Compositions and methods for enhancing cognitive function

• US 20060171938A1
• Filed: 02/03/2006
• Published: 08/03/2006
• Est. Priority Date: 02/03/2005
• Status: Active Grant

• Current Assignee: The Trustees of Princeton University (Princeton University), Signum Biosciences, Inc.
• Original Assignee: The Trustees of Princeton University (Princeton University)
• Inventors: Li, Zhu, Stock, Gregory B., Wolanin, Peter Michael, Haoming, Gu, Stock, Jeffry B., Stock, Maxwell
• Granted Patent: US 8,221,804 B2
• Time in Patent Office: Days
• US Class Current: 424/94.600
• CPC Class Codes: A23F 5/24 Extraction of coffee; Coffee extracts with reduced alkaloid content A23F5/20; Making instant coffee methods of roasting extracted coffee A23F5/06
• CPC Class Codes: A23F 5/267 using additives, specific extraction media or specific coffee blends
• CPC Class Codes: A23G 3/36 characterised by the composition containing organic or inorganic compounds
• CPC Class Codes: A23G 3/48 containing plants or parts thereof, e.g. fruits, seeds, extracts containing gums A23G3/42
• CPC Class Codes: A23G 4/06 characterised by the composition containing organic or inorganic compounds
• CPC Class Codes: A23G 4/068 containing plants or parts thereof, e.g. fruits, seeds, extracts containing gums A23G4/10
• CPC Class Codes: A23L 2/02 containing fruit or vegetable juices
• CPC Class Codes: A23L 2/38 Other non-alcoholic beverages drinks from legumes A23L11/60
• CPC Class Codes: A23L 33/105 Plant extracts, their artificial duplicates or their derivatives
• CPC Class Codes: A23L 33/40 Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A23V 2200/322 having an effect on the health of the nervous system or on mental function
• CPC Class Codes: A23V 2250/21 Plant extracts
• 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 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 36/16 Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
• CPC Class Codes: A61K 36/185 Magnoliopsida (dicotyledons)
• CPC Class Codes: A61K 36/258 Panax (ginseng)
• CPC Class Codes: A61K 36/28 Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
• CPC Class Codes: A61K 36/38 Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
• CPC Class Codes: A61K 36/55 : Linaceae (Flax family), e.g. Linum
• CPC Class Codes: A61K 36/74 : Rubiaceae (Madder family)
• CPC Class Codes: A61K 36/81 : Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
• CPC Class Codes: A61K 36/82 : Theaceae (Tea family), e.g. camellia
• CPC Class Codes: A61K 36/87 : Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
• CPC Class Codes: A61K 36/8962 : Allium, e.g. garden onion, leek, garlic or chives
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The invention encompasses novel compositions containing a methylation modifying compound isolated from botanical raw materials, including a fruit of the genus Coffea, and microbial raw materials, methods of making such compositions, and methods of treating or preventing human disease using such compositions. The methylation modifying compound in botanical extracts of the present invention can dramatically increase the level of methylation of PP2A, thus increasing cognitive function, particularly in persons suffering from or prone to developing Alzheimer'"'"'s disease.

Claims

23. A comestible for promoting general health and well-being in a mammalian subject, including a human, comprising a composition containing an isolated methylation modifying compound.

24. The comestible according to claim 23, wherein the compound is isolated from a botanical raw material.

25. The comestible according to claim 23, wherein the compound is isolated from a microbial raw material.

26. The comestible according to claim 23, wherein the composition inhibits a demethylating activity of a demethylating enzyme that acts on a protein phosphatase 2A enzyme and thereby stimulates methylation of the protein phosphatase 2A enzyme.

27. The comestible according to claim 26, wherein the composition inhibits at least about 50% of the demethylating activity of the demethylating enzyme.

28. The comestible according to claim 26, wherein the demethylating enzyme is protein phosphatase 2A specific protein methylesterase.

29. The comestible according to claim 26, wherein the level of protein methylesterase demethylating activity is determined by measuring levels of protein phosphatase 2A methyl esterification.

30. The comestible according to claim 24, wherein the botanical raw material comprises at least one substance selected from the group consisting of gingko, allicin, bacopa;

butcher'"'"'s broom;

flaxseed oil;

a tocopherol;

vitamin E;

ginseng, grape seed, St. John'"'"'s wort;

artichoke-powder;

choline;

inositol;

coffee;

tea;

tobacco; and

cocoa.

31. The comestible according to claim 24, wherein the botanical raw material comprises a fruit of a species of plant genus Coffea.

32. The comestible according to claim 31, wherein the fruit of the plant genus Coffea is a coffee bean.

33. The comestible according to claim 24, wherein the botanical raw material comprises a nutritional supplement.

34. The comestible according to claim 33, wherein the nutritional supplement comprises at least one tocopherol.

35. The comestible according to claim 33, wherein the nutritional supplement comprises Vitamin E.

36. The comestible according to claim 24, wherein the botanical raw material comprises a leaf of a tobacco plant.

37. The comestible according to claim 24, wherein the botanical raw material comprises a ground coffee.

38. The comestible according to claim 24, wherein the botanical raw material comprises an instant coffee.

39. The comestible according to claim 24, wherein the methylation modifying compound is isolated from the botanical raw material by extracting the botanical raw material with a polar solvent.

40. The comestible according to claim 39, wherein the polar solvent is a lower alcohol.

41. The comestible according to claim 40, wherein the lower alcohol is ethanol.

42. The comestible according to claim 39, wherein the polar solvent is ethyl acetate.

43. The comestible according to claim 42, wherein the methylation modifying compound is soluble in ethyl acetate below a pH of about 5 and insoluble in ethyl acetate above a pH of about 10.

44. The comestible according to claim 23, wherein the composition is essentially free of at least one substance selected from the group consisting of caffeine, caffeic acid and chlorogenic acid.

45. The comestible according to claim 23, wherein the comestible is a beverage.

46. The comestible according to claim 45, wherein the beverage is selected from the group consisting of a drink comprising water, a fruit drink, a coffee, a tea, an energy drink, a baby formula, an adult nutritional drink, a health drink, and a sports drink.

47. The comestible according to claim 23, wherein the comestible is a food.

48. The comestible according to claim 47, wherein the comestible is a cereal.

49. The comestible according to claim 23, wherein the comestible is a chewing gum.

50. The comestible according to claim 23, wherein the comestible is a candy.

51. The comestible according to claim 23, wherein the comestible is an ingredient of an inhalant.

52. The comestible according to claim 23, wherein the comestible is an ingredient of a transdermal delivery system.

53. A pharmaceutical preparation for promoting general health and well-being in a mammalian subject, including a human, comprising a cognitive function-enhancing amount of a composition containing an isolated methylation modifying compound and a pharmaceutically acceptable carrier.

1. A composition for promoting general health and well-being in a mammalian subject, including a human, comprising an isolated methylation modifying compound.

2. The composition according to claim 1, wherein the compound is isolated from a botanical raw material.

3. The composition according to claim 1, wherein the compound is isolated from a microbial raw material.

4. The composition according to claim 1, wherein the composition inhibits a demethylating activity of a demethylating enzyme that acts on a protein phosphatase 2A enzyme and thereby stimulates methylation of the protein phosphatase 2A enzyme.

5. The composition according to claim 4, wherein the composition inhibits at least about 50% of the demethylating activity of the demethylating enzyme.

6. The composition according to claim 4, wherein the demethylating enzyme is a protein phosphatase 2A specific protein methylesterase.

7. The composition according to claim 6, wherein the demethylating activity of the protein phosphatase 2A specific protein methylesterase is determined by measuring levels of protein phosphatase 2A methyl esterification.

8. The composition according to claim 2, wherein the botanical raw material comprises at least one substance selected from the group consisting of gingko, allicin, bacopa;

butcher'"'"'s broom;

flaxseed oil;

a tocopherol;

vitamin E;

ginseng, grape seed, St. John'"'"'s wort;

artichoke-powder;

choline;

inositol;

coffee;

tea;

tobacco; and

cocoa.

9. The composition according to claim 2, wherein the botanical raw material comprises a fruit of a species of plant genus Coffea.

10. The composition according to claim 9, wherein the fruit of the plant genus Coffea is a coffee bean.

11. The composition according to claim 2, wherein the botanical raw material comprises a nutritional supplement.

12. The composition according to claim 11, wherein the nutritional supplement comprises at least one tocopherol.

13. The composition according to claim 11, wherein the nutritional supplement comprises Vitamin E.

14. The composition according to claim 2, wherein the botanical raw material comprises a leaf of a tobacco plant.

15. The composition according to claim 2, wherein the botanical raw material comprises a ground coffee.

16. The composition according to claim 2, wherein the botanical raw material comprises an instant coffee.

17. The composition according to claim 2, wherein the methylation modifying compound is isolated from the botanical raw material by extracting the botanical raw material with a polar solvent.

18. The composition according to claim 17, wherein the polar solvent is a lower alcohol.

19. The composition according to claim 18, wherein the lower alcohol is ethanol.

20. The composition according to claim 17, wherein the polar solvent is ethyl acetate.

21. The composition according to claim 20, wherein the methylation modifying compound is soluble in ethyl acetate below a pH of about 5 and insoluble in ethyl acetate above a pH of about 10.

22. The composition according to claim 1, wherein the composition is essentially free of at least one substance selected from the group consisting of caffeine, caffeic acid and chlorogenic acid.

54. The pharmaceutical preparation according to claim 53, wherein the compound is isolated from a botanical raw material.

55. The pharmaceutical preparation according to claim 53, wherein the compound is isolated from microbial raw material.

56. The pharmaceutical preparation according to claim 53, wherein the compound inhibits a demethylating enzyme that acts on a protein phosphatase 2A and thereby stimulates methylation of the protein phosphatase 2A enzyme.

57. The pharmaceutical preparation according to claim 56, wherein the composition inhibits at least about 50% of the demethylating activity of the demethylating enzyme.

58. The pharmaceutical preparation according to claim 56, wherein the demethylating enzyme is a protein phosphatase 2A specific protein methylesterase.

59. The pharmaceutical preparation according to claim 58, wherein the demethylating activity of the protein phosphatase 2A specific protein methylesterase is determined by measuring levels of protein phosphatase 2A methyl esterification.

60. The composition according to claim 54, wherein the botanical raw material comprises at least one substance selected from the group consisting of gingko;

allicin, bacopa;

butcher'"'"'s broom;

flaxseed oil;

a tocopherol;

vitamin E;

ginseng, grape seed, St. John'"'"'s wort;

artichoke-powder;

choline, inositol;

tea;

tobacco; and

cocoa.

61. The pharmaceutical preparation according to claim 54, wherein the botanical raw material comprises a fruit of a species of plant genus Coffea.

62. The pharmaceutical preparation according to claim 61, wherein the fruit of the plant genus Coffea is a coffee bean.

63. The pharmaceutical preparation according to claim 54, wherein the botanical raw material comprises a ground coffee.

64. The pharmaceutical preparation according to claim 54, wherein the botanical raw material comprises an instant coffee.

65. The pharmaceutical preparation according to claim 54, wherein the botanical raw material is a nutritional supplement.

66. The pharmaceutical preparation according to claim 65, wherein the nutritional supplement comprises at least one tocopherol.

67. The pharmaceutical preparation according to claim 65, wherein the nutritional supplement comprises vitamin E.

68. The pharmaceutical preparation according to claim 54, wherein the botanical raw material comprises a leaf of a tobacco plant.

69. The pharmaceutical preparation according to claim 54, wherein the methylation modifying compound is isolated from the botanical raw material by extracting the botanical raw material with a polar solvent.

70. The pharmaceutical preparation according to claim 69, wherein the polar solvent is a lower alcohol.

71. The pharmaceutical preparation according to claim 70, wherein the lower alcohol is ethanol.

72. The pharmaceutical preparation according to claim 69, wherein the polar solvent is ethyl acetate.

73. The pharmaceutical preparation according to claim 72, wherein the methylation modifying compound is soluble in ethyl acetate below a pH of about 5 and insoluble in ethyl acetate above a pH of about 10.

74. The pharmaceutical preparation according to claim 53, wherein the preparation is essentially free of at least one substance selected from the group consisting of caffeine, caffeic acid and chlorogenic acid.

75. The pharmaceutical preparation according to claim 53, wherein the preparation is administered orally.

76. The pharmaceutical preparation according to claim 53, wherein the preparation is in the form of a powder.

77. The pharmaceutical preparation according to claim 53, wherein the preparation is in the form of a capsule.

78. The pharmaceutical preparation according to claim 53, wherein the preparation is in the form of a lozenge.

79. The pharmaceutical preparation according to claim 53, wherein the preparation is in the form of a suppository.

76-1. The pharmaceutical preparation according to claim 53, wherein the preparation is in the form of a tablet.

80. A method for promoting general health and well-being in a mammalian subject, including a human, the method comprising the steps

(a) isolating a methylation modifying compound;

and

(b) administering a cognitive function-enhancing amount of a composition comprising the isolated methylation modifying compound to a subject in need thereof.

81. The method according to claim 80, wherein in step (a) the methylation modifying compound is isolated from a botanical raw material.

82. The method according to claim 80, wherein in step (a) the methylation modifying compound is isolated from a microbial raw material.

83. The method according to claim 80, wherein the methylation modifying compound inhibits a demethylating enzyme that acts on a protein phosphatase 2A enzyme and thereby stimulates methylation of the protein phosphatase 2A enzyme.

84. The method according to claim 83, wherein the composition inhibits at least about 50% of the demethylating activity of the demethylating enzyme.

85. The method according to claim 83, wherein the demethylating enzyme is a protein phosphatase 2A specific protein methylesterase.

86. The method according to claim 85, further comprising the step of (c) determining the demethylating activity of the protein phosphatase 2A specific protein methylesterase.

87. The method according to claim 80, wherein the cognition function-enhancing amount of the composition is from about 1 mg to about 10 g.

88. The method according to claim 81, wherein the botanical raw material comprises at least one substance selected from the group consisting of gingko, allicin, bacopa;

butcher'"'"'s broom;

flaxseed oil;

a tocopherol;

vitamin E;

ginseng, grape seed, St. John'"'"'s wort;

artichoke-powder;

choline;

inositol;

tea;

tobacco; and

cocoa.

89. The method according to claim 81, wherein the botanical raw material comprises a fruit of a species of plant genus Coffea.

90. The method according to claim 89, wherein the fruit of the plant genus Coffea is a coffee bean.

91. The method according to claim 81, wherein the botanical raw material comprises a ground coffee.

92. The method according to claim 81, wherein the botanical raw material comprises an instant coffee.

93. The method according to claim 81, wherein the botanical raw material comprises a nutritional supplement.

94. The method according to claim 93, wherein the nutritional supplement comprises at least one tocopherol.

95. The method according to claim 93, wherein the nutritional supplement comprises vitamin E.

96. The method according to claim 81, wherein the botanical raw material comprises a leaf of a tobacco plant.

97. The method according to claim 81, step (a) further comprising the step of extracting the botanical raw material with a polar solvent.

98. The method according to claim 97, wherein the polar solvent is a lower alcohol.

99. The method according to claim 98, wherein the lower alcohol is ethanol.

100. The method according to claim 97, wherein the polar solvent is ethyl acetate.

101. The method according to claim 100, step (a) further comprising the steps of solubilizing the methylation modifying compound in ethyl acetate below a pH of about 5 and partitioning the methylation modifying compound between an aqueous phase and ethyl acetate above a pH of about 10.

102. The method according to claim 80, wherein the extracted composition is essentially free of at least one substance selected from the group consisting of caffeine, caffeic acid and chlorogenic acid.

103. The method according to claim 80, wherein in step (b), the composition is administered orally.

104. The method according to claim 80, wherein the composition is a powder.

105. The method according to claim 80, wherein the composition is in the form of a tablet

106. The method according to claim 80, wherein the composition is in the form of a capsule.

107. The method according to claim 80, wherein the composition is in the form of a lozenge.

108. The method according to claim 80, wherein the composition is in the form of a suppository.

109. A composition for promoting general health and well-being in a mammalian subject, including a human, prepared by a process, the process comprising the steps of:

a) contacting a botanical raw material with a polar solvent for a time sufficient to form an extract solution from the botanical raw material;

b) isolating the extract solution and removing the polar organic solvent to form a concentrated primary extract; and

c) dissolving the composition in a solvent at a pH ranging from about 7 to about 10 to form a concentrated purified extract.

110. The composition according to claim 109 wherein the polar solvent in step (a) of the process is a lower alcohol.

111. The composition according to claim 110, wherein the lower alcohol is ethanol.

112. The composition according to claim 119, wherein the polar solvent in step (a) of the process is ethyl acetate.

113. The composition according to claim 112, wherein step (a) of the process further comprises the step of solubilizing the composition in ethyl acetate below a pH of about 5.

114. The composition according to claim 112, wherein step (b) of the process further comprises the step of partitioning the methylation modifying compound between an aqueous phase and ethyl acetate above a pH of about 10.

115. The composition according to claim 109, wherein the composition inhibits a demethylating activity of a demethylating enzyme that acts on a protein phosphatase 2A enzyme and thereby stimulates methylation of the protein phosphatase 2A enzyme.

116. The composition according to claim 115, wherein the composition inhibits at least about 50% of the demethylating activity of the demethylating enzyme.

117. The composition according to claim 115, wherein the demethylating enzyme is a protein phosphatase 2A specific protein methylesterase.

118. The composition according to claim 109, wherein the botanical raw material comprises at least one substance selected from the group consisting of gingko;

allicin;

bacopa;

butcher'"'"'s broom;

flaxseed oil;

a tocopherol;

vitamin E;

ginseng;

grape seed;

St. John'"'"'s wort;

artichoke-powder;

choline;

inositol;

coffee;

tea;

tobacco; and

cocoa.

119. The composition according to claim 109, wherein the botanical raw material comprises a fruit of a species of plant genus Coffea.

120. The composition according to claim 119, wherein the fruit of the plant genus Coffea is a coffee bean.

121. The composition according to claim 109, wherein the botanical raw material comprises a ground coffee.

122. The composition according to claim 109, wherein the botanical raw material comprises an instant coffee.

123. The composition according to claim 109, wherein the botanical raw material comprises a nutritional supplement.

124. The composition according to claim 123, wherein the nutritional supplement comprises at least one tocopherol.

125. The composition according to claim 123, wherein the nutritional supplement comprises Vitamin E.

126. The composition according to claim 109, wherein the botanical raw material comprises a leaf of a tobacco plant.

127. The composition according to claim 109, wherein the concentrated purified extract is essentially free of at least one substance selected from the group consisting of caffeine, caffeic acid and chlorogenic acid.

128. The composition according to claim 109, wherein the composition is administered orally.

129. The composition according to claim 109, wherein the composition is in the form of a powder.

130. The composition according to claim 109, wherein the composition is in the form of a tablet.

131. The composition according to claim 109, wherein the composition is in the form of a capsule.

132. The composition according to claim 109, wherein the composition is in the form of a lozenge.

133. The composition according to claim 109, wherein the composition is in the form of a suppository.

134. A method of treating or preventing cognitive effects of a disease, condition, or disorder involving defective methylation metabolism in a mammalian subject, including a human, the method comprising the steps of

(a) isolating a methylation modifying compound;

and

(b) administering a therapeutically effective amount of a composition comprising the isolated methylation modifying compound to a subject in need thereof.

135. The method according to claim 134, wherein in step (a) the methylation modifying compound is isolated from a botanical raw material.

136. The method according to claim 134, wherein in step (a) the methylation modifying compound is isolated from a microbial raw material.

137. The method according to claim 134, wherein the disease, condition, or disorder is associated with higher than normal levels of plasma homocysteine.

138. The method according to claim 134, wherein the disease condition or disorder is at least one disease, condition or disorder selected from the group consisting of a cardiac disorder;

atherosclerosis;

a neurodegenerative disorder;

a cerebrovascular disorder;

a neuropsychiatric disorder; and

diabetes.

139. The method according to claim 134, wherein the methylation modifying compound inhibits a demethylating activity of a demethylating enzyme that acts on a protein phosphatase 2A enzyme and thereby stimulates methylation of the protein phosphatase 2A enzyme.

140. The method according to claim 139, wherein the composition inhibits at least about 50% of the demethylating activity of the demethylating enzyme.

141. The method according to claim 139, wherein the demethylating enzyme is a protein phosphatase 2A specific protein methylesterase.

142. The method according to claim 134, wherein the therapeutically effective amount of the composition is from about 1 mg to about 10 g of the composition.

143. The method according to claim 134, wherein the botanical raw material comprises at least one substance selected from the group consisting of gingko, allicin, bacopa;

butcher'"'"'s broom;

flaxseed oil;

a tacopherol;

Vitamin E;

ginseng, grape seed, St. John'"'"'s wort;

artichoke-powder;

choline;

inositol;

tea;

tobacco; and

cocoa.

144. The method according to claim 134, wherein the botanical raw material comprises a fruit of a species of plant genus Coffea.

145. The method according to claim 144, wherein the fruit of the plant genus Coffea is a coffee bean.

146. The method according to claim 134, wherein the botanical raw material comprises a ground coffee.

147. The method according to claim 134, wherein the botanical raw material comprises an instant coffee.

148. The method according to claim 134, wherein the botanical raw material comprises a nutritional supplement.

149. The method according to claim 148, wherein the nutritional supplement comprises at least one tocopherol.

150. The method according to claim 148, wherein the nutritional supplement comprises Vitamin E.

151. The method according to claim 134, wherein the botanical raw material comprises a leaf of a tobacco plant.

152. The method according to claim 134, step (a) further comprising the step of extracting the botanical raw material with a polar solvent.

153. The method according to claim 152, wherein the polar solvent is a lower alcohol.

154. The method according to claim 152, wherein the polar solvent is ethyl acetate.

155. The method according to claim 154, wherein step (a) further comprises the steps of solubilizing the methylation modifying compound in ethyl acetate below a pH of about 5 and partitioning the methylation modifying compound between an aqueous phase and ethyl acetate above a pH of about 10.

156. The method according to claim 134, wherein the composition is essentially free of at least one substance selected from the group consisting of caffeine, caffeic acid and chlorogenic acid.

157. The method according to claim 134, wherein in step (b) the composition is administered orally.

158. The method according to claim 134, wherein the composition is a powder.

159. The method according to claim 134, wherein the composition is in the form of a tablet.

160. The method according to claim 134, wherein the composition is in the form of a capsule.

161. The method according to claim 134, wherein the composition is in the form of a lozenge.

162. The method according to claim 134, wherein the composition is in the form of a suppository.