Clark D J, Lipworth B J
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, UK.
Thorax. 1997 Jan;52(1):55-8. doi: 10.1136/thx.52.1.55.
In a previous single dosing comparison between fluticasone propionate and budesonide differences in cortisol levels measured at 08.00 hours were observed at doses in excess of 1000 micrograms. The aim of this study was to compare the adrenal suppression caused by chronic twice daily dosing with inhaled fluticasone propionate (FP) and budesonide (B) given on a microgram equivalent basis by metered dose inhaler to asthmatic patients.
Twelve stable asthmatic patients of mean age 29.7 years with forced expiratory volume in one second (FEV1) 89.0% predicted and mid forced expiratory flow (FEF25-75) 58.9% predicted, on 400 micrograms/day or less of inhaled corticosteroid, were studied in a double blind, placebo controlled, crossover design comparing inhaled budesonide and fluticasone propionate in doses of 250 micrograms, 500 micrograms, and 1000 micrograms twice daily. Each dose was given at 08.00 hours and 22.00 hours for four days by metered dose inhaler with mouth rinsing. Measurements were made of overnight urinary cortisol excretion and plasma cortisol levels at 08.00 hours, 10 hours after the eighth dose.
The plasma cortisol levels (nmol/ l) at 08.00 hours showed that fluticasone propionate produced lower cortisol levels than budesonide at all three dose levels: F500 333.8, B500 415.2 (95% CI 28.9 to 134.0); F1000 308.3, B1000 380.3 (95% CI 10.5 to 133.5); F2000 207.3, B2000 318.5 (95% CI 5.8 to 216.7); placebo 399.9. Fluticasone produced greater effects than budesonide on the overnight urinary cortisol/creatinine ratio (nmol/mmol) at all three dose levels: F500 3.12, B500 5.55 (95% CI 0.16 to 3.79); F1000 2.54, B1000 6.12 (95% CI 1.25 to 5.91); F2000 2.07, B2000 6.09 (95% CI 0.88 to 7.18); placebo 5.23.
With repeated dosing across a dose range of 250-1000 micrograms twice daily, fluticasone propionate produced significantly greater adrenal suppression than budesonide for both plasma and urinary cortisol. It was therefore possible to demonstrate differences between fluticasone and budesonide at lower doses with chronic dosing from those previously found with single dosing when given on a microgram equivalent basis in asthmatic patients. Factors contributing to the systemic adverse activity profile of fluticasone comprise enhanced receptor potency, prolonged receptor residency time, greater tissue retention, and a longer elimination half life.
在先前进行的丙酸氟替卡松和布地奈德单次给药比较中，发现在剂量超过1000微克时，于08:00测得的皮质醇水平存在差异。本研究的目的是比较通过定量吸入器以微克等效剂量每日两次对哮喘患者吸入丙酸氟替卡松（FP）和布地奈德（B）所引起的肾上腺抑制作用。
12名平均年龄29.7岁的稳定哮喘患者，一秒用力呼气容积（FEV1）为预测值的89.0%，用力呼气中期流速（FEF25 - 75）为预测值的58.9%，吸入皮质类固醇剂量为每日400微克或更低，采用双盲、安慰剂对照、交叉设计，比较每日两次吸入250微克、500微克和1000微克的布地奈德和丙酸氟替卡松。每次剂量于08:00和22:00通过定量吸入器给药，持续4天，并进行漱口。在第八次给药10小时后的08:00测量过夜尿皮质醇排泄量和血浆皮质醇水平。
08:00时的血浆皮质醇水平（nmol/l）显示，在所有三个剂量水平下，丙酸氟替卡松产生的皮质醇水平均低于布地奈德：F500为333.8，B500为415.2（95%可信区间28.9至134.0）；F1000为308.3，B1000为380.3（95%可信区间10.5至133.5）；F2000为207.3，B2000为318.5（95%可信区间5.8至216.7）；安慰剂为399.9。在所有三个剂量水平下，丙酸氟替卡松对过夜尿皮质醇/肌酐比值（nmol/mmol）的影响均大于布地奈德：F500为3.12，B500为5.55（95%可信区间0.16至3.79）；F1000为2.54，B1000为6.12（95%可信区间1.25至5.91）；F2000为2.07，B2000为6.09（95%可信区间0.88至7.18）；安慰剂为5.23。
在每日两次250 - 1000微克的剂量范围内重复给药时，丙酸氟替卡松对血浆和尿皮质醇产生的肾上腺抑制作用明显大于布地奈德。因此，在哮喘患者中，以微克等效剂量进行慢性给药时，能够证明丙酸氟替卡松和布地奈德在较低剂量下的差异，这与先前单次给药时发现的情况不同。导致丙酸氟替卡松全身不良反应特征的因素包括增强的受体效力、延长的受体驻留时间、更大的组织潴留以及更长的消除半衰期。
