Methods of treating blood cell depletion
AssigneeImmuneRegen Biosciences, Inc.
InventorsHal Siegel, Michael K. Wilhelm
Life of this patent
Estimating the term…
Abstract
Provided herein are methods and compositions useful for the replenishment of blood cells in a mammal after exposure to therapeutic radiation or drugs. Radiation illness can be reduced in animals by treatment with substance P analogs. In one embodiment, granulocytes can be regenerated after therapeutic radiation by the administration of a substance P analog. In one embodiment, substance P analogs are useful for reducing PARP activity or PARP expression. In one embodiment, substance P analogs are useful for preventing, reducing or ameliorating adverse effects of drugs. In one embodiment, drug induced blood dyscrasias can be ameliorated by the methods and compositions provided herein.
Claims61
A method of treating or ameliorating therapeutic radiation myelosuppression in an animal comprising administering to the animal an effective amount of a substance P analog according to Formula (I):
- Z1-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-
- (I)
- Xaa9-Xaa10-Xaa11-Z2
- or a pharmaceutically acceptable salt thereof, wherein:
- Xaa1 is Arg, Lys, 6-N methyllysine or (6-N, 6-N) dimethyllysine;
- Xaa2 is Pro or Ala;
- Xaa3 is Lys, Arg, 6-N-methyllysine or (6-N, 6-N) dimethyllysine;
- Xaa4 is Pro or Ala;
- Xaa5 is Gln or Asn;
- Xaa6 is Gln or Asn;
- Xaa7 is Tyr, Phe or Phe substituted with chlorine at position 2, 3 or 4;
- Xaa8 is Tyr, Phe, or Phe substituted with chlorine at position 2, 3 or 4;
- Xaa9 is Gly, Pro, Ala or N-methylglycine;
- Xaa10 is Leu, Val, Ile, Norleucine, Met, Met sulfoxide, Met sulfone, N-methylleucine, or N-methylvaline;
- Xaa11 is Met, Met sulfoxide, Met sulfone, or Norleucine (SEQ ID NO.:
- 12);
- Z1 is R2N— or RC(O)NR—;
- Z2 is —C(O)NR2 or —C(O)OR or a salt thereof;
- each R is independently R is —H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl;
- and
- each “-” between residues Xaa1 through Xaa11 independently designates an amide linkage, a substitute amide linkage or an isostere of an amide.
A method of treating or ameliorating drug-induced blood dyscrasia in an animal comprising:
- administering to the animal an effective amount of a substance P analog according to Formula (I):
- Z1-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-
- (I)
- Xaa9-Xaa10-Xaa11-Z2
- or a pharmaceutically acceptable salt thereof, wherein:
- Xaa1 is Arg, Lys, 6-N methyllysine or (6-N, 6-N) dimethyllysine;
- Xaa2 is Pro or Ala;
- Xaa3 is Lys, Arg, 6-N-methyllysine or (6-N, 6-N) dimethyllysine;
- Xaa4 is Pro or Ala;
- Xaa5 is Gln or Asn;
- Xaa6 is Gln or Asn;
- Xaa7 is Tyr, Phe or Phe substituted with chlorine at position 2, 3 or 4;
- Xaa8 is Tyr, Phe, or Phe substituted with chlorine at position 2, 3 or 4;
- Xaa9 is Gly, Pro, Ala or N-methylglycine;
- Xaa10 is Leu, Val, Ile, Norleucine, Met, Met sulfoxide, Met sulfone, N-methylleucine, or N-methylvaline;
- Xaa11 is Met, Met sulfoxide, Met sulfone, or Norleucine (SEQ ID NO.:
- 12);
- Z1 is R2N— or RC(O)NR—;
- Z2 is —C(O)NR2 or —C(O)OR or a salt thereof;
- each R is independently R is —H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl;
- and
- each “-” between residues Xaa1 through Xaa11 independently designates an amide linkage, a substitute amide linkage or an isostere of an amide.
A composition for ameliorating drug-induced blood dyscrasia in an animal comprising an effective amount of a substance P analog according to Formula (I):
- Z1-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-
- (I)
- Xaa9-Xaa10-Xaa11-Z2
- or a pharmaceutically acceptable salt thereof, wherein:
- Xaa1 is Arg, Lys, 6-N methyllysine or (6-N, 6-N) dimethyllysine;
- Xaa2 is Pro or Ala;
- Xaa3 is Lys, Arg, 6-N-methyllysine or (6-N, 6-N) dimethyllysine;
- Xaa4 is Pro or Ala;
- Xaa5 is Gln or Asn;
- Xaa6 is Gln or Asn;
- Xaa7 is Tyr, Phe or Phe substituted with chlorine at position 2, 3 or 4;
- Xaa8 is Tyr, Phe, or Phe substituted with chlorine at position 2, 3 or 4;
- Xaa9 is Gly, Pro, Ala or N-methylglycine;
- Xaa10 is Leu, Val, Ile, Norleucine, Met, Met sulfoxide, Met sulfone, N-methylleucine, or N-methylvaline;
- Xaa11 is Met, Met sulfoxide, Met sulfone, or Norleucine (SEQ ID NO.:
- 12);
- Z1 is R2N— or RC(O)NR—;
- Z2 is —C(O)NR2 or —C(O)OR or a salt thereof;
- each R is independently R is —H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl;
- and
- each “-” between residues Xaa1 through Xaa11 independently designates an amide linkage, a substitute amide linkage or an isostere of an amide.
A composition for treating or ameliorating therapeutic radiation myelosuppression in an animal comprising an effective amount of a substance P analog according to Formula (I):
- Z1-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-
- (I)
- Xaa9-Xaa10-Xaa11-Z2
- or a pharmaceutically acceptable salt thereof, wherein:
- Xaa1 is Arg, Lys, 6-N methyllysine or (6-N, 6-N) dimethyllysine;
- Xaa2 is Pro or Ala;
- Xaa3 is Lys, Arg, 6-N-methyllysine or (6-N, 6-N) dimethyllysine;
- Xaa4 is Pro or Ala;
- Xaa5 is Gln or Asn;
- Xaa6 is Gln or Asn;
- Xaa7 is Tyr, Phe or Phe substituted with chlorine at position 2, 3 or 4;
- Xaa8 is Tyr, Phe, or Phe substituted with chlorine at position 2, 3 or 4;
- Xaa9 is Gly, Pro, Ala or N-methylglycine;
- Xaa10 is Leu, Val, Ile, Norleucine, Met, Met sulfoxide, Met sulfone, N-methylleucine,
- or N-methylvaline;
- Xaa11 is Met, Met sulfoxide, Met sulfone, or Norleucine (SEQ ID NO.:
- 12);
- Z1 is R2N— or RC(O)NR—;
- Z2 is —C(O)NR2 or —C(O)OR or a salt thereof;
- each R is independently R is —H, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C5-C20) aryl, (C6-C26) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl;
- and
- each “-” between residues Xaa1 through Xaa11 independently designates an amide linkage, a substitute amide linkage or an isostere of an amide.
Dependencies are inferred from the claim text.