Colds as predictors of the onset and severity of COPD exacerbations.

RATIONALE: Common colds are associated with acute respiratory symptom exacerbations in COPD patients. OBJECTIVE: To determine exacerbation risk and severity in COPD patients with/without coincident self-reported colds. METHODS: Global initiative for chronic Obstructive Lung Disease stage I-IV COPD patients electronically transmitted respiratory symptom diaries to research staff daily between December 2006 and April 2009. Respiratory symptom worsening prompted contact by a study nurse and patient assessment to determine if a cold was present or an exacerbation underway. A composite daily symptom score was derived for each subject from diarized symptom data. The exacerbation/cold/virus relation was examined using a Poisson regression model, the relation of colds to respiratory symptom severity using generalized estimating equation models. RESULTS: Daily diary transmission compliance of >97% enabled detection of all possible exacerbations. Among 262 exacerbations meeting Anthonisen criteria, 218 (83%) had cold-like symptoms present at their inception, but respiratory viruses were detected in only 106 (40%). Within-subject exacerbation risk was 30 times (95% confidence interval [CI]: 20, 47; P<0.001) greater with colds present. Compared to cold- and virus-negative exacerbations (n=57), the mean increase in composite symptom score in those cold and virus positive (n=79) was 0.93 (95% CI: 0.61, 1.25; P<0.001), cold-positive and virus-negative exacerbations (n=100) 0.51 (95% CI: 0.21, 0.81; P<0.001), cold-negative and virus-positive exacerbations (n=26) 0.58 (95% CI: 0.23, 0.94; P<0.001). CONCLUSION: This study emphasizes the importance of colds in COPD exacerbation risk and severity, even in the absence of virus detection. COPD patients should act promptly when cold symptoms appear to facilitate early intervention for exacerbation prevention or management.

Efficacy and Tolerability of an Inhaled Selective Glucocorticoid Receptor Modulator - AZD5423 - in Chronic Obstructive Pulmonary Disease Patients: Phase II Study Results.

AZD5423 is a novel, inhaled, selective glucocorticoid receptor modulator (SGRM), which in an allergen challenge model in asthma patients improved lung function and airway hyper-reactivity. In the current trial, AZD5423 was for the first time tested in patients with chronic obstructive pulmonary disease (COPD). In this double-blind, randomized and parallel group study, we examined airway and systemic effects of two doses of AZD5423, inhaled via Turbuhaler for 12 weeks, in 353 symptomatic patients with COPD (average pre-bronchodilator forced expiratory volume in one-second (FEV1) at screening was 50-52% of predicted normal). Pre-bronchodilator FEV1 was primary variable, with other lung function parameters plus symptoms and 24-hr plasma cortisol being secondary variables. Plasma concentrations of AZD5423 were also measured. Effects were compared against placebo and a reference glucocorticoid receptor agonist control. Neither AZD5423, at doses which have shown to be efficacious in allergen-induced asthma, nor the reference control, at double the approved dose, had any clinically meaningful effect in the patient population studied in regard to lung function or markers of inflammation. Both GR modulators were well tolerated and did suppress 24-hr cortisol. This study suggests that the selected population of patients with COPD does not respond to treatment with AZD5423 as regards lung function, while showing the expected systemic effects. It cannot be ruled out that a favourable lung function response of AZD5423 can be evoked using another experimental setting and/or within a different population of patients with COPD.

Seasonal and geographic variations in the incidence of asthma exacerbations in the United States.

BACKGROUND: Exacerbations drive the burden of asthma and lead to significant morbidity and consumption of health care resources. Many prior studies of the epidemiology of asthma exacerbations have relied upon data from hospital care. OBJECTIVE: The objective of this study was to determine US patterns of geographic and seasonal variations of asthma exacerbations being defined as asthma episodes requiring hospital care and/or a prescription for oral steroid. METHODS: The study was a retrospective observational cohort study using administrative claims data for insured individuals from the HealthCore Integrated Research Database, including around 43 million members in the United States. Analyses examined 3 age groups, 6-17, 18-64, and ≥65 years and four US regions, Northeast, Southeast, Central, and Western. RESULTS: Monthly rates of asthma exacerbations showed the greatest variation over the year in children, less so in adults and in the elderly. Clinically important differences in rates of asthma exacerbation were observed between regions with the Western Region having the lowest in all three age groups followed by the Northeast, Central, and Southeast regions. Peaks in children occurred in the early fall following troughs in the summer months, and peaks at year-end occurred in adults, particularly in those over 65 years. CONCLUSIONS: There is a striking seasonal variation in asthma exacerbations in the United States. Substantial differences between regions of the United States in asthma exacerbation rates cannot readily be explained and invite further investigation.

Safety, Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers.

AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This study reports the initial, first-in-man, single and repeat dose-escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once-daily treatment. Plasma exposure suggested dose-proportional pharmacokinetics and dose-related effects on 24-hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (osteocalcin, TRAP5b, DHEA-S and 4ß-OH-cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished between the two study populations, although hypothalamus-pituitary-adrenal (HPA) effects appeared to be marginally greater in the Japanese- versus the Caucasian-dominant study population. AZD5423, inhaled via nebulization, can be used in healthy individuals at doses of at least 300 µg for 2 weeks. The effects on the HPA axis reported herein, together with efficacy data reported elsewhere, indicate that benefit-risk ratio may be improved relative to conventional inhaled steroids.

Tissue accumulation kinetics of ciclesonide-active metabolite and budesonide in mice.

Inhaled corticosteroids (ICS) are mainstay treatment of asthma and chronic obstructive pulmonary disease. However, highly lipophilic ICS accumulate in systemic tissues, which may lead to adverse systemic effects. The accumulation of a new, highly lipophilic ICS, ciclesonide and its active metabolite (des-CIC) has not yet been reported. Here, we have compared tissue accumulation of des-CIC and an ICS of a moderate lipophilicity, budesonide (BUD), after 14 days of once-daily treatment in mice. Single, three or 14 daily doses of [(3) H]-des-CIC or [(3) H]-BUD were administered subcutaneously to male CD1 albino mice, which were killed at 4 hr, 24 hr or 5 days after the last dose. Distribution of tissue concentration of radioactivity was studied by quantitative whole-body autoradiography. Pattern of radioactivity distribution across most tissues was similar for both corticosteroids after a single as well as after repeated dosing. However, tissue concentration of radioactivity differed between des-CIC and BUD. After a single dose, concentrations of radioactivity for both corticosteroids were low for most tissues but increased over 14 days of daily dosing. The tissue radioactivity of des-CIC at 24 hr and 5 days after the 14th dose was 2-3 times higher than that of BUD in majority of tissues. Tissue accumulation, assessed as concentration of tissue radioactivity 5 days after the 14th versus 3rd dose, showed an average ratio of 5.2 for des-CIC and 2.7 for BUD (p < 0.0001). In conclusion, des-CIC accumulated significantly more than BUD. Systemic accumulation may lead to increased risk of adverse systemic side effects during long-term therapy.

Vasoconstriction after inhalation of budesonide: a study in the isolated and perfused rat lung.

INTRODUCTION: Clinical studies have shown that inhaled corticosteroids can induce rapid vasoconstriction in the airways, leading to decreased mucosal blood flow. The aim of this study was to investigate whether vasoconstriction of the pulmonary circulation after short inhalation of a corticosteroid can be detected in the isolated and perfused rat lung (IPL) - a model which could serve as a substitute or a complement to clinical models. METHODS: IPLs were briefly exposed to dry powder aerosol of budesonide. The pulmonary perfusate flow rate was assessed during 100min post-exposure. A reduction in perfusion flow rate was interpreted as vasoconstriction. MAIN RESULTS: Vasoconstriction was more pronounced after brief inhalation of 10 and 50microg budesonide than 2microg. The onset of vasoconstriction became statistically significant within 10-40min after inhalation. Co-administration of a selective alpha(1)-adrenoceptor antagonist (prazosin 50nM added to the perfusate) reduced vasoconstriction by approximately 50% during 100min of perfusion (p=0.003). CONCLUSIONS: Inhaled budesonide rapidly induces pulmonary vasoconstriction suggesting a nongenomic mechanism probably related to disposition of noradrenaline at the neuro-muscular junction. This ex vivo model could serve as a substitute or a complement to clinical models for investigating rapid effects of glucocorticoid receptor agonists on the pulmonary/bronchial circulation.

The bioavailability and airway clearance of the steroid component of budesonide/formoterol and salmeterol/fluticasone after inhaled administration in patients with COPD and healthy subjects: a randomized controlled trial.

BACKGROUND: Airway absorption and bioavailability of inhaled corticosteroids (ICSs) may be influenced by differences in pharmacokinetic properties such as lipophilicity and patient characteristics such as lung function. This study aimed to further investigate and clarify the distribution of budesonide and fluticasone in patients with severe chronic obstructive pulmonary disease (COPD) by measuring the systemic availability and sputum concentration of budesonide and fluticasone, administered via combination inhalers with the respective long-acting beta2-agonists, formoterol and salmeterol. METHODS: This was a randomized, double-blind, double-dummy, two-way crossover, multicenter study. Following a run-in period, 28 patients with severe COPD (mean age 65 years, mean forced expiratory volume in 1 second [FEV1] 37.5% predicted normal) and 27 healthy subjects (mean age 31 years, FEV1 103.3% predicted normal) received two single-dose treatments of budesonide/formoterol (400/12 microg) and salmeterol/fluticasone (50/500 microg), separated by a 4-14-day washout period. ICS concentrations were measured over 10 hours post-inhalation in plasma in all subjects, and over 6 hours in spontaneously expectorated sputum in COPD patients. The primary end point was the area under the curve (AUC) of budesonide and fluticasone plasma concentrations in COPD patients relative to healthy subjects. RESULTS: Mean plasma AUC values were lower in COPD patients versus healthy subjects for budesonide (3.07 microM x hr versus 6.21 microM x hr) and fluticasone (0.84 microM x hr versus 1.50 microM x hr), and the dose-adjusted AUC (geometric mean) ratios in healthy subjects and patients with severe COPD for plasma budesonide and fluticasone were similar (2.02 versus 1.80; primary end point). In COPD patients, the Tmax and the mean residence time in the systemic circulation were shorter for budesonide versus fluticasone (15.5 min versus 50.8 min and 4.41 hrs versus 12.78 hrs, respectively) and Cmax was higher (1.08 microM versus 0.09 microM). The amount of expectorated fluticasone (percentage of estimated lung-deposited dose) in sputum over 6 hours was significantly higher versus budesonide (ratio 5.21; p = 0.006). Both treatments were well tolerated. CONCLUSION: The relative systemic availabilities of budesonide and fluticasone between patients with severe COPD and healthy subjects were similar. In patients with COPD, a larger fraction of fluticasone was expectorated in the sputum as compared with budesonide. TRIAL REGISTRATION: Trial registration number NCT00379028.

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.

Airway selectivity: an update of pharmacokinetic factors affecting local and systemic disposition of inhaled steroids.

Topical corticosteroids remain the most efficacious single treatment for asthma and rhinitis, despite the emergence of newer drugs in recent years. The antiinflammatory properties of these products, combined with the targeting of formulations and optimization of the intrinsic pharmacokinetic features of the newer corticosteroid molecules has resulted in substantially improved airway selectivity. This review sets out to summarize the pharmacokinetic properties of inhaled corticosteroids that are important for the achievement of high levels of airway selectivity, with additional focus on the use of prodrugs/softdrugs relative to those of conventional corticosteroid molecules, mechanisms (such as esterification) by which retention at the target site is achieved while minimizing systemic exposure, and the role of plasma protein binding.

Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn's disease.

This overview summarises available pharmacokinetic data on budesonide capsules (Entocort EC), approved for the treatment of mild-to-moderate active Crohn's disease involving the ileum and/or ascending colon and for prolongation of symptom control. Budesonide is a locally-acting glucocorticosteroid with an extensive, primarily hepatic, metabolism after oral administration. It is rapidly absorbed and biotransformed by cytochrome P450 (CYP) 3A to metabolites with negligible glucocorticoid activity. Entocort EC, a pH- and time-dependent oral formulation of budesonide, was developed to optimise drug delivery to the ileum and throughout the colon. Pharmaco-scintigraphic studies have confirmed that the Entocort EC formulation delays budesonide absorption and prolongs the rate of elimination but maintains complete absorption. This improves the delivery of budesonide to the intestinal lumen relative to a plain formulation. A low systemic availability of 9-21% indicates extensive first-pass elimination. Food appears to have little impact on the absorption of budesonide from Entocort EC capsules and the pharmacokinetics are dose-proportional between 3 and 15 mg. On average, systemic availability was 2.5-fold higher in patients with cirrhosis compared with healthy controls; however, mild liver impairment had little effect on systemic exposure. Pharmacokinetics appear unaffected by gender and age, although this has not been tested in younger children. Renal impairment is not expected to have an impact on the kinetics of Entocort EC. Budesonide is unlikely to inhibit the metabolism of other drugs, including CYP3A4 substrates, mainly because of the very low plasma concentrations obtained with the compound even after high doses of Entocort trade mark EC capsules. Strong CYP3A4 inhibitors, such as ketoconazole, will inhibit the metabolism of budesonide, resulting in several-fold increases in the area under the concentration-time curve of budesonide. Also, grapefruit juice intake may increase systemic availability of budesonide, probably by inhibition of intestinal CYP3A4 activity. Unlike prednisolone, oral contraceptives do not alter plasma budesonide concentrations. An increased pH obtained by gastric acid inhibitory drugs, such as omeprazole, does not affect the pharmacokinetics of budesonide. In summary, budesonide capsules (Entocort EC) possess many pharmacological features that make the formulation well adapted for a targeted treatment of inflammatory disorders, such as Crohn's disease involving the ileum and ascending colon.

Once-daily inhaled budesonide for the treatment of asthma: clinical evidence and pharmacokinetic explanation.

BACKGROUND: Budesonide, a widely used inhaled corticosteroid (ICS) with a favorable therapeutic ratio, is available via a dry powder inhaler (Pulmicort Turbuhaler) and as a suspension for nebulization (Pulmicort Respules). METHODS: MEDLINE and an AstraZeneca database were searched to identify relevant controlled clinical trials published between 1986 and 2002 using the key words budesonide OR inhaled corticosteroid, AND once daily. RESULTS: Thirty-four controlled clinical studies involving once-daily administration of budesonide to asthmatic patients were identified. Excluding long-term studies, this review presents data from 23 controlled studies for 4466 adults or adolescents and 1532 children with asthma and demonstrates efficacy of budesonide in both corticosteroid-naïve patients and patients previously treated with ICS. Once-daily administration of budesonide achieves clinical efficacy comparable with that of twice-daily regimens in patients with mild-to-moderate asthma and is equally effective when given in the morning or evening. Once-daily administration simplifies treatment regimens and may improve patient compliance. The tolerability profiles of budesonide once-daily via Turbuhaler or as budesonide inhalation suspension are good and comparable with those for twice-daily dosing. CONCLUSIONS: Once-daily budesonide is effective and well tolerated as initial treatment for adults and children with mild asthma and as maintenance therapy in patients with more severe asthma once asthma control has been achieved.

Gut delivery of budesonide, a locally active corticosteroid, from plain and controlled-release capsules.

OBJECTIVE: To compare the pharmacokinetics and site of uptake of budesonide from a controlled-release formulation and a deuterium-labelled standard formulation given before and after a meal. METHODS: Six healthy volunteers were randomized into an open, crossover study. They received 4.5 mg controlled-release budesonide (mixed with In pellets to trace gastrointestinal transit) and 4.8 mg 2H8-budesonide simultaneously at each of two visits: one visit before a standardized breakfast and the other after breakfast. Plasma concentrations of budesonide were followed over 24 h. The transit of the (111)In pellets through the gastrointestinal tract was followed for 36 h. Data on the site of absorption were calculated from transit times and absorption curves. RESULTS: The time to peak plasma concentration was significantly increased with controlled-release budesonide when compared with the deuterium-labelled standard formulation (before breakfast, 4.5 h vs 1.8 h; after breakfast, 5.2 h vs 2.9 h). When given after breakfast, the controlled-release formulation was associated with a mean residence time 1.6 h longer than that seen with the standard formulation. However, the areas under the plasma concentration curves were similar with the two formulations, regardless of when the treatments were given (before breakfast, 18.0 +/- 3.8 nmol/l vs 18.0 +/- 6.0 nmol/l; after breakfast, 16.9 +/- 7.0 nmol/l vs 18.5 +/- 9.0 nmol/l). Over 60% of the total budesonide absorbed from controlled-release capsules was delivered and absorbed in the ileum and colon. The corresponding proportion for the standard formulation was approximately 33%. CONCLUSIONS: Controlled-release budesonide effectively delivers most of the budesonide dose to the ileum and colon, the regions that are most often affected by inflammatory bowel disease. In addition, the time of food intake has little effect on the site of absorption or the bioavailability of the controlled-release formulation. Delivery to the colon and ileum was independent of whether the drug was given before or after breakfast.

Budesonide fatty-acid esterification: a novel mechanism prolonging binding to airway tissue. Review of available data.

AIMS: Evidence is accumulating that budesonide (BUD) forms intracellular esters in airways. which may affect both duration of action and therapeutic ratio of this drug. The aim of the present paper is to review the preclinical and human experimental evidence supporting the esterification of BUD, and to discuss the clinical implications this may have on asthma and rhinitis treatment. RESULTS: After inhalation, intact BUD binds primarily to available steroid receptors, and mainly excess (unbound) BUD is esterified. Esterification of BUD is a rapid process: within 20 minutes of inhalation in the rat of radiolabeled BUD, approximately 80% of radioactivity within the trachea and main bronchi was associated with BUD esters, primarily BUD oleate. After 4 hours, the proportion of BUD esters/total cellular BUD was typically 40 to 50% for lung, 70 to 90% for trachea, and only 10 to 15% for peripheral muscle. Comparative in vitro and in vivo studies have shown that esterification prolongs BUD's anti-inflammatory activity longer than that of corticosteroids that can not form esters. Clinical studies have confirmed the prolonged presence of BUD esters, as well as intact BUD, in human airway tissues: 6 hours postdosing, nasal biopsy concentrations of intact BUD were >10-fold greater than those of fluticasone propionate and at 24 hours BUD was detectable in threefold more biopsies than fluticasone propionate. The impact of esterification on airway selectivity of BUD has also been demonstrated in vivo and using pharmacokinetic/pharmacodynamic models. CONCLUSIONS: BUD is retained in airways as esters, a novel kinetic mechanism for synthetic glucocorticoids. In preclinical studies this esterification is correlated to a prolonged local tissue binding and efficacy, which is not found when the esterification is inhibited by an esterification blocker. Because less esters are formed in the systemic compartment than in airways/lung, the local benefit:systemic risk ratio may also be improved by this mechanism. BUD possesses favorable clinical properties, including its approved once-daily efficacy in asthma, which is probably in part attributable to esterification. However, a direct proof of the latter in patients requires effective and safe inhibitors of the esterification, which are not yet available. Therefore, evidence to support the therapeutic impact of esterification is still circumstantial.