Combination therapy for the treatment of immunoinflammatory disorders

A technology of immune factors and compositions, applied in allergic diseases, skin diseases, bone diseases, etc., can solve problems such as adverse side effects

Inactive Publication Date: 2008-08-06
COMBINATORX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The effects of these drugs can vary and their use is often accompanied by unwanted side effects

Method used

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  • Combination therapy for the treatment of immunoinflammatory disorders
  • Combination therapy for the treatment of immunoinflammatory disorders
  • Combination therapy for the treatment of immunoinflammatory disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0207] Example 1: Determination of pro-inflammatory cytokine-inhibitory activity

[0208] Compound dilution models were assayed for inhibition of IL-2 or TNFα as described below.

[0209] IL-2

[0210]Stimulation in the IL-2 was secreted from 100 μL of the diluted human leukocyte suspension contained in each well of a polystyrene 384-well plate (NalgeNunc). Various concentrations of each test compound were added at the time of stimulation. After 16-18 hours of incubation at 37°C in a humidified incubator, the plate was centrifuged and the supernatant was transferred to white opaque polystyrene 384 wells coated with anti-IL-2 antibody (PharMingen, #555051) plate (NalgeNunc, Maxisorb). After two hours of incubation, the plate (Tecan Power Washer 384) was washed with PBS containing 0.1% Tween 20 and another anti-IL-2 antibody labeled with biotin (Endogen, M600B) and streptavidin (PharMingen, #13047E)-coupled HRP was incubated for 1 hour. After the plate was washed with 0.1%...

Embodiment 2

[0217] Embodiment 2: the preparation of compound

[0218] Stock solutions containing NsIDI and group A enhancers were prepared at final concentrations between 0 and 40 μΜ in dimethyl sulfoxide (DMSO). Prepare plates containing dilutions of the above compound stock solutions. The template was sealed and stored at -20°C until use.

[0219] NsIDI and Group A enhancer stock solution

[0220] A stock solution containing cyclosporine A at a concentration of 1.2 mg / ml was prepared in DMSO. A stock solution of tacrolimus was prepared at a concentration of 0.04 mg / ml in DMSO.

[0221] A stock solution containing acyclovir was prepared at a concentration of 10 mg / ml in DMSO. A clotrimazole-containing stock solution was prepared at a concentration of 10 mg / ml in DMSO. Zinc-containing stock solutions were prepared at a concentration of 10 mg / ml in DMSO. A stock solution containing urea was prepared at a concentration of 10 mg / ml in DMSO. Oxybenzone-containing stock solutions were p...

Embodiment 3

[0224] Example 3: Combination of Tacrolimus and Acyclovir Reduces IL-2 Secretion in Vitro

[0225] After stimulation with phorbol-12-myristate-13-acetate and ionomycin, IL-2 secretion was determined by ELISA as described above. The effects of different concentrations of tacrolimus, acyclovir, and combinations of tacrolimus and acyclovir were compared to control wells stimulated without tacrolimus or acyclovir. The results of this experiment are shown in Table 3 below. The effects of individual drugs and combined drugs were expressed as percent inhibition of IL-2 secretion. The data below represent data from one experiment for individual drugs and combinations. Wells without serial numbers indicate artificial data that have been omitted.

[0226] table 3

[0227]

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Abstract

The invention features a method for treating a patient diagnosed with, or at risk of developing, an iminunoinflainpiatory disorder by administering a non-steroidal immunophilin-dependent immunosuppressant (NsIDI) and a Group A enhancer (e.g., antifungal agent, antigout agent, anti-infective agent, antiprotozoal agent, antiviral agent, humectant, sunscreen, vitamin D compound, microtubuline inhibitor, or zinc salt) or analog or metabolite thereof to the patient. The invention also features a pharmaceutical composition containing an NsIDI and Group A enhancer or analog or metabolite thereof for the treatment or prevention of an immunoinflammatory disorder.

Description

Background of the Invention [0001] The present invention relates to the treatment of immunoinflammatory diseases. [0002] Immunoinflammatory diseases characterized by inappropriate activation of the body's immune defenses. The immune response targets and damages the body's own tissue or transplanted tissue, not an infectious invader. The tissues targeted by the immune system vary with disease. For example, in inflammatory skin diseases, the immune response is directed against the skin. Inflammatory skin diseases affect millions of individuals and include conditions such as atopic dermatitis, psoriasis, pyoderma gangrenosum, lichen planus, rosacea, and seborrheic dermatitis. Targeted tissues for immune inflammatory diseases include, in addition to the skin, for example, asthma, allergic intraocular inflammatory disease, arthritis, diabetes, hemolytic anemia, inflammatory bowel or gastrointestinal disease (eg, Crohn's disease). disease and ulcerative colitis), multiple scle...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61F13/00
CPCA61K45/06A61K38/13A61K31/4745A61K31/385A61K31/4523A61K31/522A61K31/4178A61P1/04A61P11/00A61P11/06A61P17/00A61P19/02A61P21/00A61P21/04A61P29/00A61P31/00A61P37/00A61P37/02A61P43/00A61P9/00A61K2300/00A61K31/436A61K31/44
Inventor B·A·奥斯皮茨B·B·布拉谢尔T·W·查佩尔M·G·弗兰克D·格劳E·R·约斯特-普赖斯S·列德曼P·马尼瓦萨坎N·萨赫斯B·史密斯
Owner COMBINATORX
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