Pharmacokinetics of intravenous fluticasone propionate in healthy subjects

1 Fluticasone propionate (FP) is a potent glucocorticoid used in the treatment of asthma. Prior to reporting the pharmacokinetics following the inhaled and oral routes, the pharmacokinetics need to be established following intravenous dosing. The present study determines the intravenous pharmacokinetics of FP, using non-compartmental analysis, in healthy male subjects over the 250 to 1000μg dose range.
2 The pharmacokinetics of FP can be regarded as being linear over this dosing range. FP was extensively distributed within the body ( V _ss 318  l), rapidly cleared (CL 1.1 l min⁻¹) with a terminal elimination half-life of 7.8  h and a mean residence time of 4.9  h.
3 In order that future pharmacokinetic/pharmacodynamic and other modelling can be carried out, the plasma concentration-time profiles were parameterized using a model based on sums of exponentials, the appropriateness of this model was justified as the secondary kinetic parameters from the model were similar to those obtained using non-compartmental analysis.     

An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers

The systemic effects of single and multiple doses of inhaled fluticasone propionate (FP) and budesonide were examined in 24 healthy male volunteers (age range 18–29 years). The study was of an open, placebo-controlled, randomized, three-way crossover design. On each study day, multiple blood samples were taken over a 20 h period after drug administration (after a single dose and after the last of seven doses) and area under the curve (AUC_0–20) for plasma cortisol and white blood cell (WBC) counts was calculated. Results: The present study shows that multiple dosing with FP 1.0 mg b.i.d. for 3.5 days (seven doses) resulted in a marked cortisol suppression from placebo which, at 55%, was more than double that seen with a single dose (25% suppression). Multiple dosing with budesonide 0.8 mg b.i.d. resulted in a 34% suppression in plasma cortisol compared with a suppression of 26% with a single dose. The increase in systemic activity of FP after multiple dosing is confirmed by both the number of subjects with 0800 hours plasma cortisol values below normal limits and by the changes in WBC and differential counts. Conclusion: The results of the present study confirm previous findings with regard to the more marked systemic effect of FP following multiple dosing as compared with a single dose. This increase in systemic effect from single dosing to multiple dosing is significantly greater for FP than for budesonide.     

Adrenal suppression with high doses of inhaled fluticasone propionate and triamcinolone acetonide in healthy volunteers

Study objective: This study was conducted to compare the adrenal suppression of inhaled fluticasone propionate and triamcinolone acetonide in healthy volunteers, both given via their respective pressurised metered dose inhaler (pMDI) devices at high doses within the manufacturers recommended dose range. Design: We used a single (investigator) blind, randomised, crossover design comparing a total daily dose of 1.625 mg fluticasone propionate delivered via a pMDI, 1.60 mg daily of triamcinolone acetonide delivered via a pMDI with integrated spacer, or placebo pMDI; each drug was given in two divided doses at 0800 hours and 2200 hours over a 24-h period. Each drug treatment was separated by a 1-week washout. Patients: Twelve normal subjects mean age 27.5 years were studied. Measurements: Blood samples were taken for 0800 hours plasma cortisol, i.e. 10 h following the second dose. Ten hour urine collections (2200 hours until 0800 hours) were taken for urinary cortisol and creatinine excretion. Results: For the 0800 hours plasma cortisol (geometric mean, nmol · l⁻¹) compared with placebo (353) fluticasone propionate (138) produced significant (P<0.05) suppression (2.57-fold difference), whereas triamcinolone acetonide (263) did not (1.34-fold difference). Fluticasone propionate produced a 1.91-fold greater adrenal suppression than triamcinolone acetonide (95% CI 1.10 to 3.33). Individual subjects with abnormally low 0800 hours cortisol values <150 nmol · l⁻¹ (<5.4 μg/dl) were n=4 for fluticasone propionate and n=0 for triamcinolone acetonide. Overnight urinary cortisol/creatinine ratio (geometric mean, nmol/mmol) did not show any difference between fluticasone propionate (1.48) and triamcinolone acetonide (1.60), with both producing significant suppression versus placebo (4.01): triamcinolone acetonide 2.50-fold difference (95% CI 1.45–4.24); fluticasone propionate 2.71-fold difference (95% CI 1.57–4.69). Conclusion: Fluticasone propionate 1.625 mg/day (pMDI) produced an approximately two-fold greater adrenal suppression of 0800 hours plasma cortisol than triamcinolone acetonide 1.60 mg per day (Oral Inhaler) when given twice daily, and one third of subjects with fluticasone had abnormally low 0800 hours cortisol values <150 nmol · l⁻¹ (<5.4 μg · dl⁻¹). There were no differences between the drugs for urinary cortisol excretion. Further dose-ranging studies are required at steady-state in asthmatic subjects in order to see whether differences occur at lower doses on the steep part of the dose–response curve for both plasma and urinary cortisol suppression. Received: 28 January 1997 / Accepted in revised form: 11 April 1997     

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.     

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.     

Detection of fluticasone propionate in horse plasma and urine following inhaled administration

Fluticasone propionate (FP) is an anti‐inflammatory agent with topical and inhaled applications commonly used in the treatment of asthma in steroid‐dependent individuals. The drug is used in racehorses to treat Inflammatory Airway Disease; this work was performed in order to advise on its use and detect potential misuse close to racing. Methods were developed for the extraction and analysis of FP from horse plasma and a carboxylic acid metabolite (FP‐17βCOOH) from horse urine. The methods utilize ultra high performance liquid chromatography coupled to tandem mass spectrometry (UPLC‐MS/MS) in order to detect the extremely low concentrations of analyte present in both matrices. The developed methods were used to analyse plasma and urine samples collected following inhaled administration of FP to six thoroughbred horses. FP was detected in plasma for a minimum of 72 h post‐administration and FP‐17βCOOH was detected in urine for approximately 18 h post‐administration. The results show that it is possible to detect FP in the horse following inhaled administration. Copyright © 2012 John Wiley & Sons, Ltd.     

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.     

丙酸氟替卡松的合成工艺改进

目的 制备丙酸氟替卡松。方法 以醋酸地塞米松为原料,经乙酰化、氟化、水解3步反应制得中间体双氟米松,该中间体再通过氧化、巯基化、酯化、氟甲基化反应制得目标化合物。结果 目标化合物的结构经质谱和核磁共振谱确证,总收率为52.85 ％;高效液相色谱检测含量大于98 ％。结论 由醋酸地塞米松成功地制备丙酸氟替卡松,且有较好的收率和纯度,该工艺路线成本较低,操作简单。     

Pharmacokinetics and systemic effects of inhaled fluticasone propionate in chronic obstructive pulmonary disease

AIMS: We have previously shown that the systemic exposure to inhaled fluticasone propionate (FP) is reduced in asthmatics compared with healthy subjects. We have now compared its pharmacokinetics in patients suffering from chronic obstructive pulmonary disease (COPD, n = 10) and matched healthy subjects (n = 13). METHODS: A double-blind, randomized, cross-over study design was used. Plasma FP and serum cortisol were measured for 12 h after subjects received hydrofluoroalkane FP 1000 microg day-1 inhaled (via an MDI and spacer) for 7 days and following a single 1000- microg intravenous dose. RESULTS: The pharmacokinetics differed in the two groups. After inhalation, geometric least square means were significantly lower in the COPD group for the plasma AUC (1961 vs 2996 pg ml-1 h-1 for COPD and controls, respectively; P = 0.03) and the Cmax (235 vs 421 pg ml-1 for COPD and controls, respectively; P = 0.03). Suppression of serum cortisol concentration over 12 h was greater in healthy controls. Weighted mean serum cortisol concentration (nmol l-1) in healthy subjects and COPD was 93 and 170, respectively (P = 0.03). The intravenous pharmacokinetic parameters for FP were comparable in the two groups, resulting in similar suppression of serum cortisol. CONCLUSIONS: We conclude that the altered pharmacokinetics of inhaled fluticasone propionate in COPD caused less hypothalamic-pituitary-adrenal suppression than in healthy controls. This is further evidence that the systemic effects of inhaled corticosteroids should be assessed in patients and not healthy subjects.     

Pharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjects

AIM

The aim of the study was to evaluate the pharmacokinetics (PK) of inhaled and intravenous (i.v.) fluticasone furoate (FF) in healthy Caucasian, Chinese, Japanese and Korean subjects.

METHOD

This was an open label, randomized, two way crossover study in healthy Caucasian, Chinese, Japanese and Korean subjects (n = 20 per group). Inhaled FF (200 μg for 7 days, then 800 μg for 7 days from a dry powder inhaler [DPI]) was administered in one treatment period and i.v.FF (250 μg infusion) in the other. FF PK and serum cortisol (inhaled 200 μg only) were compared between the ethnic groups using analysis of variance. P450 CYP3A4 activity and safety were also assessed.

RESULTS

Ethnic differences in i.v. FF PK were accounted for by body weight differences. CYP3A4 activity was similar across the groups. Higher FF systemic exposure was seen following inhaled dosing in Chinese, Japanese and Korean subjects compared with Caucasian subjects. Absolute bioavailability was greater (36%–55%) in all East Asian groups than for Caucasian subjects following inhaled FF 800 μg. Deconvolution analysis suggested inhaled FF resided in the lung of East Asian subjects longer than for Caucasians (time for 90% to be absorbed [t90]: 29.1–30.8 h vs. 21.4 h). In vitro simulation method predicted comparable delivered lung dose across ethnic groups. Serum cortisol weighted mean was similar between Caucasians and Chinese or Koreans, while in Japanese was on average 22% lower than in Caucasians. All FF treatments were safe and well tolerated.

CONCLUSION

Modestly higher (<50%) FF systemic exposure seen in East Asian subjects following inhaled dosing was not associated with a clinically significant effect on serum cortisol, suggesting that a clinical dose adjustment in East Asian subjects is not required.     

Systemic bioavailability of fluticasone propionate administered as nasal drops and aqueous nasal spray formulations

AIMS: To measure and compare the systemic bioavailability of fluticasone propionate aqueous nasal spray and a new nasal drop formulation, using a sensitive analytical method and high dose regimen. METHODS: Volunteers received four 800 microg doses of fluticasone propionate as a nasal spray or drops over 2 days, separated by an 8 h dose interval. On day 2, blood samples were collected for assay of fluticasone propionate plasma concentrations. RESULTS: The mean systemic exposure, for both formulations was 8.5 pg x ml(-1) x h (drops) and 67.5 pg x ml(-1) x h (spray). Mean absolute bioavailabilities were estimated to be 0.06% (drops) and 0.51% (spray), by reference to historical intravenous data. CONCLUSIONS: Both formulations exhibited low systemic bioavailability, even at 12 times the normal daily dose. The bioavailability from the nasal drops was approximately eight times lower than from the nasal spray.     

The presence of emphysema does not affect the systemic bioactivity of inhaled fluticasone in severe chronic obstructive pulmonary disease

AIMS: To assess the systemic bioactivity of fluticasone proprionate (FP) 2000 micro g daily on sensitive adrenal and bone markers in severe chronic obstructive pulmonary disease (COPD) patients with or without significant emphysema. METHODS: Ten patients without emphysema (COPD group: age 55 years, FEV(1) 51% predicted and DL(CO) 83% predicted) and 10 patients with emphysema (COPDE group: age 59 years, FEV(1) 43% predicted and DL(CO) 49% predicted) received FP 2000 micro g daily via a spacer for 2 weeks. There was a 1-week washout period prior to FP treatment where patients were given salmeterol and oxitropium, after stopping their usual inhaled corticosteroids for the duration of the study. Measurements including overnight 10 h urinary cortisol excretion corrected for creatinine (OUCC) and serum osteocalcin concentrations were performed at baseline following washout and after 2 weeks of FP. RESULTS: Values for OUCC and serum osteocalcin concentrations pre- and post-FP were not significantly different between the COPD and COPDE groups. There was significant suppression of OUCC (nmol mmol(-1)) by FP treatment within the COPD group (P = 0.03): 7.86 vs 4.64 (95% CI on the difference 0.47, 5.98), and within the COPDE group (P = 0.006): 7.13 vs 4.27 (95% CI on the difference: 1.03, 4.69). Likewise, there was significant suppression of osteocalcin concentration (nmol l(-1)) by FP treatment within the COPD group (P = 0.04): 7.24 vs 6.34 (95% CI on the difference: 0.01, 1.78), and within the COPDE group (P = 0.03): 6.92 vs 5.72 (95% CI on the difference: 0.12, 2.29). CONCLUSIONS: Severe COPD patients who are receiving high dose FP are susceptible to the development of systemic adverse effects, irrespective of the presence of emphysema.     

Dose–response for adrenal suppression with hydrofluoroalkane formulations of fluticasone propionate and beclomethasone dipropionate

AIMS: With the recent introduction of hydrofluoroalkane (HFA) inhalers it is important to know the relative systemic safety profiles of inhaled corticosteroids. We therefore decided to compare systemic bioavailability of HFA-beclomethasone dipropionate (BDP) vs HFA-fluticasone propionate (FP). METHODS: Sixteen healthy volunteers were randomised in placebo-controlled single blind cross-over fashion to receive 3 weeks with HFA-FP or HFA-BDP, given as 1 week cumulative doubling doses (nominal ex-valve) of 500, 1000 and 2000 microg day(-1), with a 1 week placebo run-in and wash-out. Overnight (22.00 h to 08.00 h) and early morning (08.00 h) urinary cortisol/creatinine excretion and 08.00 h serum cortisol were measured after each placebo and dosing period. All data were log-transformed to normalize their distribution. RESULTS: Urine and serum cortisol were suppressed by 2000 microg FP and BDP vs placebo and by 1000 microg BDP vs placebo for urinary cortisol/creatinine (P < 0.05). Overnight urinary cortisol/creatinine ratio (the primary endpoint) was suppressed more by 1000 microg BDP vs 1000 microg FP (P < 0.05), amounting to a geometric mean fold difference (95% CI) of 1.64 (1.04-2.56). There were also more individual low values less than 3 nmol mmol(-1) with BDP than FP at 1000 microg: n = 8/16 vs n = 2/16 (P < 0.05). CONCLUSIONS: There was dose-related suppression of corrected urinary cortisol/creatinine with the HFA formulations of BDP and FP. Suppression of overnight urinary cortisol/creatinine ratio was significantly greater with HFA-BDP than HFA-FP at 1000 microg. This suggests that the greater glucocorticoid potency of HFA-FP may be offset by the greater lung bioavailability of HFA-BDP.     

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.

     

Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration

Objective: To evaluate the pharmacokinetic and systemic pharmacodynamic properties of inhaled fluticasone propionate (FP). Methods: Single doses of 0.25, 0.5, 1.0 and 3.0 mg FP were administered to groups of six healthy subjects. Serum concentration profiles of FP were monitored over 24 h by means of high-performance liquid chromatography/mass spectrometry (HPLC/MS–MS). Systemic pharmacodynamic effects were evaluated by measuring endogenous serum cortisol and circulating white blood cells, and analyzed with previously developed integrated pharmacokinetic/pharmacodynamic (PK/PD) models. Results: FP showed a dose-independent terminal half-life with a mean (SD) of 6.0 (0.7) h. Maximum serum concentrations occurred 1.0 (0.5) h after administration, ranging from 90 pg · ml⁻¹ for the 0.25 mg dose to 400 pg · ml⁻¹ for the 3.0 mg dose. This, together with an estimated mean absorption time of nearly 5 h and a known oral bioavailability of less than 1%, indicates prolonged residence at and slow absorption from the lungs. In the investigated dose range, the cumulative systemic effect was dose-dependent for both markers of pharmacodynamic activity. For doses of 0.25, 0.50, 1.0 and 3.0 mg FP, the PK/PD-based cumulative systemic-effect parameters were 159, 186, 257 and 372% · h for lymphocyte suppression, 107, 186, 202 and 348% · h for granulocyte induction and 23.6%, 33.8%, 51.0% and 73.6% for cortisol reduction, respectively. The time courses of lymphocytes, granulocytes and endogenous cortisol could be sufficiently characterized with the applied PK/PD models. The measured in vivo EC₅₀ values, 30 pg · ml⁻¹ and 7.3 pg · ml⁻¹ for white blood cells and cortisol, respectively, were in good agreement with predictions based on the in vitro relative receptor affinity of FP. Conclusion: After inhalation, FP follows linear pharmacokinetics and exhibits dose-dependent systemic pharmacodynamic effects that can be described by PK/PD modeling. Received: 27 January 1997 / Accepted in revised form: 5 August 1997     

Pharmacokinetic/pharmacodynamic evaluation of urinary cortisol suppression after inhalation of fluticasone propionate and mometasone furoate

AIM: Fluticasone propionate (FP) and mometasone furoate (MF) are inhaled corticosteroids that possess a high ratio of topical to systemic activity. The systemic bioavailability of MF has been claimed to be minimal (1%). FP has been shown to exhibit the same degree of systemic effects, but its systemic availability is between 13 and 17%. We hypothesize that FP and MF have comparable systemic availabilities that can explain their potential to cause systemic effects. METHODS: Steady-state FP and MF trough plasma samples were determined from a clinical study by Fardon et al. in patients with persistent asthma (forced expiratory volume in 1 s = 91%). The percent plasma protein binding of FP and MF was measured using ultracentrifugation. Free FP plasma concentrations were normalized for their differences in receptor binding affinity compared with MF and linked to overnight urinary cortisol/creatinine with an inhibitory E(max). RESULTS: A plot of steady-state FP and MF total trough plasma concentrations vs. dose showed that both drugs exhibit dose linearity. MF has comparable bioavailability to FP based on the steady-state concentrations observed for the different doses. The free plasma concentration producing 50% of urinary cortisol suppression (IC(50)) for MF was not statistically different from the free, normalized IC(50) for FP. CONCLUSION: FP and MF have similar pulmonary deposition and the same potential to cause systemic side-effects due to their similar IC(50) values. The observed urinary cortisol suppression of FP and MF is in agreement with their systemic availability, their differences in plasma protein binding and receptor binding affinity.     

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.     

沙美特罗替卡松治疗小儿毛细支气管炎的疗效观察

目的观察吸入沙美特罗替卡松气雾剂辅助治疗小儿毛细支气管炎的疗效。方法将78例第二次患毛细支气管炎的患儿按住院顺序随机分为两组,治疗组和对照组各39例,两组均给予抗感染、吸氧平喘等基础治疗,治疗组在此基础上吸入沙美特罗替卡松气雾剂1周。结果治疗组的临床症状、体征消失时间及住院时间显著短于对照组（P〈0.05）差异有统计学意义;治疗组总有效率（87.18%）高于对照组（66.67%）,两组比较差异有统计学意义（χ2=4.6222,P〈0.05）。结论沙美特罗替卡松气雾剂辅助治疗毛细支气管炎,疗效确切,不良反应少,值得临床推广。     

沙美特罗替卡松吸入剂联合布地奈德治疗哮喘的疗效

目的　探究沙美特罗替卡松吸入剂联合布地奈德治疗哮喘的临床疗效,分析对患者血清白细胞介素-21（IL-21）、IL-18水平的影响。方法　选取2020年1月至2021年12月于海阳市人民医院接受治疗的86例支气管哮喘患者,采用抛硬币法进行随机分组,分为观察组（47例）和对照组（39例）。观察组男22例,女25例,年龄（43.48±5.57）岁;对照组男25例,女14例,年龄（44.39±6.01）岁。所有患者均接受常规对症治疗,在此基础上对照组采用沙美特罗替卡松吸入剂治疗,观察组采用沙美特罗替卡松吸入剂联合布地奈德治疗。比较两组患者临床疗效、临床症状改善时间,治疗前后肺功能及血清IL-21、IL-18水平变化,记录患者治疗后3个月的哮喘复发情况及治疗期间不良反应发生情况。计量资料行t检验,计数资料行χ²检验。结果　观察组的治疗总有效率为91.49%（43/47）,高于对照组的71.79%（28/39）（P<0.05）。治疗后,观察组的临床症状改善时间均短于对照组（均P<0.05）,第1秒用力呼气量（FEV₁）、FEV₁/用力肺活量（FVC）和最大呼气流速（PEF）水平高于对照组（均P<0.05）,血清IL-21、IL-18水平低于对照组（均P<0.05）。观察组的哮喘复发率为6.38%（3/47）明显低于对照组的23.08%（9/39）（P<0.05）;两组患者的不良反应发生率比较,差异无统计学意义（P>0.05）。结论　沙美特罗替卡松吸入剂联合布地奈德治疗可明显改善哮喘患者的临床症状,提高患者肺功能,且复发率低,临床疗效可靠,安全性较好,其机制可能与调节血清IL-21、IL-18水平有关。     

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.