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Weight Loss Patent Abstract
Phenolic compounds with a phenolic molecule to which are covalently
linked an oxygen-containing group, a nitrogen or another oxygen
containing group, and a C.sub.1-C.sub.4 alkoxy group, obtainable
from monocotyledonous plants, or by chemical synthesis, have been
found to act as weight loss agents, appetite suppressants, mood
enhancers and adjunctive therapy for arthritis, sleep apnea, fibromyalgia,
diabetes and hyperglycemia. Additional chemical compounds of the
present invention may include benzoxazinoids-cyclic hydroxyamic
acids, lactams, and corresponding glucosides, which may serve as
precursors to phenolic compounds. The phenolic compounds and precursors
of phenolic compounds of the present invention, at concentrations
suitable for human therapeutic use, may be obtained from monocotyledonous
plants such as corn in their early growth states which are timely
harvested for optimum yield.
Weight Loss Patent Claims
1. A process for promoting weight loss in mammals by the administration
of a therapeutically effective amount of one or more chemical compositions
defined as: Wherein "R" represents C.sub.1-C.sub.4 alkoxy,
with the provision the R is in the 4 or 5 ring position; Wherein
"n" represents one of the integers 0, 1 or 2; Wherein
"B" represents H and "A" represents --OH, --NH.sub.2
or NHCR', where R' denotes C.sub.1-C.sub.4 alkyl; and "B A"
represents or pharmaceutically acceptable salts thereof.
2. A process as defined in claim 1, further comprising the administration
of a therapeutically effective amount of one or more chemical compositions
defined as:: Wherein "R.sup.1" is selected from the group
consisting of H and OCH.sub.3; Wherein "R.sup.2" is selected
from the group consisting of H and Glucose (as a glucoside) Wherein
"R.sup.3" is selected from the group consisting of H,
OH, and OCH.sub.3; or pharmaceutically acceptable salts thereof.
3. A process as defined in claim 1, wherein said administered chemical
composition comprises a daily dosage of between about 5 mcg and
about 60 mg.
4. A process as defined in claim 1, wherein the administered chemical
composition comprises a daily dosage of 15 mg.
5. A process as defined in claim 1, wherein at least one of said
chemical compositions is obtained from one or more monocotyledonous
plants selected from the group consisting of corn, wheat, barley,
rye, oats, rice, sorghum, millet, bamboo, Job's Tears, barley-like
grasses, and wild grasses, by growing the plant to an immature life
history stage and harvesting the plant.
6. A process as defined in claim 5, wherein said harvested plant
is dried.
7. A process as defined in claim 6, wherein said harvested plant
is dried at a temperature in the range of between about 40.degree.
C. and about 45.degree. C.
8. A process as defined in claim 6, wherein said dried harvested
plant contains phenols in total amounts greater than 17.0 mg/gm
(dry weight).
9. A process as defined in claim 6, wherein said dried harvested
plant contains combined amounts of 4-hydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic
acid totaling no more than 1.5 mg/gm (dry weight).
10. A process as defined in claim 5, wherein said harvested plant
is immature corn, Zea mays.
11. A process as defined in claim 10, wherein said immature corn
has been grown to a height between about 45 centimeters and about
122 centimeters.
12. A process as defined in claim 10, wherein said immature corn
has been grown to a height that does not exceed between about 30
centimeters and about 45 centimeters.
13. A process as defined in claim 10, wherein said immature corn
has been grown for less than ten weeks after planting.
14. A process as defined in claim 1, wherein said chemical composition
is administered in a manner selected from the group consisting of:
(1) orally, in the form of tablets, capsules, suspensions, solutions
and other means suitable for ingestion, including sublingual dosage
forms; (2) intranasal administration; (3) transmucosal administration;
(4) parenteral injection, in the form of subcutaneous, intramuscular,
intravenous; (5) implant for sustained release; and (6) transdermal
patch.
15. A process as defined in claim 1, wherein therapeutically effective
amounts of said chemical composition further comprise adjunctive
therapy for a condition selected from the group consisting of arthritis,
sleep apnea, fibromyalgia, diabetes, and hyperglycemia.
16. A process for promoting weight loss in mammals by the administration
of a therapeutically effective amount of one or more chemical compositions
defined as: Wherein "R" represents C.sub.1-C.sub.4 alkoxy,
with stipulation that R is in the 4 or 5 ring position; Wherein
"n" represents one of the integers 0, 1 or 2; or pharmaceutically
acceptable salts thereof.
17. A process as defined in claim 16, wherein one of said chemical
compositions comprise 6-methoxy-2,3-benzoxazolinone defined as:
or pharmaceutically acceptable salts thereof.
18. A process as defined in claim 16, wherein one of said chemical
compositions comprise 5-methoxy-2,3-benzoxazolinone defined as:
or pharmaceutically acceptable salts thereof.
19. A process as defined in claim 18, wherein said administered
chemical composition comprises a daily dosage of between about 5
mcg and about 60 mg.
20. A process as defined in claim 17, wherein the administered
chemical composition comprises a daily dosage of 15 mg.
21. A process as defined in claim 16, wherein at least one of said
chemical compositions is obtained from one or more monocotyledonous
plants selected from the group consisting of corn, wheat, barley,
rye, oats, rice, sorghum, millet, bamboo, Job's Tears, barley-like
grasses, and wild grasses, by growing the plant to an immature life
history stage and harvesting the plant.
22. A process as defined in claim 21, wherein said harvested plant
is dried.
23. A process as defined in claim 22, wherein said harvested plant
is dried at a temperature in the range of between about 40.degree.
C. and about 45.degree. C.
24. A process as defined in claim 22, wherein said dried harvested
plant contains phenols in total amounts greater than 17.0 mg/gm
(dry weight).
25. A process as defined in claim 22, wherein said dried harvested
plant contains combined amounts of 4-hydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic
acid totaling no more than 1.5 mg/gm (dry weight).
26. A process as defined in claim 21, wherein said harvested plant
is immature corn, Zea mays.
27. A process as defined in claim 26, wherein said immature corn
has been grown to a height between about 45 centimeters and about
122 centimeters.
28. A process as defined in claim 26, wherein said immature corn
has been grown to a height that does not exceed between about 30
centimeters and about 45 centimeters.
29. A process as defined in claim 26, wherein said immature corn
has been grown for less than ten weeks after planting.
30. A process as defined in claim 16, wherein said chemical composition
is administered in a manner selected from the group consisting of:
(1) orally, in the form of tablets, capsules, suspensions, solutions
and other means suitable for ingestion, including sublingual dosage
forms; (2) intranasal administration; (3) transmucosal administration;
(4) parenteral injection, in the form of subcutaneous, intramuscular,
intravenous; (5) implant for sustained release; and (6) transdermal
patch.
31. A process as defined in claim 16, wherein therapeutically effective
amounts of said chemical composition further comprise adjunctive
therapy for a condition selected from the group consisting of arthritis,
sleep apnea, fibromyalgia, diabetes, and hyperglycemia.
32. A process for suppressing appetite in mammals by the administration
of a therapeutically effective amount of one or more chemical compositions
defined as: Wherein "R" represents C.sub.1-C.sub.4 alkoxy,
with the provision the R is in the 4 or 5 ring position; Wherein
"n" represents one of the integers 0, 1 or 2; Wherein
"B" represents H and "A" represents --OH, --NH.sub.2
or NHCR', where R' denotes C.sub.1-C.sub.4 alkyl; and "B A"
represents or pharmaceutically acceptable salts thereof.
33. A process as defined in claim 32, further comprising the administration
of a therapeutically effective amount of one or more chemical compositions
defined as:: Wherein "R.sup.1" is selected from the group
consisting of H and OCH.sub.3; Wherein "R.sup.2" is selected
from the group consisting of H and Glucose (as a glucoside) Wherein
"R.sup.3" is selected from the group consisting of H,
OH, and OCH.sub.3; or pharmaceutically acceptable salts thereof.
34. A process as defined in claim 32, wherein said administered
chemical composition comprises a daily dosage of between about 5
mcg and about 60 mg.
35. A process as defined in claim 32, wherein the administered
chemical composition comprises a daily dosage of 15 mg.
36. A process as defined in claim 32, wherein at least one of said
chemical compositions is obtained from one or more monocotyledonous
plants selected from the group consisting of corn, wheat, barley,
rye, oats, rice, sorghum, millet, bamboo, Job's Tears, barley-like
grasses, and wild grasses, by growing the plant to an immature life
history stage and harvesting the plant.
37. A process as defined in claim 36, wherein said harvested plant
is dried.
38. A process as defined in claim 37, wherein said harvested plant
is dried at a temperature in the range of between about 40.degree.
C. and about 45.degree. C.
39. A process as defined in claim 37, wherein said dried harvested
plant contains phenols in total amounts greater than 17.0 mg/gm
(dry weight).
40. A process as defined in claim 37, wherein said dried harvested
plant contains combined amounts of 4-hydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic
acid totaling no more than 1.5 mg/gm (dry weight).
41. A process as defined in claim 36, wherein said harvested plant
is immature corn, Zea mays.
42. A process as defined in claim 41, wherein said immature corn
has been grown to a height between about 45 centimeters and about
122 centimeters.
43. A process as defined in claim 41, wherein said immature corn
has been grown to a height that does not exceed between about 30
centimeters and about 45 centimeters.
44. A process as defined in claim 41, wherein said immature corn
has been grown for less than ten weeks after planting.
45. A process as defined in claim 32, wherein said chemical composition
is administered in a manner selected from the group consisting of:
(1) orally, in the form of tablets, capsules, suspensions, solutions
and other means suitable for ingestion, including sublingual dosage
forms; (2) intranasal administration; (3) transmucosal administration;
(4) parenteral injection, in the form of subcutaneous, intramuscular,
intravenous; (5) implant for sustained release; and (6) transdermal
patch.
46. A process as defined in claim 32, wherein therapeutically effective
amounts of said chemical composition further comprise adjunctive
therapy for a condition selected from the group consisting of arthritis,
sleep apnea, fibromyalgia, diabetes, and hyperglycemia.
47. A process for suppressing appetite in mammals by the administration
of a therapeutically effective amount of one or more chemical compositions
defined as: Wherein "R" represents C.sub.1-C.sub.4 alkoxy,
with stipulation that R is in the 4 or 5 ring position; Wherein
"n" represents one of the integers 0, 1 or 2; or pharmaceutically
acceptable salts thereof.
48. A process as defined in claim 47, wherein one of said chemical
compositions comprise 6-methoxy-2,3-benzoxazolinone defined as:
or pharmaceutically acceptable salts thereof.
49. A process as defined in claim 47, wherein one of said chemical
compositions comprise 5-methoxy-2,3-benzoxazolinone defined as:
or pharmaceutically acceptable salts thereof.
50. A process as defined in claim 47, wherein said administered
chemical composition comprises a daily dosage of between about 5
mcg and about 60 mg.
51. A process as defined in claim 47, wherein the administered
chemical composition comprises a daily dosage of 15 mg.
52. A process as defined in claim 47, wherein at least one of said
chemical compositions is obtained from one or more monocotyledonous
plants selected from the group consisting of corn, wheat, barley,
rye, oats, rice, sorghum, millet, bamboo, Job's Tears, barley-like
grasses, and wild grasses, by growing the plant to an immature life
history stage and harvesting the plant.
53. A process as defined in claim 52, wherein said harvested plant
is dried.
54. A process as defined in claim 53, wherein said harvested plant
is dried at a temperature in the range of between about 40.degree.
C. and about 45.degree. C.
55. A process as defined in claim 53, wherein said dried harvested
plant contains phenols in total amounts greater than 17.0 mg/gm
(dry weight).
56. A process as defined in claim 53, wherein said dried harvested
plant contains combined amounts of 4-hydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic
acid totaling no more than 1.5 mg/gm (dry weight).
57. A process as defined in claim 52, wherein said harvested plant
is immature corn, Zea mays.
58. A process as defined in claim 57, wherein said immature corn
has been grown to a height between about 45 centimeters and about
122 centimeters.
59. A process as defined in claim 57, wherein said immature corn
has been grown to a height that does not exceed between about 30
centimeters and about 45 centimeters.
60. A process as defined in claim 67, wherein said immature corn
has been grown for less than ten weeks after planting.
61. A process as defined in claim 47, wherein said chemical composition
is administered in a manner selected from the group consisting of:
(1) orally, in the form of tablets, capsules, suspensions, solutions
and other means suitable for ingestion, including sublingual dosage
forms; (2) intranasal administration; (3) transmucosal administration;
(4) parenteral injection, in the form of subcutaneous, intramuscular,
intravenous; (5) implant for sustained release; and (6) transdermal
patch.
62. A process as defined in claim 47, wherein therapeutically effective
amounts of said chemical composition further comprise adjunctive
therapy for a condition selected from the group consisting of arthritis,
sleep apnea, fibromyalgia, diabetes, and hyperglycemia.
63. A process for promoting weight loss in a mammal by the administration
of a therapeutically effective amount of one or more chemical compositions
defined as: Wherein "R.sup.1" is selected from the group
consisting of H and OCH.sub.3; Wherein "R.sup.2" is selected
from the group consisting of H and Glucose (as a glucoside) Wherein
"R.sup.3" is selected from the group consisting of H,
OH, and OCH.sub.3; or pharmaceutically acceptable salts thereof.
64. A process as defined in claim 63, wherein said administered
chemical composition comprises a daily dosage of between about 5
mcg and about 60 mg.
65. A process as defined in claim 63, wherein the administered
chemical composition comprises a daily dosage of 15 mg.
66. A process as defined in claim 63, wherein at least one of said
chemical compositions is obtained from one or more monocotyledonous
plants selected from the group consisting of corn, wheat, barley,
rye, oats, rice, sorghum, millet, bamboo, Job's Tears, barley-like
grasses, and wild grasses, by growing the plant to an immature life
history stage and harvesting the plant.
67. A process as defined in claim 66, wherein said harvested plant
is dried.
68. A process as defined in claim 67, wherein said harvested plant
is dried at a temperature in the range of between about 40.degree.
C. and about 45.degree. C.
69. A process as defined in claim 67, wherein said dried harvested
plant contains phenols in total amounts greater than 17.0 mg/gm
(dry weight).
70. A process as defined in claim 67, wherein said dried harvested
plant contains combined amounts of 4-hydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic
acid totaling no more than 1.5 mg/gm (dry weight).
71. A process as defined in claim 66, wherein said harvested plant
is immature corn, Zea mays.
72. A process as defined in claim 71, wherein said immature corn
has been grown to a height between about 45 centimeters and about
122 centimeters.
73. A process as defined in claim 71, wherein said immature corn
has been grown to a height that does not exceed between about 30
centimeters and about 45 centimeters.
74. A process as defined in claim 71, wherein said immature corn
has been grown for less than ten weeks after planting.
75. A process as defined in claim 63, wherein said chemical composition
is administered in a manner selected from the group consisting of:
(1) orally, in the form of tablets, capsules, suspensions, solutions
and other means suitable for ingestion, including sublingual dosage
forms; (2) intranasal administration; (3) transmucosal administration;
(4) parenteral injection, in the form of subcutaneous, intramuscular,
intravenous; (5) implant for sustained release; and (6) transdermal
patch.
76. A process as defined in claim 63, wherein therapeutically effective
amounts of said chemical composition further comprise adjunctive
therapy for a condition selected from the group consisting of arthritis,
sleep apnea, fibromyalgia, diabetes, and hyperglycemia.
77. A process for suppressing appetite in mammals by the administration
of a therapeutically effective amount of one or more chemical compositions
defined as: Wherein "R.sup.1" is selected from the group
consisting of H and OCH.sub.3; Wherein "R.sup.2" is selected
from the group consisting of H and Glucose (as a glucoside) Wherein
"R.sup.3" is selected from the group consisting of H,
OH, and OCH.sub.3; or pharmaceutically acceptable salts thereof.
78. A process as defined in claim 77, wherein said administered
chemical composition comprises a daily dosage of between about 5
mcg and about 60 mg.
79. A process as defined in claim 77, wherein the administered
chemical composition comprises a daily dosage of 15 mg.
80. A process as defined in claim 77, wherein at least one of said
chemical compositions is obtained from one or more monocotyledonous
plants selected from the group consisting of corn, wheat, barley,
rye, oats, rice, sorghum, millet, bamboo, Job's Tears, barley-like
grasses, and wild grasses, by growing the plant to an immature life
history stage and harvesting the plant.
81. A process as defined in claim 80, wherein said harvested plant
is dried.
82. A process as defined in claim 81, wherein said harvested plant
is dried at a temperature in the range of between about 40.degree.
C. and about 45.degree. C.
83. A process as defined in claim 81, wherein said dried harvested
plant contains phenols in total amounts greater than 17.0 mg/gm
(dry weight).
84. A process as defined in claim 81, wherein said dried harvested
plant contains combined amounts of 4-hydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic
acid totaling no more than 1.5 mg/gm (dry weight).
85. A process as defined in claim 80, wherein said harvested plant
is immature corn, Zea mays.
86. A process as defined in claim 85, wherein said immature corn
has been grown to a height between about 45 centimeters and about
122 centimeters.
87. A process as defined in claim 85, wherein said immature corn
has been grown to a height that does not exceed between about 30
centimeters and about 45 centimeters.
88. A process as defined in claim 85, wherein said immature corn
has been grown for less than ten weeks after planting.
89. A process as defined in claim 77, wherein said chemical composition
is administered in a manner selected from the group consisting of:
(1) orally, in the form of tablets, capsules, suspensions, solutions
and other means suitable for ingestion, including sublingual dosage
forms; (2) intranasal administration; (3) transmucosal administration;
(4) parenteral injection, in the form of subcutaneous, intramuscular,
intravenous; (5) implant for sustained release; and (6) transdermal
patch.
90. A process as defined in claim 77, wherein therapeutically effective
amounts of said chemical composition further comprise adjunctive
therapy for a condition selected from the group consisting of arthritis,
sleep apnea, fibromyalgia, diabetes, and hyperglycemia.
Weight Loss Patent Description
1. RELATED APPLICATION
[0001] This application claims the benefit of U.S. patent application
Ser. No. 09/834,592, filed Apr. 13, 2001, and entitled "NOVEL
COMPOUNDS FOR USE AS ANTIDEPRESSANTS, APHRODISIACS AND ADJUNCTIVE
THERAPIES IN HUMANS", which claims the benefit of U.S. provisional
patent application Ser. No. 60/196,829, filed Apr. 13, 2000, and
entitled "ANTIDEPRESSANT, APHRODISIAC, WEIGHT-LOSS AIDE, THERAPY
FOR QUITTING NICOTINE OR ADDICTIVE DRUGS AND TREATMENT OF BETTERING
REPRODUCTION IN HUMANS", which are both incorporated herein
by reference.
2. FIELD OF THE INVENTION
[0002] This invention relates to compositions and methods to induce
weight loss, appetite suppression and as adjunctive therapies for
fibromyalgia, sleep apnea, diabetes, hyperglycemia and arthritis
and more particularly, to novel compositions of phenolic and indoleamine-like
compounds which are obtainable in concentrations and amounts suitable
for human use from certain botanicals or from chemical synthesis,
together with methods for using, producing and harvesting same.
3. THE BACKGROUND ART
[0003] An estimated 35-40 million living Americans will suffer
major depressive episodes, and many more will experience lesser
bouts. Of the approximately 17.5 million Americans with ongoing
depressions, about 9.2 million are at a clinically debilitating
level. Clinical depression is characterized by a list of symptoms
that last over a long time span. It is a serious problem that is
usually or initially caused by outside stressors. As stresses escalate
or persist, a chemical imbalance can result. Clinical depression
can be very debilitating both physically and mentally and even lead
to death by means of suicide. However, lost productivity and relationship
problems are also consequences of lesser depressions. At present,
antidepressant medications are the cornerstones of treating depression,
especially those that are at least moderately severe. Although depressed
people tend to improve when treated with antidepressants, many do
not respond to the first one. Such individuals may eventually benefit
from a different antidepressant or a combination of antidepressants.
[0004] Sexual dysfunction is a pervasive disorder. In the overall
population, 43 percent of women and 31 percent of men between the
ages of 18 and 59 repeatedly experience it. Sexual dysfunction includes
lacking interest in sex, problems with arousal, not enjoying sex,
and anxiety about sexual performance. Indeed, feeling good in general
has significant impact on sexual function, with those people unhappy
or depressed more likely to experience difficulties. Arousal problems
affect over 20 million American males, about two in 10 adult men,
with such difficulties often associated with or accompanied by some
sort of depression. Meanwhile, prescription antidepressants actually
exacerbate the situation, since a frequent side effect of their
use is sexual dysfunction. In fact, sexual response diminishes in
up to 75% of prescription antidepressant users.
[0005] There is a need for treatments to reduce depression or otherwise
better mood with an accompanying enhancement of sexual response
or desire, or at least no sexual dysfunction.
[0006] Prior work on the compounds of the invention has solely
been on 6-methoxy-2,3-benzoxazolinone (6-MBOA). Its role in strengthening
the resistance of monocotyledonous plants against a wide range of
insect pests has been much studied. 6-MBOA and its chemical precursors
also have allelopathic properties that inhibit root and shoot growth
in competing species. Furthermore, it has antimicrobial properties.
6-MBOA appears constitutively during early stages of growth, localized
in those tissues most exposed to microbial and insect attack.
[0007] It had been long suspected that compounds in plants affect
the seasonal reproductive output of wild rodents. In 1981, 6-MBOA
became the first naturally occurring compound in a plant verified
as impacting seasonal reproductive cycling. Since then, a substantial
body of work has accumulated on 6-MBOA as an initiator of seasonal
breeding and an effector of population size for many rodents and
a few birds. Compounds related to and possibly co-occurring with
6-MBOA remain unexplored in this regard.
[0008] Excessive weight (i.e., overweight) and obesity are part
of the most rapidly growing public health concerns facing the world
today. By the end of the 1980s, nearly one-fourth of Americans were
overweight (a Body Mass Index (BMI) greater than 25, calculated
as weight in kilograms/height in meters squared; Calle et al., "Body
mass index and mortality in a prospective cohort of US adults",
New England Journal of Medicine 341:1097-1105, 1999) or obese (excess
body weight more than 20 percent above average for height, bone
structure and age, or a BMI exceeding 30). The number of overweight
children has nearly tripled over the previous 20 years; and, the
prevalence and incidence of type 2 diabetes, a disease for which
obesity is a major factor, in adolescents has significantly increased
over the same time. By 1999, about thirty-six percent (36%) of the
total population, or more than 97,000,000 adults, may be considered
overweight. Currently, it has been estimated that about sixty percent
(60%) of American are overweight and about thirty percent (30%)
of Americans may be considered obese.
[0009] Obesity has a similar epidemic pattern in Europe, and in
2002 it was estimated that more than 200 million people (about thirty-three
percent (33%)) of the population could be considered overweight.
In many European countries more than fifty percent (50%) of adults
are now overweight, nearly triple the level prior to 1980. Germany
has the most overweight men in Europe, with an incidence of seventy-one
percent (71%). The United Kingdom is not far behind Germany with
excess weight in more than sixty percent (60%) of the adult population.
[0010] Overweight and obesity are commonly associated with other
serious health conditions. These conditions may be causes of increased
morbidity in overweight and obese individuals. These serious health
conditions and obesity are often referred to as being "co-morbid."
Being overweight is known to increase the risk of dying from many
conditions, including 4 of the 10 leading causes of death: coronary
heart disease, cancer, stroke and type 2 diabetes. Some epidemiological
information suggests increases in mortality tend to parallel increases
in body weight. In the United States, being overweight has become
the second leading cause of preventable, premature death, with the
associated annual loss of life exceeding 2,800,000 people (Allison
et al., "Annual deaths attributable to obesity in the United
States", Journal of the American Medical Association 282:1530-1538,
1999).
[0011] Excessive weight and/or obesity may be due to uncontrollable
and/or controllable factors. Uncontrollable factors may include
heredity (i.e., genetics) and metabolic disorders. Controllable
factors may include environment, physical inactivity, psychological
circumstances, and poor eating habits established in childhood.
Poor eating habits may include excessive intake as well as poor
selection of foods with nutritional value. The controllable factors
are often more responsible for the development of overweight and
obesity.
[0012] Therapeutic approaches to overweight and obesity have included
educational, physical, psychological and pharmacological modalities.
Educational efforts have focused on informing individuals about
caloric intake and making proper nutritional selections. Physical
approaches have emphasized increasing physical activity in an effort
to increase metabolism. Psychological approaches have focused on
controlling appetite, manipulating mood and improving sense of well-being.
Pharmacological approaches may include drugs and other agents to
suppress appetite and/or increase cellular metabolism. There are
a broad range of opinions as to how successful these therapeutic
approaches have been either individually or collectively, but nevertheless,
incidence and prevalence of overweight and obesity continue to increase.
Regardless of cause, there is obvious need for treatments that can
induce or otherwise promote weight loss.
[0013] Medications prescribed for losing weight often suppress
appetite by way of mood enhancing attributes (Halpern et al., "Treatment
of obesity. An update on anti-obesity medications", Obesity
Reviews 4:25-42, 2003) and may include, beta-phenethylamine derivatives
(fenfluramine, phentermine, phendimetrazine, diethylpropion, and
sibutramine); tricyclic derivatives (mazindol); a naftilamine derivative
(sertraline); phenylpropanolamine derivatives (ephedrine, phenylpropanolamine);
and a phenylpropanolamine oxytrifluorphenyl derivative (fluoxetine).
[0014] Ethnobotanists, pharmacognosists and medicinal chemists
are constantly in search of new compounds from plant materials that
have mood enhancing properties and possible therapeutic roles in
weight loss. It had been long suspected that compounds in some plants
effect the mood of wild rodents. These effects are sometimes examined
by observing seasonal reproductive output. In 1981, 6-methoxy-2,3-benzoxazolinone
(6-MBOA) became the first naturally occurring compound in a plant
verified as impacting seasonal reproductive cycling. 6-MBOA may
be found in varying concentrations in monocotyledonous plants. Since
its discovery, a substantial body of work has accumulated on 6-MBOA
as an initiator of seasonal breeding and an effector of population
size for many rodents and a few birds.
[0015] 6-MBOA is passed from adult females to offspring during
gestation and lactation, with increased growth and larger gonads
in the recipient young. Juveniles rely on the interaction of maternal
photoperiod history and 6-MBOA to time the onset of growth and puberty.
Adults fed a diet containing 6-MBOA produce more female progeny.
When 6-MBOA is fed to pregnant females, gonadal development in the
male offspring is enhanced.
[0016] For rodents, the inhibitory effects of melatonin on growth
and reproduction are blocked partially by 6-MBOA (Gower et al.,
"Reproductive responses of male Microtus montanus to photoperiod,
melatonin, and 6-MBOA", Journal of Pineal Research, 8: 297-312,
1990). 6-MBOA may obstruct melatonin at the melatonin receptors
or act independently to check melatonin action (Sweat et al., "Uterotropic
6-methoxybenzoxazolinone is an adrenergic agonist and melatonin
analog, Molecular and Cellular Endocrinology, 57:131-138, 1988).
[0017] The high melatonin levels induced by 6-MBOA may cause desensitization
of melatonin receptors (Daya et al., "Effect of 6-methoxy-2-benzoxazolinone
on the activities of rat pineal N-acetyltransferase and hydroxyindole-O-methyltransferase
and on melatonin production", Journal of Pineal Research, 8:57-66,
1990), but not for all rodents (Anderson et al., "Effects of
melatonin and 6-methoxybenzoxazolinone on photoperiodic control
of testis size in adult male golden hamsters", Journal of Pineal
Research, 5:351-65, 1988).
[0018] This compound stimulates rather than inhibits melatonin
biosynthesis and does not prevent stimulation of melatonin synthesis
by norepinephrine (Yuwiler et al., "Effects of 6-methoxy-2-benzoxazolinone
on the pineal melatonin generating system. J. Pharmacol. Exp. Ther.
233:45-50, 1985). 6-MBOA acts at both the alpha- (.alpha.-) and
beta- (.beta.-) adrenergic receptors (Daya et al., "Effect
of 6-methoxy-2-benzoxazolinone on the activities of rat pineal N-acetyltransferase
and hydroxyindole-O-methyltransferase and on melatonin production",
Journal of Pineal Research, 8:57-66, 1990), and stimulates adenylcyclase
activity in the pineal, hypothalmus and pituitary glands (Sweat
et al., "Uterotropic 6-methoxybenzoxazolinone is an adrenergic
agonist and melatonin analog, Molecular and Cellular Endocrinology,
57:131-138, 1988).
[0019] Certain responses to 6-MBOA, like uterine hypertrophy, can
be duplicated with estrogen, but 6-MBOA is not an estrogenic compound
(Gower, "Endocrine effects of the naturally occurring reproductive
stimulant, 6-methoxybenzoxazolinone", Ph.D. Thesis, University
of Utah, Salt Lake City, Utah, 1990). Also, 6-MBOA increases the
rate of synthesis of follicle stimulating hormone (Butterstein et
al., "The plant metabolite 6-methoxybenzoxazolinone interacts
with follicle-stimulating hormone to enhance ovarian growth",
Biology of Reproduction, 39:465-71, 1988) and pituitary prolactin
(Vaughan et al., "Hormonal consequences of subcutaneous 6-methoxy-2-benzoxazolinone
pellets or injections in prepubertal male and female rats",
Journal of Reproduction and Fertility, 83:859-66, 1988).
[0020] Hypothalamic luteinizing hormone-releasing hormone contents
and pituitary gland weights are greater for at least one rodent
species implanted with capsules containing 6-MBOA (Urbanski et al.,
"Influence of photoperiod and 6-methoxybenzoxazolinone on the
reproductive axis of inbred LSH/Ss Lak male hamsters. Journal of
Reproduction and Fertility, 90:157-163, 1990). The above studies
cumulatively point to 6-MBOA acting in an area of the brain, which
may be referred to as the pineal hypothalamic pituitary axis (PHPA),
possibly as a melatonin agonist and at the .alpha.- and .beta.-adrenergic
receptors in its own right. The inventors recognized that 6-MBOA
and the indoleamine, melatonin, share a structural similarity. However,
melatonin exacerbates symptoms of dysphoria in depressed people.
6-MBOA, as a melatonin agonist, could prove contrary in this regard
and actually improve mood. Yet, the inventors are not aware of any
prior art that has explored or suggested the use of 6-MBOA and related
compounds as having psychotropic effects in humans, particularly
with respect to depression or mood.
[0021] An object of the invention is to develop therapies for depression
and sexual dysfunction entailing use of compounds belonging to related
chemical families, of which 6-MBOA is a member. Pursuant to this
end, a further object is to develop methods for getting said compounds
from plant and animal sources in amounts suitable for human therapeutic
use.
[0022] While past research by those skilled in the art has attempted
to isolate, identify and characterize new plant compounds with mood
stimulating properties, 6-MBOA has heretofore previously not been
identified or evaluated for mood elevation leading to appetite suppression
and weight loss. Therefore, as readily appreciated by those skilled
in the art, novel compounds isolated, produced and harvested from
monocotyledonous plants and methods for using the same to suppress
appetite and promote weight loss in mammals would be a significant
advancement in the art. Such novel compositions and methods are
disclosed and taught herein.
BRIEF SUMMARY AND OBJECTS OF THE INVENTION
[0023] A primary object of the present invention is to provide
novel chemical compositions derived, isolated, and/or extracted
from monocotyledonous plants or by chemical synthesis, and methods
of use to achieve weight loss in mammals.
[0024] It is another object of the present invention to provide
novel chemical compositions derived, isolated, and/or extracted
from monocotyledonous plants or by chemical synthesis, and methods
of use to suppress appetite in mammals.
[0025] It is also an object of the present invention to provide
novel chemical compositions derived, isolated, and/or extracted
from monocotyledonous plants or by chemical synthesis, and methods
of use to elevate mood in mammals.
[0026] It is a further object of the present invention to provide
novel chemical compositions derived, isolated, and/or extracted
from monocotyledonous plants or by chemical synthesis, which function
as melatonin analogs and/or agonists in mammals.
[0027] In addition, it is an object of the invention to provide
novel methods for growing monocotyledonous plants which results
in an increased yield of 6-MBOA and other phenolic and indole-amine
compounds.
[0028] It is a further object of the present invention to provide
novel methods for harvesting monocotyledonous plants which are efficient
for producing 6-MBOA and other phenolic and indoleamine compounds.
[0029] In addition, it is a further object of the present invention
to provide novel chemical compositions derived, isolated, and/or
extracted from monocotyledonous plants or by chemical synthesis,
and methods of use as adjunctive therapy in fibromyalgia.
[0030] It is also an object of the present invention to provide
novel chemical compositions derived, isolated, and/or extracted
from monocotyledonous plants or by chemical synthesis, and methods
of use as adjunctive therapy in sleep apnea.
[0031] Additionally, it is an object of the present invention to
provide novel chemical compositions derived, isolated, and/or extracted
from monocotyledonous plants or by chemical synthesis, and methods
of use as adjunctive therapy in diabetes.
[0032] It is a further object of the present invention to provide
novel chemical compositions derived, isolated, and/or extracted
from monocotyledonous plants or by chemical synthesis, and methods
of use as adjunctive therapy in hyperglycemia.
[0033] It is a still further object of the present invention to
provide novel chemical compositions derived, isolated, and/or extracted
from monocotyledonous plants or by chemical synthesis, and methods
of use as adjunctive therapy in arthritis. It is also an object
of the present invention to provide novel methods for growing and
harvesting monocotyledonous plants to obtain phenolic compounds
with a phenolic molecule to which are covalently linked an oxygen-containing
group, a nitrogen or second oxygen containing group, and at least
one C.sub.1-C.sub.4 alkoxy group.
[0034] Additionally, it is an object of the present invention to
provide novel methods for promoting weight loss in mammals by administering
phenolic compounds with a phenolic molecule to which are covalently
linked an oxygen-containing group, a nitrogen or second oxygen containing
group, and at least one C.sub.1-C.sub.4 alkoxy group.
[0035] It is a further object of the present invention to provide
novel methods for suppressing appetite in mammals by administering
phenolic compounds with a phenolic molecule to which are covalently
linked an oxygen-containing group, a nitrogen or second oxygen containing
group, and at least one C.sub.1-C.sub.4 alkoxy group.
[0036] It is also an object of the present invention to provide
novel methods for growing and harvesting monocotyledonous plants
to obtain precursors of phenolic compounds comprising benzoxazinoids-cyclic
hydroxamic acid, lactams and their corresponding glucosides.
[0037] Additionally, it is an object of the present invention to
provide novel methods for promoting weight loss in mammals by administering
precursors of phenolic compounds comprising benzoxazinoids-cyclic
hydroxamic acid, lactams and their corresponding glucosides.
[0038] It is a further object of the present invention to provide
novel methods for suppressing appetite in mammals by administering
precursors of phenolic compounds comprising benzoxazinoids-cyclic
hydroxamic acid, lactams and their corresponding glucosides.
[0039] Consistent with the foregoing objects, and in accordance
with the invention as embodied and broadly described herein, it
has been found that certain phenolic compounds and precursors of
phenolic compounds, related to each other by shared structural similarities
and having structural similarities with melatonin, are effective
in bettering mood, improving sexual desire and performance, and
as an adjunctive therapy for weight loss and substance abuse and
addiction. The novel compounds of the present invention naturally
exist as plant secondary metabolites in the early growth of monocotyledonous
plants, become concentrated from their ingestion within certain
animal parts, or can be synthesized by chemical means. The invention
includes therapies using the novel compounds of the present invention
for treating depression and sexual dysfunction, as well as adjunctive
therapies for achieving weight loss and problems of substance abuse
and addiction. The therapeutic method comprises the ingestion of
the novel compounds of the present invention over a certain period
of time, or other means for getting the compounds of the invention
into the body. Both males and females benefit from ingesting the
compounds of the invention, while still contained in dried leaves
from monocotyledonous plants with such compounds or taken as purified
and/or synthesized preparations. It appears that the compounds of
the invention act as antidepressants without the undesirable side
effects of currently used antidepressants.
[0040] As discussed in greater detail hereinbelow, one presently
preferred embodiment of the present invention comprises administration
of phenolic compounds belonging to related chemical families of
which 6-methoxy-2,3-benzoxazolinone (6-MBOA) is a member. These
phenolic compounds share a structural similarity with melatonin
and indoleamine compound. Based on structural similarities with
melatonin, compounds of the invention were studied for their effects
on weight loss, appetite suppression and mood properties. In therapeutically
effective amounts, novel compounds of the present invention may
also be helpful as adjunctive therapies for conditions selected
from the group consisting of arthritis, sleep apnea, fibromyalgia,
diabetes and hyperglycemia.
[0041] In one presently preferred embodiment of a method of the
present invention, particular emphasis is placed on promoting weight
loss in mammals by the administration of a therapeutically effective
amount of a composition of 6-methoxy-2,3-benzoxazolinone or pharmaceutically
acceptable salts thereof. In yet another presently preferred embodiment
of the present invention, particular emphasis is placed on novel
methods of suppressing appetite in mammals by the administration
of a therapeutically effective amount of a composition of 6-methoxy-2,3-benzoxazolinone
or pharmaceutically acceptable salts thereof.
[0042] A source of the novel compounds of the present invention
is in monocotyledonous plants in their early growth stages. To obtain
these compounds at concentrations suitable for human therapeutic
use from such monocotyledonous plants, harvest of these plants at
an early life history stage and drying using explicit parameters,
as well as specific analytical criteria to ascertain suitability,
are employed. However, it is also possible to get the compounds
of the invention at concentrations suitable for human therapeutic
use from animals parts, including, but not necessarily limited to,
the velvet antler tips of deer and elk (Cervidae), where they become
concentrated after ingestion by the animal of sprouting and otherwise
immature grasses. The compounds of the invention can also be obtained
through chemical synthesis.
DETAILED DESCRIPTIONS OF THE PREFERRED EMBODIMENTS
[0043] It will be readily understood that the components of the
present invention, as generally described and illustrated in the
formulae and tables herein, could be arranged and designed in a
wide variety of different configurations. Those of ordinary skill
in the art will, of course, appreciate that various modifications
to the details herein may be made without departing from the essential
characteristics of the invention, as described. Thus, the following
more detailed description of the embodiments of the compositions
and methods of the present invention is not intended to limit the
scope of the invention, as claimed, but it is merely representative
of the presently preferred embodiments of the invention.
[0044] Referring to Formulae I-IV, below, the compounds of the
invention have in common a phenol molecule to which are covalently
linked an oxygen-containing group, a nitrogen- or another oxygen-containing
group, and a C.sub.1-C.sub.4 alkoxy group. Using standard conventions
for depicting chemical structures, Formulas I-III disclose the chemical
structures and specific parameters defining the compounds of the
invention. Formula IV is a unifying formula depicting all compositions
of the invention. Wherein "R" represents C.sub.1-C.sub.4
alkoxy, with the proviso that R is in the 4 or 5 ring position;
Wherein "n" represents one of the integers 0, 1 or 2;
Wherein "A" represents --OH, --NH.sub.2, or NHCR', where
R' represents C.sub.1-C.sub.4 alkyl; or pharmaceutically acceptable
salts thereof. Wherein "R" represents C.sub.1-C.sub.4
alkoxy, with the proviso that R is in the 5 or 6 ring position;
Wherein "n" represents one of the integers 0, 1 or 2;
or pharmaceutically acceptable salts thereof. Wherein "R"
represents C.sub.1-C.sub.4 alkoxy, with the proviso that R is in
the 6 or 7 ring position; Wherein "n" represents one of
the integers 0, 1 or 2; or pharmaceutically acceptable salts thereof.
Wherein "R" represents C.sub.1-C.sub.4 alkoxy, with the
proviso that R is in the 4 or 5 ring position; Wherein "n"
represents one of the integers 0, 1 or 2;
[0045] Wherein "B" represents H and "A" represents
--OH, --NH.sub.2, or NHCR', where R' denotes C.sub.1-C.sub.4 alkyl;
and "B A" represents or pharmaceutically acceptable salts
thereof.
[0046] It has been found that compounds of the invention, when
ingested or otherwise introduced into the user's body, are effective
for achieving weight loss, suppress appetite, improve mood and appear
likewise effective in adjunctive treatment of fibromyalgia, sleep
apnea, diabetes, hyperglycemia and arthritis. The term adjunctive
therapy is defined as a therapy which is joined or added to the
primary therapy, but is not meant to substitute for the primary
therapy. The compounds may be administered in the form of ground
parts of plants in which they naturally occur, like the ground leaves
of immature plants, or as purified or chemically synthesized compounds
in a pharmaceutically acceptable carrier.
[0047] The compounds of the invention may be administered orally
in the form of tablets, capsules, suspensions, solutions or other
means suitable for such ingestion, perhaps as an admixture with
other compounds to enhance absorption into the blood stream or to
otherwise assist in achieving the desired effects. Likewise, oral
administration is contemplated to include sublingual (i.e., under
the tongue) dosage forms. The compounds of the invention may also
be delivered by intranasal (i.e., through the nasal structures)
or transmucosal (i.e., across mucous membranes) administration.
[0048] The compounds of the invention may also be administered
parenterally, as a subcutaneous, intramuscular or intravenous injection,
or by way of an implant for sustained release. When administered
parenterally, the compounds of the invention are to be dissolved
in physiologically acceptable liquid media and/or otherwise compounded
in accordance with the known pharmaceutical art. Another mode of
administering the compounds of the invention may be a transdermal
patch, in which entry of the compounds of the invention into the
body is facilitated via acceptable and appropriate carrier molecules.
[0049] Unless otherwise defined, the technical, scientific and
medical terminology used herein has the same meaning as understood
by those informed of the art to which this invention belongs.
[0050] 6-MBOA and related compounds may have actions in an area
of the brain, which may be referred to as the pineal hypothalamic
pituitary axis (PHPA), as melatonin agonists and at the .alpha.-
and .beta.-adrenergic cell receptors in their own right. These properties
may be considered to indicate desirable psychotropic effects in
humans consequent to the administration of 6-MBOA and related compounds.
Whereas melatonin exacerbates symptoms of dysphoria in depressed
people, 6-MBOA, as a melatonin agonist, works in contrary fashion
and actually stimulates a better mood.
[0051] There has previously been no suggestion to implicate the
administration of 6-MBOA and related compounds as conducive to weight
loss and/or appetite suppression. Mood improvement with the compounds
of the invention appears to be accomplished through biochemical
or physiological pathways different than are those affected by the
above mentioned prescription medications. Improved mood typically
means that serotonin levels have been somehow raised, and increased
amounts of serotonin may impart a feeling of satiety in a mammal.
One result of this feeling may be a reduced food intake and there
may additionally be a reduction in body weight.
[0052] The following examples will illustrate the practice of the
present invention in further detail. It will be readily understood
by those skilled in the art that the following methods, formulations,
and compositions of novel compounds of the present invention, as
generally described and illustrated in the Example herein, are to
be viewed as exemplary of the principles of the present invention,
and not as restrictive to a particular structure or process for
implementing those principles. Thus, the following more detailed
description of the presently preferred embodiments of the methods,
formulations, and compositions of the present invention, as represented
in Examples 1-7, is not intended to limit the scope of the invention,
as claimed, but is merely representative of presently preferred
embodiments of the invention.
Example 1
The Similar Physiological Effects of the Compounds of the Invention
[0053] Representative compounds of Formulas I, II, and III are
shown below as compounds 1-7. The compounds of Formulas I, II and
III have like physiological properties, and as such may be considered
as similar or equivalent for therapeutic purposes, and were tested
via a rodent model. [0054] 1. 2-amino-5-methoxyphenol [Member of
Formula I] [0055] 2. 6-methoxy-2-benzoxazolinone [Member of Formula
II] [0056] 3. 2,4-dihydroxy-7-methoxy-1,4-(2H)-benzoxazin-3-one
[Member of Formula III] [0057] 4. 2-hydroxy-4-methoxyacetanilide
[Member of Formula I] [0058] 5. 2-hydroxy-4-ethoxyacetanilide [Member
of Formula I] [0059] 6. 5-methoxy-2-benzoxazolinone [Member of Formula
III] [0060] 7. 2-hydroxy-5-methoxyacetanilide [Member of Formula
I]
[0061] Female montane voles, Microtis montanus, received intra
peritoneal injections of representative compounds belonging to Formulas
I, II and III for three consecutive days and sacrificed twenty-four
(24) hours after the last injection to examine uterine weight response.
To assess the properties of each representative compound, pure ones
made by chemical means (University of Utah Department of Chemistry,
Salt Lake City, Utah) were prepared specifically for this test.
All compounds were injected at a dose level of 5 mcg/day, dissolved
in five percent (5%) propylene glycol for a total injection volume
of 0.5 ml. Control animals received 0.5 ml of five percent (5%)
propylene glycol only. All voles were 4-5 weeks old and weighed
25-29 g.
[0062] As illustrated in Table 1 below, all compounds belonging
to Formulas I, II and III caused a statistically significant increase
in uterine weights. TABLE-US-00001 TABLE 1 Effect of injecting compounds
of the invention, members of Formulas I, II and III on uterine weight
in the montane vole, Microtus montanus. Number Average Formula of
Uterine Weight Compound Injected Numeral Animals (mg) Control (Propylene
Glycol) -- 8 15.2 .+-. 2.4 6-methoxy-2-benzoxazolinone II 11 27.7
.+-. 5.6* 5-methoxy-2-benzoxazolinone III 8 20.0 .+-. 4.7** 2-hydroxy-4-methoxyacetanilide
I 8 23.1 .+-. 2.7* 2-hydroxy-4-ethoxyacetanilide I 8 22.2 .+-. 3.9*
2-amino-5-methoxyphenol I 8 21.8 .+-. 3.5* 2-hydroxy-5-methoxyacetanilide
I 8 21.1 .+-. 4.4*** 2-amino-4-methoxyphenol I 8 22.2 .+-. 3.2*
*Significantly different from control at P < 0.001 **Significantly
different from control at P < 0.015 ***Significantly different
from control at P = 0.004
[0063] On average, the uterine weight in voles receiving these
was 22.8 g, fifty percent (50%) greater than for the control group.
The greatest average weight increase, eighty-two percent (82%) more
than the uterine weight for the control voles, was in those females
administered 6-methoxy-2-benzoxazolinone, but even the least effect
of a compound belonging to Formulas I, II or III, that for 5-methoxy-2-benzoxazolinone,
entailed a thirty-two percent (32%) increase in uterine weight.
The results show that physiological effects or modes of action are
held in common by the compounds of the invention.
Example 2
Compounds of the Invention as an Antidepressant and Aphrodisiac
in Human Males
[0064] This component of the invention relates to a method for
lessening depression and otherwise bettering mood or feelings of
well-being, said method comprising the administration to human males
of an effective amount of one or more of the compounds of the invention
defined herein. This component of the invention also relates to
a method for treating sexual dysfunction or otherwise increasing
sexual desire and performance, including but not necessarily limited
to lacking interest in sex, problems with arousal, not enjoying
sex, and anxiety about sexual performance, said method comprising
the administration of an effective amount of one or more of the
active compounds of the invention.
[0065] A double-blind crossover study was done on human males to
test compounds of the invention as a therapeutic agent for treating
depression or otherwise elevating mood as well as bettering sexual
function. The trial had three phases, each two weeks in duration,
during which participants took compounds of the invention for one
phase or two weeks. The daily dose was made up from compounds of
the invention naturally contained in the ground leaves from immature
corn plants, 30-45 cm tall, standardized with synthesized 6-methoxy-2-benzoxazolinone,
to a total of 15 mg 6-methoxy-2-benzoxazolinone. A dose of fifteen
milligrams (15 mg) was selected because this was considered a likely
minimum effective daily amount for humans, extrapolated from prior
studies on rodents, rabbits and other animals. Previous anecdotal
trials on humans done by the inventors suggested that a 15 mg daily
dose had a desirable effect, but no adverse consequences to health.
In general, therapeutically effective amounts of compounds of the
invention may be found in a daily dosage range of between about
5 micrograms (mcg) to about 60 mg.
[0066] Weekly assessments of depression or mental well being and
sexual function were done via widely accepted indices: to quantify
depression and generalized anxiety disorders, the Hospital Anxiety
and Depression Scale (HAD); and for sexual desire, psychological
arousal, and overall sexual outlook, the Arizona Sexual Experience
Index (SEX).
[0067] Phase One lasted 14 days, during which participants took
daily doses of the invention or a placebo. Assignation of the invention
or placebo to male participants was done randomly. Immediately prior
to the 14 days comprising Phase One, an initial physical examination
and blood analysis were done. At that time, each male filled out
HAD and SEX forms to assess mental well being and sexual function,
was checked for sitting and standing blood pressure and pulse, and
gave the blood sample needed for the biochemical analyses.
[0068] Phase Two consisted of a seven-day period immediately after
Phase One, during which neither invention nor placebo was taken.
During Phase Two, physical examination and laboratory analyses were
again done. In Phase Three which lasted 14 days, participants again
took either invention or a placebo. Assignation of the invention
or placebo was done according to the sort of capsule taken during
Phase One. If a participant took a compound of the invention in
Phase One, then placebo was administered during Phase Three, and
vice versa. Immediately after finishing Phase Three, a physical
examination and laboratory analyses were again done. After completing
Phase Three, each participant was asked prepared questions as well
as solicited for any comments and impressions concerning invention
use.
[0069] Table 2 is a tabular summary of a presently preferred embodiment
of the results that may be observed in Example 2. TABLE-US-00002
TABLE 2 HAD and ASEX summaries for administration of the compounds
of invention to adult males. With Compounds of Invention: With Placebo:
Initial After Initial After Participant Value Two-Weeks Value Two-Weeks
1 9.0, 12.0 8.0, 11.0 8.0, 10.0 8.0, 13.0 2 16.0, 13.0 14.0, 12.0
16.0, 13.0 16.0, 15.0 3 15.0, 10.0 9.0, 11.0 15.0, 14.0 17.0, 14.0
4 12.0, 9.0 7.0, 10.0 9.0, 10.0 9.0, 12.0 5 14.0, 10.0 10.0, 10.0
12.0, 10.0 14.0, 10.0 6 Participant not reliable - Data incomplete
and deleted from study 7 12.0, 9.0 7.0, 9.0 9.0, 10.0 8.0, 9.0 8
12.0, 11.0 8.0, 11.0 12.0, 11.0 12.0, 10.0 9 12.0, 15.0 12.0, 10.0
7.0, 10.0 7.0, 10.0 10 4.0, 15.0 0.0, 13.0 9.0, 12.0 12.0, 12.0
11 21.0, 10.0 6.0, 10.0 9.0, 12.0 12.0, 12.0 12 13.0, 9.0 2.0, 9.0
13.0, 9.0 13.0, 9.0 13 14.0, 12.0 13.0, 10.0 12.0, 10.0 12.0, 10.0
14 12.0, 10.0 13.0, 10.0 18.0, 7.0 16.0, 7.0 15 23.0, 8.0 18.0,
9.0 16.0, 9.0 16.0, 8.0 Average 13.5, 10.9 9.1, 10.4 11.8, 10.5
12.3, 10.8 The HAD value precedes the ASEX one, and these are separated
from each other by a comma. Two-Sample Paired Sign Test - This is
one of the stronger or more reliable statistical tests when significance
is detected. The question is whether INVENTION affects feelings
of well-being or sexual function. The Sign-Test is used to statistically
ask "how often compounds of invention impact feelings of well
being and/or sexual function". Results are as follows: HAD
(with invention), p < 0.003, Very Significant ASEX (with invention,
p < 0.727, Not Significant HAD (with placebo), p < 0.688,
Not Significant ASEX (with placebo), p < 1.310, Not Significant
[0070] These data indicate that the compounds of the invention
have significant positive effect on depression or mood. Fourteen
(14) of the fifteen (15) participants properly completed the study
and only data for these individuals were used for analysis. HAD
scores exceeding 20.0 denote clinical depression, but lower ones
can also be associated with dispirited mood. Only two males entered
the trial with HAD values exceeding the clinical minimum (21.0 and
23.0). Still, twelve (12) of fourteen (14) subjects showed bettered
mood, improved feelings of well being or lessened depression after
taking compounds of the invention. Decreases in HAD scores over
the two-week timespan were as much as 15 and averaged 5.2. The two
clinically depressed subjects showed decreases in HAD values of
5.0 and 15.0. The average HAD score went from 13.5 at the onset
of the study to 9.1 after two weeks of taking compounds of the invention,
very significant statistically. Participants showed no statistically
detectable changes while taking placebo.
[0071] After taking compounds of the invention for two weeks, five
(5) of fourteen (14) participants had lessened ASEX values, indicating
improved sexual response or lessened sexual anxiety, while only
two (2) of fourteen (14) males showed the same after two weeks on
placebo. Statistical significance was not found for the ASEX changes,
but such could be attributed to a small sample size. Sexual benefits
of the compounds of the invention were also obviated in the trial
through the exit interviews given to all participants. While taking
these, a majority of males reported morning erections of the penis
greater in size, duration or frequency than usually experienced
when not taking the compound. Also, comments by the majority centered
about feeling "like a teenager" (direct quote) in terms
of energy, sexual and otherwise. It should be noted that personal
situations were complicated by unwilling or lacking sex partners.
Twelve (12) of fifteen (15) participants also expressed an unsolicited
desire to continue using the compounds of the invention. They stated
a belief that the compounds of the invention could prove useful
to them in a sexual context.
Example 3
Compounds of the Invention as an Antidepressant in Human Females
[0072] This example further relates to a method for lessening depression
and otherwise bettering mood or feelings of well-being, said method
comprising the administration to human females of an effective amount
of the compounds of the invention, defined above. Compounds of the
invention were used to treat eight females with clinical depression,
which for three females had been ongoing for at least one year.
Participants took the same dose of compounds of the invention as
in Example 2, 15-mg each day. A HAD was administered to participants
prior to beginning daily doses. Each participant was interviewed
every two weeks to check for adverse side effects and for comments
on use of the compounds of the invention. A HAD Index was again
administered upon completion of the six-week trial.
[0073] Referring to Table 3, the results of the study are tabulated.
TABLE-US-00003 TABLE 3 HAD summary for clinically-depressed females
taking compounds of the invention for six weeks. Initial After Participant.sup.1
Value Six-Weeks 1 23.0 18.0 2 21.0 8.0 3 21.0 21.0 4 24.0 14.0 5
22.0 12.0 6 21.0 13.0 7 23.0 7.0 8 20.0 22.0 Average 21.9 14.4 .sup.1Participants
1-4 initially [Weeks 1-2] were given compounds of invention under
guise of its being a vitamin/mineral mixture. Two-Sample Paired
Sign Test - This is one of the stronger or more reliable statistical
tests when significance is detected. The question is whether compounds
of invention affect depression or feelings of well-being. The Sign-Test
is used to statistically ask "how often compounds of invention
positively impact depression or feelings of well being". Results
are as follows: HAD, p < 0.0313, Significant
[0074] These data indicate that the compounds of the invention
significantly lessen depression. Initial HAD scores exceeded 20
for all subjects. All females were clinically depressed, and their
HAD scores averaged 21.9. Six (6) of eight (8) participants showed
responses to compounds of the invention in which HAD values decreased
5-16 points, an average decrease of 10.5 over the six-week timespan.
The overall average HAD score decreased from 21.9 (clinically depressed)
at trial onset to 14.4 (not clinically depressed) after six weeks
of use, with two participants ending with HAD values of eight (8)
and seven (7). There were only eight females in the trial, but decreases
in HAD scores were still statistically significant (p<0.031).
The antidepressant properties of the compounds of the invention
are obviated.
[0075] Both excess weight and substance abuse are characterized
by either primary or secondary depression. Since such psychological
factors affecting excess weight and substance abuse must be treated
along with the physiological ones for therapies to be effective
in the long term, the compounds of the invention comprise adjunctive
treatments for achieving weight loss or reducing the risk of relapse
in persons with substance abuse or addiction problems.
Example 4
Compounds of the Invention at Concentrations Suitable for Human
Therapies from Plants Harvested and Processed in Unique Fashion
[0076] Example 4 relates to a method for obtaining compounds of
the invention at concentrations suitable for human therapies from
plants grown to an immature stage of growth. "Concentrations
suitable for human therapies" means that compounds of the invention
in 10 grams or less of dried plant material make up a daily dose
(e.g., 15 mg compounds of the invention as 6-methoxy-2-benzoxazolinone;
however, general therapeutically effective daily dosages of compounds
of the invention may be between about 5 mcg to about 60 mg). Said
dosage may include either the novel compound as it naturally occurs
or synthetically, or a combination of both natural and synthetic
novel compounds of the present invention.
[0077] Specific harvesting and drying conditions are specified
herein, as are analytical parameters for determining crop quality.
By "specific harvesting and drying conditions", it is
meant that compounds of the invention are obtained from plants via
circumstances differing from the usual manner in which the plants
are handled for the terminal product.
[0078] As an example, corn, Zea mays, is typically grown to its
adult or matured states for its seed-laden cob. At the immature
growth stage at which compounds of the invention occur, corn plants
have a biomass that portends harvest of a substantial amount of
leaf material containing the compounds of the invention at concentrations
suitable for human therapies. Hence, dried corn leaves from immature
plants become appropriate for the human therapies elucidated herein,
or the dried leaves are a resource for the concentration, extraction
and purification of the compounds of the invention. There are other
monocotyledonous plants with the natural production of compounds
of the invention at concentrations suitable for human therapies.
[0079] Monocotyledonous flowering plants belong to the plant order
of Lilidae (sometimes referred to as a subclass or superorder),
which may comprise the following plant families: Alismataceae (water-plantains),
Araceae (lords-and-ladies), Butomaceae, Cyperaceae (cotton-grasses,
spike-rushes and sedges; sometimes referred to as a plant order),
Dioscoreaceae (black bryony), Hydrocharitaceae (waterweeds), Iridaceae
(irises), Juncaceae (rushes and wood-rushes), Juncaginaceae, Lemnaceae
(duck-weeds), Liliaceae (lilies, onions and bluebells), Orchidaceae
(orchids), Poaceae (grasses--also named Graminae), Potamogetonaceae
(pondweeds), Sparganiaceae (bur-reeds), Typhaceae (bulrushes), and
Zosteraceae. It is contemplated that compounds of the invention
may be derived, isolated, harvested and/or extracted from monocotyledonous
plants selected from any of the above identified plant families
and/or orders. Preferred embodiments of compounds of the invention
may be selected from the families of Cyperaceae and Poaceae (also
referred to as Graminae). These families include the cereal grasses
(e.g., corn, wheat, barley, oats, rice and rye) and the hay and
pasture plants (e.g., sorghum, sugarcane, timothy, bent grass, bluegrass,
orchard grass, and fescue). These families may also include wild
grasses, millet, bamboo, Job's Tears (Coix lachryma-jobi; Coix aquatica)
and other barley-like grasses.
[0080] Monocotyledonous plants as sources of compounds from preferred
embodiments of the invention may be selected from the group consisting
of corn, wheat, barley, rye, oats, rice, sorghum, millet, bamboo,
Job's Tears, barley-like grasses, and wild grasses, by growing the
plant to an immature life history stage (i.e., before plant maturity)
and harvesting the plant. The example of corn, Zea mays, is not
intended to be limiting to the scope of the source of compounds
of the invention. In all cases, harvest and processing needs to
be done in a novel and unique fashion relative to the usual manner
in which the plants are handled, and the analytical parameters for
indirectly determining crop quality with respect to the compounds
of the invention, described below, are applicable.
[0081] Growing corn to obtain the compounds of the invention is
initially done in a conventional fashion, but seeds are planted
more densely than is the case for conventional crops because of
the smaller size of plants at harvest. Harvest time is done while
plants are immature. For corn, this immature plant harvesting may
happen when plants are no more than about thirty (30) to about forty-five
(45) centimeters tall, about five weeks after planting. Preferably,
embodiments of the invention may also utilize harvesting immature
corn plants that are between about forty-five (45) centimeters to
about 122 centimeters in height, and between about five weeks to
about eight weeks after planting are sought and preferably less
than ten weeks. As a general reference, mature corn plants are typically
more than 180 centimeters in height and are grown for about four
(4) to about five (5) months after planting. For corn, harvesting
is preferably done by cutting plants at 3-4 centimeters above the
ground. Severed plants may be gathered and may be dried at temperatures
held at about 40.degree. Celsius (C.) to about 45.degree. C. Empirical
studies showed that this temperature range helps maximize conversion
of the precursors of compounds of the invention to the active molecules.
[0082] In a trial plot in southern Illinois, approximately 38,000
corn plants yielded 137 kilograms (300 pounds) of dried (96% dry
weight) corn leaves with suitable levels of compounds of the invention.
Analyses via mass spectroscopy showed that substantive amounts of
the compounds of the invention were in dried corn leaves after five
(5) weeks of growing time. Five (5) random samples of dried corn
leaves were obtained for analysis. For each dried corn leaf sample,
a one-gram portion was homogenized in 10-ml distilled water, incubated
at 25.degree. C. for one (1) hour, boiled for thirty (30) min, and
then centrifuged for ten (10) min at 3600 rpm. The resulting supernatant
was extracted three (3) times with ten (10) ml reagent-grade dichloromethane
per extraction. The three (3) extracts were combined and allowed
to air dry, after which the dried residue was stored in a tightly
stoppered glass tube.
[0083] The dried residue was analyzed for 6-MBOA by gas-chromatographic
mass spectroscopy. A Dupont Model DP102 device with an integrator
and a SP2250 GC column isothermal at 200.degree. C. (Dupont, Wilmington,
Del.) was used. A standard curve for 6-MBOA was obtained using 0.06-,
0.60- and 1.20-.mu.g injections of pure, synthetic 6-MBOA (Sigma,
Saint Louis, Mo.) in methanol solution and was reproducible at a
five percent (5%) level.
[0084] 6-MBOA occurred in dried corn leaves at levels suitable
for human consumption. Samples averaged ten (10) mg/g 6-MBOA, with
individual samples assaying as follows: eight (8), nine (9), ten
(10), ten (10), and twelve (12) mg/g 6-MBOA, respectively. At such
concentrations, less than two (2) grams dried corn leaves are needed
to make up a daily human dose. This makes corn leaves, as uniquely
grown, harvested and dried herein, a suitable source of compounds
of the invention. For comparison purposes, leaves from plants grown
more than eight (8) weeks were analyzed for 6-MBOA. Virtually none
was present.
[0085] Previous work by the inventors indicated that higher levels
of the compounds of the invention are associated with multiple biochemical
parameters that indicate crop quality or adequacy with respect to
the compounds of the invention. In those plants containing compounds
of the invention at concentrations suitable for human use total
phenols are at concentrations greater than 17.0 mg/gm (dry weight)
but combined amounts of 4-hydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic
acid total no more than 1.5 mg/gm (dry weight), as determined through
chromatography. For invention, the above mentioned parameters for
total phenols and combined amounts of 4-hydroxycinnamic acid and
4-hydroxy-3-methoxycinnamic acid are instituted here as elements
of the invention as it pertains to plants. For the corn leaf samples
of Example 2, total phenols averaged 19.1 mg/gm and the cumulative
total for cinnamic acids averaged 0.9 mg/gm.
Example 5
Compounds of the Invention from Parts of Animals
[0086] The main food of deer and elk (Cervidae) for most of the
year is browse, the growing tips of low-growing, woody plants. However,
casting of hard antlers from the previous year coincides with a
spring flush in natural pasturage and an accompanying shift to a
diet of grasses, chiefly sprouting and immature ones. Such grasses
are at developmental stages in which 6-MBOA and related compounds
are most prevalent.
[0087] After casting, new antlers begin their development. These
growing antlers are nourished by blood vessels from a covering of
skin, called velvet. An antler grows from the tip with tissue laid
down as the tip advances. A velvet antler tip has a soft cartilaginous
internal structure and high fat content, contrasting the rest of
the antler with its ossified cartilage and little fat.
[0088] Air-dried and freeze-dried velvet antler samples were obtained.
These came from commercially farmed Canadian Wapiti and New Zealand
red deer, both subspecies of elk, Cervus elaphus. All animals had
been maintained on grassy pasturage. The samples were from velvet
antlers that had been growing fifty-five (55) to sixty-five (65)
days, and included both tips, defined as the region five (5) cm
or less in length starting at the apex, as well as other, more matured
parts of the antler.
[0089] For each sample of dried antler, a one-gram portion was
homogenized in ten (10)-ml distilled water, incubated at 25.degree.
C. for one (1) hour, boiled for thirty (30) min, and then centrifuged
for ten (10) min at 3600 rpm. The resulting supernatant was extracted
three (3) times with ten (10) ml reagent-grade dichloromethane per
extraction. The three (3) extracts were combined and allowed to
air dry, after which the dried residue was stored in a tightly stoppered
glass tube.
[0090] The dried residue was analyzed for 6-MBOA by gas-chromatographic
mass spectroscopy. A Dupont Model DP102 device with an integrator
and a SP2250 GC column isothermal at 200.degree. C. (Dupont, Wilmington,
Del.) was used. A standard curve for 6-MBOA was obtained using,
0.06-, 0.60- and 1.20-mcg injections of pure, synthetic 6-MBOA (Sigma,
Saint Louis, Mo.) in methanol solution and was reproducible at a
five percent (5%) level.
[0091] Referring to Table 4, the observations of Example 5 may
be summarized as follows: TABLE-US-00004 TABLE 4 6-MBOA in Dried
Velvet Antler from Elk, Cervus elaphus. Drying 6-MBOA Animal Origin
Tip or Other Method (mg/g dry weight) Wapiti Canada Tip Air 2.5
Wapiti Canada Tip Air 2.8 Wapiti Canada Other Air 0.3 Red Deer New
Tip Freeze 1.9 Zealand Red Deer New Other Freeze 0.5 Zealand
[0092] These data indicate 6-MBOA was present in all tip samples,
with little or none present in those from the more matured parts
of the antler. Notably, amounts of 6-MBOA from velvet antler tips
exceeded those typically found in grasses less than a week after
sprouting, the stage of growth with the most 6-MBOA. These results
show that ingested 6-MBOA is accumulated or concentrated in velvet
antler tips, and as such represent a means for obtaining the compounds
of the invention in concentrations suitable for human use.
[0093] Many animals eat grasses and other monocotyledonous plants.
Such animals may also be accumulating compounds of the invention
in body parts, most likely in those characterized by high fat contents.
Obtaining compounds of the invention from body parts other than
the antlers of elk and deer and from animals other than elk or deer
are not precluded from invention.
Example 6
Compounds of the Invention for Weight Loss
Recruitment of Participants
[0094] Overweight human females and males were preferentially recruited
for this look at weight loss properties of the compounds of the
invention. For reasons of safety, precluded from participation were
individuals with moderate or worse hypertension (Systolic>160,
Diastolic>100); Class 2 or Morbid Obesity (Body Mass Index>35,
see below); and/or health problems of a debilitating, life-threatening
or otherwise serious nature (multiple sclerosis, emphysema, diabetes,
etc.). Twenty-four (24) individuals had been initially screened,
while fourteen (14) females and six (6) males ultimately took part
in the study. Ages of the twenty (20) participants ranged from thirty-one
(31) to fifty-four (54) years, and averaged thirty-eight (38) years.
Test and Control Groups
[0095] The twenty (20) participants were randomly assigned to Test
and Control Groups, with ten (10) participants in each group. In
particular, those participants in the "Test Group" were
given the novel compounds of the present invention which were produced
and delivered in gelatin capsules (e.g., Size 00). The novel compounds
of the invention were obtained from appropriately chosen, grown,
dried and ground leaves from the corn plant (Zea mays), further
to the methods of harvesting as described hereinabove. In one presently
preferred embodiment, the dosage was standardized to 6-MBOA content,
for which daily cumulative dose was ninety (90) micrograms for each
participant. Although it will be appreciated that compounds having
the general chemical structure as set forth in formulae I, II, III,
and generally as IV, 6-MBOA was used in the present exemplary study.
It will be appreciated, therefore, that other novel compounds of
the present invention, consistent with the general chemical structure
as set forth in formulae I, II, III, and IV are within the spirit
and scope of the present invention.
[0096] Moreover, the novel compounds of the present invention may
be derived, isolated, and/or extracted from monocotyledonous flowering
plants belong to the plant order of Lilidae, consistent with the
harvesting methods described hereinabove or by means of chemical
synthesis. It is further contemplated that the novel compounds of
the invention may be obtained by a combination of harvesting from
natural sources, as described hereinabove, and by chemical synthesis.
Delivery of a dosage of the novel compounds of the present invention
may include either the novel compound as it naturally occurs or
synthetically, or a combination of both natural and synthetic.
[0097] Those participants in the "Control Group" were
given ground, dried parsley leaves (Petroselinum hortense) delivered
in gelatin capsules (e.g., Size 00). This placebo preparation comprising
parsley visually resembled capsules containing the compounds of
the invention, but was instead made from a plant well recognized
as having no effects on weight loss or other aspects of weight control;
on mood, depression or feelings of well being; and/or on sexual
function, arousal, or performance.
Study Design
[0098] Participants were subjected to the same administration schedules
without-knowledge as to whether they belonged to the Test Group
or the Control Group. All were instructed to take two (2) capsules
at 0.5-1.0 hour before meals, three (3) times per day, for thirty
(30) successive days. Participants were told that they were receiving
a dietary supplement that might better mood and otherwise improve
disposition or outlook, but were not instructed that the formulation
might affect weight or effect weight loss. Furthermore, "overweight"
had been a long-term condition for virtually all participants. Because
of these pre-existing eating behaviors and the fact that participants
were blinded to the knowledge that involvement in the study might
lead to weight loss, independent assignment of participants to either
the Test Group or Control Group was not believed to significantly
effect eating behaviors and associated weight consequences.
Visits and Measurements
[0099] At the beginning of the study, participants in both the
Test Group and the Control Group were given the self administered
Goldberg Depression Scale to maintain the illusion of a mood-related
study. All participants also had their blood pressures taken and
were weighed (done before breakfast while nude or in underwear;
measured on a calibrated electronic scale to the nearest 0.1 kilograms)
prior being given the novel compounds of the present invention or
placebo, respectively. All participants were also weighed at the
end of the study (e.g., thirty (30) days). The height of each participant,
while barefoot or wearing socks, was determined only at the onset
of the study, whereas Body Mass Index (BMI) values were calculated
both at the onset and at the end of the study. As known in the art,
BMI is a measure of body fat, and thus weight-related health risks,
based on height and weight that applies to both adult men and women.
BMI is generally calculated as follows:
[0100] BMI equals a person's weight in kilograms divided by height
in meters squared; or BMI = Weight .times. .times. in .times. .times.
Kilograms ( Height .times. .times. in .times. .times. Meters ) .times.
( Height .times. .times. in .times. .times. Meters ) = kg .times.
/ .times. m .times. .times. 2
[0101] A BMI over thirty (30) is typically considered obese; a
BMI between twenty-five (25) and 29.9 is typically considered overweight;
and a BMI between 18.5 and 24.9 is typically considered healthy.
Older people tend to have more body fat than younger adults with
the same BMI, and some clinicians consider BMI values under twenty-seven
(27) to be normal and healthy for individuals over forty (40) years
old.
Statistical Analysis
[0102] With only ten (10) participants in each Group, assuming
normal distributions for the data was inappropriate. In order to
compensate for a potentially non-normal distribution of study data,
a non-parametric test was utilized for statistical analysis. As
known in the art, the Wilcoxon-Mann-Whitney U Test (sometimes referred
to as the Wilcoxon Rank Sum Test) is one of the more powerful of
non-parametric tests for comparing data distributions in two populations
(e.g., Test Group and Control Group).
Results
[0103] Referring to Table 5, the weight and BMI for each of the
study participants is illustrated showing the pre-treatment and
post-treatment results following thirty (30) days of oral administration
of the 6-MBOA compound of the present invention, or alternatively,
a placebo. TABLE-US-00005 TABLE 5 Weight and Body Mass Indices before
and after a 30-day administration of compounds of the invention
or a control. Weight (kg) Body Mass Index (BMI).sup.1 Height 30
30 Sex (cm) Beginning Days Difference Beginning Days Difference
Test Group F 165 74.9 73.5 -1.4 27.5 27.0 -0.5 F 175 81.7 83.0 +1.3
26.6 27.1 +0.5 F 173 89.0 87.5 -1.5 29.8 29.2 -0.6 F 173 91.3 88.7
-2.6 30.6 29.6 -1.0 F 175 79.9 78.8 -1.1 26.0 25.7 -0.3 F 175 81.3
78.4 -2.9 26.4 25.6 -0.8 F 168 84.0 82.6 -1.4 29.9 29.3 -0.6 M 178
78.5 78.8 +0.3 24.8 24.9 +0.1 M 175 85.8 86.7 +0.9 27.9 28.3 +0.4
M 178 89.9 88.4 -1.5 28.4 27.9 -0.5 Avg 173.5 83.6 82.6 -0.9 27.8
27.5 -0.3 Control Group F 178 80.4 80.0 -0.4 25.4 25.2 -0.2 F 163
82.2 82.8 +0.6 31.1 31.2 +0.1 F 173 89.4 88.0 -1.4 30.0 29.4 -0.6
F 178 89.9 90.3 +0.4 28.4 28.5 +0.1 F 175 87.2 87.6 +0.4 28.4 28.6
+0.2 F 173 79.0 77.7 -1.3 26.5 26.0 -0.5 F 170 83.5 83.0 -0.5 28.8
28.7 -0.1 M 180 90.8 91.5 +0.7 28.0 28.2 -0.2 M 183 99.9 99.4 -0.5
29.8 29.7 -0.1 M 185 94.9 95.7 +0.8 27.6 28.0 +0.4 Avg 175.8 87.7
87.6 -0.1 28.4 28.4 -0.1 .sup.1BMI = weight in kilograms/(height
in meters).sup.2 = kg/m.sup.2 F = female; M = male; cm = centimeters;
kg = kilograms; Avg. = average.
[0104] The test group was given compounds of the invention packaged
in gelatin capsules. The dosage was standardized to 6-MBOA content
for which the total daily dose was 90 micrograms (.mu.g). The control
group took ground, dried parsley leaves in gelatin capsules. The
Wilcoxon-Mann-Whitney U Test was used to assess differences between
the test and control groups. With 20 participants equally divided
into two groups, homogeneity of variance and normal distributions,
data attributes required by most parametric statistics, could not
be assumed. Thus, a nonparametric test, the Mann-Whitney U Test,
was used to compare the equivalency of changes in the Test and Control
Groups. For the Wilcoxon-Mann-Whitney U Test, the value calculated
for determining significance is called the "U" statistic.
[0105] Primary interests centered about changes in absolute body
weight after talking the 6-MBOA compound of the invention for thirty
(30) days. Both the participants in Test Group and the Control Group
showed weight loss and BMI decreases, but magnitudes of the weight
loss differed. For "Weight", the Test Group showed a nine-fold
greater loss than did the Control Group, or almost about one (1)
kilogram on average in the Test Group contrasting to about 0.1 kilograms
in the Control Group. BMI values also decreased three-fold more
for the Test Group, in comparison to the Control Group.
[0106] On a case-by-case basis, differences between participants
in the Test and Control Groups were even more striking. Seven (7)
of the ten (10) participants in the Test Group experienced losses
ranging from about 1.1 to about 2.9 kilograms, and averaging about
1.8 kilograms. In the Control Group, some of the participants (five
(5) of the ten (10)) lost weight. However, the amount of weight
lost in the Control Group was substantively less than in the weight
loss of the participants in the Test Group. The weight lost in the
Control Group ranging from about 0.4 to about 1.3 kilograms and
averaging only about 0.8 kilograms.
[0107] With the Wilcoxon-Mann-Whitney U Test, the null hypothesis
was that medians did not differ between the participants in the
Test and Control Groups. In "Difference" for "Weight",
the Test Group median differed significantly from the Control one
(U=27.0; P=0.04). On average, more weight was lost by Test Group
participants than by Control Group participants. Differences between
the Test and Control Groups for "Weight" at the "Beginning"
were not significant (U=32.5; P=0.10), meaning that baseline weights
in the Test and Control Groups may have been similar. On the other
hand, "Weight" at the "End" did significantly
differ (U=98.5; P=0.05). The results therefore support a finding
that weight reduction is better associated with having taking the
novel compounds of the present invention for a period of about one
month.
[0108] BMI comparisons did not reveal statistical differences,
but this was largely due to the small sample size. The statistical
problem with smaller sample size may be appreciated for example,
and not by way of limitation, by looking at differences in "End"
values for the Test Group versus the Control Group. These "End"
values between the groups were not great enough to show as significantly
different (U=34.0; P=0.12). Results for "Difference" between
the Test Group and Control Group (U=31.5; P=0.08) were also not
significant. However, the mean value for "Difference"
decreased three-fold more in the Test Group (-0.3) than in the Control
Group (-0.1). This disparity in the mean values for "Difference"
is further evidence that the novel compounds (e.g., 6-MBOA) of the
present invention may contain weight loss properties. With a greater
number of participants (i.e., greater study size sample), significant
results between the Test and Control Groups comparisons and even
more profound demonstration of weight reduction from using the novel
compounds of the present invention are considered to be highly likely.
Discussion and Conclusions
[0109] As disclosed herein, novel compounds of the present invention
positively affect mood. It was therefore hypothesized by the inventors
that the novel compounds of the present invention may have weight
loss properties. This example or study is consistent with the initial
hypothesis and premise.
[0110] Weight loss by the Control Group participants (significantly
less than the Test Group), may be attributed to the placebo effect.
The placebo effect is a psychological phenomenon, due to belief
in a treatment or to a subjective feeling of improvement. According
to the placebo effect it was believed plausible that participants
in the Control Group might have some weight loss due to their expectation
that they might be receiving an agent which could improve mood.
It is possible that the expectation of an improved mood, regardless
of reason, could result in a reduced caloric intake, and subsequently
result in weight loss. Even with the possible placebo effect, the
significant nine-fold greater weight loss in the Test Group versus
the Control Group is supportive that the novel compounds of the
present invention are an effective weight loss treatment or regimen.
[0111] Given the weight loss demonstrated herein, both beta-adrenergic
agonistic and alpha-adrenergic antagonistic receptor effects are
considered consequences of using the novel compounds of the present
invention. As earlier stated, the novel compounds of the present
invention have been shown to be beta-adrenergic agonists. In regard
to fat cells, beta-adrenergic agonist activity is considered fundamental
for releasing lipids and thus achieving lipolysis or fat loss. Not
only did the compounds of the present invention effect mobilization
of fatty acids or lipids from fat cells, but these compounds did
this without harsh side effects, such as the jitters and hypertension
associated with ephedrine-based products. The weight loss realized
by participants in the Test Group also indicates alpha-adrenergic
(e.g., alpha 2-adrenergic) antagonist activity with the novel compounds
of the present invention, given that such activity facilitates mobilization
from fat cells of lipids that otherwise might not be released very
easily. Alpha-adrenergic antagonists like the novel compounds comprising
the present invention are particularly desirable for purposes of
reducing those areas of fat storage considered more difficult to
trim, like the obliques in men and lower body in women.
[0112] In consort with their weight loss properties, the novel
compounds of the present invention also act as appetite suppressants,
sometimes referred to as appetite depressants. As known in the art,
appetite suppressants are generally referred to as agents for decreasing
appetite such that caloric intake and perhaps ingestion of certain
foods are reduced. These properties of the novel compounds of the
present invention may be demonstrated by the effect on food consumed,
both by type of food and caloric intake, by those participants who
were administered the novel compounds of the present invention.
[0113] Interviews with the participants revealed that, prior to
the onset of the study, caloric intake by certain overweight female
participants, (four (4) of the seven (7) Test Group women--the lesser
overweight participants (BMI average 26.6)), was 2,100 kilocalories
(kcal) per day on average. The average value for women of normal
body weight is 1,900 kcal per day. This is a difference of only
ten percent (10%) and may have included such factors as poor diet
selections and physical inactivity in the overweight female participants.
[0114] Women of normal body weight tend to eat whole grains, fruits,
vegetables, low-fat protein sources and foods otherwise considered
to be of a healthful and nutritious nature. Items high in carbohydrates
and fats, along with low quantities of fiber and protein figured
prominently in the diets of the overweight women in the study. For
example, one female participant had a propensity to eat an abundance
of bread or pastries in lieu of or along with other foods, while
another female participant routinely skipped breakfast but also
snacked on chocolate candy bars and sugar-fortified carbonated beverages.
[0115] The three (3) remaining participants had been routinely
eating even more at the onset of the study, with their initial caloric
consumption ranging from about 2,400 kcal to about 3,000 kcal per
day, with about 2,700 kcal on average. These participants had a
mean BMI of 30.1 and were generally more overweight than the other
four (4) Test Group females (BMI average 26.6). Although the three
(3) remaining female participants consumed about 600 kcal per day
more than did the other females participants in the Test Group,
all female participants were uniform in that foods of lesser nutritional
quality made up prominent portions of their diets.
[0116] After administering the compounds of the invention for thirty
(30) days, the average caloric intake for the four (4) females with
lesser BMI (average 26.6) had decreased by more than 100 kcal per
day. These participants also reported lessened cravings for certain
food items. For example, the female participant who skipped breakfast
and consumed chocolate candy bars and sugar-fortified carbonated
beverages experienced decreased desire for these food items and
decreased her body weight by 2.9 kilograms. In addition, the female
participant who ate a higher proportion of bread and pastries decreased
her intake of such items and decreased her body weight by 1.4 kilograms.
[0117] Similar results and observations were seen in the overweight
females with an average BMI of 30.1 when the study began. They also
experienced reduced caloric intakes while receiving compounds of
the invention, and decreased body weight, on average, by about 1.8
kilograms. Moreover, these three (3) female participants reported
their desire to eat had abated by the end of the thirty (30) day
test period. The data and observations of the study illustrate significant
activity of the compounds of the present invention in reducing a
desire to consume sugars, simple carbohydrates (e.g., snack foods)
and unhealthy saturated fats (e.g., snack foods and meats). In this
group of overweight female participants, average daily food intake
was reduced by about 230 kcal following the thirty (30) days administration
of the compounds of the present invention. It has been found, therefore,
that compounds of the present invention are responsible for suppression
or depression of appetite in the participants in the Test Group.
[0118] Given that the novel compounds of the present invention
have both weight loss and mood bettering properties, such properties
may prove to be a beneficial therapy for arthritis. It is well known
in the art, that osteoarthritis is a degenerative joint disease
and the most common form of arthritis. Unlike joint problems caused
by swelling or inflammation, osteoarthritis stems primarily from
a breakdown of the connective tissues that bind muscles and bones
together. The ensuing damage includes deterioration of joint surfaces,
which no longer mesh smoothly and instead cause considerable pain.
Joint problems are usually worsened by excessive weight. For example,
the knees bear a considerable load even during such simple activities
as walking, whereas any decrease in overall body weight can positively
affect the performance or quality of life in arthritic individuals.
Meanwhile, preparations that improve mood have been found to ameliorate
the debilitating pain associated with arthritis or otherwise better
tolerance of arthritic conditions.
[0119] Likewise, the novel compounds of the present invention may
be advantageous to diabetic and hyperglycemic people, for whom weight
loss and mood enhancing medications can improve glycemic control.
The compounds of the present invention also provide applicable therapy
for other disorders. For example, weight loss may improve physical
functioning in fibromyalgia patients, while mood-enhancing medications
may alleviate other adverse symptoms of this condition. Weight loss
may also help eliminate or otherwise diminish sleep apnea, making
the novel compounds of the present invention valuable for treatment
of this condition.
Example 7
Alternative Embodiments of the Novel Compounds
[0120] Any number of alternative embodiments of precursors of phenolic
compounds of the present invention may be contemplated as falling
within the spirt and scope of the present invention. In particular,
Formula V, below, is a general chemical formula depicting a generic
representation of alternative embodiments of precursors of phenolic
compounds of the present invention. Formula V - A compound according
to the formula: Wherein "R.sup.1" is selected from the
group consisting of H and OCH.sub.3; Wherein "R.sup.2"
is selected from the group consisting of H and Glucose (as a glucoside)
Wherein "R.sup.3" is selected from the group consisting
of H, OH, and OCH.sub.3; or pharmaceutically acceptable salts thereof.
[0121] As shown, such embodiments of novel compounds of the present
invention may include benzoxazinoids-cyclic hydroxyamic acids, lactams,
and corresponding glucosides. As contemplated herein, substitution
at the "R.sup.1" position may be accomplished with a member
selected from the group consisting of H and OCH.sub.3. Substitution
at the "R.sup.2" position may be accomplished with a member
selected from the group consisting of H and glucose (as a glucoside).
Substitution at the "R.sup.3" position may be accomplished
with a member selected from the group consisting of H, OH, and OCH.sub.3.
[0122] Referring now to Compounds 8-17, below, a series of chemical
formulae, according to the generic representation shown in Formula
V, illustrate chemical structures for representative compounds of
further embodiments of novel compounds of the present invention.
[0123] 8. 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA) [0124] 9. 2,4-dihydroxy-1,4-benzoxazin-3-one-glucoside
(DIBOA-Glc) [0125] 10. 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one
(DIMBOA) [0126] 11. 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one-glucoside
(DIMBOA-Glc) [0127] 12. 2-hydroxy-1,4-benzoxazin-3-one (HBOA) [0128]
13. 2-hydroxy-1,4-benzoxazin-3-one-glucoside (HBOA-Glc) [0129] 14.
2-hydroxy-7-methoxy-1,4-benzoxazin-3-one (HMBOA) [0130] 15. 2-hydroxy-7-methoxy-1,4-benzoxazin-3-one-glucoside
(HMBOA-Glc) [0131] 16. 2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one
(HDMBOA) [0132] 17. 2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one-glucoside
(HDMBOA-Glc)
[0133] Specifically, compound 8 illustrates a chemical formula
for 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA). DIBOA may also have
a glucose molecule to form a glucoside (also referred to as a glycoside),
DIBOA-Glc, which is shown as compound 9. As illustrated, compound
10 depicts a chemical formula for 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one
(DIMBOA). DIMBOA may also exist in combination with glucose molecule
to form a glycoside compound (DIMBOA-Glc), which is shown compound
11. Compound 12 illustrates a chemical formula for 2-hydroxy-1,4-benzoxazin-3-one
(HBOA). A glycoside may also form between HBOA and a glucose molecule
(HBOA-Glc) and is shown compound 13. Compound 14 depicts a chemical
formula for 2-hydroxy-7-methoxy-1,4-benzoxazin-3-one (HMBOA). HMBOA
may also contain a glucose molecule to form HMBOA-Glc, which is
depicted compound 15. Additionally, compound 16 illustrates a chemical
formula for 2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one (HDMBOA).
Wherein, compound 17 illustrates a glucoside formed between HDMBOA
and glucose (HDMBOA-Glc).
[0134] In the foregoing examples, glucose molecules may be bonded
to a respective aglycone (i.e., non-sugar) compound (e.g., DIBOA,
DIMBOA, HBOA, HDMBOA, 6-MBOA) to form a glycoside. As appreciated,
glucose molecules typically are in the form of a pyranose (i.e.,
cyclic 6-carbon ring), which may be referred to as a glucopyranose.
Glucopyranose compounds usually bond with the aglycone portion as
an hemiacetal. Configurations of glycoside compounds in yet other
presently preferred embodiments of the present invention may be
found in the (2R)-configuration. It is intended, however, that other
forms of glucose and configurations of glycosides are contemplated
to be within the spirt and scope of the novel compounds of the present
invention. It is intended, therefore, that the presently preferred
embodiments of novel compounds of the present invention, as shown
in Example 7, be viewed as exemplary of the principles of the present
invention, and not as restrictive to any particular formula, structure,
or method for implementing and/or practicing the present invention.
[0135] Since the novel compositions of phenolic compounds and precursors
of phenolic compounds of the present invention are configured to
promote weight loss, suppress appetite, and enhance mood, it will
be readily appreciated that a method for promoting weight loss,
suppressing appetite and for enhancing mood includes phenolic compounds
belonging to related chemical families of which 6-methoxy-2,3-benzoxazolinone
(6-MBOA) is a member as described hereinabove. It is intended, therefore,
that the examples provided herein be viewed as exemplary of the
principles of the present invention, and not as restrictive to a
particular structure or method for implementing those principles.
[0136] It will be further appreciated that the novel compositions
of phenolic compounds and precursors of phenolic compounds belonging
to related chemical families as defined herein of which 6-methoxy-2,3-benzoxazolinone
(6-MBOA) is a member, may be administered in any manner known to
those ordinary skill in the art, including but not limited to, oral,
parenteral, sublingual, topical, transdermal, intramuscular, or
inhalation, and may also contain excipients chosen in accordance
with the dosage form adopted. Moreover, the dosage of the extract
compositions given to an individual may vary on the basis of several
considerations without departing from the spirit and scope of the
present invention and will, accordingly, depend on the targeted
individual's particular case to be treated.
[0137] From the above discussion, it will be appreciated that the
present invention provides methods of promoting weight loss, suppressing
appetite or enhancing mood using phenolic compounds and precursors
of phenolic compounds belonging to related chemical families of
which 6-methoxy-2,3-benzoxazolinone (6-MBOA) is a member. While
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