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Medical research on vanceril
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.
Anal Chim Acta. 2008 Jun 9; 617(1-2): 216-24
Andersen JH, Hansen LG, Pedersen M
A solid phase extraction (SPE) method for extraction and clean up of 9 synthetic corticosteroids was optimized for quantification by reversed-phase high-performance liquid chromatography/negative electrospray ionisation mass spectrometry. Clean up was accomplished using a mixed mode polymeric strong anion exchange SPE column. The final method was validated according to EU regulations for determination of residues of veterinarian drugs in products of animal origin. Initial results showed a large difference in ion suppression between samples of porcine and bovine urine. The aim of optimisation was to design a procedure that minimised this difference while using a single SPE procedure and a fast HPLC method that enabled sufficient separation of the epimers beta- and dexamethasone. To include conjugated corticosteroids in the analysis, the sample was hydrolysed with Helix Pomatia beta-glucuronidase/aryl sulfatase. For the final method, which included fluocinolone acetonid, triamcinolone acetonid, beclomethasone, flumethasone, dexamethasone, betamethasone, 6alpha-methylprednisolone, prednisone and prednisolone, a quantification based on spiked samples carried through the entire analytical procedure was used. For quantification of triamcinolone acetonid an internal standard (triamcinolone acetonid-D6) was used. Relative average recoveries from 96 to 103% were found, except for beclomethasone (113%). Absolute average recoveries were 81-99%. Quantification limits (decision limits, CCalpha) were demonstrated to be not higher than 1 microg L(-1) (3 microg L(-1) for prednisone and prednisolone). The internal reproducibility, determined by triplicates from spiking at three different levels in six analytical series was 7-19% (at 2-4 microg L(-1)) except for prednisone and prednisolone (26-27% at 3-6 microg L(-1)).
Cluster Analysis and Clinical Asthma Phenotypes.
Am J Respir Crit Care Med. 2008 May 14;
Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH
RATIONALE: Heterogeneity in asthma expression is multidimensional, including variability in clinical, physiological and pathological parameters. Classification requires consideration of these disparate domains in a unified model. OBJECTIVES: To explore the application of a multivariate mathematical technique, k-means cluster analysis, for identifying distinct phenotypic groups. METHODS: We performed k-means cluster analysis in three independent asthma populations. Clusters of a population managed in primary care (n=184) with predominantly mild to moderate disease, were compared with a refractory asthma population managed in secondary care (n=187). We then compared differences in asthma outcomes (exacerbation frequency and change in corticosteroid dose at 12 months) between clusters in a third population of 68 subjects with predominantly refractory asthma, clustered at entry into a randomised trial comparing a strategy of minimising eosinophilic inflammation (inflammation guided strategy) with standard care. RESULTS: Two clusters (early onset atopic and obese, non-eosinophilic) were common to both asthma populations. Two clusters characterised by marked discordance between symptom expression and eosinophilic airway inflammation (early onset symptom predominant and late onset inflammation predominant) were specific to refractory asthma. Inflammation guided management was superior for both discordant subgroups leading to a reduction in exacerbation frequency in the inflammation predominant cluster [3.53 (SD 1.18) vs 0.38 (SD 0.13) exacerbation/patient/year, p=0.002] and a dose reduction of inhaled corticosteroid in the symptom predominant cluster (mean difference 1829microg beclomethasone equivalent/ day (95% CI 307 - 3349 microg) p=0.02). CONCLUSIONS: Cluster analysis offers a novel multidimensional approach for identifying asthma phenotypes that exhibit differences in clinical response to treatment algorithms.
HIV Med. 2008 May 3;
Foisy MM, Yakiwchuk EM, Chiu I, Singh AE
Objective The purpose of this article is to provide a systematic overview of the literature on adrenal suppression and Cushing's syndrome secondary to an interaction between inhaled/intranasal fluticasone and ritonavir. The clinical presentation, diagnosis and management will be discussed. Methods A literature search using Medline and EMBASE and a search of abstracts of the three previous years of major HIV-related conferences were carried out. Results There were 25 cases (15 adult and 10 paediatric) of significant adrenal suppression secondary to an interaction between ritonavir and inhaled fluticasone, and three cases involving ritonavir and intranasal fluticasone. Cases with other steroids were not reported; however, there were cases of adrenal suppression with itraconazole [also a potent cytochrome p (CYP) 3A4 inhibitor] and inhaled budesonide. Clinicians need to differentiate between antiretroviral-induced lipodystrophy syndrome and iatrogenic Cushing's syndrome secondary to glucocorticoid use. Long-term fluticasone and ritonavir should be avoided. If ritonavir is required, another inhaled steroid such as low-dose budesonide or beclomethasone can be used cautiously. Upon discontinuation of inhaled corticosteroids, close monitoring for symptoms of adrenal insufficiency is warranted. The need for steroid replacement therapy at physiological doses should be assessed. Conclusions The combination of ritonavir and fluticasone should be avoided. Budesonide, beclomethasone, triamcinolone and flunisolide appear to be safer options.