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1. WO2007003007 - METHODS AND COMPOSITIONS FOR IMPROVING PREGNANCY OUTCOME

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Claims

1. A method of increasing pregnancy rate in a female subject, the female subject or an oocyte for introduction into the female subject being fertilized by a sperm from a male subject, the method including the steps of administering to the male subject prior to fertilization:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

2. A method of improving pregnancy outcome in a female subject, the female subject or an oocyte introduced into the female subject being fertilized by a sperm from a male subject, the method including the steps of administering to the male subject prior to fertilization:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

3. A method according to claims 1 or 2, wherein the pregnancy is a naturally conceived pregnancy.

4. A method according to claims 1 or 2, wherein the pregnancy is a pregnancy produced by an assisted reproduction technology.

5. A method according to claim 4, wherein the assisted reproduction technology is selected from one of the group consisting of artificial insemination, in vitro fertilization, gamete intrafallopian transfer (GIFT), intra-uterine insemination (IUI), intracytoplasmic sperm injection (ICSI), testicular sperm extraction (TESE), and percutanenous epididymal sperm aspiration (PESA).

6. A method of reducing free radical damage to sperm produced by a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

7. A method of reducing generation of free radicals m the reproductive tract and/or in semen of a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

8. A method of reducing activity and/or concentration of leukocytes in the reproductive tract and/or semen of a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

9. A method of reducing inflammatory cytokine production in the reproductive tract and/or semen of a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

10. A method of improving sperm function in a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

11. A method of improving sperm motility in a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

12. A method of reducing free radical damage to sperm DNA in a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

13. A method of improving sperm production in a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

14. A method of improving quality of an embryo produced by fertilization of an oocyte by a sperm from a male subject, the method including the steps of administering to the male subject prior to fertilization of the oocyte with the sperm from the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

15. A method of improving development of an embryo produced by fertilization of an oocyte by a sperm from a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

16. A method of increasing the rate of implantation of an embryo, the embryo produced by fertilization of an oocyte by a sperm from a male subject, the method including the steps of administering to the male subject prior to fertilization:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

17. A method according to claims 15 or 16, wherein the embryo is an embryo produced by an assisted reproduction technology.

18. A method according to claim 17, wherein the assisted reproduction technology is assisted reproduction technology is selected from one of the group consisting of artificial insemination, in vitro fertilization, gamete intrafallopian transfer (GIFT), intrauterine insemination (IUI), intracytoplasmic sperm injection (ICSI), testicular sperm extraction (TESE), and percutanenous epididymal sperm aspiration (PESA).

19. A method of improving fertility in a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

20. A method of preventing and/or treating infertility in a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

21. A method of increasing testosterone concentration in a male subject, the method including the steps of administering to the male subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

22. A method of reducing the extent of DNA damage in a subject inherited from the father of the subject, the DNA damage being due to free radical damage to sperm DNA in the father of the subject, the method including the steps of administering to the father prior to conception of the subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

23. A method of preventing a disease or condition in a subject, the disease or condition associated with DNA damage inherited from the father of the subject due to free radical damage to sperm DNA, the method including the steps of administering to the father prior to conception of the subject:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

24. A method according to any one of claims 1 to 23, wherein the anti-oxidant agent is selected from one or more of the group consisting of a β-carotenoid, including lycopene, lutein, and zeaxanthin; Vitamin C; Vitamin E; Co-Enzyme QlO; selenium; zinc; L-carnitme; acetylcarnitme; N-acetylcysteine; glutathionine; pyruvate; and hypotaurine.

25. A method according to any one of claims 1 to 24, wherein the anti-oxidant agent is a combination of lycopene, Vitamin C, Vitamin E, selenium, zinc and optionally Co-Enzyme QlO.

26. A method according to claim 25, wherein the administration to the subject includes daily administration of 0.5 to 50 mg lycopene, 10 to 1000 mg Vitamin C, 40 to 4000 LU. Vitamin E, 10 to 250 μg selenium, 2.5 to 100 mg zinc, and optionally 4 to 400 mg Co-Enzyme QlO.

27. A method according to claim 26, wherein the administration to the subject includes daily administration of 2 to 10 mg lycopene, 20 to 200 mg Vitamin C, 200 to 600 LU. Vitamin E, 20 to 50 μg selenium, 10 to 50 mg zinc, and optionally 10 to 100 mg Co-Enzyme QlO.

28. A method according to claim 27, wherein the administration to the subject includes daily administration of about 6 mg lycopene, about 100 mg Vitamin C, about 400 LU. Vitamin E, about 26 μg selenium, about 25 mg zinc, and optionally about 40 mg Co-Enzyme QlO.

29. A method according to any one of claims 1 to 28, wherein the administration to the subject is for a period of at least 10 weeks.

30. A method according to any one of claims 1 to 29, wherein the administration of the anti-oxidant agent is oral administration to the subject.

31. A method according to any one of claims 1 to 30, wherein the agent that reduces inflammation in the male reproductive tract is selected from one or more of the group consisting of garlic, or an extract, oil or active compound derived therefrom; green tea, or an extract or active compound derived therefrom; N- 3 fatty acids, docosahexaenoic acid, ginger or an extract or active compound derived therefrom; an agent that decreases leukocyte production of TNFα, including pentoxyphylline; an agent that blocks the action of TNFα once produced, including infliximab; and lipid extract from marine mollusk.

32. A method according to any one of claims 1 to 30, wherein the agent that reduces inflammation in the male reproductive tract is garlic, or an extract, oil or an active compound derived therefrom.

33. A method according to any one of claims 1 to 32, wherein the agent that increases testicular testosterone concentration is selected from one or more of the group consisting of garlic, or an extract, oil or an active compound derived therefrom; zinc; tribulus terrestris or an extract or active compound derived therefrom; an agent that reduces inducible nitric oxide synthase in macrophages; and an agent that reduces nitric oxide production.

34. A method according to claim 33, wherein the agent that increases testicular testosterone concentration is garlic, or an extract, oil or an active compound derived therefrom.

35. A method according to claim 34, wherein the administration to the subject includes daily administration of greater than 500 mg garlic oil.

36. A method according to claim 35, wherein the method includes daily administration of about 1000 mg garlic oil.

37. A method according to any one of claims 1 to 36, wherein the administration of the agent that reduces inflammation in the male reproductive tract to the subject is for a period of at least 10 weeks.

38. A method according to any one of claims 1 to 37, wherein administration of the agent that reduces inflammation in the male reproductive tract and/or administration of the agent that increases testicular testosterone concentration is oral administration.

39. A method according to any one of claims 1 to 38, wherein the method further includes administration to the subject of folic acid, or a salt thereof.

40. A method according to claim 39, where the method further includes administration of about 500 μg folate.

41. A method according to any one of claims 1 to 40, wherein the male subject is a human subject.

42. A method according to claim 41, wherein the male subject is selected from the group consisting of a subject with increased levels of sperm membrane oxidation, including a subject with increased levels of malondialdehyde or other biochemical markers of oxidative stress; a smoker; a subject with reduced fertility, including reduced fertility due to poor sperm motility, or reduced fertility of unknown origin; a subject having undergone vasectomy reversal; a subject with a reproductive tract infection such as epididymitis; and a subject having a varicocele.

43. Semen or sperm isolated from a male subject treated according to the method of any one of claims 6 to 13.

44. A composition including:
Vitamin E;
Vitamin C, or a salt thereof;
Lycopene;
Selenium;
Zmc; and
greater than 500 mg Garlic, or an extract or oil thereof; or a pharmaceutically acceptable derivative of any of the aforementioned components; the composition optionally further including folic acid, or a salt thereof, and/or Co Enzyme QlO.

45. A composition according to claim 44, wherein the composition includes 0.5 to 50 mg lycopene, 10 to 1000 mg Vitamin C, 40 to 4000 LU. Vitamin E, 10 to 250 μg selenium, 2.5 to 100 mg zinc, and optionally 4 to 400 mg Co-Enzyme QlO.

46. A composition according to claim 44, wherein the composition includes 2 to 10 mg lycopene, 20 to 200 mg Vitamin C, 200 to 600 LU. Vitamin E, 20 to 50 μg selenium, 10 to 50 mg zinc, and optionally 10 to 100 mg Co-Enzyme QlO.

47. A composition according to claim 44, wherein the composition includes about 6 mg lycopene. aboutlOO mg Vitamin C, about 400 LU. Vitamin E, about 26 μg selenium, about 25 mg zinc, and optionally about 40 mg Co-Enzyme QlO.

48. A composition according to any one of claims 44 to 47, wherein the composition includes about 1000 mg garlic oil.

49. A composition according to any one of claims 44 to 48, wherein the composition includes about 500 μg folate.

50. A composition including:
about 400 LU. Vitamin E;
about 100 mg Vitamin C, or a salt thereof;
about 6 mg Lycopene;
about 26 μg Selenium;
about 25 mg Zinc;
about 40 mg Co-Enzyme QlO; and
about 1000 mg Garlic.

51. A composition including :
about 400 LU. Vitamin E;
about 100 mg Vitamin C, or a salt thereof;
about 6 mg Lycopene;
about 26 μg Selenium;
about 25 mg Zinc;
about 500 μg Folate; and
about 1000 mg Garlic.

52. A combination product including the following components:
an anti-oxidant agent; and
an agent that reduces inflammation in the male reproductive tract; and/or
an agent that increases testicular testosterone concentration;
wherein the said components in the combination product are not the same, and the components are provided in a form for separate administration to the subject, or m a form for co- administration of one or more of the components to the subject.

53. A combination product according to claim 52, wherein the anti-oxidant agent is selected from one or more of the group consisting of a β-carotenoid, including lycopene, lutein, and zeaxanthin; Vitamin C; Vitamin E; Co-Enzyme QlO; selenium; zinc; L-carnitme; acetylcarnitme; N-acetylcysteine; glutathionine; pyruvate; and hypotaurine.

54. A combination product according to claims 52 or 53, wherein the anti-oxidant agent is a combination of lycopene, Vitamin C, Vitamin E, selenium, zinc and optionally Co-Enzyme QlO.

55. A combination product according to claim 54, wherein the combination product includes 0.5 to 50 mg lycopene, 10 to 1000 mg Vitamin C, 40 to 4000 LU. Vitamin E, 10 to 250 μg selenium, 2.5 to 100 mg zinc, and optionally 4 to 400 mg Co-Enzyme QlO.

56. A combination product according to claim 54, wherein the combination product includes 2 to 10 mg lycopene, 20 to 200 mg Vitamin C, 200 to 600 I.U. Vitamin E, 20 to 50 μg selenium, 10 to 50 mg zinc, and optionally 10 to 100 mg Co-Enzyme QlO.

57. A combination product according to claim 54, wherein the combination product includes about 6 mg lycopene, about 100 mg Vitamin C, about 400 LU. Vitamin E, about 26 μg selenium, about 25 mg zinc, and optionally about 40 mg Co-Enzyme QlO.

58. A combination product according to any one of claims 52 to 57, wherein the agent that reduces inflammation in the male reproductive tract is selected from one or more of the group consisting of garlic, or an extract, oil or active compound derived therefrom; green tea, or an extract or active compound derived therefrom; N- 3 fatty acids, docosahexaenoic acid, ginger or an extract or active compound derived therefrom; an agent that decreases leukocyte production of TNFα, including pentoxyphylline; an agent that blocks the action of TNFα once produced, including infliximab; and lipid extract from marine mollusk

59. A combination product according to any one of claims 52 to 57, wherein the agent that reduces inflammation in the male reproductive tract is garlic, or an extract, oil or an active active compound derived therefrom.

60. A combination product according to any one of claims 52 to 59, wherein the agent that increases testicular testosterone concentration is selected from one or more of the group consisting of garlic, or an extract, oil or an active compound derived therefrom; zinc; tnbulus terrestris or an extract or active compound derived therefrom; an agent that reduces inducible nitric oxide synthase in macrophages; and an agent that reduces nitric oxide production.

61. A combination product according to claim 60, wherein the agent that increases testicular testosterone concentration is garlic, or an extract, oil or an active compound derived therefrom.

62. A combination product according to any one of claims 59 to 61, wherein the combination product includes greater than 500 mg garlic oil.

63. A combination product according to claim 62, wherein the combination product includes about 1000 mg garlic oil.

64. A combination product according to any one of claims 52 to 63, wherein the combination product further includes folic acid, or a salt thereof.

65. A combination product according to claim 64, where the combination product further includes about 500 μg folate.

66. A combination product according to any one of claims 52 to 65, wherein the combination product is used for administration to a male subject for one or more of the following purposes: to reduce free radical damage to sperm produced by the male subject; to reduce generation of free radicals in the reproductive tract and/or semen of the male subject; to reduce activity and/or concentration of leukocytes in the reproductive tract and/or semen of the male subject; to reduce inflammatory cytokine production in the reproductive tract and/or semen of the male subject; to improve sperm function in the male subject; to improve sperm motility in the male subject; to reduce free radical damage to sperm DNA m the male subject; to improve sperm production in the male subject; to improve quality of an embryo produced by fertilization of an oocyte by a sperm from the male subject; to improve development of an embryo produced by fertilization of an oocyte by a sperm from the male subject; to improve pregnancy outcome or rate in a female partner fertilized by the male subject; to reduce the extent of DNA damage in progeny of the male subject due to free radical damage to sperm DNA in the male subject; to prevent a disease or condition occurring m progeny of the male subject due to free radical damage to sperm DNA in male subject; to improve and/or treat fertility in the male subject; and to increase testosterone concentration in the male subject

67. A composition including:
(i) an effective amount of an anti-oxidant agent; and
(ii) an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration.

68. A composition according to claim 67, wherein the anti-oxidant agent is selected from one or more of the group consisting of a β-carotenoid, including lycopene, lutein, and zeaxanthin; Vitamin C; Vitamin E; Co-Enzyme QlO; selenium; zinc; L-carnitine; acetylcarnitine; N-acetylcysteine; glutathionine; pyruvate; and hypotaurine

69. A composition according to claims 67 or 68, wherein the anti-oxidant agent is a combination of lycopene, Vitamin C, Vitamin E, selenium, zinc and optionally Co-Enzyme QlO.

70. A composition according to claim 69, wherein the composition includes 0.5 to 50 mg lycopene, 10 to 1000 mg Vitamin C, 40 to 4000 LU. Vitamin E, 10 to 250 μg selenium. 2.5 to 100 mg zinc, and optionally 4 to 400 mg Co-Enzyme QlO.

71. A composition according to claim 69, wherein the composition includes 2 to 10 mg lycopene, 20 to 200 mg Vitamin C, 200 to 600 LU. Vitamin E, 20 to 50 μg selenium, 10 to 50 mg zinc, and optionally 10 to 100 mg Co-Enzyme QlO.

72. A composition according to claim 69, wherein the composition includes about 6 mg lycopene, about 100 mg Vitamin C, about 400 LU. Vitamin E, about 26 μg selenium, about 25 mg zinc, and optionally about 40 mg Co-Enzyme QlO.

73. A composition according to any one of claims 67 to 72, wherein the agent that reduces inflammation m the male reproductive tract is selected from one or more of the group consisting of garlic, or an extract, oil or active compound derived therefrom; green tea, or an extract or active compound derived therefrom; N- 3 fatty acids, docosahexaenoic acid, ginger or an extract or active compound derived thereform; an agent that decreases leukocyte production of TNFα, including pentoxyphylline; an agent that blocks the action of TNFα once produced, including infliximab; and lipid extract from marine mollusk.

74. A composition according to any one of claims 67 to 73, wherein the agent that reduces inflammation in the male reproductive tract is garlic, or an extract, oil or an active compound derived therefrom.

75. A composition according to any one of claims 67 to 74, wherein the agent that increases testicular testosterone concentration is selected from one or more of the group consisting of garlic, or an extract, oil or an active compound derived therefrom; zinc; tribulus terrestris and or an extract or active compound derived therefrom; an agent that reduces inducible nitric oxide synthase in macrophages; and an agent that reduces nitric oxide production.

76. A composition according to claim 75, wherein the agent that increases testicular testosterone concentration is garlic, or an extract, oil or an active compound derived therefrom.

77. A composition according to any one of claims 74 to 76, wherein the composition includes greater than 500 mg garlic oil.

78. A composition according to claim 767 wherein the composition includes about 1000 mg garlic oil.

79. A composition according to any one of claims 67 to 78, wherein the composition further includes folic acid, or a salt thereof.

80. A composition according to claim 79, where the composition further includes about 500 μg folate.

81. A method of isolating sperm from a male subject, the method including the steps of:
(i) administering to the male subject an effective amount of an anti-oxidant agent;
(ii) administering to the male subject an effective amount of an agent that reduces inflammation in the male reproductive tract and/or an effective amount of an agent that increases testicular testosterone concentration; and
(iii) isolating sperm from the male subject.

82. Sperm isolated from a male subject according to claim 81.

83. A non-human animal arising from fertilization of a female non-human animal with the sperm according to claim 82.