丙酸氟替卡松鼻喷雾剂对儿童哮喘控制及过敏性鼻炎症状改善的作用

目的 比探讨丙酸氟替卡松鼻喷雾剂在改善儿童过敏性鼻炎症状以及控制哮喘反复发作方面的作用.方法 将100例过敏性鼻炎合并哮喘综合征患儿按照随机数字表法分为对照组和观察组.对照组应用氯雷他定及经口腔吸人糖皮质激素,观察组在此基础上使用丙酸氟替卡松鼻喷雾剂治疗,观察两组疗效.结果 观察组总有效率（94％）明显优于对照组（76％）（x2=6.35,P＜0.05）.10 ～ 12周以后,观察组与对照组鼻炎症状评分及哮喘症状评分差异均有统计学意义（t=2.47、2.64、3.41;2.30、3.17、2.47,均P＜0.05）.不良反应方面两组鼻腔干燥、鼻出血发生率差异均有统计学意义（x2 =7.11、7.53,均P＜0.05）.结论 丙酸氟替卡松鼻喷雾剂在改善儿童过敏性鼻炎和哮喘症状复发方面有很好疗效,值得临床大力推广.     

丙酸氟替卡松局部治疗鼻息肉作用机制的探讨

目的 观察丙酸氟替卡松对体外培养的鼻息肉成纤维细胞生长及凋亡的影响,以探讨其局部治疗鼻息肉的可能机制.方法 取11例鼻息肉患者的鼻息肉组织进行传代培养后获得鼻息肉成纤维细胞,观察在不同体积分数(2%、4%、8%)丙酸氟替卡松作用铝、72、96和120 h对成纤维细胞活力的影响;采用流式细胞仪和Hoechest染色观察丙酸氟替卡松(体积分数为4%)作用48、72、96和120 h时对成纤维细胞凋亡的影响,并与空白对照组进行对比.结果 与空白对照组相比,当丙酸氟替卡松的体积分数>4%时能显著抑制成纤维细胞的生长(P<0.05).流式细胞仪和Hoechest染色结果表明,体积分数为4%的丙酸氟替卡松能导致成纤维细胞凋亡.与空白对照组对比差异有统计学意义(P<0.05).结论 丙酸氟替卡松体外能抑制鼻息肉成纤维细胞的生长并诱导其凋亡.     

Bioavailability and disposition of azelastine and fluticasone propionate when delivered by MP29-02, a novel aqueous nasal spray

AIM(S)

To determine azelastine hydrochloride (AZE) and fluticasone propionate (FP) bioavailabilities of the novel nasal spray combination product MP 29-02, compared with MP29-02-based products containing only AZE (MP29-02-AZE-mono), FP (MP29-02-FP-mono), marketed AZE and FP single entity products (Astelin® and FP Boehringer-Ingelheim; FP-BI).

METHODS

Two randomized, three period, six sequence, three treatment crossover studies were conducted in healthy subjects. Study 1 administered 200 µg FP as MP29-02, MP29-02-FP-mono or FP-BI. Study 2 administered 548 µg AZE as MP29-02, MP29-02-AZE-mono or Astelin®. Each dose consisted of two sprays/nostril. Serum FP and plasma AZE were followed over 24 (FP) and 120 h (AZE) and quantified by LC-MS/MS. Peak (C_max) and total exposures AUC(0,t_last) were compared between the treatments by anova.

RESULTS

Study 1: Average FP C_max was very low with all products (≤10 pg ml⁻¹). FP AUC(0,t_last) point estimates (90% CIs) for MP29-02 : MP29-02-FP-mono and MP29-02 : FP-BI ratios (%) were 93.6 (83.6, 104.7) and 161.1 (137.1, 189.3). Corresponding ratios for C_max were 91.0 (82.5, 100.4) and 157.4 (132.5, 187.1). Study 2: AZE AUC(0,t_last) point estimates (90% CIs) for MP29-02 : MP29-02-AZE-mono and MP29-02 : Astelin® ratios (%) were 98.8 (91.0, 107.4) and 105.5 (95.6, 116.4). Corresponding outcomes for C_max were 102.7 (92.1, 114.4) and 107.3 (92.6, 124.3).

CONCLUSIONS

No interactions of AZE and FP were found with the MP29-02 formulation. Azelastine bioavailability was similar for MP29-02 and Astelin®. Maximum and total FP exposure was higher for MP29-02-based products compared with FP-BI. FP concentrations were generally very low with all investigational products and did not suggest clinically meaningful differences concerning systemic safety.     

含有苯扎氯胺防腐剂的鼻用类固醇对豚鼠鼻黏膜作用的组织形态学观察

目的 观察体内应用含苯扎氯胺防腐剂的鼻用类固醇对豚鼠鼻黏膜是否产生不良影响。方法 选用健康实验成年豚鼠50只，随机分成喷药组和对照组，喷药组用辅舒良进行双侧鼻腔喷药，一侧一喷，1次／1d，分别于喷药后1周、1个月、2个月、3个月、4个月随机活杀动物各5只，取中鼻甲前端黏膜，HE染色，并制作电镜标本，光镜，扫描、透射电镜观察及显微图象分析测量。结果 喷药后1周～4个月鼻腔黏膜组织形态及纤毛未发生明显的异常改变。结论 辅舒良鼻喷剂鼻腔腔局部应用是安全的，短期和长期的使用都有很好的耐受。     

Differences in inhaled fluticasone bioavailability between holding chambers in children with asthma

STUDY OBJECTIVE: To determine if differences between holding chambers in previous in vitro aerosol studies would agree with the bioavailability of inhaled fluticasone propionate between the same holding chambers in children with asthma. DESIGN: Double-blind, randomized, crossover study SETTING: University of Florida Clinical Research Center. PATIENTS: Eight children (aged 5-9 yrs) with stable asthma. INTERVENTION: Under observation, the children inhaled two 110-microg puffs of fluticasone twice/day through the InspirEase or E-Z Spacer holding chamber. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected at baseline and then at 0.5, 1, 1.5, 2, 4, and 6 hours after the last dose of fluticasone. Primary outcome measures were peak fluticasone steady-state plasma concentration (Cmax) and area under the fluticasone plasma concentration-time curve from 0-6 hours (AUC0-6). The fluticasone plasma concentrations were determined by high-performance liquid chromatography-mass spectrometric assay. Mean +/- SD Cmax from InspirEase (245 +/- 77 pg/ml) was 18% higher than that after E-Z Spacer (199 +/- 58 pg/ml, p < 0.05). Mean +/- SD AUC0-6 from InspirEase (1103 +/- 305 pg x hr(-1) x ml(-1) was 22% higher than that delivered from E-Z Spacer (863 +/- 258 pg x hr(-1) x ml(-1), p = 0.06). CONCLUSION: Differences in inhaled fluticasone bioavailability between these holding chambers in children with asthma corroborate differences reported in earlier in vitro aerosol studies.     

沙美特罗替卡松粉吸入剂中沙美特罗和丙酸氟替卡松的HPLC测定

建立了HPLC法测定沙美特罗替卡松粉吸入剂中的沙美特罗和丙酸氟替卡松.采用C_(18)色谱柱,以甲醇-0.05 mol/L乙酸铵溶液(68:32)为流动相,检测波长228 nm.沙美特罗和丙酸氟替卡松分别在0.14～27.4 μg/ml和0.3～60μg/ml浓度范围内线性关系良好;回收率为101.3%和101.5%.     

Short-term dose-response relationships for the relative systemic effects of oral prednisolone and inhaled fluticasone in asthmatic adults

AIMS: To determine the systemic dose-response relationships with oral prednisolone and inhaled fluticasone propionate administered in a putative 11:1 mg equivalent basis, in terms of effects on adrenal, bone and haematological markers. METHODS: Twelve asthmatic patients mean (s.e.) age, 28.8 [3.3] years, FEV1 94.7 [3.6]% predicted, FEF(25-75) 65.5 [6.1]% predicted were studied in a double-blind, double dummy randomised crossover design comparing placebo, inhaled fluticasone propionate via volumatic spacer given twice a day (ex actuator dose 0.44 mg day-1, 0.88 mg day-1, 1.76 mg day-1 ) and oral prednisolone given once daily (5 mg day-1, 10 mg day-1, 20 mg day-1 ). All treatments were for 4 days at each dose level with a 7-day washout at crossover. Measurements were made at 08.00 h after the last dose of each dose level for plasma cortisol, serum osteocalcin and blood eosinophil count. RESULTS: There were significant dose-related effects for suppression of all three endpoints with both prednisolone and fluticasone propionate. Parallel slope analysis revealed a calculated dose ratio for relative potency of 8. 5:1 mg (95% CI 5.7-11.2) comparing Pred with FP for morning cortisol. The magnitude of suppression with FP was less for osteocalcin and eosinophils than for cortisol. CONCLUSIONS: Systemic tissues exhibit different dose-response relationships for the effects of inhaled and oral corticosteroids with suppression of cortisol being greater than osteocalcin or eosinophils. For cortisol suppression we observed an 8.5:1 mg relative potency ratio comparing prednisolone with fluticasone propionate. Patients taking high dose inhaled fluticasone propionate should therefore be screened for evidence of impaired adrenal reserve.     

Effect of fluticasone propionate nasal spray on bioavailability of intranasal hydromorphone hydrochloride in patients with allergic rhinitis

STUDY OBJECTIVE: To investigate the effect of the nasal corticosteroid fluticasone propionate on the bioavailability and pharmacokinetics of single-dose intranasal hydromorphone hydrochloride in patients with allergic rhinitis. DESIGN: Randomized, three-way, crossover pharmacokinetic study. SETTING: University clinical research unit. PATIENTS: Twelve patients with allergic rhinitis. INTERVENTION: Hydromorphone hydrochloride 2.0 mg was administered by intravenous infusion (treatment A), intranasal spray without allergic rhinitis treatment (treatment B), and intranasal spray after 6 days of fluticasone propionate (treatment C). Blood samples were collected serially from 0-16 hours. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters were determined by noncompartmental methods. An analysis of variance (ANOVA) model was used for statistical analysis. Mean (% coefficient of variation) absolute bioavailability of intranasal hydromorphone was 51.9% (28.2) and 46.9% (30.3) in patients with allergic rhinitis with and without treatment with fluticasone propionate, respectively. Mean maximum concentration (Cmax) values were 3.02 and 3.56 ng/ml, respectively. No statistical differences in Cmax and area under the concentration versus time curve were detected between intranasal treatments. Bioavailability values for both intranasal treatments were lower than those in healthy volunteers (57%). Median time to Cmax (Tmax) values were significantly different (p=0.02) for treatments B and C (15 and 30 min, respectively) using rank-transformed Tmax for ANOVA. Adverse effects were consistent with known effects of hydromorphone administered by other routes, with the exception of bad taste after intranasal administration. CONCLUSION: Hydromorphone was rapidly absorbed after nasal administration, with maximum concentrations occurring for most subjects within 30 minutes. Allergic rhinitis may affect pain management strategies for intranasal hydromorphone, with a delay in onset of action for patients treated with fluticasone propionate.     

孟鲁司特联合丙酸氟替卡松鼻喷雾剂治疗儿童腺样体肥大疗效观察

目的:探讨孟鲁司特联合丙酸氟替卡松鼻喷雾剂治疗儿童腺样体肥大的临床效果。方法:选取2013 年3 月至2015年3月我院儿科收治的腺样体肥大患儿90例,依据随机数字表法分为观察组和对照组各45例。对照组给予丙酸氟替卡松气雾剂喷鼻腔治疗,观察组在对照组的治疗基础上给予孟鲁司特口服治疗,评估两组患儿临床症状积分改善情况、腺样体大小及治疗后的不良反应。结果:治疗前两组患儿症状积分、腺样体体积比较差异无统计学意义(P>0郾05);治疗后两组患儿症状积分、腺样体体积均有明显改善,差异有统计学意义(P<0.05);治疗后观察组患儿症状积分、腺样体体积改善明显优于对照组,差异有统计学意义(P<0.05);两组患儿不良反应发生率比较差异无统计学意义(P>0.05)。结论:应用孟鲁司特联合丙酸氟替卡松气雾剂治疗儿童腺样体肥大,能够显著改善患儿临床症状,减小腺样体体积,不良反应小,值得临床推广应用。     

HPLC法测定丙酸氟替卡松乳膏中丙酸氟替卡松的含量

目的 建立丙酸氟替卡松乳膏中丙酸氟替卡松含量测定的方法.方法 采用高效液相色谱法,色谱柱为C18柱(250 mm×4.6 mm,5 μm),流动相为0.02 M磷酸溶液(三乙胺调pH=4.5)-甲醇(24:76),流速1.0 ml·min-1,检测波长为240 nm,柱温35℃.结果 丙酸氟替卡松进样浓度在10～35 mg·L-1范围内与峰面积呈良好线性关系(r=0.999 9),平均回收率为98.83%,RSD为0.47%(n=9).结论 测定方法专属性强、精密、准确、灵敏、简便可行,可作为丙酸氟替卡松乳膏的质量控制方法.     

Bioavailability of fluticasone propionate and mometasone furoate aqueous nasal sprays

Objectives To compare the systemic exposure for intranasal mometasone furoate (MF) and fluticasone propionate (FP) aqueous nasal sprays (ANS) in terms of serum and urinary cortisol parameters and plasma pharmacokinetics.Methods Twelve healthy subjects completed this three-way, cross-over study. They received FPANS (50 g/spray), MFANS (50 g/spray) or placebo ANS, eight sprays per nostril every 8 h for 4 days. Cortisol measurements were made at baseline and day 4. FP and MF plasma concentrations were also measured on day 4.Results MFANS produced similar mean plasma AUC (123 pmol/l h) to FPANS (112 pmol/l h). Despite the use of high doses, necessary to generate adequate pharmacokinetic data, only minor reductions in cortisol parameters were found, with no difference between FPANS and MFANS.Conclusions FP and MF have similar and very low systemic bioavailability when administered intranasally using a high-dose regimen. It is therefore unlikely that therapeutic doses of intranasal FP or MF will produce dissimilar or significant degrees of systemic exposure or systemic effects.     

Systemic bioavailability of nasally applied chlorphenamine maleate (0.4% nasal spray) relative to tablets administered perorally

AIM: This study investigated the bioavailability of single doses of 1.12 and 2.24 mg chlorphenamine maleate applied intranasally (0.4% nasal spray) relative to a single peroral dose of 8 mg chlorphenamine maleate (tablets). METHODS: Twenty-four (24) subjects were treated with single nasal doses of 1.12 mg and 2.24 mg chlorphenamine maleate (0.4% nasal spray) and two 4 mg chlorphenamine maleate tablets (Piriton) on 3 separate study days according to a 3-way cross-over design with a 7-day wash-out between periods. Blood was sampled before and at 0.25, 0.50, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12, 16 and 24 hours after drug administration. Additional blood samples were obtained 36, 48 and 72 hours after peroral administration only. All subjects were included in the pharmacokinetic analysis. RESULTS: Nasally applied chlorphenamine maleate was readily absorbed, reaching peak plasma levels after 0.25 to 3.0 hours. The dose-normalized estimated mean Cmax values were 1.24, 1.43 and 1.21 ng/ml for the peroral tablet and the 1.12 mg and 2.24 mg nasal dose, respectively. The dose-normalized estimated mean AUC(0-infinity) values were 25.91, 26.44 and 25.56 ng x h/ml for the tablet and the 1.12 and 2.24 mg nasal dose, respectively. The estimated treatment ratios (nasal dose to tablet) of the dose-normalized values for the 1.12 mg nasal dose were 1.15 (900 CI: 1.0-1.32) and 1.02 (90% CI: 0.88-1.18) for Cmax and AUC(0-infinity), respectively, for the 2.24 mg nasal dose they were 0.98 (90% CI: 0.85-1.13) and 0.99 (90% CI: 0.85-1.13) for Cmax and AUC(0-infinity), respectively. The other pharmacokinetic characteristics (tmax, t(1/2), lambda(z), AUC(0-tf), MRTtot, CL/f and Vz/f) were comparable across all treatments. These data indicate that the disposition of chlorphenamine maleate was independent of the route and dose of administration. CONCLUSIONS: Chlorphenamine maleate is readily absorbed after nasal application using a 0.4% nasal spray. The nasal administration showed that the systemic bioavailability at the two dose levels used was comparable to that for the tablet. Maximum concentrations on the low dose, however, were higher and those on the high dose were comparable to those for the tablet. The nasal application of chlorphenamine maleate does not alter the overall systemic exposure compared to the oral route.     

盐酸氮卓斯汀与丙酸氟替卡松喷鼻剂治疗变应性鼻炎临床对比观察

目的观察并比较盐酸氮卓斯汀与丙酸氟替卡松喷鼻剂在治疗变应性鼻炎中的效果。方法 146例变应性鼻炎患者,随机分为观察组和对照组,观察组应用盐酸氮卓斯汀喷鼻剂,对照组应用丙酸氟替卡松喷鼻剂(辅舒良),比较两组疗效及不良反应。结果两组治疗效果比较差异无统计学意义。但观察组起效快、不良反应明显少于对照组。结论对于常年性变应性鼻炎的治疗,应首选盐酸氮卓斯汀,该药起效快、安全有效,值得临床推广应用。     

丙酸氟替卡松对鼻黏膜上皮细胞表达的天然免疫分子的免疫调节作用

目的检测丙酸氟替卡松对人鼻黏膜上皮细胞表达天然免疫分子的影响。方法 采用丙酸氟替卡松和/或聚肌胞苷酸(Polyinosinic:polycytidylic acid,Poly I:C)、细菌脂多糖(Lipopolysaccharides,LPS)等刺激离体培养的鼻黏膜上皮细胞后,通过实时定量PCR检测Toll样受体(Toll like receptor,TLR)的表达,采用酶联免疫吸附试验检测细胞培养上清中血清淀粉样蛋白A(Serum amyloidA,SAA)、骨桥蛋白(Osteopontin,OPN)等的表达水平。结果丙酸氟替卡松单独刺激能够增加鼻黏膜上皮细胞表达TLR-3 mRNA(7.5倍)和TLR-4 mRNA(4.5倍),Poly I:C单独刺激能够增加鼻黏膜上皮细胞表达TLR-3 mRNA 28.5倍,LPS单独刺激能够增加鼻黏膜上皮细胞表达TLR-4 mRNA 18.4倍,丙酸氟替卡松刺激后细胞培养上清中SAA和OPN水平也出现显著增加。丙酸氟替卡松和Poly I:C以及LPS对增加细胞培养上清中SAA和OPN水平具有协调效应。结论丙酸氟替卡松能够增强鼻黏膜上皮细胞的天然免疫反应。     

Intranasal loteprednol etabonate in healthy male subjects: pharmacokinetics and effects on endogenous cortisol

Loteprednol etabonate (LE) is a glucocorticoid soft drug that is currently in development for intranasal use. The main objectives of this study were to examine the pharmacokinetics and potential effects on systemic cortisol of two intranasal suspension formulations of LE and to compare these findings with placebo and fluticasone propionate (FP, Flonase) control treatments. In this randomized, double-blind (except for FP), parallel-group study (n = 8/group), all subjects received for 14 days once daily in the morning two puffs of the following nasal spray formulations into each nostril: LE 0.1% (400 microg/day), LE 0.2% (800 microg/day), FP 0.05% (200 microg/day), and placebo. Drug trough levels were determined on days 1, 5, 12, 13, and 14, and a full pharmacokinetic profile was established on day 14, and 24-hour serum cortisol profiles were assessed prior to treatment (i.e., at baseline) and after the last dose. All subjects completed the protocol without treatment-emergent adverse findings. All formulations were rapidly absorbed (t(max) less than 1 h). The rather short mean terminal half-lives of 2.2 +/- 1.5 hours and 1.8 +/- 1.0 hours for LE 400 microg and LE 800 microg, respectively, and 4.2 +/- 1.8 hours for the 200-microg FP treatment explained the lack of any accumulation. Mean peak concentrations (C(max)) were 139 +/- 57 pg/mL with LE 400 microg and 164 +/- 54 pg/mL with LE 800 microg and thus fairly independent from dose. The 200-microg FP treatment resulted in a C(max) of only 15.5 +/- 5.9 pg/mL. Mean measured AUC(0-t) values (193 +/- 87 pg/h/mL(-1), 300 +/- 183 pg/h/mL(-1), and 40 +/- 34 pg/h/mL(-1) for LE 400 microg, LE 800 microg, and FP 200 microg, respectively) showed high variability and suggested nonlinear pharmacokinetics for the LE formulations, indicative of a less complete systemic uptake of LE from the 0.2% concentration. None of the treatments (LE 400 microg, LE 800 microg, and FP 200 microg) showed evidence for serum cortisol suppression when compared with placebo, respectively. The uptake and systemic exposure appears less complete from the 0.2% LE concentration, which principally favors this formulation for further clinical development.     

Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects

Aims The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate (FP) can be explained by systemic accumulation.
Methods Twelve healthy subjects (six women) were given, in a crossover fashion, a single dose inhalation (1000  &;mgr;g) of FP via Diskhaler and repeated inhalations (1000  &;mgr;g twice daily) every 12  h during 7 days. There was a washout period of 2 weeks between the treatments. An intravenous dose of 20  μg FP was given as a reference. Plasma concentrations of FP for each treatment were determined by liquid chromatography plus tandem mass spectrometry. Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values.
Results The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose. Systemic availability, mainly attributable to pulmonary deposition, was 15.6 [13.6–18.0]% of the nominal dose. Daytime plasma cortisol suppression vs baseline was 47 [20–65]% and 95 [93–97]% for the single and repeated doses, respectively.
Conclusions To conclude, a slow elimination of FP leads to accumulation during repeated dosing. This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range.     

Absolute bioavailability of nicotine applied to different nasal regions

Summary The absolute bioavailability of nicotine administered nasally, as drops to the nasal conchae and nasal septum, and as a nasal spray, has been studied in eight healthy volunteers. Single nasal doses of 1 mg nicotine were given and plasma concentrations of nicotine were followed for 6 h.Compared to an intravenous infusion of nicotine, the bioavailability of the nasal administrations was 60 to 75%. The rate of absorption was fast, the maximum concentration being reached after about 10 min.In the present study, there was no significant difference in the rate or extent of absorption between the different nasal treatments.     

丙酸氟替卡松鼻喷雾剂辅治急性分泌性中耳炎的疗效观察

目的观察丙酸氟替卡松鼻喷雾剂辅治急性分泌性中耳炎的临床疗效。方法将72例急性分泌性中耳炎患者随机分为治疗组36例（39耳）和对照组36例（40耳）。对照组予常规治疗,治疗组加用丙酸氟替卡松鼻喷雾剂治疗,观察治疗7d、14d时2组治疗效果。结果治疗7d、14d后,治疗组治愈率和总有效率均高于对照组,差异均有统计学意义（P〈0．05）。结论丙酸氟替卡松鼻喷雾剂辅治急性分泌性中耳炎疗效显著,值得临床推广应用。     

Respirable dose delivery of fluticasone propionate from a small valved holding chamber, a compact breath actuated integrated vortex device and a metered dose inhaler

AIMS

To compare the respirable dose delivery of the hydrofluroalkane fluticasone propionate (HFA-FP) via an optimally prepared Aerochamber Plus spacer (AP), via a Synchro-Breathe (SB) device, and pMDI Evohaler (EH).

METHODS

Seventeen mild to moderate asthmatics completed the study using a randomized, double-blind, double-dummy, three way crossover design. Single doses of placebo or HFA-FP 2.0 mg were administered via the EH, AP, and SB devices. The overnight urinary cortisol : creatinine ratio (OUCC) was measured at baseline and after each dose.

RESULTS

Significant suppression of OUCC occurred from baseline with AP and SB but not EH devices (geometric mean fold suppression, 95% CI): AP: 3.18 (2.29, 4.36), P < 0.001; SB: 1.79 (1.31, 2.40), P = 0.001; EH: 1.12 (0.69, 1.44), p = 0.37 (equating to 68%, 45% and 9% falls, respectively). Significant differences in OUCC between devices were as follows: (geometric mean fold difference, 95% CI): AP vs. EH. 2.83 (2.09, 3.82), P < 0.001; AP vs. SB: 1.78 fold (1.21, 2.60), P = 0.003; SB vs. EH: 1.59 (1.09, 2.31), P = 0.013 (equating to 65%, 44% and 37% differences, respectively).

CONCLUSIONS

The use of an optimally prepared AP spacer and breath actuated SB device, when compared with pMDI, significantly increased the respirable dose of HFA-FP.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Respirable dose delivery of inhaled steroids may be improved by the use of conventional valved holding chambers (such as the Aerochamber Plus spacer), but these are bulky and cumbersome to use.
• A novel compact breath actuated device with integrated vortex chamber (Synchro-Breathe) has been developed to overcome these problems,
• The lung bioavailability of inhaled fluticasone propionate is dependant on respirable dose delivery, and hence the performance of inhaler devices can be quantified by measuring the degree of adrenal suppression as a surrogate for relative lung dose.

WHAT THIS STUDY ADDS

• This study compares the respirable dose delivery (as relative adrenal suppression) of inhaled fluticasone delivered via Synchro-Breathe, conventional pMDI (Evohaler), and an optimally prepared Aerochamber Plus spacer in patients with asthma.
• The Aerochamber Plus and the Synchro-Breathe devices produced significantly higher respirable dose delivery of inhaled fluticasone than the pMDI, in terms of the relative degree of adrenal suppression.

     

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.