Pharmacokinetics of epimeric budesonide and fluticasone propionate after repeat dose inhalation--intersubject variability in systemic absorption from the lung

AIMS: Pharmacokinetic variability is likely to be a significant factor contributing to the interindividual differences in dose requirements, anti-inflammatory response and side-effects with inhaled corticosteroids (ICS), but there is limited information about the disposition of ICS during regular dosing with a pressurized metered dose inhaler (pMDI). This study uses a mixed effects modelling approach to quantify and compare the interindividual variability in pharmacokinetics of epimeric budesonide (BUD) and fluticasone propionate (FP) after repeat-dose inhalation. METHODS: This pharmacokinetic substudy was part of a previously published open-label, randomised, placebo-controlled, 7-period crossover study to evaluate the short-term effects on plasma cortisol levels of inhaled BUD (400, 800, 1600 microg twice daily) and FP (375, 750, 1000 microg twice daily) via pMDI in a group of healthy male volunteers. On the fifth day of each high-dose treatment period (BUD 1600 microg twice daily and FP 1000 microg twice daily), venous blood samples were collected in nine subjects prior to the last dose and at 15 min, 30 min, 1, 2, 4, 6 and 8 h postdose for measurement of plasma drug concentrations to determine the pharmacokinetics of epimeric BUD and FP following inhalation. Non-compartmental analysis and a mixed effects model were used to characterize the disposition profiles. RESULTS: Both drugs had a rapid absorption half-life (BUD 10 min vs FP 11.3 min), but quite different elimination half-lives (BUD 2.4 h vs FP 7.8 h). Although there were intraindividual differences in the handling of the 22R-and 22S-epimers of BUD, there were no consistent pharmacokinetic differences between the two enantiomers in the group as a whole. Consistent with previous reports of FP's higher volume of distribution (V) and lower systemic bioavailability (F), the V/F ratio was lower for BUD than FP (498 l vs 8100 l). The parameter with the greatest interindividual variability for both BUD and FP was the rate of systemic absorption from the lung. CONCLUSIONS: This is the first report describing the pharmacokinetics of epimeric BUD and FP after repeat dose inhalation via pMDI. Three observations may be of clinical relevance: (1) there is considerable intersubject variability in the rate of absorption of both drugs from the lung; (2) in some individuals there was a long t(1/2),z for BUD, resulting in higher and more sustained plasma drug levels in the 4-12 h postdose period than would be predicted from single-dose pharmacokinetic data; and (3) there is evidence of diurnal variation in FP pharmacokinetics, with higher-than-expected plasma drug concentrations in the morning compared with the evening.     

The use of atomic force microscopy to study the conditioning of micronised budesonide

Patent literature describes “conditioning” techniques which employ organic vapours to recrystallise amorphous regions in micronised particles, with the aim of improving their processability and physico-chemical stability. This report describes a preliminary study investigating the efficacy of PhaseImaging™ atomic force microscopy (AFM) for the investigation of such processes. AFM phase images demonstrated variation in mechanical properties across the surface of milled budesonide particles, which diminished upon exposure to ethanol vapour. No variation was seen in phase images of unmilled budesonide. Dynamic vapour sorption confirmed the presence amorphous material in the milled sample and its subsequent recrystallisation following exposure to ethanol vapour under the same conditions as those used in the AFM experiment. It was therefore hypothesised that variation in the phase images indicated the presence of amorphous regions which were subsequently conditioned. PhaseImaging™ AFM may therefore be a useful method for the study of conditioning techniques, enabling the efficacy and kinetics of the process to be observed.     

沙美特罗和布地奈德的脂质体/水分配系数测定及影响因素考察

目的测定沙美特罗和布地奈德的脂质体/水分配系数(P_L/w)，考察影响两种药物P_L/w的因素，揭示药物与磷脂双分子层的作用机制。方法用平衡透析法测定两种药物在不同脂质体组成和不同介质中的P_L/w。结果两种药物P_L/w随脂质体中胆固醇含量及磷脂饱和程度增加而减小；脂质体表面负电荷、介质pH值及离子强度增加，沙美特罗的P_L/w增加。脂质体表面电荷、介质pH值及离子强度对布地奈德的P_L/w影响较小。结论药物P_L/w受药物性质、脂质体磷脂种类、饱和程度、胆固醇含量和表面电荷以及介质pH和离子强度等因素影响，在测定时应选择与生物膜环境相近的P_L/w测定条件，以反映药物在生物膜中的分配。     

普米克令舒雾化吸入干预毛细支气管炎后哮喘发病率的效果探讨

目的　观察布地奈德 (budesonide,普米克令舒 )吸入疗法对减少毛细支气管炎后哮喘发病率的作用。方法　分组观察毛细支气管炎的患儿临床缓解后吸入和不吸入普米克令舒雾化液后 2年哮喘的发病率。结果　吸入组患儿发病率 14 .0 % ,对照组发病率为 33.3% ,二者有显著性差异 (P <0 .0 5 )。结论　在毛细支气管炎缓解后吸入普米克令舒可明显降低哮喘的发病率。     

Vibrational spectroscopic study of salbutamol hemisulphate

Salbutamol hemisulphate is a relatively selective β₂‐adrenergic agonist and is used as a bronchodilator. In this work, we present a detailed vibrational spectroscopic investigation of salbutamol hemisulphate using mid‐infrared and near‐infrared Fourier‐transform (NIR‐FT) Raman spectroscopies. These data are supported by quantum chemical calculations, which allow us to characterise the vibrational spectra of this compound reasonably. As such, this study could be viable for examining the way in which this drug interacts with its target molecules. Copyright © 2009 John Wiley & Sons, Ltd.     

奥亭联合布地奈德治疗咳嗽变异性哮喘的临床观察

目的:观察奥亭止咳露联合布地奈德气雾剂治疗咳嗽变异性哮喘(CVA)的效果及安全性。方法:将CVA72例分为3组:奥亭+布地奈德组30例,布地奈德组21例,泼尼松组21例,分别给予相应的药物治疗28d,观察咳嗽消失时间和支气管激发试验结果,并以积分法统计有效率和显效率,同时观察药物不良反应。结果:治疗14d,3组总有效率分别为90.00%、90.48%和90.48%,无统计学差异(P>005);但奥亭+布地奈德组显效率60%明显优于布地奈德组14.29%,(P<0.01),与泼尼松组(61.90%)相当(P>0.05)。奥亭+布地奈德组平均止咳时间(5.9±1.9)d,也与泼尼松组(6.8±2.2)d相当(P>0.05),但明显优于布地奈德组(9.9±3.2)d(P<0.01)。奥亭+布地奈德组有1例(3.33%)和布地奈德组有1例(4.76%)分别发生口腔霉菌感染和声音嘶哑,而泼尼松组共有8例(38.09%)出现不良反应,明显大于前两组(P<0.01)。结论:奥亭联合布地奈德是治疗CVA快速有效安全的新方法。     

缬草属常见药用植物的红外光谱鉴别

目的：对缬草属6种常见药用植物20个样品进行红外光谱鉴别研究。方法：对各样品粉末直接压片，采用傅立叶变换中红外光谱进行测定分析。结果：缬草属不同种药用植物具有各自光谱特征，并根据相似情况明显分为三大类；种内样品间的光谱特征反映出成分稳定性和产地差异。结论：红外光谱是一种高效、快速的鉴别方法。     

布地奈德雾化吸入对悬雍垂腭咽成形术后咽部水肿及疼痛的作用

目的探讨悬雍垂腭咽成形术后应用布地奈德雾化吸入对咽部粘膜水肿及疼痛的影响。方法对52例阻塞性睡眠呼吸暂停低通气综合征患者行悬雍垂腭咽成形术,随机分为治疗组和对照组,治疗组术后1～6 d应用布地奈德雾化吸入,观察患者咽部水肿及疼痛情况并与对照组进行对比。结果治疗组患者咽部水肿消失在（4.23±0.71）d;对照组患者咽部水肿消失在（5.38±0.70）d;两组差异有显著性。治疗组患者咽部疼痛评分第2天开始较对照组差异有显著性。结论悬雍垂腭咽成形术后患者应用布地奈德雾化吸入可有效减少咽部粘膜水肿及疼痛,值得临床推广。     

Applications of Fourier transform infrared spectroscopic imaging to tablet dissolution and drug release

Introduction: Solid oral dosage forms are the most commonly used method for administering active pharmaceutical ingredients to patients. Understanding the mechanisms and processes of drug release is essential for improving the design of pharmaceutical tablets.

Areas covered: In this review, recent approaches where attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic imaging has been applied to study tablet dissolution and drug release have been investigated. Drug release studies of model pharmaceutical systems composed of drug/polymer mixtures in the presence of aqueous solutions have been discussed, as has the subsequent combination with UV/Vis spectroscopic detection to quantify the amount of drug dissolved as a function of time. The use of a single-reflection ATR accessory with a diamond crystal allows for in situ FTIR imaging of tablet compaction and dissolution.

Expert opinion: ATR-FTIR imaging can address the challenges of investigating the mechanisms of drug release from a range of innovative new delivery systems. Unlike standard dissolution tests, this spectroscopic imaging method obtains insight and information about changes within the tablet during dissolution. Areas where ATR-FTIR imaging has shown further potential to be particularly useful are for the study of multi-layered solid tablets, high-throughput analysis, use of microfluidic devices and for surface-enhanced ATR-FTIR spectroscopy.     

布地奈德联合盐酸肾上腺素雾化吸入治疗小儿急性感染性喉炎的疗效观察

目的 观察布地奈德联合盐酸肾上腺素雾化吸入治疗小儿急性感染性喉炎的疗效.方法 对该院2012年3月-2013年3月确诊为急性喉炎的门诊及住院患儿采用随机数字表法分别选入三个治疗组.除常规治疗之外,分别给予患儿地塞米松静脉滴注（A组）,或地塞米松静脉滴注联合盐酸肾上腺素雾化吸入（B组）,或布地奈德联合盐酸肾上腺素雾化吸入（C组）,观察比较三种不同治疗方法对患儿的治疗效果.结果 研究共纳入患儿116例.C组与A组患儿相比较,症状改善的时间、病程显著缩短（P＜0.05）,总有效率显著提高（P＜0.05）,C组与B组患儿相比较,病程明显缩短（P＜0.05）.A、B、C 三组的总有效率分别为81.58％、90.00％、97.36％.结论 布地奈德联合盐酸肾上腺素雾化吸入治疗小儿急性感染性喉炎较单用地塞米松静脉滴注或地塞米松静脉滴注联合使用盐酸肾上腺素雾化吸入效果更好,起效迅速,安全可靠,值得临床推广.     

孟鲁斯特联合布地奈德治疗咳嗽变异性哮喘的疗效及对肺功能的影响

目的 探讨孟鲁斯特联合布地奈德治疗咳嗽变异性哮喘（CVA）患儿的临床疗效及对肺功能的影响。方法 选取2014年3月-2017年3月渭南市第一医院收治的CVA患儿280例,按照治疗方式分为对照组和观察组,各140例。对照组在常规治疗的基础上给予患儿布地奈德治疗,观察组在对照组的基础上给予孟鲁斯特治疗,两组均治疗60 d。比较两组的临床疗效,治疗前后肺功能指标呼气流量峰值（PEF）、1s用力呼吸容积（FEV1）及一秒率（FEV1/FVC）,比较两组不良反应的发生情况。结果 治疗后,观察组临床疗效的总有效率是94.29%,显著高于对照组的77.14%,差异有统计学意义（P<0.05）。两组患儿治疗前的肺功能指标比较无明显差异,两组治疗后以上检测指标较治疗前均显著提高,同组治疗前后比较差异有统计学意义（P<0.05）;治疗后,观察组PEF、FEV1、FEV1/FVC水平均显著高于对照组,差异有统计学意义（P<0.05）。两组患儿在治疗期间均无严重不良反应的发生,不良反应发生情况无显著差异。结论 孟鲁斯特联合布地奈德治疗咳嗽变异性哮喘比单用布地奈德治疗的临床效果好,可有效改善患儿的肺功能,值得临床推广。     

布地奈德与地塞米松雾化吸入治疗急性喉炎临床疗效比较

目的比较布地奈德与地塞米松雾化吸入治疗急性喉炎临床效果。方法将62例急性喉炎患者随机分为两组,A组30例给予地塞米松氧驱雾化吸入,B组32例给予布地奈德空气压缩雾化吸入,观察两组治疗效果。结果 A组治疗总有效率为73.33%,低于B组的96.88%(P0.05);A组呼吸困难、喉鸣、咳嗽、声嘶消失时间及住院时间均长于B组的;A组不良反应发生率为33.33%,高于B组的6.25%(P0.01)。结论布地奈德治疗小儿急性喉炎疗效优于地塞米松,可促进临床症状消除,患儿耐受性好,可作为急性喉炎的有效治疗药物。     

布地奈德对变应性鼻炎豚鼠鼻粘膜嗜酸性粒细胞及组胺的影响

目的：制备变应性鼻炎动物模型,评价布地奈德对变应性鼻炎嗜酸性粒细胞和组胺的影响.方法：将豚鼠随机分成自然对照组、变应性鼻炎组和布地奈德治疗组,采用甲苯-2,4-二异氰酸酯对豚鼠鼻腔局部致敏激发制备变应性鼻炎模型,通过观察动物临床症状、鼻粘膜病理切片和鼻粘膜组织中组胺含量等指标来评价药物的药效.结果：变应性鼻炎组鼻粘膜组织中嗜酸细胞浸润和组胺含量均显著高于自然对照组（P＜0.01或P＜0.05）;经治疗后,动物的嗜酸细胞浸润和组织中组胺含量均明显地降低（P＜0.01）.在临床症状指标上,变应性鼻炎组和药物治疗组评分均明显高于自然对照组（P＜0.01）,但变应性鼻炎组和药物治疗组间无显著差异（P＞0.05）.结论：布地奈德能有效地降低变应性鼻炎豚鼠鼻粘膜组织中嗜酸细胞浸润和组胺的含量,但未能改善动物的鼻部临床症状,这可能与造模的方法有关.     

Efficacy of budesonide therapy in the early phase of treatment of adult coeliac disease patients with malabsorption: An in vivo/in vitro pilot study

• 1 Budesonide is a glucocorticosteroid with a local anti‐inflammatory effect. Coeliac disease is an immune‐mediated disease caused by gluten ingestion in intolerant patients. The aim of the present study was to investigate the efficacy of budesonide in malabsorptive coeliac patients and its effect in an in vitro gliadin challenge.
• 2 Twenty coeliac patients with malabsorption were enrolled in the present study and were randomly assigned to one of two 4 week treatments: (i) a gluten‐free diet alone; or (ii) a gluten‐free diet plus 6 mg budesonide daily. At the end of 4 weeks treatment, all patients underwent clinical evaluation, laboratory tests and self‐evaluation of well‐being using a visual analogue scale. Intestinal biopsies from five coeliac patients (selected randomly) and four non‐coeliac disease controls who underwent upper endoscopy for intestinal bleeding were challenged with gliadin (0.5 mg/mL) and budesonide (10–30 µg/mL) for 3 and 24 h. Biopsies were tested by immunohistochemistry and immunofluorescence for known markers of inflammation.
• 3 Treatment of patients with 6 mg budesonide daily for 4 weeks resulted in increased bodyweight, a decreased number of evacuations and decreased stool weight compared with patients on a gluten‐free diet alone for 4 weeks. Well‐being scores were higher in patients treated with both a gluten‐free diet and budesonide compared with those receiving a gluten‐free diet alone.
• 4 In vitro studies showed that budesonide reduced epithelial tyrosine phosphorylation and expression of histocompatibility leucocyte antigen complex DR (HLA‐DR) elicited by gliadin‐derived peptides. In addition, the expression of cyclo‐oxygenase (COX)‐2 and intercellular adhesion molecule (ICAM)‐1 in the lamina propria was reduced in patients treated with both gliadin and budesonide compared with patients treated with gliadin alone. Budesonide alone decreased HLA‐DR in crypt enterocytes, as well as ICAM‐1 and COX‐2 expression in the lamina propria of biopsy specimen of coeliac patients. Budesonide had no effect in control samples.
• 5 In conclusion, the results of the present study indicate that budesonide shows efficacy in the treatment of symptoms in adult coeliac patients with overt malabsorption. The mechanism underlying the effects of budesonide in reducing symptoms was elucidated by in vitro studies involving a gliadin challenge.

     

布地奈德对毛细支气管炎患儿炎性因子的调节作用及临床疗效分析

目的 分析布地奈德对毛细支气管炎患儿炎性因子的调节作用及临床疗效.方法 选取该院2009-2014年期间收治的300例毛细支气管炎患儿为研究对象,按随机数字表法将患者分为对照组和观察组,每组各150例.对照组给予临床常规治疗,观察组在对照组的基础上给予布地奈德雾化吸入持续治疗1周,比较两组毛细支气管炎患儿炎性因子的水平变化,并分析临床疗效.结果 与对照组比较,观察组的治疗效果较明显,观察组患儿治疗总有效率98.00%明显高于对照组的76.67%,且差异有统计学意义(P<0.05);观察组患儿治疗后临床症状恢复时间较短,且经8周治疗后,观察组患儿的炎性因子肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、白细胞介素-8(IL-8)的水平较低,分别为(159.3 ±26.8)、(148.3 ±30.6)、(350.1 ±69.2)ng· L-1,而干扰素-γ(INF-γ)的水平较高(P<0.05);观察组患儿治疗1 h后的呼吸频率(30.26 ±7.64)次/分钟和心率(127.96 ±10.64)次/分钟水平明显低于对照组的(38.04 ±9.73)次/分钟、(132.79 ±11.42)次/分钟,而血氧饱和度(96.13 ±3.07)%明显高于对照组的(89.75 ±2.43)%(P<0.05).结论 布地奈德可有效调节毛细支气管炎患儿的炎性因子水平,且治疗效果显著,值得临床推广应用.     

Nasal bioavailability and systemic effects of the glucocorticoid budesonide in man

Summary Budesonide, a topically potent glucocorticoid, was administered to 4 healthy volunteers by i.v. infusion and by nasal instillation of 100 µg tritium-labelled drug. Plasma was analyzed by liquid chromatography plus scintillation counting of collected fractions. After i.v. administration the plasma clearance was 0.92 l/min and the apparent volume of distribution was 2.8 l/kg. After nasal administration, the time to reach the peak plasma level was approximately 30 min, and the systemic availability was 102%. Budesonide had marginal effects on plasma cortisol and white blood cell counts either after i.v. or nasal administration. Thus, nasally instilled budesonide in solution is rapidly and completely absorbed from the nasal mucosa. The systemic effects after this clinically recommended nasal dose were negligible.     

沙丁胺醇气雾剂与布地奈德混悬液治疗儿童哮喘的临床观察

目的探讨氧气驱动雾化吸入沙丁胺醇气雾剂、布地奈德混悬液联合治疗儿童哮喘急性发作的疗效。方法将112例儿童哮喘急性发作患儿随机分为对照组58例和治疗组54例。对照组静滴地塞米松、氨茶碱，治疗组氧气驱动雾化吸入沙丁胺醇气雾剂、布地奈德混悬液，观察比较2组的疗效和副作用。结果症状缓解、总显效率、肺功能改善情况，治疗组与对照组疗效相比有显著性差异（P〈0．01），且未发现明显副作用。结论应用氧气驱动雾化吸入沙丁胺醇气雾剂、布地奈德混悬液为目前治疗儿童哮喘急性发作为安全有效的方法。     

A randomized controlled assessment of the effects of different dosing regimens of budesonide on the HPA-axis in healthy subjects

AIMS: To investigate the effect on the hypothalamo-pituitary-adrenal (HPA) axis of treatment with budesonide, 400 microg once daily, morning or evening, or 200 microg twice daily, and 800 microg twice daily via Turbuhaler in a randomized, placebo-controlled, double-blind, double-dummy crossover study. METHODS: Healthy men received budesonide, 400 microg in the morning (08.00-09.00 h) or evening (20.00-21.00 h), budesonide, 200 microg twice daily, 800 microg twice daily, and placebo twice daily, for 1 week each. Plasma and urine samples were obtained over 24 h on day 7 for cortisol determination. Twenty-five subjects completed all treatments, and 27 were included in the analysis. RESULTS: The 24 h plasma cortisol concentrations vs placebo (95% CI) were 98% (89, 108) for 400 microg in the morning, 92% (83, 100) for 400 microg in the evening, 95% (86, 104) for 200 microg twice daily, and 76% (70, 84) for 800 microg twice daily. CONCLUSIONS: Budesonide at a dose of 400 microg day-1 via Turbuhaler had no statistically significant effect on 24 h cortisol production, irrespective of whether treatment is given once or twice daily, whereas a dose of 800 microg twice daily resulted in a statistically significant suppression vs placebo. Neither could a significant difference be found between morning and evening dosing.     

布地奈德对哮喘大鼠碱性成纤维细胞生长因子蛋白和mRNA表达的影响

目的：观察碱性成纤维细胞生长因子在急性哮喘大鼠肺组织的表达情况及布地奈德的干预影响.方法：36只雄性SD大鼠随机分为对照组、哮喘组和布地纳德治疗组,以卵清白蛋白激发法制备哮喘模型,采用ELISA法测定支气管肺泡灌洗液中碱性成纤维细胞生长因子的含量,免疫组化和原位杂交法测定肺组织中碱性成纤维细胞生长因子蛋白和mRNA的表达情况.结果：支气管肺泡灌洗液中的碱性成纤维细胞生长因子浓度、肺组织碱性成纤维细胞生长因子蛋白和mRNA的表达水平哮喘组显著高于对照组（P＜0.01）,治疗组显著低于哮喘组（P＜0.01）,但与对照组相比仍较高（P＜0.01）,上皮细胞为主要表达细胞.结论：碱性成纤维细胞生长因子参与了哮喘的发病机制,布地奈德可抑制哮喘急性期碱性成纤维细胞生长因子蛋白和mRNA的表达增加效应,这可能是布地奈德抑制哮喘气道重塑的重要机制之一.