Glucocorticoid receptor

Fluticasone propionate 可抑制 TNFα 诱导的 E-选择素表达，IC50 为 1 nM[1]。

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丙酸氟替卡松是一种以雄甾核为基础的新型皮质类固醇。它比二丙酸倍氯米松（BDP）和布地奈德更亲脂，并且更容易与人体肺组织结合。它对糖皮质激素受体的绝对亲和力（KD）为0.5 nM，相对亲和力分别是17-单丙酸倍氯米松（17-BMP）和布地奈德的1.5倍和3.0倍。与标准皮质类固醇相比，与受体结合的速度更快，解离的速度更慢。因此，糖皮质激素受体复合物的半衰期为10h。丙酸氟替卡松对糖皮质激素受体也具有高度选择性，而对其他类固醇受体几乎没有活性。丙酸氟替卡松预处理可显著抑制长期暴露于甲苯二异氰酸酯（TDI）大鼠鼻黏膜肥大细胞数量的增加，并抑制TDI诱导的肥大细胞脱颗粒。它在体外比地塞米松、BDP和布地奈德更有效地抑制抗cd3诱导的人t淋巴细胞增殖，减弱肿瘤坏死因子诱导的内皮细胞粘附分子表达，增加气道上皮细胞分泌白细胞蛋白酶抑制剂水平。在抑制水肿形成、白细胞介素-5 （IL-5）诱导的血液嗜酸性粒细胞增多和IL-5或血小板活化因子刺激的肺嗜酸性粒细胞积聚方面，它也比其他皮质类固醇更有效、更长效。因此，丙酸氟替卡松具有增强的内在糖皮质激素效力和高局部抗炎活性。[2]

氟替卡松治疗可抑制鼻病毒诱导的体内气道炎症，但也会削弱抗病毒免疫反应，增加病毒滴度，导致粘液分泌过多。由于哮喘和慢性阻塞性肺病都与对鼻病毒固有的IFN反应不足有关，吸入皮质类固醇可能与疾病协同作用，抑制IFN，从而导致病情恶化的严重程度增加。这些发现的临床适用性需要在人类疾病模型中得到证实。[3]
在感染后24小时，氟替卡松治疗抑制了鼻病毒在气道中诱导I型和III型IFN（与对照组相比：平均IFNβBAL蛋白20.2 pg/mL[SD 16.7]vs 103.0[30.9]；平均IFNλBAL蛋白102.6 pg/mL[17.4]vs 217[44.6]，p<0.001）；它还损害了病毒清除率，增加了肺组织病毒RNA拷贝数（4.7×。尽管病毒载量增加，但与对照小鼠相比，氟替卡松抑制了鼻病毒诱导的气道炎症，其表现为抑制了BAL中性粒细胞的数量（021×10（5）[0.012]vs 0.59×（5）[0.39]，p<0.001），并抑制了淋巴细胞的数量（092×10（五）[0.044]vs 0.45×10（五月）[0.11]，p<0.0001）。相反，在感染后第7天，氟替卡松增加了BAL中的MUC5AC蛋白（158.2个任意单位[29.9]vs 107.6个[7.1]，p=0.0165）和MUC5B蛋白（623.8个任意单位[317.9]vs 413.5个[70.5]，p=0.0476）。与单独用氟替卡松和鼻病毒治疗的对照小鼠相比，与氟替卡森和鼻病毒1B一起鼻内施用重组IFN-β（10（4）个单位）导致干扰素诱导型细胞因子OAS和CXCL10/IP-10的上调，并改善了病毒清除率，而对氟替卡逊抑制炎症没有任何作用。[3]
丙酸氟替卡松在诱导严重起伏加重后给药，可完全缓解临床症状，使肺功能测试正常化，并显著降低马的支气管肺泡灌洗液（BAL）中性粒细胞增多症。

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丙酸氟替卡松是一种有效的局部抗炎皮质类固醇，具有较低的全身活性。现有的药效学数据只是初步的；然而，大型安慰剂和药物对照临床研究，涉及近4000例季节性变应性鼻炎患者和1500例常年性变应性和非变应性鼻炎患者，证实了丙酸氟替卡松鼻内治疗鼻症状的疗效。丙酸氟替卡松与鼻用二丙酸倍氯米松、醋酸氟尼索内酯和口服阿司咪唑相比，一般表现出相似的疗效，与口服氯雷他定、特非那定、西替利嗪和鼻用色甘酸钠（色甘酸钠）相比，对鼻症状的疗效更好或有更好的趋势。鼻内丙酸氟替卡松的不良反应发生率似乎与安慰剂相当；最常见的报告效果是鼻干/灼烧、鼻出血和头痛。与其最小的全身有效度一致，丙酸氟替卡松鼻内剂量高达4mg /天不会引起肾上腺抑制。因此，基于大型临床试验的早期数据，每日给药一次丙酸氟替卡松为季节性和常年性变应性鼻炎患者提供了一种有效且方便的治疗选择，其特点是其口服生物利用度低。[1]

丙酸氟替卡松是一种基于雄甾烷核的新型皮质类固醇。它比二丙酸倍氯米松（BDP）和布地奈德更亲脂性，与人体肺组织的结合更为强烈。它对糖皮质激素受体的绝对亲和力（KD）为0.5nM，相对受体亲和力分别是17-单丙酸倍氯米松（17-BMP）和布地奈德的1.5倍和3.0倍。与标准皮质类固醇相比，与受体的结合速率更快，解离速率较慢。因此，皮质类固醇受体复合物的半衰期>10小时。丙酸氟替卡松对皮质类固醇受体也具有高度选择性，对其他类固醇受体几乎没有活性。丙酸氟替卡松预处理显著抑制长期暴露于甲苯二异氰酸酯（TDI）的大鼠鼻粘膜肥大细胞数量的增加，并抑制TDI诱导的肥大细胞脱颗粒。它在体外比地塞米松、BDP和布地奈德更有效地抑制抗CD3诱导的人类T淋巴细胞增殖，减弱肿瘤坏死因子-α诱导的内皮细胞粘附分子表达，并提高气道上皮细胞中分泌性白细胞蛋白酶抑制剂的水平。在抑制水肿形成、白细胞介素-5（IL-5）诱导的血液嗜酸性粒细胞增多和IL-5或血小板活化因子刺激的肺嗜酸性粒聚集方面，它也比其他皮质类固醇更有效、作用更长。因此，丙酸氟替卡松具有增加固有糖皮质激素效力和高局部抗炎活性[2]。

C57BL/6 mice were intranasally dosed with fluticasone propionate (1 mg/kg) or vehicle (dimethyl sulfoxide, control), 1 h before infection with rhinovirus 1B. We assessed bronchoalveolar lavage (BAL) inflammatory cell numbers, and measured gene expression, protein production of innate mediators, or both by quantitative RT-PCR or ELISA. We compared mice treated with fluticasone with controls at various timepoints after infection. In additional experiments, recombinant interferon (IFN) beta was administered with fluticasone and rhinovirus 1B in both groups of mice[3].

Absorption, Distribution and Excretion
Intranasal bioavailability of fluticasone propionate is <2%, and oral bioavailability is <1%. Intranasal exposure results in the majority of the dose being swallowed. Topical absorption of fluticasone propionate is very low but can change depending on a number of factors including integrity of the skin and the presence of inflammation or disease. A study of 24 healthy Caucasian males showed an inhaled bioavailability of 9.0%.
Fluticasone propionate is mainly eliminated in the feces with <5% eliminated in the urine.
The volume of distribution of intravenous fluticasone propionate is 4.2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration.
1093mL/min for fluticasone propionate. A study of 24 healthy Caucasian males showed a clearance of 63.9L/h following intravenous administration.

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Metabolism / Metabolites
Fluticasone propionate is cleared from hepatic metabolism by cytochrome P450 3A4. Fluticasone propionate is hydrolysed at the FIVE-S-fluoromethyl carbothioate group, forming an inactive metabolite.

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Biological Half-Life
7.8 hours for intravenous fluticasone propionate. A study of 24 healthy Caucasian males shows a half life of 14.0 hours following intravenous administration and 10.8 hours following inhalation.

Protein Binding
Fluticasone propionate is 99% protein bound in serum. Topical fluticasone propionate is only 91% protein bound in serum however.

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444036 rat LD50 oral >2 gm/kg Yakuri to Chiryo. Pharmacology and Therapeutics., 20(1493), 1992
444036 rat LC inhalation >40770 ug/m3/1 CARDIAC: CHANGES IN HEART WEIGHT Yakuri to Chiryo. Pharmacology and Therapeutics., 20(1501), 1992
444036 rat LD50 subcutaneous >1 gm/kg ENDOCRINE: OTHER CHANGES; BLOOD: CHANGES IN SERUM COMPOSITION (E.G., TP, BILIRUBIN, CHOLESTEROL) Yakuri to Chiryo. Pharmacology and Therapeutics., 20(1493), 1992

[1]. Intranasal fluticasone propionate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in allergic rhinitis. Drugs. 1992;43(5):760-775.

[2]. Johnson M. The anti-inflammatory profile of fluticasone propionate. Allergy. 1995;50(23 Suppl):11-14.

[3]. Effect of fluticasone propionate on virus-induced airways inflammation and anti-viral immune responses in mice. Lancet. 2015 Feb 26;385 Suppl 1:S88.

Fluticasone Propionate can cause developmental toxicity according to state or federal government labeling requirements.
Fluticasone propionate is a trifluorinated corticosteroid that consists of 6alpha,9-difluoro-11beta,17alpha-dihydroxy-17beta-{[(fluoromethyl)sulfanyl]carbonyl}-16-methyl-3-oxoandrosta-1,4-diene bearing a propionyl substituent at position 17; has anti-inflammatory, anti-asthmatic and anti-allergic activity. It has a role as an anti-allergic agent, an anti-asthmatic drug, an anti-inflammatory drug, a dermatologic drug, a bronchodilator agent and an adrenergic agent. It is a corticosteroid, a steroid ester, an 11beta-hydroxy steroid, a propanoate ester, a fluorinated steroid, a thioester and a 3-oxo-Delta(1),Delta(4)-steroid. It is functionally related to a fluticasone. It derives from a hydride of an androstane.
Fluticasone propionate is a synthetic glucocorticoid. These drugs are available as inhalers, nasal, sprays, and topical treatments for various inflammatory indications. Fluticasone propionate was first approved in 1990.
Fluticasone Propionate is the propionate salt form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with antiallergic, antiinflammatory and antipruritic effects. Binding and activation of the glucocorticoid receptor results in the activation of lipocortin that in turn inhibits cytosolic phospholipase A2, which triggers cascade of reactions involved in synthesis of inflammatory mediators, such as prostaglandins and leukotrienes. Secondly, mitogen-activated protein kinase (MAPK) phosphatase 1 is induced, thereby leads to dephosphorylation and inactivation of Jun N-terminal kinase directly inhibiting c-Jun mediated transcription. Finally, transcriptional activity of nuclear factor (NF)-kappa-B is blocked, thereby inhibits the transcription of cyclooxygenase 2, which is essential for prostaglandin production.
A STEROID with GLUCOCORTICOID RECEPTOR activity that is used to manage the symptoms of ASTHMA; ALLERGIC RHINITIS, and ATOPIC DERMATITIS.
See also: Fluticasone (has active moiety); Fluticasone propionate; salmeterol xinafoate (component of); Azelastine hydrochloride; fluticasone propionate (component of) ... View More ...

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Drug Indication
Fluticasone propionate is indicated as an inhaler for the treatment and management of asthma by prophylaxisas well as inflammatory and pruritic dermatoses. Fluticasone propionate nasal spray is indicated for managing allergic and nonallergic rhinitis.
FDA Label
Treatment of asthma

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Mechanism of Action
Fluticasone propionate works through an unknown mechanism to affect the action of various cell types and mediators of inflammation. Fluticasone propionate activates glucocorticoid receptors and inhibits lung eosinophilia in rats.

C25H31F3O5S

500.57

500.184

C, 59.99; H, 6.24; F, 11.39; O, 15.98; S, 6.41

80474-14-2

Fluticasone furoate;397864-44-7;Fluticasone propionate-d5;1093258-28-6;Fluticasone propionate-d3;Fluticasone;90566-53-3

444036

Endogenous Metabolite

White to off-white solid powder

1.3±0.1 g/cm3

568.3±50.0 °C at 760 mmHg

275 °C

297.5±30.1 °C

0.0±3.5 mmHg at 25°C

1.556

3.73

105.97

1

9

6

34

984

9

O([C@@]1([C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(C=C[C@]4(C)[C@]3([C@H](C[C@]12C)O)F)=O)C(=O)SCF)C(=O)CC

WMWTYOKRWGGJOA-CENSZEJFSA-N

InChI=1S/C25H31F3O5S/c1-5-20(31)33-25(21(32)34-12-26)13(2)8-15-16-10-18(27)17-9-14(29)6-7-22(17,3)24(16,28)19(30)11-23(15,25)4/h6-7,9,13,15-16,18-19,30H,5,8,10-12H2,1-4H3/t13-,15+,16+,18+,19+,22+,23+,24+,25+/m1/s1

(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.99 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
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2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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