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Medical research on beconase
Ann Allergy Asthma Immunol. 2008 Jun; 100(6): 601-7
Robroeks CM, van de Kant KD, van Vliet D, Kester AD, Hendriks HJ, Damoiseaux JG, Wodzig WK, Rijkers GT, Dompeling E, Jöbsis Q
BACKGROUND: Extra-fine hydrofluoroalkane-beclomethasone differs from other inhaled corticosteroids by its fine aerosol characteristics. Therefore, extra-fine hydrofluoroalkane-beclomethasone may be particularly useful for treating peripheral airway inflammation in asthma. OBJECTIVE: To analyze the anti-inflammatory effects of extra-fine hydrofluoroalkane-beclomethasone vs fluticasone dry powder inhaler (DPI) in asthmatic children by measuring bronchial and alveolar nitric oxide (NO) and inflammatory markers in exhaled breath condensate (EBC). METHODS: In a 6-month crossover study, 33 children aged 6 to 12 years with moderate persistent asthma were randomly treated with extra-fine hydrofluoroalkane-beclomethasone (200 microg daily via an Autohaler) and fluticasone DPI (200 microg daily via a Diskus). The primary outcome variables were alveolar NO concentration and bronchial NO flux. The secondary outcome variables were levels of inflammatory markers in EBC, lung function indices, symptoms, exacerbations, and adverse effects. All the variables were recorded at baseline and after each treatment period. RESULTS: Mean +/- SE alveolar NO concentration and bronchial NO flux were comparable after treatment with hydrofluoroalkane-beclomethasone vs fluticasone DPI (4.7 +/- 0.5 vs 4.3 +/- 0.5 ppb, P = .55, and 1,124.3 +/- 253.6 vs 1,029.1 +/- 195.5 pL/s, P = .70, respectively). In addition, levels of inflammatory markers in EBC, lung function indices, and symptoms did not differ between treatments. Patients used fewer beta2-agonists during the last 2 weeks of hydrofluoroalkane-beclomethasone treatment. CONCLUSION: The anti-inflammatory effects of hydrofluoroalkane-beclomethasone are similar to those of fluticasone DPI in children with moderate persistent asthma.
Inhaled corticosteroid use in asthmatic children receiving Ohio Medicaid: trend analysis, 1997-2001.
Ann Allergy Asthma Immunol. 2008 Jun; 100(6): 538-44
Stevenson MD, Heaton PC, Moomaw CJ, Bean JA, Ruddy RM
BACKGROUND: In 1997, national guidelines emphasized that inhaled corticosteroids (ICSs) are key therapy for individuals with all classes of persistent asthma, including children. OBJECTIVE: To examine the effect of these guidelines via time-trend analysis of ICS dispensation among children with asthma and Ohio Medicaid insurance. METHODS: A retrospective cross-sectional analysis by yearly cohorts was performed. From January 1, 1997, to December 31, 2001, all children from birth to the age of 18 years with 6 months of Ohio Medicaid enrollment or more, 1 or more asthma diagnoses associated with a provider claim, and 1 or more prescription claims for an asthma medication in a given calendar year were identified using claims data. The daily beclomethasone equivalent (BME) dose, the daily albuterol equivalent dose, and asthma-related health care use were calculated for each child within each yearly cohort. A time-trend regression analysis of subjects enrolled in all 5 years examined factors associated with BME. RESULTS: A total of 77,557 children met the study criteria. Among the 1,475 children enrolled during all 5 years, year of enrollment was a positive independent predictor of BME after adjustment for age, race, sex, systemic steroid bursts, albuterol equivalent dose, and health care use (P < .001). CONCLUSIONS: The daily BME dose significantly increased for children with asthma insured by Ohio Medicaid from 1997 to 2001. However, the percentages of children receiving both ICS and a therapeutic BME dose were alarmingly low. The mean BME dose was particularly low among children with 1 or more emergency department visits, no hospitalizations, and 3 or fewer physician visits for asthma per year, suggesting that broader efforts to target this group are needed.
Beclometasone Oral - DOR BioPharma: Beclomethasone Oral - DOR BioPharma.
Drugs R D. 2008; 9(4): 271-6
DOR BioPharma is developing an oral tablet formulation of beclometasone diproprionate for the treatment and prevention of gastrointestinal graft-versus-host disease (GvHD) and for the treatment of gastrointestinal radiation injury. Beclometasone is a potent corticosteroid that has been marketed worldwide since the early 1970s as the active ingredient in a nasal spray and in a metered-dose inhaled formulation for the treatment of allergic rhinitis and asthma.The oral formulation under development with DOR, known as orBec((R)), is a single product consisting of two enteric-coated tablets. One tablet is intended to release beclometasone in the proximal portions of the gastrointestinal tract, while the other tablet is intended to release the agent in the more distal portions of the tract. orBec((R)) is designed to reduce the need for systemic immunosuppressive drugs, thereby improving the outcome of bone marrow and stem cell transplantation. DOR is awaiting regulatory approval of orBec((R)) in the EU and the US for the treatment of acute gastrointestinal GvHD. The product is also the subject of a phase II trial for the prevention of GvHD, and a preclinical animal study in radiation injury. orBec((R)) may also have application in treating other gastrointestinal disorders characterized by severe inflammation including irritable bowel syndrome, ulcerative colitis and Crohn's disease. DOR BioPharma has stated that orBec((R)) has the potential to be of significant benefit to paediatric patients with Crohn's disease.The oral beclometasone formulation was initially in development with Enteron Pharmaceuticals, a subsidiary of Corporate Technology Development. Enteron obtained the rights to oral beclometasone through an exclusive, worldwide, royalty-bearing license agreement with George B. McDonald, M.D., in October 1998. The agreement provided Enteron with the option to grant sublicenses for the rights to the intellectual property and know-how relating to the agent. However, Corporate Technology Development was acquired by Endorex Corporation in December 2001 and the resulting company underwent a name change to become DOR BioPharma.In February 2008, DOR BioPharma entered into a Letter of Intent with BL&H in regard to the administration of a Named Patient Program (NPP) for orBec((R)) to patients with gastrointestinal GvHD in South Korea. This agreement gives the right for medical practitioners to prescribe investigational drugs to patients who qualify. DOR will be responsible for the manufacture and supply of orBec((R)) while BL&H will be covering distribution costs in Korea.According to a letter of intent signed in November 2007, Orphan Australia has agreed to act as a sponsor for DOR BioPharma with regard to the administration of a Named Patient Access Program (NPAP) for orBec((R)) to patients with gastrointestinal GvHD in Australia, New Zealand and South Africa. Under the NPAP compassionate use drug supply programme, the Therapeutic Goods Administration (TGA) allows medical practitioners to supply investigational drugs to patients who qualify. Both Orphan Australia and DOR will receive revenue for supplying orBec((R)) under the NPAP. New Zealand and South Africa also have similar access mechanisms for supply under a named patient basis.DOR BioPharma received $US3 million under a non-binding letter of intent from Sigma-Tau Pharmaceuticals in January 2007. The agreement granted Sigma-Tau an exclusive right to negotiate terms and conditions for a possible business transaction or strategic alliance regarding orBec((R)) and potentially other DOR BioPharma pipeline compounds until 1 March 2007. Under the terms of the agreement, Sigma-Tau purchased $US1 million of DOR BioPharma's common stock, with an additional $US2 million paid in cash. However, as no agreement was reached by the specified date, DOR returned the $US2 million to Sigma-Tau in June 2007. DOR BioPharma received an unsolicited proposal from Cell Therapeutics, Inc. to acquire DOR BioPharma in January 2007. Because of the non-binding agreement already signed with Sigma-Tau, DOR BioPharma was not able to consider the merger proposal.In November 2001, Corporate Technology Development (now DOR BioPharma) initiated a phase II trial in the US to evaluate the efficacy of orBec((R)) in the treatment of Crohn's disease. This trial is no longer active but DOR BioPharma is exploring the possibility of continuing the testing of orBec((R)) for Crohn's Disease.The US FDA issued a non-approvable letter in October 2007 in response to the NDA submitted by DOR BioPharma for the use of orBec((R)) in the treatment of gastrointestinal GvHD. The non-approvable letter followed on from a ruling by the Oncologic Drugs Advisory Committee (ODAC) of the FDA in May 2007 that the data package supporting the product did not show substantial evidence of efficacy for the treatment of gastrointestinal GvHD. The FDA requested data from additional clinical trials to demonstrate safety and efficacy of the product, as well as information regarding other sections of the NDA.Research for this compound has been aided by a $8.5 million common stock purchase agreement between DOR BioPharma and Fusion Capital Fund II, LLC, which was confirmed in February 2008.In February 2008, DOR BioPharma completed clinical trials for the use of the drug in the treatment of gastrointestinal GvHD. It showed that signficantly fewer patients randomized to orBec((R)) had deterioration of pulmonary diffusing capacity by transplant day 80 compared with placebo. It may have a protective effect accompanied by prevention of clinical pulmonary events. These beneficial effects on the lungs may be due to the delivery of the immunosuppressant 17-BMP, an active metabolite of BDP, to the pulmonary artery. Therefore oral BDP may prevent pulmonary interstitial inflammation and subsequent lung injury.The data provided in the MAA and NDA submissions demonstrated that orBec((R)) provided a lower risk of mortality compared with the standard of care. Both filings were supported by data from two randomized, double-blind, placebo-controlled clinical trials. The first trial was a 60-patient phase II trial conducted at the Fred Hutchinson Cancer Research Centre. The additional trial was a 129-patient pivotal phase III trial of orBec((R)) conducted at 16 centres in the US and France. The phase III trial failed to meet its primary endpoint of treatment failure through 50 days after allogeneic haemopoietic stem cell transplantation. However, orBec((R)) did achieve statistical significance in the secondary endpoints of time to treatment failure through day 80, and a reduction in mortality compared with placebo. In this trial, patient survival at the pre-specified endpoint of 200 days post-transplant showed a statistically significant 66% reduction in mortality among patients randomized to orBec((R)). DOR BioPharma believes the primary endpoint was not achieved as a result of a higher than expected rate of treatment failures during the initial 10 days in both treatment groups.The EMEA commenced a review of the MAA for orBec((R)) in the treatment of gastrointestinal GvHD, in November 2006. A response is expected by DOR BioPharma in the first half of 2008.DOR BioPharma has commenced a phase II trial of orBec((R)) to prevent gastrointestinal GvHD in patients undergoing a donor stem cell transplant for haematological cancer. The trial is supported by a National Institutes of Health (NIH) grant awarded to the Fred Hutchinson Cancer Research Center. The randomized, double-blind trial will enroll 138 patients, with 92 patients in the orBec((R)) arm and 46 patients in the placebo arm. Treatment will be administered in conjunction with a conditioning regimen and will continue for 75 days after transplant. The trial aims to determine if prophylactic administration of orBec((R)) can favourably influence the incidence and severity of acute GvHD, thereby decreasing the need for high-dose systemic corticosteroid treatment. DOR received FDA clearance to conduct the phase II trial in March 2007. Patient enrolment is expected to be completed in the second quarter of 2008.
Eur J Pharmacol. 2008 Jun 11;
Goto K, Chiba Y, Sakai H, Misawa M
Glucocorticoids are the most effective anti-inflammatory treatment for asthma, and inhaled corticosteroids are the most effective long-term control therapy for persistent asthma. In the present study, to determine the mechanism of the inhibitory effect of glucocorticoids on airway hyperresponsiveness, the effects of glucocorticoids on the expression and activation of PKC-potentiated protein phosphatase 1 inhibitory protein of 17 kDa (CPI-17) were examined in bronchial smooth muscles of antigen-induced airway hyperresponsive rats. Repeated antigen inhalation to animals sensitized with DNP-Ascaris antigen caused a marked bronchial smooth muscle hyperresponsiveness to acetylcholine, accompanied by upregulation and acetylcholine-induced activation of CPI-17 to result in an increase in myosin light chain (MLC) phosphorylation. Treatment with glucocorticoids (prednisolone or beclomethasone, 10 mg/kg, i.p., respectively) significantly inhibited the airway hyperresponsiveness, and markedly reduced both the protein and mRNA levels of CPI-17 in bronchial smooth muscle. The acetylcholine-induced activation of CPI-17, i.e., phosphorylation of CPI-17, was also significantly inhibited by glucocorticoids. Glucocorticoids also prevented the augmented acetylcholine-induced MLC phosphorylation observed in the airway hyperresponsive rats. Therefore, glucocorticoids might inhibit the airway hyperresponsiveness through the inhibition of overexpression and activation of CPI-17.
Respir Med. 2008 Jun 21;
Ko FW, Ip M, Chan PK, Ng SS, Chau SS, Hui DS
AIM: This study assessed the infectious etiology of patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) with concomitant pneumonia. METHODS: Patients admitted to medical wards in an acute hospital were recruited prospectively from May 1, 2004 to April 30, 2005. Sputum culture, blood culture, paired serology, and nasopharyngeal aspirates (NPA) viral culture and polymerase chain reaction (PCR) studies were performed. Spirometry was assessed in stable phase at 2-3 months post-hospital discharge. RESULTS: Seventy eight subjects were admitted for AECOPD with concomitant pneumonia. The mean (SD) age was 77.1 (7.5) years, with FEV(1) of 41.5 (20.8)% predicted normal. Overall, an infectious etiology could be established in 48.7% of the subjects. Among the 71 subjects with sputum collected, 40.8% had positive bacterial culture. The commonest bacteria identified were Streptococcus pneumoniae (8[11.3%]), Pseudomonas aeruginosa (7[9.9%]) and Haemophilus influenzae (7[9.9%]). Among the 66 subjects with NPA collected, 9.0 and 12.2% had positive viral culture and PCR results, respectively. The commonest viruses identified by NPA PCR were influenza A (4[6.1%] subjects) and rhinovirus (2[3.0%]). Paired serology was positive in 4.4%. Patients on high dose inhaled corticosteroid (ICS) (>1000mcg beclomethasone-equivalent/day) had a higher rate of positive sputum bacterial culture than those on low-medium dose of ICS (50.0% vs 18.2%, p=0.02). CONCLUSION: An infectious etiology could be established in about half of patients hospitalized with AECOPD and concomitant pneumonia. The majority of identifiable causes were bacterial. Patients on high dose ICS might have impaired airway defense as reflected by the higher rate of positive sputum culture.
Biochemical markers as a response guide for steroid therapy in asthma.
J Asthma. 2008 Jun; 45(5): 425-8
Al Obaidi AH, Al Samarai AM
BACKGROUND: Exhaled breath condensate pH and hydrogen peroxide concentration is a non-invasive, simple and inexpensive assay that can be performed for monitoring in patients with asthma. OBJECTIVE: To evaluate the possibility of usefulness of expired breath condensate pH and H(2)O(2) concentration as well as serum total antioxidant capacity and malondialdehyde as markers for steroid treatment response. PATIENTS AND METHODS: A total of 153 patients were included in this study (age range 18 to 64 years). Asthmatic patients, regularly followed for at least 3 months, were randomly recruited for the study over a period of one month. All patients received inhaled beclomethasone dipropionate (1,000 microg daily in four divided doses) and salbutamol inhalers (800 microg daily in four divided doses) for 4 weeks. Expired breath condensate was collected at the end of the study to determine hydrogen peroxide concentration and pH. Venous blood samples were collected for determination of total antioxidant capacity and malondialdehyde as markers of peroxidation. RESULTS: In asthmatic patients with poorly controlled asthma, expired breath condensate hydrogen peroxide concentration was higher and the pH was lower than stable asthma. Serum malondialdehyde concentration in poorly controlled asthma was higher (6.98 micromol/L), and total antioxidant capacity was lower (589 micromol/L) than in stable asthma. CONCLUSION: Exhaled hydrogen peroxide concentration and pH can be used as predictors for monitoring of nonresponse to asthma treatment.
J Pharm Sci. 2008 Jun 11;
Jones SA, Reid ML, Brown MB
A transiently supersaturated drug delivery system has the potential to enhance topical drug delivery via heightened thermodynamic activity. The aim of this work was to quantify the degree of saturation (DS) for transiently supersaturated formulations using three traditional and one novel in vitro assessment methods. Metered dose aerosols (MDA) were formulated containing saturated levels of beclomethasone dipropionate monohydrate (BDP) or betamethasone 17-valerate (BMV) within a pressurised canister, and included ethanol (EtOH), hydrofluoroalkane 134a propellant and poly(vinyl pyrrolidone). Attempts to determine the DS via the measurement of drug flux through synthetic membranes did not correlate and was shown to be dependent on the EtOH concentration. The inability of these methods to accurately assess the drug DS may be due to the transient nature of the formulation and the volatile solvents dehydrating the membrane. A mathematical equation that used the evaporation rate of the formulation was derived to determine the theoretical DS at various time points after MDA actuation. It was shown that the MDAs became supersaturated with a high DS, this enhanced drug release from the formulation and therefore these preparations have the potential to increase the amount of drug delivered into the skin. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci.
Dose-response relationship for risk of non-vertebral fracture with inhaled corticosteroids.
Clin Exp Allergy. 2008 Jun 3;
Weatherall M, James K, Clay J, Perrin K, Masoli M, Wijesinghe M, Beasley R
Objective To determine the strength of association between the dose of inhaled corticosteroids (ICS) and risk of non-vertebral fracture in adults. Methods A systematic review and meta-analysis of case-control studies of non-vertebral fractures in adults, in which at least two doses of ICS were reported as the dose of beclomethasone dipropionate (BDP) or equivalent. Results Five case-control studies were identified, with a total of 43 783 cases and 259 936 controls. There was an association between the risk of non-vertebral fracture and increasing dose of BDP. The random-effects odds ratio of relative risk for a non-vertebral fracture was 1.12 (95% confidence interval 1.00-1.26) per 1000 mug increase in the daily dose of BDP or equivalent. Conclusion In older adults, the relative risk of non-vertebral fractures increases by about 12% for each 1000 mug/day increase in the dose of BDP or equivalent. The magnitude of this risk was considerably less than other common risk factors for fracture in the older adult.
[Treatment of allergic rhinitis rats by intranasal interferon gamma]
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2008 Feb; 43(2): 134-8
Li Q, Zhang YD, Sun CW, Chen YL, Du YH, Zhao GJ, Zhang DL
OBJECTIVE: To investigate the effects and mechanism of intranasal interferon gamma (IFN-gamma) in the treatment of allergic rhinitis. METHODS: Ovalbumin (OVA) absorbed to aluminum hydroxide was used to construct the allergic rhinitis model (group C), and the normal control group (group A), the allergic rhinitis model group (group B) and beclomethasone dipropionate group (group D) consisted of 8 rats for each. PBS 50 microl was absorbed to group B, IFN-gamma 1 microg was absorbed to group C and beclomethasone dipropionate 3.5 microg was absorbed to group D on day 31 to day 38 once daily once nasal cavity. The nasal lavage fluid was collected on day 39, and the cellular constituents, levels of interleukin-4 (IL-4), interleukin-5 (IL-5) and IgE were determined, together with the pathologic changes and expression of GATA-3 were observed. RESULTS: Decrease of eosinophils [(0.005 +/- 0.003) x 10(4)/ml, x +/- s] was seen in nasal lavage fluid of group C as comparing with group B [(0.225 +/- 0.060) x 10(4)/ml, (P < 0.01)], and the levels of IL-4 (7.8 +/- 3.5) pg/ml and IL-5 (12.5 +/- 4.3) pg/ml decreased significantly in comparing with group B (P < 0.01). The serum levels of total IgE (38.5 +/- 9.6) microg/ml and ovalbumin-specific IgE (19.8 +/- 5.4) IU/ml decreased significantly in comparing with those of group B (P < 0.01). In group B, mucosal congestion and edema thickening with inflammatory cells infiltration mainly of eosinophils; in group C, the above mentioned changes were much more ameliorated. Immunohistochemistry showed significant increase of GATA-3 expression in the nosal tissue of group B but much lesser than that in group C. CONCLUSIONS: IFN-gamma can inhibit the composition of IL-4 and IL-5, and inhibit the airway inflammation with eosinophilic infiltration and the serum levels of total IgE and ovalbumin specific IgE, probably through the mechanism of restraining the Th2 reaction by blockade of GATA-3 expression in the nasal tissue.
Allergol Int. 2008 Jun 1; 57(3):
Ohbayashi H, Adachi M
Background: To evaluate whether hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP) controls eosinophilic inflammation, including that in the distal airways, more effectively than fluticasone propionate (FP) Diskus. Methods: Fifty patients with well-controlled mild to moderate persistent asthma using FP for more than 6 months were randomly assigned to FP and HFA-BDP groups, and the treatment regimens of the two groups were switched twice between FP and HFA-BDP in a double cross-over manner at 3-month intervals after 2-week washout periods. Evidence of eosinophilic inflammation in blood and induced sputum samples was assessed, together with pulmonary function testing and an Asthma-related Quality of Life Questionnaire (AQLQ) survey after each treatment period. Results: The peripheral blood differential eosinophil count and sputum levels of eosinophil cationic protein (ECP) showed reciprocal changes during the study periods in both groups. The blood differential eosinophil count was significantly lower during the HFA-BDP than during the FP treatment period in both the FP (p = 0.004) and the HFA-BDP (p = 0.020) group. The late-phase induced sputum ECP level was significantly decreased during the HFA-BDP treatment period in both the FP (p = 0.016) and the HFA-BDP group (p = 0.023). The significant elevation of surfactant protein D values in the late-phase sputum observed in both groups indicated that late-phase sputum was obtained mainly from proximal peripheral airways. Both symptom and activity limitation domains of the AQLQ in the HFA-BDP group significantly increased after switching from FP to HFA-BDP. There were no significant changes in pulmonary function indices in either group at any time during the study. Conclusions: HFA-BDP improved residual eosinophilic inflammation in asthmatic airways, including distal airways, more effectively than FP.