Methods and compositions for modulating responsiveness to corticosteroids
First Claim
1. A method for modulating responsiveness to a corticosteroid in a subject, comprising administering to the subject suffering from a condition normally responsive to corticosteroid therapy:
- an interleukin-1 β
converting enzyme (ICE) inhibitor being administered at a dosage and by a route sufficient to inhibit production of IFN-γ
in the subject; and
a corticosteroid,such that responsiveness of the subject to the corticosteroid is modulated as compared to when a corticosteroid alone is administered to the subject.
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Accused Products
Abstract
Method for modulating responsiveness to corticosteroids in a subject are provided. In the method of the invention, an agent which antagonizes a factor that regulates production of IFN-γ in the subject is administered to the subject in combination with a corticosteroid such that responsiveness of the subject to the corticosteroid is modulated as compared to when a corticosteroid alone is administered to the subject. In one embodiment, the agent is an interferon-γ inducing factor (IGIF) antagonist. In another embodiment, the agent is an interleukin-12 (IL-12) antagonist. In a preferred embodiment, the agent is an inhibitor of a caspase family protease, preferably an ICE inhibitor. In another preferred embodiment, the agent is an anti-IL-12 monoclonal antibody. Other preferred agents include phosphodiesterase IV inhibitors and beta-2 agonists. The methods of the invention can be used in the treatment of a variety of inflammatory and immunological diseases and disorders. Pharmaceutical compositions comprising an agent which antagonizes a factor that regulates production of IFN-γ in a subject, a corticosteroid and a pharmaceutically acceptable carrier are also provided. A preferred composition comprises an ICE inhibitor, a corticosteroid and a pharmaceutically acceptable carrier.
84 Citations
46 Claims
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1. A method for modulating responsiveness to a corticosteroid in a subject, comprising administering to the subject suffering from a condition normally responsive to corticosteroid therapy:
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an interleukin-1 β
converting enzyme (ICE) inhibitor being administered at a dosage and by a route sufficient to inhibit production of IFN-γ
in the subject; anda corticosteroid, such that responsiveness of the subject to the corticosteroid is modulated as compared to when a corticosteroid alone is administered to the subject. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 35, 36, 37, 38, 39, 40)
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15. A method for modulating responsiveness to corticosteroids in a subject, comprising administering to the subject suffering from a condition normally responsive to corticosteroid therapy,
an interleukin-1 β - converting enzyme (ICE) inhibitor; and
a corticosteroid, such that responsiveness of the subject to the corticosteroid is modulated as compared to when a corticosteroid alone is administered to the subject. - View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 41, 42, 43, 44, 45, 46)
- converting enzyme (ICE) inhibitor; and
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28. A method for modulating responsiveness to a corticosteroid in a subject, comprising:
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selecting a subject in need of modulation of responsiveness to a corticosteroid, wherein the subject suffers from a condition normally responsive to corticosteroid therapy; and administering to the subject an interleukin-1 β
converting enzyme (ICE) inhibitor which antagonizes a factor that regulates production of interferon (IFN-γ
) in the subject, the ICE inhibitor being administered at a dosage and by a route sufficient to inhibit production of IFN-γ
in the subject,such that responsiveness of the subject to a corticosteroid is modulated as compared to when a corticosteroid alone is administered to the subject. - View Dependent Claims (29, 30, 31, 32)
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33. A method for modulating responsiveness to corticosteroids in a subject comprising administering to the subject suffering from a condition normally responsive to corticosteroid therapy:
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an interleukin-1β
converting enzyme (ICE) inhibitor compound having the structure of Formula I;
##STR6## wherein R1 is hydrogen, C1 -C6 alkyl, or benzyl;R2 is --CHO, --CORa, or --CN; each Ra is independently hydrogen or C1 -C6 alkyl; X is a bond, CH2, CHR5, NH, NR5, or O; R3 is aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, cycloalkyl, substituted-cycloalkyl, heterocycle, or substituted-heterocycle; Y is absent, NR5, CO, S, O, SO2, --O(CHR5)n --, CHR5, NR5 CO, NC(O)R5, CONR5, OCHR5, CHR5 O, SCHR5, CHR5 S, SO2 NR5, C1 -C6 alkyl, NR5 SO2, CH2 CHR5, CHR5 CH2, COCH2, or CH2 CO; R4 is absent, aryl, substituted-aryl, C1 -C8 alkyl, heteroaryl, substituted-heteroaryl, cycloalkyl, C1 -C6 alkyl, substituted-cycloalkyl, heterocycloalkyl, or substituted-heterocycloalkyl; each R5 is independently hydrogen, C1 -C6 alkyl, aryl, --(CH2)n aryl, or --(CH2)n cycloalkyl; each n is independently 0 to 5, m is 1 or 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof; and a corticosteroid, such that responsiveness of the subject to the corticosteroid is modulated as compared to when a corticosteroid alone is administered to the subject.
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34. A method for modulating responsiveness to a corticosteroid in a subject, comprising:
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selecting a subject in need of modulation of responsiveness to a corticosteroid, wherein the subject suffers from a condition normally responsive to corticosteroid therapy; and administering to the subject an interleukin-1β
converting enzyme (ICE) inhibitor compound having The structure of Formula I;
##STR7## wherein R1 is hydrogen, C1 -C6 alkyl, or benzyl;R2 is --CHO, --CORa, or --CN; each Ra is independently hydrogen or C1 -C6 alkyl; X is a bond, CH2, CHR5, NH, NR5, or O; R3 is aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, cycloalkyl, substituted-cycloalkyl, heterocycle, or substituted-heterocycle; Y is absent, NR5, CO, S, O, SO2, --O(CHR5)n --, CHR5, NR5 CO, NC(O)R5, CONR5, OCHR5, CHR5 O, SCHR5, CHR5 S, SO2 NR5, C1 -C6 alkyl, NR5 SO2, CH2 CHR5, CHR5 CH2, COCH2, or CH2 CO; R4 is absent, aryl, substituted-aryl, C1 -C8 alkyl, heteroaryl, substituted-heteroaryl, cycloalkyl, C1 -C6 alkyl, substituted-cycloalkyl, heterocycloalkyl, or substituted-heterocycloalkyl; each R5 is independently hydrogen, C1 -C6 alkyl, aryl, --(CH2)n aryl, or --(CH2)n cycloalkyl; each n is independently 0 to 5, m is 1 or 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, the compound being administered at a dosage and by a route sufficient to inhibit production of IFN-γ
in the subject,such that responsiveness of the subject to a corticosteroid is modulated as compared to when a corticosteroid alone is administered to the subject.
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Specification