The effect of inhaled corticosteroids on hypothalamic-pituitary-adrenal axis

Objectives:

The aim of this study was to compare systemic effects of high-dose fluticasone propionate (FP) and beclomethasone dipropionate (BDP) via pressurized metered dose inhaler on adrenal and pulmonary function tests.

Materials and Methods:

A total of 66 patients with newly diagnosed moderate persistent asthma without previous use of asthma medications participated in this single blind, randomized, parallel design study. FP or BDP increased to 1 500 μg/d in 62 patients who had not received oral or IV corticosteroids in the previous six months. Possible effects of BDP and FP on adrenal function were evaluated by free cortisol level at baseline and after Synacthen test (250 μg). Fasting plasma glucose and pulmonary function tests were also assessed. Similar tests were repeated 3 weeks after increasing dose of inhaled corticosteroids to 1 500 μg/d.

Results:

No statistically significant suppression was found in geometric means of cortisol level post treatment in both groups. After treatment in FP group, mean forced expiratory volume in one second (FEV1) and mean forced vital capacity (FVC) values improved by 0.17 l (5.66% ± 13.91, P=0.031) and 0.18 l (5.09% ± 10.29, P=0.010), respectively. Although FEV1 and FVC improved in BDP group but was not statistically significant. Oral candidiasis and hoarseness were observed in 6.5% patients receiving BDP, but hoarseness was found in 3.2% patients in FP group (P=0.288).

Conclusions:

The results indicate that safety profiles of high doses of BDP and FP with respect to adrenal function are similar, but FP is more efficacious than that of BDP in improving pulmonary function test.KEY WORDS: Adrenal cortex function tests, adrenal insufficiency, asthma, beclomethasone dipropionate, fluticasone     

顺尔宁联合糖皮质激素吸入和单纯糖皮质激素吸入治疗儿童哮喘的效果对比

目的探讨顺尔宁联合糖皮质激素吸入和单纯糖皮质激素吸入治疗儿童哮喘的临床效果。方法将2014年2月~2016年12月在我院接受治疗的60例儿童哮喘患者作为本次研究对象,将其按照随机数字法平均分为两组,30例采用单纯糖皮质激素吸入治疗(对照组),30例给予顺尔宁联合糖皮质激素吸入治疗(研究组)。将两组患者临床疗效、湿啰音消失时间、哮鸣音消失时间、咳嗽消失时间、住院时间、FEV1、PEF、Eos指标及不良反应发生情况进行比较。结果研究组临床总有效率为86.66%,对照组临床总有效率为63.33%,研究组患者临床总有效率显著高于对照组(P<0.05)。研究组患者湿啰音消失时间、哮鸣音消失时间、咳嗽消失时间及住院时间均显著短于对照组(P<0.05)。干预前两组患者FEV1、PEF、Eos指标比较差异无统计学意义(P>0.05),干预后两组患者FEV1、PEF指标均显著升高,Eos指标均显著降低(P<0.05),且研究组较对照组改善显著(P<0.05)。研究组不良反应发生率为6.66%,对照组不良反应发生率为10.00%。两组患者不良反应发生率比较差异无统计学意义(P>0.05)。结论在儿童哮喘患者治疗中选择顺尔宁联合糖皮质激素吸入治疗可显著缩短患者临床症状消失时间及住院时间,提高治疗效果,降低患者经济负担,改善患者肺功能,且不良反应低安全有效,值得在临床上推广使用。     

Chronic fatigue syndrome: circadian rhythm and hypothalamic-pituitary-adrenal (HPA) axis impairment

Chronic Fatigue Syndrome (CFS) is a clinical condition characterized by a persistent or relapsing debilitating fatigue at rest, lasting more than 6 months, and made worse by exercise. At the present moment, there are three potential etiopathogenic factors: immunologic, viral and neuroendocrine. The purpose of our study was to evaluate possible alterations of the hypothalamic-pituitary-adrenal (HPA) axis in our CFS patients by studying the circadian rhythms of prolactin (PRL), thyrotropic hormone (TSH), adrenocorticotropic hormone (ACTH), and cortisol (CS). A total of 36 patients were enrolled according to the Centers for Disease Control and Prevention case-definition criteria. Twenty healthy subjects were included as controls. Blood samples were taken every 4 hours during a single 24-hour period. We performed a fluorometric enzyme immunoassay with serum PRL, cortisol and TSH, and an immunoradiometric assay with plasma ACTH. The circadian rhythms of PRL, TSH, ACTH and CS were statistically significant in both CFS and control groups. At 24:00 and 04:00 hrs the CFS patients showed lower ACTH levels than healthy subjects (p < 0.001); the PRL levels were higher at 04.00 h in CFS patients than in healthy subjects.     

Underuse of inhaled corticosteroids in adults with asthma

Despite strong evidence that inhaled corticosteroids are beneficial in treating asthma, a number of small studies suggest a use rate of only 34-56%. The primary objective of this study was to determine patterns of prescribing inhaled corticosteroids for high-risk patients with asthma. Secondary objectives were to assess patterns of practice with respect to other agents prescribed before and at hospital discharge, and to determine if an emergency room asthma care map at one of the study hospitals was being followed. We retrospectively reviewed charts of 1022 patients with an acute attack of asthma treated in the emergency rooms of the Royal Alexandra Hospital and University of Alberta Hospital from January 1, 1996, to March 31, 1997. A forward stepwise logistic regression analysis was performed with the dependent variable defined as whether or not the patient was using an inhaled or oral corticosteroid during the index visit, and the independent variable being all major demographic variables. Inhaled corticosteroids were prescribed for 460 patients (52.0%) at the index visit. Overall, antiinflammatory drugs were prescribed for 548 patients (62.1%). An asthma care map was followed for 107 (16.8%) patients treated at the Royal Alexandra Hospital at the index visit. Logistic regression analysis showed that women and patients with more than one emergency room visit most likely were to be using inhaled or inhaled plus oral corticosteroids at the index visit. Documentation of drug therapy at discharge was poor for 42% of patients; therefore, analysis of practice patterns in this group was not attempted. This study shows that inhaled corticosteroids were prescribed for only about one-half of patients with an acute asthma attack. Given this low use by high-risk patients, the need for programs designed to improve asthma therapy is evident.     

The use of inhaled corticosteroids in adults with asthma

Inhaled corticosteroids have now been used for the treatment of asthma for over 25 years. They have largely replaced oral corticosteroids for the prevention of asthma symptoms and asthma attacks, and for most patients they have become the first line of preventive drug therapy. We recently discussed the role of inhaled corticosteroids in the management of childhood asthma. Here, we review their place in the management of adults with asthma. A forthcoming article will review the various types of inhaler now available for delivering drugs for asthma.     

Once-daily inhaled corticosteroids in children with asthma: nebulisation

Current guidelines on the management of childhood asthma have emphasised the important preventive role of inhaled corticosteroids, which should be used at the lowest possible doses that are compatible with good disease control. However, some children do not respond to inhaled corticosteroids, the most common reasons for which are inability to use conventional hand-held inhalers (plus spacers and face masks) effectively or lack of cooperation with them, particularly among infants and young children. In these patients, nebulisers have proved effective in administering corticosteroids, and this form of delivery is often preferred by both the children and their parents, despite their longer administration times (commonly around 10 minutes). Compliance with these devices may therefore be better than with a conventional pressurised metered-dose inhaler plus spacer and face mask. Recent studies with nebulised budesonide have demonstrated that once-daily administration is as effective in maintaining control of asthma symptoms in children as the usual twice-daily administration. In children with moderately severe persistent asthma, the improvement provided by once-daily nebulised doses of 1.0 mg budesonide has been found to be equivalent to that with twice-daily doses of 0.25 or 0.5 mg, indicating that once-daily therapy is an effective option that can be considered in many patients. In view of the time-consuming nature of nebuliser administration, reduction of the frequency of corticosteroid administration from twice to once daily may be useful in simplifying the treatment programme and improving compliance with it. This may be beneficial in reducing under-utilisation of inhaled corticosteroids in children with asthma and improving long term control of the disease.     

Smoking influences response to inhaled corticosteroids in patients with asthma: a meta-analysis

Abstract

Objective:

To determine the effects of smoking on efficacy of inhaled corticosteroids in asthmatics.     

The use of inhaled corticosteroids in childhood asthma

In the UK around 1 in 5 children will have been diagnosed as having asthma at some stage before they reach 15 years old. The use of inhaled corticosteroids has done much to reduce morbidity in these children and current British Guidelines recommend the use of inhaled corticosteroids in all but mild childhood asthma. However, there are concerns about the long-term safety of such treatment in growing children, and the benefits and risks of their use need careful evaluation. In this article we review the place of inhaled corticosteroids in childhood asthma.     

A comparison of plethysmography, spirometry and oscillometry for assessing the pulmonary effects of inhaled ipratropium bromide in healthy subjects and patients with asthma

AIMS: We have compared the ability of plethysmography (sGaw), impulse oscillometry (IOS) and spirometry (FEV(1), MMEF) to detect bronchodilation in response to an anticholinergic. METHODS: IOS (R5, R20, X5, RF), sGaw and spirometry were measured in 12 healthy subjects and 12 asthmatics. Variability was assessed by performing two measurements, 30 min apart and the effect of increasing the number of readings for each sGaw measurement was also studied. Ipratropium bromide (IB) 10, 20, 100 and 200 microg was administered and the sensitivity of the methods compared by determining the lowest dose that caused changes greater than variability. RESULTS: In healthy subjects significant changes (P < or = 0.05) occurred at 10 microg for FEV(1) (mean [95% CI]; 1.3%[0.3-2.3]), R5 (mean [95% CI]; -7.9%, [-13.2-2.6]) and R20 (mean [95% CI], -6.4%, [-11.4-1.4]). No significant change was detected when the mean of 3 sGaw readings was used, but with 10 readings significant change was observed at 20 microg; (mean increase [95% CI] 15.2%[8.3-22.1]). In asthmatics significant changes (P < or = 0.05) occurred with IB 10 microg for sGaw (mean [95% CI] 25.6%[11.1-40.1]), R5 (mean [95% CI]-11.3%, [-15.5-7.2]), RF (mean [95% CI] 11.7%[6.1-16.3]), FEV(1) (mean [95% CI] 5.1%[2.6-7.7]) and MMEF (mean [95% CI] 12.3%[2.3-22.2]). CONCLUSION: IOS and spirometry are more sensitive than sGaw in healthy subjects, but the sensitivity of sGaw improved when the number of readings was increased. The most sensitive method for assessing bronchodilation in asthmatics was sGaw.     

吸入性皮质激素联合班布特罗治疗支气管哮喘的分析

目的观察吸入性皮质激素布地奈德联合班布特罗治疗支气管哮喘的疗效.方法将我院67例轻、中度哮喘患者随机分为两组,34例应用吸入性皮质激素布地奈德联合班布特罗与33例应用吸入性皮质激素布地奈德患者间治疗效果相比较得出结论.结果吸入性皮质激素布地奈德联合班布特罗能有效地控制哮喘急性发作及其相关症状和降低哮喘患者的住院率,减少布地奈德的吸入量.结论吸入性皮质激素布地奈德联合班布特罗治疗支气管哮喘优于单一吸入性激素布地奈德的疗效.     

Continuity of prescribing with inhaled corticosteroids and control of asthma

Purpose —Current asthma guidelines advocate early intervention with inhaled corticosteroids. The aim of the study was to examine the association between continuity of dispensed prescribing for inhaled corticosteroids, and hospitalization for asthma or use of high dose oral corticosteroids. Methods —Using the MEMO record‐linkage database we identified subjects receiving inhaled corticosteroids (aged 12 – 45 years). Compliance was estimated by calculating the number of days, for which a subject could have taken an inhaled corticosteroid. In the 90‐day exposure‐window, subjects with 90 days therapy were considered to be ‘compliant’, those with 1 – 89 days to be ‘partially compliant’, and those with zero days to be ‘non‐compliant’. Results —There were 4535 subjects who had 88 occurrences of hospitalization for asthma, and 457 subjects with either hospitalization or high dose oral corticosteroids. The proportion of hospitalizations for compliant, partially compliant and noncompliant subjects was 9, 3 and 1%. The odds‐ratios, versus compliance, were 0.34 (95% CI, 0.19 – 0.62) for partial compliance, and 0.10 (95% CI, 0.05, 0.19) for non‐compliance. This association disappeared after adjustment for beta‐agonists and other relief medication. Conclusions —As dispensed prescribing decreased, the incidence of hospitalization and high dose oral corticosteroids decreased. Patients with good continuity of prescribing had the highest rates of serious asthma‐related outcomes. Copyright © 2000 John Wiley & Sons, Ltd.     

Safety of the newer inhaled corticosteroids in childhood asthma

Inhaled corticosteroids (ICS) remain a vital part of the management of persistent asthma, but concerns have been raised about their potential adverse effects in children. This review examines the safety data on three new ICS - fluticasone propionate, mometasone, and extrafine beclomethasone in hydrofluoroalkane (HFA-134a) propellant (QVAR The use of tradenames is for product identification purposes only and does not imply endorsement. formulation) in relation to the older corticosteroids. Topical adverse effects such as thrush and dysphonia are rare, but dental erosion is a possibility with powder forms of ICS because of their low pH. Thus, it is important to stress mouth rinsing after administration and maintaining good dental hygiene to minimize this risk. Biochemical adrenal suppression can be readily demonstrated, particularly with high doses of all ICS. The clinical relevance of this was uncertain in the past, but there have now been >50 reported cases of acute adrenal crises in children receiving ICS, most of whom were on fluticasone propionate. In order to minimize the risk of symptomatic adrenal suppression, it is important to back-titrate the ICS dose and alert families of children receiving high-dose ICS of this potential adverse effect. A pediatric endocrine opinion should be sought if adrenal suppression is suspected. The older ICS cause temporary slowing of growth velocity, but the limited data available do not show any significant compromise of final adult height. The effect on growth of fluticasone propionate may not be as great as with the older ICS, but the studies have been short term and only used low doses of fluticasone propionate. There have been case reports of growth suppression in children receiving high doses of fluticasone propionate. The limited studies performed on the effect of ICS on bone mineral density in children did not show any adverse effects, but there may be an increased risk of fractures. Hydrofluoroalkane beclomethasone (QVAR) is essentially the same drug as chlorofluorocarbon beclomethasone, but with double the lung deposition owing to the smaller particle size. Thus, it could be expected that any adverse effects seen with chlorofluorocarbon beclomethasone would be the same with hydrofluoroalkane beclomethasone. However, some of the published data, particularly in adults, suggest that hydrofluoroalkane beclomethasone may be less systemically active than chlorofluorocarbon beclomethasone, even at equipotent doses. As yet, there are no long-term data on mometasone, but initial studies in adults suggest there may be less suppression of the hypothalamic-pituitary-adrenal axis, although further studies are required, particularly in children.ICS will remain a cornerstone in the management of persistent pediatric asthma, provided that the diagnosis of asthma is secure. It is very important to use ICS appropriately and to ensure the lowest possible doses are used to achieve symptom control, thus minimizing the risk of serious adverse effects.     

Once-daily inhaled corticosteroids in children with asthma: dry powder inhalers

The cornerstone of pharmacological management of asthma in childhood is inhaled corticosteroids. These drugs are intended for long term treatment and, consequently, compliance is a major issue. Once-daily administration of maintenance medication would simplify treatment and it is likely that it would lead to better compliance. Moreover, the excellent safety profile of inhaled corticosteroid treatment tailored to disease severity may, theoretically, be further improved with once-daily administration. Studies comparing inhaled corticosteroids given once or twice daily to patients with asthma indicate that unstable asthma is best treated with at least 2 daily doses. On the other hand, it has been demonstrated that, if the asthma is stabilised, most children can be treated with inhaled corticosteroids once daily without loss of efficacy. Thus, the data suggest that newly diagnosed asthma, or asthma after deterioration, should first be reliably controlled with inhaled corticosteroids divided into at least 2 daily doses. Once-daily maintenance treatment should then be tried with the aim of improving compliance and quality of life. A dry powder inhalation device is probably the best choice for children from the age of 5 years.     

Modulation by catecholamine of hypothalamus-pituitary-adrenocortical (HPA) axis activity in morphine-tolerance and withdrawal

• 1.1. Hypothalamic noradrenaline (NA), dopamine (DA) and plasma cortiocosterone concentrations were determined after acute morphine administration to both naive and morphine-tolerant rats and during naloxone-induced withdrawal.
• 2.2. Acutely administered morphine (30 mg/kg) significantly increased the plasma level of corticosterone and reduced the NA and DA content in the hypothalamus. Naloxone (1 mg/kg), administered before morphine, blocked the effect of the opiate on both plasma corticosterone and hypothalamic NA concentration.
• 3.3. In chronically morphine-treated rats, a challenge dose of morphine (30 mg/kg) neither modified the plasma corticosterone level nor the NA concentration, while DA content was significantly enhanced.
• 4.4. After naloxone-induced withdrawal, the hypothalamic content of NA was significantly reduced, simultaneously with an increase in plasma corticosterone, while DA content remained unchanged.
• 5.5. These results suggest that the hypothalamic noradrenergic neurons are mainly implicated in the effect of acute morphine on the hypothalamus-pituitary-adrenocortical (HPA) axis and in the tolerance development to this effect. The results also suggest that a hyperactivity of noradrenergic pathways in the hypothalamus would be one of the physiologically relevant mechanisms mediating the neuroendocrine opiate withdrawal at the HPA level.

     

Hyperactivity in the hypothalamic-pituitary-adrenal axis in demented patients with delirium

Occurrence of delirium is known to be related to, among other things, organic brain disorder, somatic disease and old age. It has been hypothesized that delirium is also associated with stress. Disturbances of the hypothalamic-pituitary-adrenal (HPA) system have been found in delirious patients in various studies. The aim of the present study was to determine the activity in the HPA axis in demented patients to ascertain whether the stress regulating system was more disturbed in patients with delirium than in those without delirium. Demented inpatients with no acute medical illness were included in the study. Basal cortisol levels in serum were measured and dexamethasone suppression test (DST) was performed. The most important finding of the study was a strong relationship between delirium and DST pathology irrespective of age and severity of dementia. It is suggested that certain demented individuals have an impaired HPA system and a low delirium threshold and respond to stress with delirium.     

Trends in the use of inhaled corticosteroids for childhood asthma in New Zealand

Objective To compare the dispensed volumes and prescribed doses for inhaled corticosteroids (ICS) for children in New Zealand.Design Longitudinal analysis of prescribing trends using the Royal New Zealand College of General Practitioners Research Unit database and the Pharm Warehouse database of the New Zealand Health Information System.Setting New Zealand from 1993 to 2001.Subjects Children aged 0–5 years and 6–17 years.Main outcome measures The ratio of potency-adjusted mean daily dose of fluticasone propionate (FP) to beclomethasone (BDP) and dispensed volumes of FP, BDP and budesonide .Results The ratio of potency-adjusted mean daily dose of FP to BDP prescribed to children aged 0–17 years ranged from 1.22 to 1.91. With the introduction of FP, the total amount of ICS dispensed to children aged 0–5 years in New Zealand nearly doubled, when adjusted for potency.Conclusions The introduction of FP into New Zealand corresponds with an increase in the total amount of ICS dispensed and an increase in the adjusted daily dose prescribed.