For the slowly dissolving, lipophilic steroids, the contribution of mucociliary clearance to these findings appears significant, and variability in lung and systemic exposure resulting from variable mucociliary function appears to be amplified. In addition, dose optimisation of non-stable asthma becomes more complex. The present review highlights the impact of mucociliary clearance on inhaled corticosteroid disposition and identifies critical areas where more research is needed.     

Impact of long‐term treatment with low‐dose inhaled corticosteroids on the bone mineral density of chronic obstructive pulmonary disease patients: Aggravating or beneficial?

Background and objective: Chronic obstructive pulmonary disease (COPD) is characterized by a low‐level systemic chronic inflammatory activity that is responsible for many of the disease's extra‐pulmonary manifestations, including osteoporosis and fragility fractures. These manifestations are also well‐documented side‐effects of oral corticosteroids. It was hypothesized that low levels of inhaled corticosteroids, due to their anti‐inflammatory properties and their low circulating levels, might preserve the bone mineral density (BMD) of COPD patients. Methods: Two hundred and fifty‐one male ex‐smokers with COPD patients grouped on the basis of their diffusion capacity value as predominantly bronchitic or predominantly emphysematic and 313 male controls with similar age and smoking history were enrolled in the study. Each of the patient's categories was randomized into two separate subgroups. Patients enrolled in subgroups B_neg(n = 91, 36%) and E_neg(n = 37, 14.7%) were treated with long‐acting β2‐agonists and anticholinergics, while subgroups B_ICS(n = 87, 35%) and E_ICS(n = 38, 15.1%) were additionally receiving low‐dose inhaled corticosteroids. Patients and controls were evaluated by clinical examination, lung function testing and BMD measurement every 6 months for 4 years. Results: According to the findings, emphysematic patients demonstrated an increased rate of BMD loss compared with bronchitic patients (P = 0.01). Furthermore, a reduction of the annual BMD loss in bronchitic patients on inhaled corticosteroids (P = 0.02) was measured, without a corresponding benefit for the emphysematics (P = not significant). Conclusions: Long‐term administration of low‐dose inhaled corticosteroids decelerates the annual BMD loss in bronchitic patients, possibly by reducing both pulmonary and systemic chronic inflammation caused by COPD.     

Effects of 1-year anti-TNF-α therapies on bone mineral density and bone biomarkers in rheumatoid arthritis and ankylosing spondylitis

Clinical Rheumatology - Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with generalized and localized bone loss. We conducted a comprehensive study using imaging...     

The effect of various hormonal preparations and calcium supplementation on bone mass in early menopause. Is there a predictive value for the initial bone density and body weight?

OBJECTIVES: To compare the effect of various oestrogen and oestrogen/progestin preparations on bone density over a 2-year follow-up period in early postmenopausal women. SETTING: A retrospective study on 315 women followed in a menopause clinic. DESIGN: Antero-posterior lumbar spine bone densitometry was performed at baseline and between 18 and 24 months (mean 22 months) after initiation of hormone therapy. Participants were divided into six groups: women taking conjugated equine oestrogen (CEE) (n = 30); CEE plus sequential monthly medroxyprogesterone acetate (MPA) (n = 52); CEE plus sequential bimonthly MPA (n = 51); oral estradiol plus sequential monthly norethisterone acetate (n = 52); transdermal estradiol plus sequential monthly MPA (n = 30). A control group (n = 100) was composed of nonusers of hormones. RESULTS: Hormone users, as a whole (n = 215), increased their bone mineral density (BMD) by 2.9% (4.8) as compared to the controls who lost 3.5% (3.4; P < 0. 001). There were similar gains in BMD amongst the five study groups. Calcium supplementation was associated with better results in all women: users of hormones and calcium had a gain in BMD of 4.5% (4.8) compared to only 1.5% (4.5) in those on hormones but without calcium (P < 0.001); amongst the controls, women using calcium lost 1.4% (2. 4), whilst nonusers of calcium lost 3.7% (2.4; P < 0.001). A dose-response curve was found between basal BMD and the effect of hormone therapy: women with osteoporosis (T-score <75%) demonstrated the largest increase in BMD - 6.3% (4.6), osteopenia (T-score 75-85%) was associated with a gain of 3.2% (5.6), low-borderline values (T-score 86-100%) gave a modest increase of 1.3% (4.3), and those with more than average BMD values (T-score >100%) actually lost bone despite hormone treatment [-2.1% (4.1)]. CONCLUSIONS: All hormone regimens had a similar bone conserving effect. Basal BMD value may serve as a predictor for the success of treatment. Calcium supplementation should be recommended in all postmenopausal women.     

Does continuous use of inhaled corticosteroids improve outcomes in mild asthma? A double-blind randomised controlled trial.

AIM: To compare the effects of fluticasone and placebo on asthma control in patients with mild asthma. METHOD: Adults with FEV1 >80% predicted and reliever use 相似文献   

Low-dose glucocorticoids in early rheumatoid arthritis: discordant effects on bone mineral density and fractures?

OBJECTIVE: To investigate the incidence of osteoporotic fractures and effects on bone of low-dose glucocorticoid (GC) monotherapy in a group of previously untreated patients with early active RA we performed a double blind, randomised, placebo-controlled clinical trial. The study duration was 2 years, with an open follow-up during the third year. Patients were randomly allocated to receive 10 mg prednisone or placebo. METHODS: Non-steroidal anti-inflammatory drugs (NSAIDs) were allowed in both groups. After 6 months sulphasalazine (2 gr daily) could be prescribed as rescue therapy in both groups. Except for 500 mg calcium supplement daily, no specific preventive measures were taken. This was a normal procedure at the time the study was designed (1989-1991). At the start of the study and every 6 months, X-rays of the twelfth thoracic and of all lumbar vertebrae were scored using the Kleerekoper method, and every year biochemical parameters of bone metabolism and bone mineral density (BMD, expressed in T-scores) and bone mineral content (BMC, expressed in g/cm) were assessed. RESULTS: In the prednisone group there was a higher incidence during the study of lumbar vertebral fractures than in the placebo group: 7 vs 4 respectively. This difference did not reach statistical significance however, probably because of the small numbers. One patient of the prednisone group suffered an osteoporotic fracture of the pelvis. In the 2-year study and the subsequent follow-up year, no other peripheral fractures were seen in either group. No significant changes from baseline in BMD and BMC of the hips were seen in either group during the study and the follow-up year. In the lumbar spine, BMD in the prednisone group decreased although not statistically significantly during the whole study. No correlation between changes in serum osteocalcin and BMD was observed. CONCLUSION: Low-dose prednisone monotherapy for patients with early active previously untreated RA seems to increase the risk of fractures not only by reducing the BMD but also by changes in bone strength and structure.     

Determining the influence of telomere dysfunction and DNA damage on stem and progenitor cell aging – what markers can we use?

The decline in organ maintenance and function is one of the major problems limiting quality of life during aging. The accumulation of telomere dysfunction and DNA damage appears to be one of the underlying causes. Uncapping of chromosome ends in response to critical telomere shortening limits the proliferative capacity of human cells by activation of DNA damage checkpoints inducing senescence or apoptosis. Telomere shortening occurs in the vast majority of human tissues during aging and in chronic diseases that increase the rate of cell turnover. There is emerging evidence that telomere shortening can limit the maintenance and function of adult stem cells -- a cell type of utmost importance for organ maintenance and regeneration. In mouse models, telomere dysfunction leads to a depletion of adult stem cell compartments suggesting that stem cells are very sensitive to DNA damage. Both the rarity of stem and progenitor cells in adult organs and their removal in response to damage make it difficult to assess the impact of telomere dysfunction and DNA damage on stem and progenitor cell aging. Such approaches require the development of sensitive biomarkers recognizing low levels of telomere dysfunction and DNA damage in stem and progenitor cells. Here, we review experimental data on the prevalence of telomere dysfunction and DNA damage during aging and its possible impact on stem and progenitor cell aging.     

The influence of age on disease manifestations and serological characteristics in primary Sj?gren's syndrome.

We have studied the influences of age on clinical manifestations and serological abnormalities in primary Sj?gren's syndrome (pSS). The 67 patients included were diagnosed according to the preliminary European classification criteria for pSS, and disease manifestations were assessed according to a newly developed quantitative and qualitative classification model. We found that the age at diagnosis correlated to the presence of autoantibodies anti-SSA/SSB (r=-0.31, <0.02), rheumatoid factor (RF) (r=-0.33, p<0.01) and serum levels of IgG (r=-0.27, p<0.05). Young patients diagnosed before 45 years of age had the highest positivity of the autoantibodies anti-SSA/SSB (62.5%), RF (62.5%) and high levels of s-IgG (68.8%), while the corresponding values for old patients diagnosed after 60 years of age were anti-SSA/SSB: 20.8%, RF: 20.8%, and high s-IgG: 29.2%. None of these parameters correlated to age at onset nor disease duration. By applying a model for evaluating disease manifestations, no correlation between the global index nor the indices for subgroups of disease manifestations was found to age at onset, age at diagnosis, nor disease duration. We conclude that there is a significant influence of age on serological abnormalities in pSS, but not on disease manifestations.