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Methods for the use of progestogen as a glucocorticoid sensitizer

By using progestins as glucocorticoid sensitizers, the problem of difficult-to-control diseases caused by glucocorticoid insensitivity is solved, the sensitivity to glucocorticoids is improved, and the risk of side effects and recurrence is reduced, especially during the menstrual cycle. In case of deterioration of related conditions.

Active Publication Date: 2012-12-05
SHENZHEN EVERGREEN THERAPEUTICS CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Steroid treatment increases cytosolic MAPK tyrosine phosphorylation but not enzymatic activity

Method used

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  • Methods for the use of progestogen as a glucocorticoid sensitizer
  • Methods for the use of progestogen as a glucocorticoid sensitizer
  • Methods for the use of progestogen as a glucocorticoid sensitizer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1 .Addition of IL-2 and IL-4 reduces steroid sensitivity or induces steroid resistance in male smokers

[0088] IL-2 / 4-induced steroid resistance in PBMCs, a well-known research model, was used to evaluate potential modulators of steroid resistance and sensitivity. PBMC were collected from healthy smokers. Corticosteroid insensitivity or tolerance was induced by addition of IL-2 and IL-4 in peripheral blood mononuclear cells (PBMC) from healthy male smokers (n=11). PBMCs stimulated with or without IL-2 (13ng / ml) and IL-4 (6.5ng / ml) (10 6 cells / ml) were cultured in 96-well plates for 48 hours, and then exposed to serial dilutions of dexamethasone (10 -10 M, 10 -8 M to 10 -6 M) for 1 hour, then at 37°C, 5% CO 2 Stimulated with PHA (15 μg / ml) for 24 hours. IL-2 levels were quantified using ELISA. The percent inhibition of PHA-induced IL-2 production was calculated, % inhibition = 1 - (IL-2 with dexamethasone / IL-2 without dexamethasone).

[0089] figure ...

Embodiment 2

[0090] Example 2 .Progesterone enhances corticosteroid sensitivity or reverses corticosteroid resistance in male smokers

[0091] Corticosteroid insensitivity or tolerance can be reversed pharmacologically. We investigated the effect of progestogens, currently of unknown function, in reversing steroid resistance and tested the progestogen drug 17α-hydroxyprogesterone caproate in peripheral blood mononuclear cells (PBMCs) from healthy male smokers. Effects of ketone (17HPC), medroxyprogesterone acetate (MPA) and natural progesterone (P4) on enhancing glucocorticoid sensitivity.

[0092] PBMC (10 6 cells / ml) were cultured in 96-well plates for 48 hours, followed by 17HPC (10 -10 M, 10 -7 M and 10 -5 M or P4 or MPA (10 -10 M, 10 -8 M and 10 -5 M) Stimulate for 12 hours, and then in 37 ℃, 5% CO 2 , with or without low-dose and high-dose dexamethasone (10 -10 M and 10 -6 M) exposure for 1 hour followed by 24 hours exposure to PHA (15 μg / ml) (n=11 for the combination of ...

Embodiment 3

[0096] Example 3 .17 HPC reverses corticosteroid tolerance in male smokers

[0097] PBMC (10 6 cells / ml) were cultured in 96-well plates for 48 hours, followed by 17HPC (10 -10 M, 10 -7 M and 10 -5 M stimulated for 12 hours, then at 37°C, 5% CO 2 , with or without three doses of dexamethasone (10 -10 M, 10 -8 M and 10 -6 M) exposure for 1 hour followed by 24 hours exposure to PHA (15 μg / ml). IL-2 levels were quantified using ELISA.

[0098] Figure 5 It was shown that addition of IL-2 and IL-4 significantly reduced steroid sensitivity at all three dexamethasone concentrations. Enhancement of dexamethasone inhibition of PHA-induced IL-2 release by addition of 17HPC. In a dose-response plot, 17HPC reversed glucocorticoid insensitivity. Thus, 17HPC restored corticosteroid sensitivity. For example, in the presence of dexamethasone 10 -10 M but without 17HPC, the PHA-induced IL-2 level was 2364pg / ml, vs. -10 M, 10 -7 M and 10 -5 After M, significantly increased cy...

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Abstract

Provided are methods and kits for administering progestogen as a glucocorticoid sensitizer to restore corticosteroid sensitivity or reverse the glucocorticoid insensitivity or enhance glucocorticoid sensitivity, in order to treat one or more glucocorticoid insensitivity related diseases or conditions. For example, these include methods for reversing the glucocorticoid insensitivity in a subject having no history of menstrual cycle-related exacerbation or allergy to self-hormones, particularly progesterone, such as premenstrual or perimenstrual deterioration in the symptoms, e.g., premenstrual worsening of atopic dermatitis or premenstrual exacerbations of asthma, and exhibiting relatively or totally refractory responses to glucocorticoid therapy, e.g., glucocorticoid resistance. The methods and kits provide for the administration of a sex hormone to the subject who is corticosteroid dependent or corticoid resistant or unresponsive or intolerant to corticosteroids.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 61 / 302,325, filed February 8, 2010, the entire contents of which are incorporated herein by reference. field of invention [0003] Glucocorticoid insensitivity is a difficult problem to manage in diseases / conditions treated with glucocorticoids because of the lack of effective treatments. The present invention provides methods and kits for using progestin as a glucocorticoid sensitizer (sensitizer) to restore corticosteroid sensitivity or reverse glucocorticoid insensitivity or enhance glucocorticoid sensitivity in order to treat one or more diseases associated with Diseases or symptoms associated with glucocorticoid insensitivity, for example, these methods include methods for reversing glucocorticoid insensitivity in subjects without menstrual cycle-related exacerbations or responses to autologous hormones, especially Progesterone, histor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/22A61K31/573A61P29/00A61P11/06A61P11/00A61P37/00
CPCA61K31/56A61K31/57A61P1/00A61P3/00A61P3/04A61P3/10A61P5/44A61P7/00A61P9/00A61P11/00A61P11/06A61P13/00A61P13/12A61P17/00A61P17/06A61P19/00A61P19/02A61P21/04A61P25/00A61P25/20A61P25/22A61P27/02A61P29/00A61P31/00A61P31/04A61P31/12A61P33/00A61P35/00A61P35/02A61P37/00A61P37/02A61P37/08A61P43/00Y02A50/30
Inventor 杜涛
Owner SHENZHEN EVERGREEN THERAPEUTICS CO LTD
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