Title

NEW COMPOUND FOR IMPROVEMENT OF MEMORY FUNCTION, COGNITIVE FUNCTION AND MENTAL HEALTH

BACKGROUND OF THE INVENTION

Field of the Invention

[0001] This invention relates to a new compound to improve the memory, cognitive function and mental health of individuals.

[0002] The invention comprises a daily dosage of from about 95 mg to about 145 mg ginkgo biloba and from about 160 mg to about 240 mg ginseng standardized at 4% ginsenosides, admixed together in a single compound. Alternatively, the compound may comprise from about 95 mg to about 145 mg ginkgo biloba and from about 95 mg to about 145 mg ginseng standardized at 7% ginsenosides, admixed together in a single compound. Preferably, the invention relates to a new compound which provides a daily dose of a synergistic mixture of 200 mg of ginseng standardized at 4% and 120 mg of ginkgo biloba.

Discussion of the Prior Art

[0003] The present invention relates to a new compound of a synergistic mixture of ginseng and ginkgo biloba.

[0004] Ginkgo is one of the oldest living tree species tracing back to over 250 million years ago and its leaves are among the most extensively studied botanicals in use today for its increasingly well-known medicinal properties (Fleming et al. 1998). Ginkgo belongs to the family Ginkgoaceae. It is a large tree which can grow over 100 feet high and can live for

hundreds of years. Ginkgo trees have unique fan-shaped leaves and inedible fruits that produce a strong odour and containing an edible inner seed. It is native to China, Japan and Korea but is now grown worldwide. Ginkgo leaves have been used in traditional Chinese medicine for "benefiting the brain," as an astringent to the lungs, to relieve symptoms of asthma and cough and in the treatment of filariasis (Foster 1996). It was first mentioned in Lan Mao's Dian Nan Ben Cao (Pharmaceutical Natural History of Southern Yunnan), published in 1436 during the Ming dynasty, for its external use to treat freckles, skin and head sores while internal use of the leaves was first noted in Liu Wen-Tai's Ben Cao Pin Hui Jing Yao (Essentials of the Pharmacopoeia Ranked According to Nature and Efficacy) for the treatment of diarrhea in 1505 (Foster 1996). Ginkgo leaf extracts are currently being manufactured in Europe, Asia and United States and are used for a wide variety of conditions especially for its neuroprotective properties and ability to aid circulatory problems in the elderly. These conditions include chronic cerebral insufficiency, accidents involving brain trauma, dementia and various conditions associated with senility (Foster 1996 and Crews et al. 2005). Cerebral insufficiency is a general term that essentially describes a collection of symptoms such as difficulties of concentration and of memory, absent mindedness, confusion, lack of energy, tiredness, decreased physical performance, depressive mood, anxiety, dizziness, tinnitus and headache (Kleijnen and Knipschild 1992). Although these symptoms have been associated with impaired cerebral circulation, they are thought to be early indications of dementia, of either degenerative or multiple infarct type. [0005] Canada's senior (over 65 years of age) population has grown more than twice as fast as the overall population since the early 1980s, and the trend will continue for decades to

come (Public Health Agency of Canada 2006). Forgetfulness is a problem most people associate with aging. Changes in cognitive function, including memory, reasoning and abstract thinking, affect a very small percentage of younger seniors, although the percentage does rise with age (Public Health Agency of Canada 2006). The Commission-E and WHO recognize ginkgo biloba leaf extracts for their therapeutic activity in a variety of disorders including Alzheimer's disease, failing memory, age-related dementias, poor cerebral and ocular blood flow, and intermittent claudication (Blumenthal ed. et al. 2000 and WHO 1999). According to most studies, ginkgo is helpful for enhancing memory and mental function in seniors without severe memory loss as well as for enhancing memory or alertness in younger people. Most studies reported since 1992 have supported this conclusion, including a large U.S. study published in the Journal of the American Medical Association (Le Bars et al. 1997). The trial enrolled 309 people with Alzheimer's disease or non-Alzheimer's dementia. Participants were given either 120 mg of ginkgo biloba extract or placebo daily for 52 weeks in this double blind randomized study. The results showed a significant decline in placebo group compared to the treated group. Gingko extracts typically are standardized to 24% ginkgo-flavone glycosides and 6% terpenoids.

[0006] In a 2006 study by Burns et al., the effect Ginkgo biloba on cognitive abilities and mood in healthy, young and older adults was assessed. This was a 12-week double-blind, placebo-controlled study, using a dose of 120 mg of Ginkgo biloba per day. This extract contained 24% ginkgoflavonglycosides and 6% ginkgolides. Subjects were required to administer one 40 mg capsule of ginkgo extract, 3 times a day. Ninety-three healthy adults ranging in age between 55 and 79 years in age participated in the "Older Adult" study (50

males and 43 females) and 104 healthy, male adults ranging in age between 18 and 43 years in age participated in the "Young Adult" study. In both studies, a battery of cognitive ability and chronometric tests were used to assess the efficacy of Ginkgo biloba on each group. Mood was assessed using the Profile of Mood States in both studies. In the "Older Adult" study, longer term memory assessed by associational learning tasks showed improvement with ginkgo (d = 0.52, p = 0.04); however, no other measures of cognitive ability showed any statistical difference using the ginkgo treatment. In the "Young Adult" study, the ginkgo biloba treatment did not produce any statistically significant effects. One male from the ginkgo group withdrew because of sleep disturbance. Other side effects included gastrointestinal symptoms and headaches, as have been typically reported by other ginkgo studies. It was concluded that ginkgo improves memory in older adults. [0007] In a study by Elsabagh et al. (2005), 52 participants (26 men and 26 women) were allocated to Experiment 1 which tested Gingko biloba' s acute effects and 40 participants (21 men and 19 women) were allocated to Experiment 2 which tested Gingko biloba' s chronic effects. All participants ranged in age between 18 and 26. The ginkgo extract used in this study contained 25% total ginkgo flavonoids and 6% total terpene lactones (also known as ginkgo lides). In Experiment 1, participants were randomly allocated to receive 120 mg/day of ginkgo in a single dose or a placebo and were tested 4 hours later. In Experiment 2, participants were randomly allocated to receive 120 mg/day of ginkgo or a placebo over a period of 6 weeks. In both experiments, participants underwent tests of sustained attention, episodic and working memory, mental flexibility, planning and mood. The acute dose of ginkgo significantly improved performance on the sustained-attention task (P<0.02) and

pattern recognition memory task (P=O.05); however there were no effects on working memory, planning, mental flexibility or mood. After 6 weeks of treatment, there were no significant effects of ginkgo on mood or any of the cognitive tests, this suggests that a tolerance builds up in healthy young adults.

[0008] A study conducted by Kennedy et al. (2000), assessed the cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers using the Cognitive Drug Research (CDR) computerized assessment battery to test speed of attention, accuracy of attention, speed of memory and quality of memory. The study utilized a placebo-controlled, multi-dose, double-blind, balanced, crossover design. Eighteen female and two male volunteers ranging in between 19 and 24, took part in this study. The twenty participants received 120 mg, 240 mg, and 360 mg of a standardized extract of Ginkgo or a matching placebo. The extract was standardized to 24% ginkgo flavone glycosides and 6% terpene lactones, which is the same standardization as the ginkgo used in our product. Cognitive performance in this study was assessed using the CDR computerized test battery immediately prior to dosing and at 1, 2.5, 4 and 6 hours thereafter. The various tests measured four different factors including speed of attention, accuracy of attention, quality of memory, and speed of memory. Compared to the placebo, a significant change in cognitive ability was produced from the administration of Ginkgo biloba to the volunteers. An improvement in the quality of memory was noticed compared to the placebo at 120 mg Ginkgo biloba at 1 hour (t = 2.14; P= 0.003) and 4 hours (t = 2.32; P = 0.02) after dosing. A similar pattern was

evinced for 240 mg Ginkgo, with trends towards an improvement in comparison with placebo at the same time points - 1 hour post-dosing (t = 1.82; P= 0.069), 4 hours post-

dosing (t = 1.81; P= 0.071). No significant improvements were associated with the 360

mg dose. Speed of performing memory tasks also improved after taking Ginkgo biloba. Trends towards speed of performing memory task enhancements was noted for both the 120 mg to and 360 mg to doses at 6 hours after treatment ( ^v t 171 = 2.83; ' P= 0.068 and t 171 = 1.91 ; ' P=

0.057 respectively). The 240 mg dose of Ginkgo biloba, produced underperforming results at all time points. This study concluded that acute administration of Ginkgo biloba is capable of producing a sustained improvement in healthy young volunteers. The performance of the quality of memory was most significantly enhanced for the 120 mg dose, the lowest dose in this study.

[0009] In a meta-analysis by Oken et al. (1998), more than 50 articles were reviewed to determine the effects of Ginkgo biloba extract on patients suffering from Alzheimer disease (AD). Inclusion criteria for this study were: 1.) Patients were sufficiently characterized and diagnosed with AD; 2.) Studies had a clearly stated exclusion criteria; 3.) Use of standardized ginkgo extract in any stated dose; 4.) Randomized, placebo-controlled and double - blind study design; 5.) At least 1 outcome measure was an objective assessment of cognitive function; and 6.) Sufficient statistical information to allow for meta-analysis. An attempt was made to identify all English and non-English language articles in which Ginkgo biloba was given to subjects with dementia or cognitive impairment. Of the over 50 articles identified, an overwhelming majority did not meet the inclusion criteria, due to lack of clear diagnosis of dementia and AD. Only 4 studies met all inclusion criteria. In total, there were 212 subjects in each placebo and ginkgo treatment groups. Overall there was a significant effect size of 0.40 (P < 0.0001). While there was a small significant effect of 3 to 6 month

treatment with 120 mg to 240 mg of Ginkgo biloba extract on objective measures of cognitive function of AD, further research in the area will need to determine if there are functional improvements and to determine the best dosage for AD. Only two reports of bleeding complications were reported; no other adverse effects were reported in this study. [00010] One large study of ginkgo extract found no benefit (van Dongen et al. 2000). This 24-week, double-blind, placebo-controlled study of 214 people with either mild to moderate dementia or ordinary age-associated memory loss found no effect with ginkgo extract at a dose of 160 or 240 mg daily. However, this study has been criticized for a number of serious flaws in its design (Le Bars 2002). Another study failed to find any benefit (Solomon et al. 2002). This 6-week, double-blind, placebo-controlled trial of 230 healthy people over age 60 found that 120 mg of ginkgo biloba extract daily produced no significant improvement in mental function. This study also suffers from design flaws as the placebo was administered as a capsule and ginkgo as a tablet.

[00011] In a study by Stough et al. (2001), the neuropsychological changes in healthy participants were observed after taking Gingko biloba for 30 days. Approximately 50 participants completed the trial comprising of 26 females and 24 males, ranging in age from 18-40 years. This study employed a randomized, double-blind design. Baseline assessment was determined before participants were to take the treatment or placebo tablets. Participants were administered 120 mg of Ginkgo biloba or a placebo for 30 days. Research nurses contacted each participant ever two days during the trial to check for adverse effects and to maximize compliance. A battery of well-validated neuropsychological tests, were employed to assess a wide range of cognitive variables including attention, working and short-term

memory, verbal learning, memory consolidation, executive processes, planning and problem solving, informational processing speed, motor responsiveness and decision making. Statistical analysis indicated significant improvements in speed of informational processing, and working memory (F = 5.3; p < 0.05) attributable to ginkgo. Thus it can be concluded that ginkgo administration improves memory processes with few side-effects. [00012] In a study by Rigney et al. (1999), the effects of acute doses of Gingko biloba extract (GBE) on memory and psychomotor performance were investigated using a randomized, double-blind, placebo controlled, 5 -way crossover design. Thirty-one volunteers aged 30-59 years received GBE 150 mg, GBE 300 mg, BGE 120 mg mane and GBE 240 mg mane and a placebo for 2 days. Following baseline measures, the medication was administered at 0900 h for the single doses and at 0900, 1500 and 210O h for the multiple doses. A battery of psychometric tests were administered half an hour before dosing and then at frequent intervals until 11 hours after dosing. Results from this study indicated that GBE has a pronounced effect on memory, particularly on working memory, especially at the 120 mg mane dose (F(4, 100) =1.194, p = 0.318).The results also suggest that the cognitive enhancing effects of GBE are more likely to be apparent in individuals aged 50-59 years.

[00013] The primary active constituents are flavonoids (ginkgo-flavone glycosides) and terpenoids (ginkgolides and bilobalide) while the most important flavonoids are the glycosides (Kleijnen and Knipschild 1992). Ginkgolides can be divided into types A, B, C, and very small quantities of J and have not been found in any other living species (Kleijnen and Knipschild 1992). The pharmacokinetics of ginkgo have been investigated both in

animal and human experiments. In rats, an absorption rate of 60 % was found for a radioactively labelled extract under the drug/extract ratio of 35 - 67:1 with an average of 50:1 while in humans absolute bioavailability was 98-100 % for ginkgolide A, 79 -93 % for ginkgolide B and at least 70 % for bilobalide (Blumenthal ed. et al. 1998, 2000). The flavonol glycosides are absorbed in the small intestine with peak plasma concentrations attained within 2 - 3 hours and the half-life was between 2 and 4 hours as shown in healthy volunteers (Kleijnen and Knipschild 1992). The half lives of ginkgolides A, B and bilobalide were 4, 6 and 3 hour respectively and are excreted unchanged in the urine (Kleijnen and Knipschild 1992).

[00014] The beneficial effects of ginkgo biloba could be related to several different mechanisms of action. In the past, it was believed that the cause of mental deterioration with age (senile dementia) was due to reduced circulation in the brain resulting from atherosclerosis. Since ginkgo is thought to improve circulation, it was assumed that ginkgo was simply getting more blood to brain cells and thereby making them work better. However, the contemporary understanding of age-related memory loss and mental impairment no longer considers chronically restricted circulation to be the primary issue. Ginkgo (and other drugs used for dementia) may instead function by directly stimulating nerve-cell activity and protecting nerve cells from further injury, although improvement in circulatory capacity may also play a role (Sierpina et al. 2003). In addition, ginkgolides are potent inhibitors of platelet activating factor. Due in part to its antioxidant properties and ability to enhance peripheral and cerebral circulation, ginkgo's primary application lies in the treatment of cerebrovascular dysfunctions and peripheral vascular disorders (Sierpina et al.

2003). Hence, the psychological and physiological benefits of ginkgo are said to be based on regulating neurotransmitters and exerting neuroprotective effects in the brain, protecting against or retarding nerve cell degeneration.

[00015] In all the clinical trials of ginkgo reported in the Cochrane database study the incidence of side effects produced by ginkgo extract was extremely small and comparable to placebo (Birks et al. 2002). Reports of mild gastrointestinal discomfort, headaches, dizziness, palpitations, constipation, and allergic skin reactions have been reported (Jellin ed. et al. 2007).

[00016] The acute and chronic toxicity of ginkgo biloba extract under the drug/extract ratio of 35 - 67: 1 with an average of 50: 1 is very low. The LD in mice is 7725 mg/kg body

weight and >10,000 mg/kg in rats after oral application (Blumenthal ed. et al. 1998, 2000 and Upton ed. et al. 2003). No effects were shown to be mutagenic, carcinogenic or toxic to reproduction (Blumenthal ed. et al. 1998, 2000).

[00017] The amount of toxicology information available in humans is very limited as single doses up to 600 mg ginkgo leaf extract (50:1) have been administered with very low incidence of adverse events (Upton ed. et al. 2003). In another small study, doses of up to 4 g ginkgo leaf extract were administered to humans without incidence (Upton ed. et al. 2003). Orally, ginkgo appears to be relatively safe and well tolerated. Safety in young children, pregnant or nursing women, or those with severe liver or kidney disease, however, has not been established.

[00018] There have been no interactions reported with food and laboratory tests. However, there have been reported interactions with anticoagulant/antiplatelet herbs,

supplements or drugs. There have been reports of internal bleeding associated with use of ginkgo (spontaneous as well as following surgery). Based on these reports, as well as previous evidence that ginkgo inhibits platelet function, studies have been performed to determine whether ginkgo significantly affects bleeding time or other measures of blood coagulation (Kohler et al. 2004, Kudolo et al. 2002 and BaI Dit Sollier et al. 2003). The results of these studies have generally failed to find any anti-clotting effect; prudence would still suggest that ginkgo should not be used by anyone during the periods before or after surgery or labour and delivery, or by those with bleeding problems such as haemophilia. It also seems reasonable to hypothesize that ginkgo might also interact with blood-thinning drugs, amplifying their effects on coagulation. While one study found no interaction between ginkgo and warfarin (Engelsen et al. 2002), prudence once more suggests physician supervision before combining ginkgo with blood-thinning drugs such as warfarin or heparin. [00019] Seizures have also been reported with the use of ginkgo extract (Granger 2001). Two people with well-controlled epilepsy experienced recurrent seizures when they took ginkgo extract. One possible explanation is contamination of ginkgo leaf products with ginkgo seeds. Another possibility has been proposed as well: the drug tacrine (also used to improve memory) has been associated with seizures, and ginkgo may affect the brain in ways similar to tacrine. People with epilepsy should avoid ginkgo.

[00020] There is some preliminary evidence that ginkgo mildly affects drug metabolizing enzymes like cytochrome P450. It is unlikely that this will produce clinically significant interactions (Jellin ed. et al. 2005).

[00021] There are some indications that ginkgo might alter insulin release in people with diabetes (Kudolo 2001). The effect appears to be rather complex; the herb may cause some increase in insulin output, and yet might actually lower insulin levels overall through its effects on the liver and perhaps on oral medications used for diabetes. [00022] Ginseng, the root of the araliaceous plant (Cabral de Oliveira et al. 2001), is a slow growing perennial herb native to China, Korea, and Eastern Russia (Blumenthal et al. 1998). The medicinal root is fusiform or cylindrical, grayish- yellow, with sparse, shallow, interrupted and coarse transverse-striations, and distinct longitudinal wrinkles. The lower part has 2 to 3 bifurcated roots and numerous slender rootlets with inconspicuous minor tubercles (Guoshi et al. 1992). The biologically active constituents in ginseng are a mixture of triterpine saponins known as ginsenosides. The root contains 2-3% ginsenosides of which Rg , Rc, Rd, Rb , Rb , and Rb are quantitatively the most important. At least thirty

ginsenosides have been isolated thus far (Blumenthal et al. 1998). [00023] The earliest description of ginseng and its effect on health was in the ancient Chinese Pharmacopoeia dated from the first century A.D., Shen-Nung Pen T'sao Ching. This treatise prescribes ginseng root for its calming effect, brightening of the eyes, enlightening the mind and increasing wisdom (Lieberman 2001). Ginseng was also mentioned in Jijuzhang (Interpretation of Creatures), written by Shi You of China, as early as between 48 and 33 B.C. Ginseng prescriptions are found in Shanghan Lun (Treatise on Fevers) between 196 and 200 A.D. A legendary story relates a young man, whose mother was suffering from an incurable disease, found a miraculous remedy in the deep mountains described as ginseng. Although used as a tonic for general well being (Vogler et al. 1999),

ginseng has been used to cure 23 diseases according to Bancao Gangmu (Encyclopedia of Herbs), written by Li Shizhen in China in 596 A.D. It is also included in 653 of the total 3944 prescriptions in Dongeui Bogam (Korean Clinical Pharmacopoeia), written by Huh Joon, in 1610 A.D (Yun 2001). It was first described in the United Kingdom in a letter from Father Jartoux to the Procurator General of the Missions of India and China dated Peking April 12, 1711 (Coon et al. 2002).

[00024] The name Panax derives from the Greek word pan (all) and akos (healing), whilst ginseng means 'man-root' due to the shape of the root, creating a belief that it can benefit all parts of the body. All parts of the plant have pharmacologically active constituents, but the root is most extensively used (Coon et al. 2002). Ginseng is traditionally thought to promote longevity (Lieberman 2001), and to revitalize and replenish vital energy (qi). This replenishment is not to give an energy boost like that of caffeine or amphetamine. It is traditionally used during convalescence and as a prophylactic to build resistance, decrease susceptibility to illness (Blumenthal et al. 1998), and promote longevity (Kiefer et al. 2003). These claims are bolstered by animal and human studies.

[00025] Canada's senior (over 65 years of age) population has grown more than twice as fast as the overall population since the early 1980s, and the trend will continue for decades to come (Public Health Agency of Canada 2006). Forgetfulness is a problem most people associate with aging. Changes in cognitive function, including memory, reasoning and abstract thinking, affect a very small percentage of younger seniors, although the percentage does rise with age (Public Health Agency of Canada 2006). Ginseng has been shown to have favourable effects on physical achievement, subjective well-being and mental functions

(Sørensen and Sonne 1996) and has been reported as the most popular self-administered psychoactive herbal product the US (Reay et al. 2006.) Ginseng contains several triterpene glycosides named ginsengosides which are believed to contribute to the adaptagenic and physical performance enhancing properties of ginseng extracts (Wesnes et al. 2000). Panax ginseng contains at least 28 ginsengosides (steroidal saponins), each of which are a potential active constituent (Coleman et al. 2003). Ginseng has been purported to improve general well-being in humans. A good measure of this "well-being" in modern terms is to scientifically evaluate the effect of ginseng on the quality of life. This has been done by various randomized, placebo controlled studies and it has been shown that ginseng administration increase well-being and improves cognitive functions.

[00026] Sotaniemi et al. (1995) conducted an eight week, double-blind, placebo controlled study in non-insulin dependant diabetes mellitus (NIDM) patients. 36 patients were assigned to either the placebo or one of two treatment groups. Physical activity and eating habits were monitored with patient diaries for 8 weeks prior to treatment and 8 weeks during treatment. Subjective tests of mood, vigor and well-being were self-rated on linear analogue scales before and after the treatment period. Memory and psychophysical performance were evaluated, as well as blood glucose levels and serum lipid levels. Patients received one tablet per day containing either 100 mg, 200 mg or 0 mg (placebo), depending on what group they were placed into. This ginseng extract used in this study is called Gerimax and is standardized to 8.5% ginsenosides (HerbClip 2003.) The dose of 100 mg per day used in this study contains 8.5 mg of ginsenosides. Subjects demonstrated improvements in self- ratings of mood, vigor, psychomotor performance and well-being with both doses of the

ginseng treatment. The 200 mg dose of ginseng improved physical activity in patients compared to the placebo and ginseng lowered fasting blood glucose, but not lipid values. Body weight was also reduced by the ginseng groups. Therapy with ginseng improved mood and psychophysical performance in newly diagnosed NIDM patients which led to beneficial changes in daily life, habit and diet as indicated by increased physical activity and reduced weight. There were no side effects associated with this study.

[00027] The effects of a pure ginseng extract on cognitive function were examined by Sørensen and Sonne (1996) in a placebo-controlled, double-blinded trial. One hundred and twelve subjects aged 40 to 70 completed the study, 55 in the ginseng group and 57 in the placebo group. The ginseng treatment group received a 400 mg tablet of ginseng called Gerimax, standardized to 8.5% ginsenosides (HerbClip 2003) per day and the placebo group received an inactive soluble calcium tablet. Baseline tests were conducted pre-treatment and retests were conducted after 8 to 9 weeks of treatment. Tests divided into four groups: psychomotor tests, attention and concentration tests, learning and memory tests, and abstraction tests. The ginseng group performed significantly (p<0.04) better in the most rapid auditive reaction times (a psychomotor test.) The ginseng group also made fewer errors (p<0.02) in the Wisconsin Card Sorting Test (abstraction test.) No side effects were identified with consumption of the tablet by either the placebo or the ginseng group. The increase in auditive reaction times corresponds to the previous literature which shows that ginseng increases alertness and arousal in humans. The Wisconsin Card sorting test measures mental organization, reasoning and control, all factors which are controlled by the

frontal lobe of the brain. Due to psychological adaptation an alternation in well-being is assumed to decrease in the course of a lengthy treatment.

[00028] In a 1986 study D'Angelo et al. studied the effects of ginseng on psychomotor performance. This double-blind, placebo controlled study was conducted in 32 healthy male volunteers, aged 20-24, 16 of which were in the treatment group and given a standardized preparation of Korean ginseng {Panax ginseng). The placebo tablet contained lactose. The ginseng extract was Gl 15 which is standardized to 4% ginsenosides, the active ingredient in ginseng. Subjects were given 100 mg twice daily for 12 weeks. This corresponds to a dose of 8 mg of ginsenosides per day. Laboratory tests and psychometric assessment occurred before and after the 12 week treatment period. Psychometric assessment include: tapping test, simple reaction time, choice reaction time, cancellation test, digit symbol substitution test, mental arithmetic, and logical deduction. No adverse events were reported and laboratory tests (full blood count, sodium, potassium, chloride, creatinine, alkaline phosphatise, urinalysis, etc.) all remained within normal limits. In this study, significant was defined as p<0.05. Significant improvement was initially seen in the cancellation test by the ginseng treatment group; however, at the end of the treatment period no significant difference could be seen between the placebo and ginseng treatment. Significant improvements were noted for both the placebo and ginseng group for the mental arithmetic test. The choice reaction time decreased significantly for the ginseng treatment group. The ginseng treatment group also demonstrated significant improvements in the logical deduction test. Other tests did not show significant improvements and the placebo group did not perform better than the ginseng group on any test.

[00029] A study by Reay et al. (2006) investigated the effects of Panax ginseng consumed with and without glucose, hi a double-blind, placebo controlled, balanced-crossover design 27 young adults completed a 10 minute cognitive demand battery test to determine baseline results. They then consumed a capsule containing either the ginseng extract or a placebo. Thirty minutes after consumption of the capsule they consumed a drink containing either glucose of a placebo. Thirty minutes after consumption of the drink the subjects were then required to conduct the cognitive demand test 6 times in immediate succession. The ginseng treatment consisted of 2 ginseng capsules, each containing 100 mg of ginseng standardized to 4% ginsenosides. The glucose treatment drink consisted of 180 mL of tap water, 20 mL of a sugar free fruit cordial drink and 25 g of glucose. The placebo drink contained 30 mg of saccharin instead of glucose to match the taste of the drinks. The cognitive demand battery test comprised of serial threes and serial sevens subtraction tasks, a rapid visual information processing task and a 'mental fatigue' visual analogue scale. Each subject performed the study 4 times-once in a placebo/placebo combination, once in a ginseng/placebo drink combination (ginseng group), once in a placebo/glucose drink combination (glucose group) and once in a ginseng/glucose dink combination (combination group). The blood glucose levels of the subjects were also determined before and after treatment. Following the ingestion of ginseng alone blood glucose levels were significantly reduced at the 1 hour post- dose measurement point (P=O.046). In the serial threes test significantly more serial three subtractions were performed following the administration of 200 mg ginseng alone at the third (P=0.039), fourth (PO.027) and the sixth (P=0.003) demand battery completions. Following 25 g glucose alone subjects also produced significantly more serial threes on the

third, fourth and sixth demand battery completion. No significant results were seen with the serial seven subtraction test. The rapid visual information processing task revealed that there were significantly few false alarms committed following a glucose only dose, irrespective of ginseng administration. Mental fatigue was significantly ameliorated following a glucose alone and a ginseng alone. There was no effect of the combined treatment. Single doses of 200 mg of Panax ginseng or 25 g of glucose can modulate circulating blood glucose levels, enhance cognitive performance and ameliorate the increase in subjective feelings of mental fatigue.

[00030] Ellis and Reddy examined the effects of Panax ginseng on Health related Quality of Life (HRQOL) in 2002. In this randomized, double-blind, placebo controlled study, 30 people (15 in each group) were given either a Panax ginseng or a lactose placebo capsule for 8 weeks. Subjects received 200 mg of ginseng extract per day, which was standardized to 4% ginsenosides. HRQOL was assessed at baseline, 4 weeks and 8 weeks. HRQOL was assessed by a Short Form-36 Health Survey version 2. This questionnaire consisted of 36 questions which addressed physical functioning, mental health, role limitations due to physical health, pain, social functioning, role limitations due to emotional problems, vitality, and general health perception. At baseline, there were no significant differences between the placebo and treatment group. At 4 weeks the social functioning was significantly higher in the ginseng group (p=0.014) and a trend towards a higher mental health score (p=0.075) was higher for the ginseng group. Also the mental component summary score was significantly higher for the treatment group at the 4 week mark (p=0.019). However, after 8 weeks, measurements no significant differences were seen between the placebo and treatment group.

Only one person experienced an adverse event from the ginseng group; they reported nausea/vomiting, insomnia, rebound irritability and headache. The ginseng group was likely to state that they felt different during treatment. In this study Panax ginseng was shown to improve aspects of mental health and social functioning after 4 weeks of therapy. [00031] There has been very little research published on the pharmacokinetics of the absorption, distribution, metabolism, and excretion of ginseng, due to the lack of satisfactory analytical methods to detect plasma and tissue concentrations. [00032] Studies in rats have shown that ginsenoside Rg was rapidly absorbed from the

upper digestive tract and reached peak serum concentration at 30 minutes, and peak tissue concentration at 90 min (Kennedy et al. 2003). However similar rat studies have reported only 23% absorption of ginsenoside Rb after 2.5 hours. This implies that there is a very low

bioavailability of ginsenosides in human plasma (Kitts et al. 2000).

[00033] Small recoveries of Rb were made from the heart and liver while most of the

recovery occurred from the small intestine (Kitts et al. 2000). None was recovered from the brain (Kennedy et al. 2003). In rats ginseng is preferentially distributed to the muscles and lungs (Gross et al. 2002).

[00034] Metabolic or bacterial transformation of ginseng may occur in the small intestine. Studies conducted in bacteria isolated from human intestines hydrolyze the ginsenosides Rb

and Rb to certain metabolites, which are then absorbed from the intestine (Kitts et al. 2000).

[00035] Ginseng is excreted through the urine as demonstrated by urine samples taken from athletes who had consumed ginseng within the last ten days (Kennedy et al. 2003). Ginseng is also excreted in fecal matter (Kitts et al. 2000).

[00036] Since there are many active components of ginseng known as ginsenosides there are many mechanisms of action. None of these mechanisms are conclusive because many of the trials involving ginseng have not quantified the ginsenosides present in their particular extract of ginseng. Among all the ginsenosides Rb and Rg may be the most important

(Cabral de Oliveira et al. 2001).

[00037] The mechanism by which ginseng might modulate human cognitive function is not well understood, but they may involve several central and peripheral physiological effects that are potentially relevant to human cognitive performance. These include effects on the cardiovascular system, platelet aggregation, and the Hypothalamic-Pituitary- Adrenal system, neurotransmission and nitric oxide synthesis (Reay et al. 2006).

2+

[00038] Rb has been shown to inhibit Ca -calmodulin protein kinase, which disturbs the

2+

Ca concentration and inhibits its accumulation in the liver or microsomes resulting in an

2+ inhibition of protein phosphorylation, such as glycogen synthase. Ca concentration is a critical in muscle activity and fatigue (Cabral de Oliveira et al. 2001). [00039] Ginseng enhances the production and release of neurotransmitters such as dopamine, noradrenalin and serotonin in the liver, kidneys, and the gastrointestinal tract and to increase their blood concentrations in animals. Ginseng is therefore thought to improve neuromuscular functions (Gross et al. 2002).

[00040] Ginsenosides can target cell membranes, cross that membrane, change its physical properties, interact directly with membrane proteins and can themselves become incorporated into the cell membrane (Cabral de Oliveira et al. 2001).

[00041] Ginseng suppresses lipid peroxidation through the inhibition of lipoxygenase, which is involved in the metabolism of unsaturated fatty acids, arachidonic acid to prostaglandins. These effects may be caused by a reduction in phospholipase A and by a

reinforcement of muscle fiber membranes. The reduction of A leads to a decrease in the

2+ hydrolysis of membrane phospholipids, decreased membrane fluidity, and a decreased Ca influx and muscle damage (Cabral de Oliveira et al. 2001).

[00042] Various preparations and concentrations of ginseng have the ability to reduce elevate or stabilize blood pressure. There are several probable mechanisms that may be involved in this action. Rg raises blood pressure by stimulating the central nervous system,

while Rb lowers blood pressure by central nervous system depression. Ginseng relaxes

smooth muscle and raises nitric oxide concentrations that also cause hypotensive effects. In contrast it stimulates the release of Cortisol and degrades endothelin that causes sodium and fluid retention and vasoconstriction, leading to hypertension (Caron et al. 2002). [00043] Ginseng promotes against oxidative stress by regulating Cu/Zn superoxide dismutase at the molecular level. Rb has been shown to induce superoxide dismutase

transcription by interacting with the activator protein AP in the promoter region of the SOD

gene (Kitts et al. 2000).

[00044] Fasting blood glucose concentration was reduced in patients with non-insulin dependant diabetes, who were treated with ginseng. The mechanism for this action has not been elucidated and is likely multifactorial. The theory thus far is that ginseng has been shown to increase glycogen stores in animals and this may also occur in humans. A decrease in aminoterminalpropeptide by ginseng suggests a reduced collagen synthesis and or improved elimination, which may prove to be antiatherogenic (Sotaniemi et al. 1995).

SUMMARY OF THE INVENTION

[00045] This invention relates to a new compound to improve the memory, cognitive function and mental health of individuals.

[00046] The invention comprises a daily dosage of from about 95 mg to about 145 mg ginkgo biloba and from about 160 mg to about 240 mg ginseng standardized at 4% ginsenosides, admixed together in a single compound. Alternatively, the compound may comprise from about 95 mg to about 145 mg ginkgo biloba and from about 95 mg to about

145 mg ginseng standardized at 7% ginsenosides, admixed together in a single compound.

The preferred compound provides a daily dose of a synergistic mixture of 200 mg of ginseng standardized at 4% ginsenosides and 120 mg of ginkgo biloba.

PREFERRED EMBODIMENT OF THE INVENTION

[00047] The preferred embodiment provides for administration of the preferred dosage on a three times a day regimen. In other words, the daily dosage is divided into three equal dosages administered over the course of a day.

[00048] The preferred compound contains two active ingredients. The first is ginkgo biloba administered in the amount of from about 95 mg to about 145 mg per day. Any increase over 145 mg decreases the efficacy of the product.

[00049] The second active ingredient in the product is ginseng. The dosage of ginseng is from about 160 mg to about 240 mg per day when the ginseng is standardized at 4% ginsenosides. If the ginseng is standardized at 7% ginsenosides, the preferred dosage is from about 95 mg to about 145 mg administered three times a day.

[00050] The preferred compound contains 40 mg of Panax ginseng (standardized to 7% ginsenosides) and 40 mg of Ginkgo biloba (standardized to 24% ginkgo-flavone glycosides and 6% terpenoids). The dosage amount of 120 mg per day of ginkgo was chosen for the following reasons.

[00051] A study by Burns et al. (2006) found that a dose of 120 mg per day effectively improved the memory of older adults. Elsabagh et al. (2005) also used a dose of 120 mg of ginkgo per day and found that acute ginkgo supplementation improved performance on cognitive function, particularly in the areas of sustained-attention task and pattern recognition memory task.

[00052] Kennedy et al. (2000) found that a dose of 120 mg of ginkgo extract per day most significantly enhanced the performance of the quality of memory, compared to doses of 240 mg per day and 360 mg per day.

[00053] Stough et al. (2001) found that 120 mg / day of ginkgo administration improves memory processes with few side-effects. Oken et al. (1998) and Rigney et al. (1999) both

found that 120 mg of ginkgo extract per day was effective in improving memory and other cognitive functions.

[00054] In all the clinical trials of ginkgo reported in the Cochrane database study the incidence of side effects produced by ginkgo extract was extremely small and comparable to placebo (Birks et al. 2002). In animal studies, no effects were shown to be mutagenic, carcinogenic or toxic to reproduction (Blumenthal ed. et al. 1998, 2000). Orally in humans, ginkgo appears to be relatively safe and well tolerated.

[00055] D'Angelo et al. (1986) performed a clinical trial on male volunteers using a dose of 200 mg of ginseng per day. The ginseng extract used was Gl 15 which is standardized to 4% ginsenosides. This corresponds to 8 mg of ginsenosides (the active compounds in ginseng) per day. No adverse events were reported in this trial at this dose. All laboratory test tests (full blood count, sodium, potassium, chloride, creatinine, alkaline phosphatise, urinalysis, etc.) all remained within normal limits. At this dose for 12 weeks, significant improvements were seen in the cancellation group, mental arithmetic test, choice reaction time and logical deduction tests. This demonstrates the effect of ginseng on improving certain psychomotor functions in healthy subjects, thereby increasing the well-being of these individuals.

[00056] Ellis and Reddy examined the effects of Panax ginseng on Health related Quality of Life (HRQOL) in 2002. In this study, 30 people (15 in each group) were given either a Panax ginseng or a placebo capsule for 8 weeks. Subjects received 200mg of ginseng extract per day, which was standardized to 4% ginsenosides. This corresponds to 8mg of ginsenosides (the active compounds in ginseng) per day. HRQOL was assessed at baseline,

4 weeks and 8 weeks. At 4 weeks the social functioning component of the HRQOL questionnaire was significantly higher in the ginseng group and the mental health component of the HRQOL questionnaire summary score was significantly higher for the treatment group at the 4 week mark. This demonstrates an increase the quality of life as social functioning and mental health improve with administration of ginseng. There was one person who reported an adverse event from the ginseng group of this study; they reported nausea/vomiting, insomnia, rebound irritability and headache.

[00057] Reay et al. (2006) investigated the effects of Panax ginseng consumed with and without glucose. The ginseng treatment consisted of 2 ginseng capsules, each containing 100 mg of ginseng standardized to 4% ginsenosides. This corresponds to 8 mg of ginsenosides (the active compounds in ginseng) per day. It was found that single doses of 200 mg of Panax ginseng or 25 g of glucose can modulate circulating blood glucose levels, enhance cognitive performance and ameliorate the increase in subjective feelings of mental fatigue, thus improving well-being. [00058] Studies in rats have shown that ginsenoside Rg was rapidly absorbed from the

upper digestive tract and reached peak serum concentration at 30 minutes, and peak tissue concentration at 90 min (Kennedy et al. 2003). Therefore the dosage scheme of 40 mg of ginseng extract 3 times per day would result in maximum tissue concentration for longer period through out the day as similar rat studies have reported only 23% absorption of ginsenoside Rb after 2.5 hours (Kitts et al. 2000).

[00059] Ginseng is well tolerated orally (Jellin et al. 2007.) In the studies previously mentioned by Ellis and Reddy (2002), Reay et al. (2006), D'Angelo et al. (1986), Sørensen

and Sonne (1996), and Sotaniemi et al. (1995); only one adverse reaction was reported by a participant in the study by Ellis and Reddy (2002). Therefore this dosage of 120 mg per day corresponding to 8.4 mg ginsenosides can generally be safely administered. [00060] The mixing of the two active ingredients provides a synergistic effect between the ginseng and the ginkgo biloba and has provided significant improvements in memory, cognitive function and the mental health of the individuals taking the dosage.

REFERENCES

BaI Dit Sollier C, Caplain H, Drouet L. No alteration in platelet function or coagulation induced by EGb761 in a controlled study. Clin Lab Haematol. 2003;25:251-3.

Birks J, Grimley E, Van Dongen M. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2002;4:CD003120.

Blumenthal M. German Federal Institute for Drugs and Medical Devices. Commission E. The complete German Commission E monographs: therapeutic guide to herbal medicines. Austin, Tex.: American Botanical Council, 1998.

Blumenthal M. German Federal Institute for Drugs and Medical Devices. Commission E. Herbal medicine: expanded Commission E monographs. Newton, Mass.: Integrative Medicine Communications, 2000.

Burns NR, Bryant J, Nettelbeck T. Ginkgo biloba: no robust effect on cognitive abilities or mood in healthy young or older adults. Hum Psychopharmcol Clin Exp 2006; 21 : 27-37.

Cabral de Oliveira AC, Perez AC, Merino G, Prieto JG, Alvarez AL. Protective Effects of Panax Ginseng on Muscle Injury and Inflammation after Eccentric Exercise. Comp Biochem Physiol C Toxicol Pharmacol 2001; 130(3):369-377.

Caron MF, Hotsko AL, Robertson S, Mandybur L, Kluger J, White CM. Electrocardiographic and Hemodynamic Effects of Panax Ginseng. Ann Pharmacother 2002; 36(5): 758-763.

Coleman CI, Hebert JH, Reddy P. The effects of Panax ginseng on quality of life. Journal of Clinical Pharmacy and Therapeutics 2003; 28:5-15.

Coon JT, Ernst E. Panax Ginseng: A Systematic review of Adverse Effects and Drug Interactions. Drug Saf 2002; 25(5):323-344.

Crews WD, Harrison DW, Griffin ML, Falwell KD, Crist T, Longest L et al. Herbal Gram

2005;67:43-62.

D'Angelo L. Grimaldi R, Caravaggi M, Marcoli M, Perucca E, Lecchini S, Frigo GM, Crema A. A Double-Blind, Placebo-Controlled Clinical Study on the Effect of a Standardized Ginseng Extract on Pyschomotor Performance in Healthy Volunteers. Journal of Ethnopharmacology 1986; 16:15-22.

Ellis J and Reddy P. Effects of Panax ginseng on Quality of Life. The Annals of

Pharmacotherapy 2002; 36:375-379.

Elsabagh S, Hartley DE, AIi O, Williamson EM, File SE. Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers. Psychopharmacology 2005; 179: 437-446.

Engelsen J, Nielsen JD, Winther K. Effect of coenzyme QlO and Ginkgo biloba on warfarin dosage in stable, long-term warfarin-treated outpatients. A randomised, double-blind, placebo-crossover trial. Thromb Haemost. 2002;87:1075-1076.

Fleming T, Deutsch M, Gruenwald J, Brendler T, Jaenicke C, Hamid M et al, editors. PDR: For Herbal Medicines. New Jersey: Medical Economics Company; 1998.

Foster S. Ginkgo, Ginkgo biloba. American Botanical Council 1999;304:3-7.

Granger AS. Ginkgo biloba precipitating epileptic seizures. Age and Aging 2001; 30:523-

525.

Gross D, Shenkman Z. Bleiberg B, Dayan M, Gitelson M, Efrat R. Ginseng Improves Pulmonary Functions and Exercise Capacity in Patients with COPD. Monaldi Arch Chest Dis 2002; 57(5-6):242-246.

Guoshi T, ed. Pharmacopoeia of the People's Republic of China (English Version).Beijing, China.: The Pharmacopoeia Commission of PRC, 1992.

Jellin JM, Batz F, Hitchens K. Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database. Stockton (CA): Therapeutics Research Faculty; 2007.

Kallus KW, Schmitt JAJ, Benton D. Attention, psychomotor functions and age. European Journal of Nutrition 2005; 44(8): 465-484.

Kennedy DO, Scholey AB, Wesnes KA. The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology (Berl) 2000; 151:416-423.

Kim SH, Parks KS. Effects of Panax Ginseng Extract on Lipid Metabolism in Humans. Pharmacol Res 2003; 48(5):511-513.

Kitts DD, Hue C. Efficacy and Safety of ginseng. Public Health Nutrition 2000; 3(4A): 473- 485.

Kleijnen J, Knipschild P. Ginkgo biloba. Lancet. 1992;340:l 136-1139.

Kohler S, Funk P, Kieser M. Influence of a 7-day treatment with Ginkgo biloba special extract EGb 761 on bleeding time and coagulation: a randomized, placebo-controlled, double-blind study in healthy volunteers. BloodCoagul Fibrinolysis 2004; 15:303-309.

Kudolo GB. The effect of 3-month ingestion of Ginkgo biloba extract (EGb 761) on pancreatic beta-cell function in response to glucose loading in individuals with non-insulin- dependent diabetes mellitus. J Clin Pharmacol. 2001;41 :600-611.

Le Bars PL, Kastelan J. Efficacy and safety of ginkgo baloba extract. Public Health Nutrition 2000;3(4A) 495-99.

Lieberman HR. The Effects of Ginseng, Ephedrine and Caffeine on Cognitive Performance, Mood and Energy. Nutr Rev 2001; 59(4):91-102.

Oken BS, Storzbach DM, Kaye JA. The Efficacy of Ginkgo biloba on Cognitive Function in Alzheimer Disease. Arch Neurol 1998; 55: 1409-1415.

Re: Effects of Gerimax Ginseng on lung Infections (2003). HerbalClip [internet]. [Austin, Cited March 19, 2007]. Available at: http://www.herbalgram.org/youngliving/herbclip/pdfs/120428-2 33.pdf

Reay JL, Kennedy DO, Scholey AB. Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained 'mentally demanding' tasks. Journal of Psychopharmacology 2006; 20(6): 771-781.

Rigney U, Kimber S, Hindmarch I. The Effects of Acute Doses of Standardized Ginkgo biloba Extract on Memory and Psychomotor Performance in Volunteers. Phytotherapy Research 1999; 13: 408-415.

Sierpina VS, Wollschlaeger B, Blumenthal M. Ginkgo biloba. American Family Physician 2003;68(5):923-926.

Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: a randomized controlled trial. JAMA 2002;288:835-840.

Sørensen H and Sonne J. A Double-Masked Study of the Effects of Ginseng on Cognitive Functions. Current Therapeutic Research 1996; 57(12):959-968.

Sotaniemi EA, Haapakoski E, Rautio A. Ginseng Therapy in Non-insulin Dependant Diabetic Patients. Diabetes Care 1995; 18(10):1373-1375.

Stough C, Clarke J, Lloyd J, Nathan PJ. Neuropsychological changes after 30-day Ginkgo biloba administration in health participants. International Journal of Neuropsychopharmacology 2001; 4: 131-134.

The Senior Audience: Large, Growing, Diverse (2006). Public Health Agency of Canada [internet], [Canada, cited March 13, 2007]. Available at: http://www.phac- aspc.gc.ca/seniors-aines/pubs/communicating/audience_e.htm

Upton R. Ginkgo Leaf, Ginkgo Leaf Dry Extract (Ginkgo biloba L.) American Herbal Pharmacopoeia and Therapeutic Compendium, 2003. van Dongen MC, van Rossum E, Kessels AG, Sielhorst HJ, Knipschild PG. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial. J Am Geriatr Soc. 2000;48:l 183-1194.

World Health Organization. WHO monographs on selected medicinal plants. Vol. 1, Ch. 16. Folium Gingko. Geneva: World Health Organization, 1999:154-67.