Composition and methods for the treatment of skin disorders

• US 20030032617A1
• Filed: 07/11/2002
• Published: 02/13/2003
• Est. Priority Date: 01/11/2000
• Status: Abandoned Application

• Current Assignee: Dermipsor Ltd.
• Original Assignee: Dermipsor Ltd.
• Inventors: Harel, Avikam, Bloch, Olga
• Application Number:
  US10/192,842
• Publication Number:
  US 20030032617A1
• Time in Patent Office: Days
• US Class Current: 514/46
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/455 Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 8/606 Nucleosides; Nucleotides; Nucleic acids
• CPC Class Codes: A61K 8/675 Vitamin B3 or vitamin B3 active, e.g. nicotinamide, nicotinic acid, nicotinyl aldehyde tocopheryl nicotinate A61K8/678
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61Q 19/08 Anti-ageing preparations

Abstract

Methods and pharmaceutical compositions for use in the treatment of a benign and/or a malignant proliferative pathologies are disclosed. The methods comprise administration of nicotinamide or its analogs and/or cADPR or its analogs, optionally in combination with a vitamin D3 analog or a Vitamin A analog.

Claims

1. A method of treating a benign or malignant hyperproliferative epidermal pathology in a subject in need thereof, the method comprising:

administering to said subject a therapeutically effective amount of an agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof.

2. The method of claim 1, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

3. The method of claim 1, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer NMSC).

4. The method of claim 1, further comprising:

administering to said subject, in combination with said agent, a therapeutically effective amount of an agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

5. The method of claim 1, further comprising:

administering to said subject, in combination with said agent, a therapeutically effective amount of an agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

6. The method of claim 5, wherein said Vitamin D3 metabolite is 1α

,25-dihydroxy-vitamin D3.

7. The method of claim 1, further comprising:

administering to said subject, in combination with said agent, a therapeutically effective amount of an agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

8. The method of claim 7, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

9. The method of claim 7, wherein said Vitamin A agonist is a retinoic acid receptor agonist.

10. A method of treating a benign or malignant hyperproliferative epidermal pathology in a subject in need thereof, the method comprising:

administering to said subject a therapeutically effective amount of an agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

11. The method of claim 10, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

12. The method of claim 10, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

13. The method of claim 10, further comprising:

administering to said subject, in combination with said agent, a therapeutically effective amount of an agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof.

14. The method of claim 10, further comprising:

administering to said subject, in combination with said agent, a therapeutically effective amount of an agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

15. The method of claim 14, wherein said Vitamin D3 metabolite is 1α

,25-dihydroxy-vitamin D3.

16. The method of claim 10, further comprising;

administering to said subject, in combination with said agent, a therapeutically effective amount of an agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

17. The method of claim 16, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

18. The method of claim 16, wherein said Vitamin A agonist is a retinoic acid receptor agonist.

19. A method of treating a benign or malignant hyperproliferative epidermal pathology in a subject in need thereof, the method comprising:

administering to said subject a therapeutically effective amount of a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, in combination with a second agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

20. The method of claim 19, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

21. The method of claim 19, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

22. The method of claim 19, further comprising:

administering to said subject, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

23. The method of claim 22, wherein said Vitamin D3 metabolite is 1α

,25-dihydroxy-vitamin D3.

24. The method of claim 19, further comprising:

administering to said subject, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

25. The method of claim 24, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

26. The method of claim 24, wherein said Vitamin A agonist is a retinoic acid receptor agonist.

27. The method of claim 19, wherein said first agent is nicotinamide and said second agent is cADPR.

28. A method of treating a benign or malignant hyperproliferative epidermal pathology in a subject in need thereof, the method comprising:

administering to said subject a therapeutically effective amount of a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, in combination with a therapeutically effective amount of a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

29. The method of claim 28, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

30. The method of claim 28, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

31. The method of claim 28, wherein said first agent is nicotinamide and said second agent is a Vitamin D3 metabolite.

32. The method of claim 31, wherein said Vitamin D3 metabolite is 1α

,25-dihydroxy-vitamin D3.

33. The method of claim 28, further comprising:

administering to said subject, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of an agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

34. The method of claim 28, further comprising:

administering to said subject, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

35. The method of claim 34, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

36. The method of claim 34, wherein said Vitamin A agonist is a retinoic acid receptor agonist.

37. A method of treating a benign or malignant hyperproliferative epidermal pathology in a subject in need thereof, the method comprising:

administering to said subject a therapeutically effective amount of a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, in combination with a second agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

38. The method of claim 37, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

39. The method of claim 37, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

40. The method of claim 37, wherein said first agent is nicotinamide and said second agent is a Vitamin A metabolite.

41. The method of claim 40, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

42. The method of claim 37, further comprising:

administering to said subject, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of an agent selected from the group consisting cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

43. The method of claim 37, further comprising:

administering to said subject, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

44. The method of claim 43, wherein said Vitamin D3 metabolite is 1α

,25 dihydroxy-vitamin D3.

45. A method of treating a benign or malignant hyperproliferative epidermal pathology in a subject in need thereof, the method comprising:

administering to said subject a therapeutically effective amount of a first agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, in combination with a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

46. The method of claim 45, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

47. The method of claim 45, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

48. The method of claim 45, wherein said first agent is cyclic adenosine diphosphate-ribose (cADPR) and said second agent is a Vitamin D3 metabolite.

49. The method of claim 48, wherein said Vitamin D3 metabolite is 1α

25 dihydroxy-vitamin D3.

50. The method of claim 45, further comprising:

administering to said subject, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of nicotinamide, a nicotinamide derivative, a nicotinamide metabolite, a nicotinamide agonist and prodrugs thereof.

51. The method of claim 45, further comprising:

administering to said subject in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

52. The method of claim 51, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

53. A method of treating a benign or malignant hyperproliferative epidermal pathology in a subject in need thereof, the method comprising:

administering to said subject a therapeutically effective amount of a first agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, in combination with a second agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

54. The method of claim 53, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

55. The method of claim 53, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

56. The method of claim 53, wherein said first agent of cyclic adenosine diphosphate-ribose (cADPR) and said second agent is a Vitamin A metabolite.

57. The method of claim 56, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

58. The method of claim 53, further comprising:

administering to said subject, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof

59. The method of claim 53, further comprising:

administering to said subject, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

60. The method of claim 59, wherein said Vitamin D3 metabolite is 1α

,25 dihydroxy-vitamin D3.

61. A method of increasing anti-oxidative properties of epidermal cells, the method comprising:

contacting said cells with an effective amount of an agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamnide metabolite and prodrugs thereof.

62. The method of claim 61, wherein said agent is nicotinamide and said effective amount ranges between 1 mM and 50 mM.

63. A method of increasing anti-oxidative properties of epidermal cells, the method comprising:

contacting said cells with an effective amount of an agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

64. A method of increasing anti-oxidative properties of epidermal cells, the method comprising:

contacting said cells with an effective amount of a first agent selected from the group consisting of nicotinamnide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, in combination with am effective amount of a second agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

65. A method of increasing anti-oxidative properties of epidermal cells, the method comprising:

contacting said cells with an effective amount of a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, in combination with an effective amount of a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

66. A method of increasing anti-oxidative properties of epidermal cells, the method comprising:

contacting said cells with an effective amount of an agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, in combination with an effective amount of an agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

67. A method of increasing anti-oxidative properties of epidermal cells, the method comprising:

contacting said cells with an effective amount of a first agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, in combination with an effective amount of a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

68. A method of increasing anti-oxidative properties of epidermal cells, the method comprising:

contacting said cells with an effective amount of a first agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof in combination with an effective amount of a second agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

69. A pharmaceutical, cosmetic or cosmeceutical composition, identified for use in the treatment of benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, as an active ingredient, a therapeutically effective amount of an agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, and a pharmaceutically, cosmetically or cosmeceutically acceptable carrier.

70. The pharmaceutical, cosmetic or cosmeceutical composition of claim 69, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

71. The pharmaceutical, cosmetic or cosmeceutical composition of claim 69, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

72. The pharmaceutical, cosmetic or cosmeceutical composition of claim 69, wherein said condition is aging.

73. The pharmaceutical, cosmetic or cosmeceutical composition of claim 69, wherein said condition is cancer.

74. The pharmaceutical, cosmetic or cosmeceutical composition of claim 69, wherein said agent is nicotinamide and said therapeutically effective amount ranges between 0.5 mM and 20 mM.

75. The pharmaceutical, cosmetic or cosmeceutical composition of claim 74, wherein said therapeutically effective amount ranges between 1 mM and 10 mM.

76. The pharmaceutical, cosmetic or cosmeceutical composition of claim 69, further comprising, in combination with said agent, a therapeutically effective amount of a second agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

77. The pharmaceutical, cosmetic or cosmeceutical composition of claim 76, wherein said agent is nicotinamide and said second agent is cADPR.

78. The pharmaceutical, cosmetic or cosmeceutical composition of claim 77, wherein said therapeutically effective amount of said nicotinamide ranges between 1 mM and 10 mM and said therapeutically effective amount of said cADPR ranges between 10 μ

M and 100 μ

M.

79. The pharmaceutical, cosmetic or cosmeceutical composition of claim 69, further comprising, in combination with said agent, a therapeutically effective amount of a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

80. The pharmaceutical, cosmetic or cosmeceutical composition of claim 79, wherein said agent is nicotinamide and said second agent is a Vitamin D3 metabolite.

81. The pharmaceutical, cosmetic or cosmeceutical composition of claim 80, wherein said Vitamin D3 metabolite is 1α

,25-dihydroxy-vitamin D3.

82. The pharmaceutical, cosmetic or cosmeceutical composition of claim 81, wherein said therapeutically effective amount of said nicotinamide ranges between 1 mM and 10 mM and said therapeutically effective amount of said 1α

,25-dihydroxy-vitamin D3 ranges between 1 nM and 200 nM.

83. The pharmaceutical, cosmetic or cosmeceutical composition of claim 69, further comprising, in combination with said agent, a therapeutically effective amount of a second agent selected from tie group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

84. The pharmaceutical, cosmetic or cosmeceutical composition of claim 83, wherein said agent is nicotinamide and said second agent is a Vitamin A metabolite.

85. The pharmaceutical, cosmetic or cosmeceutical composition of claim 84, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

86. The pharmaceutical, cosmetic or cosmeceutical composition of claim 85, wherein said therapeutically effective amount of said nicotinamide ranges between 1 mM and 10 mM and said effective amount of said all-trans-retinoic acid ranges between 0.1 nM and 10 nM.

87. The pharmaceutical, cosmetic or cosmeceutical composition of claim 69, packaged in a container and identified in print on or in said container for use in treatment of a benign or a malignant hyperproliferative epidermal pathology.

88. The pharmaceutical, cosmetic or cosmeceutical composition of claim 69, packaged in a container and identified in print on or in said container for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous.

89. A pharmaceutical, cosmetic or cosmeceutical composition, identified for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, as an active ingredient, a therapeutically effective amount of an agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, and a pharmaceutically, cosmetically or cosmeceutically acceptable carrier.

90. The pharmaceutical, cosmetic or cosmeceutical composition of claim 89, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

91. The pharmaceutical, cosmetic or cosmeceutical composition of claim 89, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

92. The pharmaceutical, cosmetic or cosmeceutical composition of claim 89, wherein said condition is aging.

93. The pharmaceutical, cosmetic or cosmeceutical composition of claim 89, wherein said condition is cancer.

94. The pharmaceutical, cosmetic or cosmeceutical composition of claim 89, wherein said agent is cADPR and said therapeutically effective amount ranges between 10 μ

M and 100 μ

M.

95. The pharmaceutical, cosmetic or cosmeceutical composition of claim 89, further comprising, in combination with said agent, a therapeutically effective amount of a second agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof.

96. The pharmaceutical, cosmetic or cosmeceutical composition of claim 95, wherein said agent is cADPR and said second agent is nicotinamide.

97. The pharmaceutical, cosmetic or cosmeceutical composition of claim 96, wherein said therapeutically effective amount of said nicotinamide ranges between 1 mM and to 10 mM and said therapeutically effective amount of said cADPR ranges between 10 μ

M and 100 μ

M.

98. The pharmaceutical, cosmetic or cosmeceutical composition of claim 89, further comprising, in combination with said agent, a therapeutically effective amount of a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

99. The pharmaceutical, cosmetic or cosmeceutical composition of claim 98, wherein said agent is cADPR and said second agent is a Vitamin D3 metabolite.

100. The pharmaceutical, cosmetic or cosmeceutical composition of claim 99, wherein said second Vitamin D3 metabolite is 1α

,25-dihydroxy-vitamin D3.

101. The pharmaceutical, cosmetic or cosmeceutical composition of claim 89, further comprising, in combination with said agent, a therapeutically effective amount of a second agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

102. The pharmaceutical, cosmetic or cosmeceutical composition of claim 101, wherein said agent is cADPR and said second agent is a Vitamin A metabolite.

103. The pharmaceutical, cosmetic or cosmeceutical composition of claim 102, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

104. The pharmaceutical, cosmetic or cosmeceutical composition of claim 89, packaged in a container and identified in print on or in said container for use in treatment of a benign or a malignant hyperproliferative epidermal pathology.

105. The pharmaceutical, cosmetic or cosmeceutical composition of claim 89, packaged in a container and identified in print on or in said container for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous.

106. A pharmaceutical, cosmetic or cosmeceutical composition, identified for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, as a combination of active ingredients, a therapeutically effective amount of a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, a therapeutically effective amount of a second agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, and a pharmaceutically, cosmetically or cosmeceutically acceptable carrier.

107. The pharmaceutical, cosmetic or cosmeceutical composition of claim 106, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

108. The pharmaceutical, cosmetic or cosmeceutical composition of claim 106, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

109. The pharmaceutical, cosmetic or cosmeceutical composition of claim 106, wherein said condition is aging.

110. The pharmaceutical, cosmetic or cosmeceutical composition of claim 106, wherein said condition is cancer.

111. The pharmaceutical, cosmetic or cosmeceutical composition of claim 106, wherein said first agent is nicotinamide and said second agent is cADPR.

112. The pharmaceutical, cosmetic or cosmeceutical composition of claim 111, wherein said therapeutically effective amount of said nicotinamide ranges between 0.5 mM and 20 mM and said therapeutically effective amount of said cADPR ranges between 10 μ

M and 100 μ

M.

113. The pharmaceutical, cosmetic or cosmeceutical composition of claim 106, further comprising, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

114. The pharmaceutical, cosmetic or cosmeceutical composition of claim 106, further comprising, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

115. The pharmaceutical, cosmetic or cosmeceutical composition of claim 106, packaged in a container and identified in print on or in said container for use in treatment of a benign or a malignant hyperproliferative epidermal pathology.

116. The pharmaceutical, cosmetic or cosmeceutical composition of claim 106, packaged in a container and identified in print on or in said container for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous.

117. A pharmaceutical, cosmetic or cosmeceutical composition, identified for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, as a combination of active ingredients, a therapeutically effective amount of a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, a therapeutically effective amount of a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof, and a pharmaceutically, cosmetically or cosmeceutically acceptable carrier.

118. The pharmaceutical, cosmetic or cosmeceutical composition of claim 117, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

119. The pharmaceutical, cosmetic or cosmeceutical composition of claim 117, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

120. The pharmaceutical, cosmetic or cosmeceutical composition of claim 117, wherein said condition is aging.

121. The pharmaceutical, cosmetic or cosmeceutical composition of claim 117, wherein said condition is cancer.

122. The pharmaceutical, cosmetic or cosmeceutical composition of claim 117, wherein said first agent is nicotinamide and said second agent is a Vitamin D3 metabolite.

123. The pharmaceutical, cosmetic or cosmeceutical composition of claim 122, wherein said Vitamin D3 metabolite is 1α

,25-dihydroxy-vitamin D3.

124. The pharmaceutical, cosmetic or cosmeceutical composition of claim 123, wherein said therapeutically effective amount of said nicotinamide ranges between 1 mM and 10 mM and said therapeutically effective amount of said 1α

,25-dihydroxy-vitamin D3 ranges between 1 nM and 200 nM.

125. The pharmaceutical, cosmetic or cosmeceutical composition of claim 117, further comprising, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

126. The pharmaceutical, cosmetic or cosmeceutical composition of claim 117, further comprising, in combination with said first and second agents, a therapeutically effective amount of a third agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

127. The pharmaceutical, cosmetic or cosmeceutical composition of claim 117, packaged in a container and identified in print on or in said container for use in treatment of a benign or a malignant hyperproliferative epidermal pathology.

128. The pharmaceutical, cosmetic or cosmeceutical composition of claim 117, packaged in a container and identified in print on or in said container for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous.

129. A pharmaceutical, cosmetic or cosmeceutical composition, identified for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, as a combination of active ingredients, a therapeutically effective amount of a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, a therapeutically effective amount of a second agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonists a Vitamin A derivative and prodrugs thereof, and a pharmaceutically, cosmetically or cosmeceutically acceptable carrier.

130. The pharmaceutical, cosmetic or cosmeceutical composition of claim 129, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

131. The pharmaceutical, cosmetic or cosmeceutical composition of claim 129, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

132. The pharmaceutical, cosmetic or cosmeceutical composition of claim 129, wherein said condition is aging.

133. The pharmaceutical, cosmetic or cosmeceutical composition of claim 129, wherein said condition is cancer.

134. The pharmaceutical, cosmetic or cosmeceutical composition of claim 129, wherein said first agent is nicotinamide and said second agent is a Vitamin A metabolite.

135. The pharmaceutical, cosmetic or cosmeceutical composition of claim 134, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

136. The pharmaceutical, cosmetic or cosmeceutical composition of claim 135, wherein said therapeutically effective amount of said nicotinamide ranges between 1 mM and 10 mM and said therapeutically effective amount of said all-trans-retinoic acid ranges between 0.1 nM and 10 nM.

137. The pharmaceutical, cosmetic or cosmeceutical composition of claim 129, father comprising, in combination with said first and second agents, a therapeutically effective amount of an agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

138. The pharmaceutical, cosmetic or cosmeceutical composition of claim 129, further comprising, in combination with said first and second agents, a therapeutically effective amount of a third agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

139. The pharmaceutical, cosmetic or cosmeceutical composition of claim 129, packaged in a container and identified in print on or in said container for use in treatment of a benign or a malignant hyperproliferative epidermal pathology.

140. The pharmaceutical, cosmetic or cosmeceutical composition of claim 129, packaged in a container and identified in print on or in said container for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous.

141. A pharmaceutical, cosmetic or cosmeceutical composition, identified for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, as a combination of active ingredients, a therapeutically effective amount of a first agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, a therapeutically effective amount of a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof, and a pharmaceutically, cosmetically or cosmeceutically acceptable carrier.

142. The pharmaceutical, cosmetic or cosmeceutical composition of claim 141, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

143. The pharmaceutical, cosmetic or cosmeceutical composition of claim 141, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

144. The pharmaceutical, cosmetic or cosmeceutical composition of claim 141, wherein said condition is aging.

145. The pharmaceutical, cosmetic or cosmeceutical composition of claim 141, wherein said condition is cancer.

146. The pharmaceutical, cosmetic or cosmeceutical composition of claim 141, wherein said first agent is cADPR and said second agent is a Vitamin D3 metabolite.

147. The pharmaceutical, cosmetic or cosmeceutical composition of claim 146, wherein said Vitamin D3 metabolite is 1α

,25-dihydroxy-vitamin D3.

148. The pharmaceutical, cosmetic or cosmeceutical composition of claim 141, further comprising, in combination with said fist and second agents, a therapeutically effective amount of a third agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof.

149. The pharmaceutical, cosmetic or cosmeceutical composition of claim 141, further comprising, in combination with said first and second agents, a therapeutically effective amount of a third agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

150. The pharmaceutical, cosmetic or cosmeceutical composition of claim 141, packaged in a container and identified in print on or in said container for use in treatment of a benign or a malignant hyperproliferative epidermal pathology.

151. The pharmaceutical, cosmetic or cosmeceutical composition of claim 141, packaged in a container and identified in print on or in said container for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous.

152. A pharmaceutical, cosmetic or cosmeceutical composition, identified for use in the treatment of benign or malignant hyperproliferative epidermal pathology, comprising, as a combination of active ingredients, a therapeutically effective amount of a first agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, a therapeutically effective amount of a second agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof, and a pharmaceutically, cosmetically or cosmeceutically acceptable carrier.

153. The pharmaceutical, cosmetic or cosmeceutical composition of claim 152, wherein said hyperproliferative benign epidermal pathology is selected from the group consisting of psoriasis, ichythyiosis, common warts, keratoacanthoma, seborrhoic keratosis and seborrhea.

154. The pharmaceutical, cosmetic or cosmeceutical composition of claim 152, wherein said hyperproliferative malignant epidermal pathology is selected from the group consisting of squamous-cell carcinoma (SCC), basal cell carcinoma (BCC) and a non-melanoma skin cancer (NMSC).

155. The pharmaceutical, cosmetic or cosmeceutical composition of claim 152, wherein said condition is aging.

156. The pharmaceutical, cosmetic or cosmeceutical composition of claim 152, wherein said condition is cancer.

157. The pharmaceutical, cosmetic or cosmeceutical composition of claim 152, wherein said first agent is cADPR and said second agent is a Vitamin A metabolite.

158. The pharmaceutical, cosmetic or cosmeceutical composition of claim 157, wherein said Vitamin A metabolite is an all-trans-retinoic acid.

159. The pharmaceutical, cosmetic or cosmeceutical composition of claim 152, further comprising, in combination with said first and second agents, a therapeutically effective amount of a third agent selected from the group consisting of nicotinamide, a nicotinamide derivative, a nicotinamide netabolite, a nicotinamide agonist and prodrugs thereof.

160. The pharmaceutical, cosmetic or cosmeceutical composition of claim 152, further comprising, in combination with said first and second agents, a therapeutically effective amount of a third agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

161. The pharmaceutical, cosmetic or cosmeceutical composition of claim 152, packaged in a container and identified in print on or in said container for use in treatment of a benign or a malignant hyperproliferative epidermal pathology.

162. The pharmaceutical, cosmetic or cosmeceutical composition of claim 152, packaged in a container and identified in print on or in said container for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous.

163. A method of inhibiting proliferation of benign or malignant hyperproliferative epidermal cells, the method comprising:

contacting said cells with a therapeutically effective amount of all agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof.

164. A method of inhibiting proliferation of benign or malignant hyperproliferative epidermal cells, the method comprising:

contacting said cells with a therapeutically effective amount of an agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

165. A method of inhibiting proliferation of benign or malignant hyperproliferative epidermal cells, the method comprising:

contacting said cells with a therapeutically effective amount of a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, in combination with a therapeutically effective amount of a second agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

166. A method of inhibiting proliferation of benign or malignant hyperproliferative epidermal cells, the method comprising:

contacting said cells with a therapeutically effective amount of a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, in combination with a therapeutically effective amount of a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

167. A method of inhibiting proliferation of benign or malignant hyperproliferative epidermal cells, the method comprising:

contacting said cells with a therapeutically effective amount of a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, in combination with a therapeutically effective amount of a second agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

168. A method of inhibiting proliferation of benign or malignant hyperproliferative epidermal cells, the method comprising:

contacting said cells with a therapeutically effective amount of a first agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, in combination with a therapeutically effective amount of a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof.

169. A method of inhibiting proliferation of benign or malignant hyperproliferative epidermal cells, the method comprising;

contacting said cells with a therapeutically effective amount of a first agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, in combination with a therapeutically effective amount of a second agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof.

170. A pharmaceutical, cosmetic or cosmeceutical kit, identified in print for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, as an active ingredient an agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof.

171. A pharmaceutical, cosmetic or cosmeceutical kit, identified in print for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, as an active ingredient an agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof.

172. A pharmaceutical, cosmetic or cosmeceutical kit, identified in print for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, and a second agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, said first agent and said second agent are individually packaged within the pharmaceutical, cosmetic or cosmeceutical kit.

173. A pharmaceutical, cosmetic or cosmeceutical kit, identified in print for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, and a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof, said first agent and said second agent are individually packaged within the pharmaceutical, cosmetic or cosmeceutical kit.

174. A pharmaceutical, cosmetic or cosmeceutical kit, identified in print for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, a first agent selected from the group consisting of nicotinamide, a nicotinamide agonist, a nicotinamide derivative, a nicotinamide metabolite and prodrugs thereof, and a second agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof, said first agent and said second agent are individually packaged within the pharmaceutical, cosmetic or cosmeceutical kit.

175. A pharmaceutical, cosmetic or cosmeceutical kit, identified in print for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, and/or for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous, comprising, a first agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, and a second agent selected from the group consisting of Vitamin D3, a Vitamin D3 metabolite, a Vitamin D3 agonist, a Vitamin D3 derivative and prodrugs thereof, said first agent and said second agent are individually packaged within the pharmaceutical, cosmetic or cosmeceutical kit.

176. A pharmaceutical, cosmetic or cosmeceutical kit, identified in print for use in the treatment of a benign or malignant hyperproliferative epidermal pathology, for use in the treatment of a condition whereby increasing anti-oxidative properties of epidermal cells is advantageous and/or for use in anti-cancer protection, comprising, a first agent selected from the group consisting of cyclic adenosine diphosphate-ribose (cADPR), a cADPR derivative, a cADPR metabolite, a cADPR agonist and prodrugs thereof, and a second agent selected from the group consisting of Vitamin A, a Vitamin A metabolite, a Vitamin A agonist, a Vitamin A derivative and prodrugs thereof, said first agent and said second agent are individually packaged within the pharmaceutical, cosmetic or cosmeceutical kit.