Asthma stability after oral prednisone: a clinical model for comparing inhaled steroid potency.

Clinical studies comparing the potency of inhaled corticosteroids require steep dose-response slopes (b) and minimal response variability (s), as statistical power is inversely related to the s/b ratio. To evaluate a new study model, we performed a randomized, crossover study of 12 adult asthmatics who required 800 to 2,000 microg of inhaled corticosteroids daily, and calculated s/b for 21 raw clinical outcomes and 36 mathematically derived variables based on these raw outcomes. Each of two 21-d treatment periods was preceded by 4 to 7 d of oral prednisone to maximize asthma control and minimize carry-over of previous inhaled treatment. Treatments were 100 and 800 micron/d of an HFA-134a beclomethasone dipropionate formulation. Assessments included daily home spirometry, histamine challenge, inhaled albuterol use, and asthma symptom scores. Efficacy variables with the greatest power (lowest s/b values) were A.M.FEF25-75, A.M.FEV1, and A.M.PEF, (s/b = 0.46, 0.48, and 0.59). Carry-over between treatment periods was not significant. Crossover study sample size calculations using these ratios yielded samples of 23, 25, and 37 patients, respectively. Otherwise identical parallel studies would require sample sizes of 657, 1,438, and 2,261 patients. These results support the use of a crossover asthma stability model after a short course of oral prednisone as a clinical study model for comparing topical potency of inhaled corticosteroids.

Efficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthma.

Chlorofluorocarbon (CFC)-containing inhalers are gradually being phased out and replaced with hydrofluoroalkane (HFA)-based alternatives. The reformulation provided the opportunity to improve the inhalation technology and physical characteristics of corticosteroid formulations. QVAR contains HFA-beclomethasone dipropionate (HFA-BDP) with the steroid in solution rather than suspension, which, in combination with improved inhaler technology, produces an extrafine aerosol with a mass median aerodynamic diameter of 1.1 microm (smaller than the 3.5-4.0 microm found with CFC-BDP). It was predicted and demonstrated that the smaller particle size of QVAR would be deposited in the lung to a greater extent than that found with CFC-BDP, particularly in the small airway, a major site of inflammation. Increased lung deposition of QVAR permits a reduction in dosage relative to CFC-BDP. Clinical evidence confirms that adult and elderly patients required approximately half the dose of QVAR to achieve the same degree of asthma control as with CFC-BDP. In long-term assessments, patients taking CFC-BDP could be switched to QVAR at half the daily dose without exacerbation of their asthma symptoms. QVAR was associated with a low overall incidence of side effects and, at the maximum recommended dose of 640 microg/d, caused no more adrenal suppression than 672 microg/d CFC-BDP.

Comparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone dipropionate inhalation on small airways: assessment with functional helical thin-section computed tomography.

A double-blind, randomized, parallel-group pilot study compared the relative efficacy of hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP [QVAR]; mass median aerodynamic diameter, 0. 8-1.2 m) versus cholorofluorocarbon-11/12 BDP (CFC-BDP [Beclovent]; mass median aerodynamic diameter, 3.5-4.0 m) in 31 steroid naive patients with mild to moderate asthma (PC(20,) 4 mg/mL). Functional high-resolution computed tomography was used to assess the relative efficacy of HFA-BDP and CFC-BDP on regional air trapping, as an indirect measure of small airways function and on regional hyperreactivity. Pretreatment functional computed tomography was performed at residual volume before and after methacholine challenge. After 4 weeks of treatment, functional imaging was repeated before and after the same concentration of methacholine that was administered before the treatment (n = 19 patients). Quantitative assessment of changes in distribution of lung attenuation was performed. After 4 weeks of treatment, the HFA-BDP group showed significantly more improvement in air trapping overall (a shift in the lung attenuation curve at residual volume toward more attenuation) on the posttreatment computed tomography scan (P <.05; Fisher's Exact Test). After an equal constrictor stimulus (methacholine concentration), subjects treated with HFA-BDP (n = 10 patients) showed less increase in air trapping overall than subjects treated with CFC-BDP (n = 9 patients) on the posttreatment scans compared with the pretreatment scans (P <.001; Fisher's Exact Test). No significant difference was demonstrated between the 2 treatment groups with respect to improvement in symptoms, spirometry, or methacholine responsiveness assessed by FEV(1), except for a greater reduction in breathlessness in the HFA-BDP group (P <.05). We conclude that HFA-BDP may have greater efficacy in the peripheral airways and that this effect is better assessed with functional imaging computed tomography techniques than with conventional physiologic tests.

Clinical equivalence of a novel non-chlorofluorocarbon-containing salbutamol sulfate metered-dose inhaler and a conventional chlorofluorocarbon inhaler in patients with asthma.

BACKGROUND: New formulations of non-chlorofluorocarbon-containing propellants for pressurized metered-dose inhaler delivery systems must be developed in response to the forthcoming ban on chlorofluorocarbon (CFC) production. OBJECTIVE: This study compared the bronchodilator effects of 100, 200, and 300 micrograms (base equivalent) of salbutamol in a novel CFC-free propellant system (Airomir in the 3M CFC-Free System; 3M Pharmaceuticals, St. Paul, Minn.; 108 micrograms of salbutamol sulfate or 90 micrograms of salbutamol base equivalent per inhalation) with that of 100 and 200 micrograms of salbutamol base in a conventional CFC propellant system (Ventolin, CFC-11/12; Allen and Hanburys, Division of Glaxo Inc., Research Triangle Park, N.C.; 90 micrograms of salbutamol base per inhalation) and placebo. METHODS: Twenty-six patients with chronic, stable asthma, who had a forced expiratory volume in 1 second (FEV1) between 50.0% and 75.0% of predicted normal value, entered this randomized, double-blind, double-dummy, 6-period, crossover study. FEV1 was measured before and at multiple time points (ranging from 10 to 480 minutes) after administration of one, two, and three inhalations of salbutamol/CFC-free (100, 200, and 300 micrograms); one and two inhalations of salbutamol/CFC (100 and 200 micrograms); and placebo. Safety parameters included adverse events, heart rate, blood pressure, physical examinations, electrocardiograms, and clinical laboratory tests. Parametric analysis of variance models appropriate for a 6-period crossover design were used, along with multiple comparisons according to Tukey's method. RESULTS: All active treatments produced significantly (p < 0.0001) greater bronchodilation than placebo. The bronchodilator effect, as measured by FEV1 (peak percent change, peak as a percent of predicted value, duration, and area under the curve) after two inhalations of salbutamol/CFC-free was clinically comprable to two inhalations of salbutamol/CFC, with no clinically meaningful differences in safety parameters between the two delivery systems or between different dose levels. CONCLUSION: These results suggest that salbutamol/CFC-free may offer a suitable alternative for salbutamol/CFC when the need arises to change from CFC-containing salbutamol products.

Double-blind, clinical efficacy study comparing 400 micrograms of pirbuterol versus placebo delivered by a breath-actuated aerosol inhaler.

Pirbuterol is a selective beta-2 adrenergic agonist that is indicated for the treatment of bronchospasm in patients with asthma. Traditionally, the most common form of administration of the beta-2 agonist is by inhalation from a pressurized metered-dose inhaler. The purpose of this study was to compare the bronchodilator efficacy and safety of two inhalations (400 micrograms) of pirbuterol delivered by a breath-actuated aerosol (BAA) with that of two inhalations of a matching placebo. Patients were studied on each of two study days with a baseline electrocardiogram and sequential pulmonary function testing for 6 hr. Fourteen patients completed the study. The mean age was 32 years, with a range of 21-56 years. Most of these individuals had had asthma for more than 5 years. The mean percent increase in FEV1 was 41.2% for pirbuterol compared to 25.4% for placebo (p = 0.0038). The duration of improvement of > 15% over baseline was 4.5 hr for the pirbuterol group compared to 1.8 hr for the placebo group (p = 0.0022). There was no difference between the groups with respect to onset of action or time to reach peak effect. There was no significant difference between treatments with respect to any cardiovascular parameter. We conclude that pirbuterol in the BAA device produced significantly more bronchodilatation than did placebo with respect to its peak effect, duration of effect, and percentage change from baseline. Therefore, we feel that pirbuterol administered through the BAA device is a safe, effective means of treating both acute and chronic asthma.

Corticotropin-releasing factor modulates defensive-withdrawal and exploratory behavior in rats.

The role of corticotropin-releasing factor (CRF), an endogenous neuropeptide, in modulating species-typical responses was examined in an unfamiliar open field containing a small chamber. Rats placed in this small chamber spent most of their time withdrawn in it. However, rats given an intracerebroventricular injection (20 micrograms) of alpha-helical CRF(9-41), a CRF receptor antagonist, emerged from the chamber and explored the unfamiliar open field. Additional studies showed that after 1 exposure to the test environment, vehicle-treated rats increased their time spent in the open field and returned intermittently to the chamber. This result suggests that reexposure reduces the threatening impact of an unfamiliar open field. Importantly, CRF (300 ng) injected centrally, but not peripherally, before reexposure to the test environment significantly reduced exploration in the open field and increased a pattern of defensive-withdrawal into the chamber. Data suggest that whether defensive-withdrawal or exploratory behavior is exhibited may depend on CRF actions in brain systems that mediate the perception of threat in the environment.

Stressor controllability during pregnancy influences pituitary-adrenal hormone concentrations and analgesic responsiveness in offspring.

Repeated escapable shock, yoked-inescapable shock, or no-shock treatments were administered to female rats before parturition to investigate the effects of stressor controllability on offspring pituitary-adrenal hormone concentrations and stress-induced analgesic reactions. Female rats exposed to escapable shock treatments received tail-shock in boxes containing a wheel that allowed shocks to be terminated after rotation. Rats in the yoked-inescapable shock group received an identical amount and pattern of tail-shock. However, shock was terminated only after wheel rotation by the rat undergoing escapable shock treatments. Female rats in the no-shock group were simply placed in wheel-turn boxes. Fourteen-day-old offspring were exposed for 10-min to either a separation-stress or shock-induced stress test. The former test consisted of separating and isolating the pup from the mother and siblings, whereas the latter involved the administration of five brief, 1.0 sec, low intensity, 0.5 mA, foot-shocks. Immediately after exposure to foot-shocks, pups were given a tail-flick test to assess their analgesic response. Plasma was obtained from pups immediately after separation and tail-flick tests and ACTH and corticosterone concentrations were assayed by radioimmunoassay. Results indicated that prenatal inescapable shock treatments resulted in offspring with significantly higher plasma ACTH and corticosterone concentrations than offspring exposed to prenatal escapable shock or no-shock treatments. Offspring of females exposed to inescapable shock also exhibited greater increases from basal concentrations in ACTH and corticosterone after stress. Furthermore, prenatal escapable and inescapable shock treatments significantly altered shock-induced analgesic thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)