FIELD OF THE INVENTION

The average amount of body fat in the American male is 22 to 25%, and in the American female, the average amount of fat is 33 to 35%. These values are far above optimal values, which are 15 to 19% for 20-29 year old males and 19 to 23% for 20-29 year old females. Corresponding values for 40-49 year olds are 17 to 21% and 21 to 25%, respectively; and for 60 year olds, the corresponding values are 19 to 23% and 23 to 27%, respectively. In highly overweight individuals, fat tissue can constitute up to 70% of body weight.

The remaining percentage of body composition corresponds to the lean body mass. Lean body mass is composed of muscle, vital organs, bone, connective and other non-fatty tissues in the body, and most of the body water. The body's metabolic rate is in direct proportion to the amount of lean body mass. Therefore, considering the lean body mass is important for any weight loss strategy.

The overwhelming majority of weight control means do not take into account the importance of maintaining or increasing the lean body mass in the process of weight loss. In fact, regimens to decrease body fat often contribute to the catabolic wasting of lean body mass. Increased lean body mass regulates body metabolism and helps in losing weight, as well as maintaining the accomplished weight reduction. On the other hand, diminished lean body mass slows down body metabolism and results in difficulties in maintaining an appropriate, healthy body weight. Thus, an ideal weight management approach should be to reduce body weight to acceptable levels by restoring the optimal proportions of fat to lean body mass. By maintaining or increasing the lean body mass while simultaneously reducing body fat, the weight loss regimen would serve the general purpose of improving the overall health of the individual.

Maintaining or increasing the lean body mass (for example, skeletal muscles) is one of the important considerations for any weight loss strategy because lean body mass determines the rate of metabolism and the body's thermogenic response to food, and food induced thermogenesis and the metabolic rate, in turn, control body weight by an increase in the catabolism of body fat. This is so because thermogenesis is preferentially fueled by fatty acids derived from stores of body fat and from food. In addition, a high rate of thermogenesis contributes to more food being absorbed and to the preferential build-up of lean body mass, rather than adipose tissue. As a result this invention relates to methods and compositions for producing weight loss in humans by burning fat, and increasing the buildup of lean body mass.

One of the greatest problems confronting modem society in economically successful countries today is obesity. Unfortunately, obesity brings with it the conditions that are ripe for the more serious disease of diabetes.

Among the many possible solutions for treating obesity are formulations of weight loss products that work with some of the basic biochemical processes involved in fat metabolism. This process has been exploited through pharmaceutical intervention at the neurocrine level as well as at the level of fat cells themselves, or the way fat cells metabolize fats in brown and white adipose tissue.

The term thermogenisis has been coined to describe the process whereby food intake is converted to body heat through the metabolic process of caloric conversion. In obese people, certain metabolic defects associated with the thermogenic process begin to appear. These metabolic predisposition’s manifest in a number of identifiable biochemical syndromes that can be attacked through therapeutic intervention with agents that over-ride the cascade of events leading to obesity.

One of the more natural approaches to starting artificial thermogenisis, that is, thermogenisis that is unrelated to food consumption, is the use of plant derived substances. Many of these plant substance contain ephedrine or ephedrine like compounds such as ma-haung or ephedra. Ephedra is an herb that grows wild in parts of the western United States. Ephedra contains ephedrine, an alkaloid that stimulates the production of catecholamines such as norepinephrine. Norepinephrine or noradrenaline is presumed to start the thermogenic process by stimulating metabolism in fat cells via the neurocrine axis that involves beta-adrenergic receptors. This in turn results in lipolysis, or the liberation of fat in fat cells via an increase in the basal metabolic rate. This pharmacological intervention results in weight loss in lean, obese, and post-obese human subjectsand has been demonstrated in clinical studies† (Dulloo, A G & Miller D S, Wrld Rev Nutr Diet 50: 1-56 ;1987).

BACKGROUND OF THE INVENTION

It is the object of the present invention to provide safer and more effective weight-loss compositions that combine the anti-obesity properties of eight types of metabolic formulations that involve different biochemical aspects.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The Tight formula assists in providing control over the proportion of body fat to lean body mass. The preferred embodiments assists in causing body fat loss while building or maintaining lean body mass. The preferred embodiments comprise: Caffeine Anhydrous, Green Tea Extract, Synephrine, Sclareolide, Pure Guggulsterones Z & E, Yohimbine, Vinpocetine, and Piperine (sold under the commercial and Trademarked name of Bioperine).

PURE E & Z GUGGLESTERONES

Guggul (C. wightii) is distributed mainly in Gujarat and Rajasthan states of India. It is cultivated for the oleo-gum resin, which has wide application in allopathic, ayurvedic and unani system of medicine. E and Z Guggulsterones are used as markers for standardization.

A number of reviews and research papers have appeared in various journals where the detailed chemistry of Guggul gum resin and its pharmacological properties have been discussed.

Guggul, the gum resin exudate from C. wightii is a complex mixture of phytochemicals, diterpenoids, aliphatic esters, carbohydrates and a variety of inorganic ions besides minor amount of sesamin and other unidentified constituents.

A compound known as Z-Guggulsterone has been identified as having the structural formula as identified in US Patent No. 6,113,949. The E-stereoisomer has also been identified and these ketones are known hypolipemic and antiplatelet aggregation agents. A process for the preparation of pharmacologically active synthetic Z and E stereoisomeric mixture of Guggulsterones is disclosed in EP0447,706 to Hamied. These compounds have also been isolated from the exudate of a plant known as Commiphora mukul (Hook, ex stocks) Engl. (syn. Balsamodendron mukul Hook) which is a small tree of the Burseraceae family, endemic in the Indian peninsula. If the trunk is etched, the plant emits a yellowish gummy exudate, which coagulates rapidly in the form of stalactites having a balsamic smell. In the ancient Sanskrit, this gum resin is called guggulu and is a product, which is still used in Indian popular medicine. Recently, a lipophilic extract has been prepared from this resin, this extract contains many classes of compounds, among which lignans, terpenes and some keto-steroids, named Guggulsterones. Hypolipidemic and platelet aggregation inhibiting activities are described for this lipophilic extract, which is normally obtained by simple resin extraction with ethyl acetate, or for Guggulsterone-Z and Guggulsterone-E, whose components in the extract are normally titrated. In similar fashion, Guggulsterones have also been found to be very effective in reducing total cholesterol levels and LDL levels. Nityanand et al. report in "Clinical Trials With Gugulipid, A New Hyperlipidaemic Agent" J-Assoc-Physicians-India, 1989 May; 37(5): 323-8, a multi-center clinical trial with 205 patients over a twelve (12) week period. A gugulipid dose of 500 mg twice daily after eight (8) weeks showed a significant lowering in the serum cholesterol (average 23.6%) and serum triglycerides (average 22.6%). The study also used colfibrate as a comparative. The gugulipid average fall in serum cholesterol and triglycerides was 11 and 16.8% respectively and with colfibrate 10 and 21.6% respectively. The lipid lowering effect of both substances became evident three (3) to four (4) weeks after start.

While the prior art discloses the use of Guggulsterones to reduce blood plasma lipid content and the use of phosphates to increase triiodothyronine and increase resting metabolic rate, there is no suggestion or disclosure of combining Z and E Guggulsterones with any of the compounds more fully described in this formula, in order to achieve a synergistic effect in weight control.

CAFFEINE

The term "caffeine" as used herein is intended to encompass not only caffeine as the anhydrous powder, but any salt or derivative of caffeine or any compounded mixture thereof-which is non-toxic, pharmaceutically acceptable when employed as described herein.

Caffeine’s structure, function and metabolic role is well characterized and understood in the art. Specifically caffeine is a methylxanthine, which has been directly linked to diuretic and respiratory stimulant action. Caffeine affects the central nervous system, mainly the cerebrum. Caffeine is found in coffee beans, tea, cola nuts, guarana, cacao seeds, and mate.

The chemical name for caffeine is 1,3,7-trimethylxanthine. Other common methylxanthine stimulants include 1,3-dimethylxanthine (found in tea and commonly called theophylline), and 3,7-dimethylxanthine (found in cacao seeds and tea, and commonly called theobromine).

Products containing caffeine are ubiquitous. A sampling of such products includes coffees, teas, soft drinks, chocolate products, cold-relief products, diet aids, various foods including puddings and, of course, products specifically designed to keep people awake and alert.

GREEN TEA EXTRACT (EGCG)

Green tea has many mechanisms of action in stimulating weight loss. The most important is probably the inhibition of catechol-O-methyl-transferase (COMT) by EGCG [Chantre P, Lairon D, 2002]. COMT is the enzyme that breaks down norepinephrine (NE), one of the body's most important lipolytic hormones. Caffeine also plays a synergistic role by inhibiting phosophdiesterases (enzymes that break down cAMP, which is further down the lipolytic pathway) [McArdle NJ, Clifford MN, Ioannides C, 1999]. Although EGCG is the most responsible, some flavanoids found in small amounts in green tea such as quercetin and myricetin also inhibit COMT and may play a minor role† [Dulloo AG, Duret C, Rohrer D, Girardier, 1999]. Secondly, green tea decreases the digestibility of dietary fat† [Chantre P, Lairon D, 2002]. The proposed mechanism of action is inhibition of both gastric and pancreatic lipase, which has been demonstrated in vitro [Chantre P, Lairon D, 2002]. These enzymes both play major roles in the digestion of fat, so when they are inhibited a smaller proportion of fat is absorbed and a greater proportionexcreted. Green tea is also a potent appetite suppressant. This can be partly explained by the fact that it increases both NE and dopamine [Yokogoshi H, Kobayashi M, Mochizuki M, 2002], but further mechanisms of action have been hypothesized. Specifically, tea polyphenols have been known to elevate levels of cholecystokinin (CCK) [Liao S, 2001], a hormone which depresses food intake [Liao S, 2001]. It is not yet known whether this plays a significant role in the action of green tea, and one of the effects of elevated CCK is an increase in pancreatic lipase, which is actually inhibited by green tea. It could be that green tea simultaneously elevates CCK and decreases pancreatic lipase, conferring the benefits of both appetite suppression and decreased fat digestibility.

SYNEPHRINE

Synephrine is derived from Citrus plants, and can be administered orally to humans for the purpose of producing or maintaining weight loss as well as improving the person's physical performance and increasing the person's lean muscle mass. The Citrus materials, containing synephrine, include those portions of the plant that are normally considered waste or inedible, such as the leaves, peel and immature, unripe fruit. The materials contain as least one of the alkaloids from the group consisting of synephrine, hordenine, octopamine, tyramine and N-methylamine. Two species, Citrus aurantium and Citrus reticulata are particularly useful. The Citrus materials, and in this particular embodiment synephrine extracted from the citrus materials is used in conjunction with the compounds described herein for weight loss and weight control, the burning of fat and the building of lean body mass.

Thermogenesis is a metabolic process consisting of the production of heat by the organism, especially in the muscles and in the adipose tissues, using as energy source the available fat deposits. High thermogenesis allows body weight to decrease without significant variations in the quantity of food intake. The levels of thermogenesis vary from individual to individual, in a genetically predetermined way and for this reason body weight also varies from individual to individual regardless of the energetic limits set by the diet. The processes of thermogenesis are managed by the adrenergic system, through beta-1, beta-2 and beta-3-adrenergic receptors.

Accordingly, the levels of thermogenesis can be altered with some adrenergic-like substances (adrenergic or sympathomimetic) such as, for instance synephrine, etc. Adrenergic-like compounds are not very active alone in the activation of thermogenesis, and therefore, they are commonly used together with stimulants, such as the methylxanthines: caffeine, theophylline and theobromine, which have a synergistic action with adrenergic substances.

The adrenergic amines stimulate beta-receptors in a predominantly indirect fashion thereby stimulating thermogenesis, increased metabolic rate and lipolysis. Adrenergic amines have been shown to have utility in regulating or treating weight problems. Still another aspect of this formula is a method for promoting weight control, weight loss, enhanced physical performance, and/or the addition of lean muscle mass, which includes the step of administering to a subject an effective amount of Sclareolide

SCLAREOLIDE

It is well known in the art that Sclareolide, sometimes interchangeably referred to as Fermented Sage Extract, is related to lipolysis in isolated fat cells in vitro. The following relates to the use of sclareolides and related compounds as selective activators of the adenylyl cyclase system. It also relates to the use of sclareolide as a probe to selectively activate second messenger pathways such as cAMP. The biological mechanism for this action seems to be that Sclareolide increases the levels of cyclic AMP (cAMP) or exerts action similar to cAMP. The increase levels of cAMP in the tissues correspond well to enhancing the thermogenic response to food. An increase in the thermogenic response to food, in turn, improves absorption of nutrients and their preferential incorporation into lean body mass. Thus, the formation of lean body mass is promoted. Our data indicates that sclareolide has similar potency than forskolin, a well established adenylyl cyclase activator, at interaction with ligand gated ion channels (Bensherif, M and Lukas, R.L, 1991) reported forskolin use for the promotion of lean body mass. Forskolin has also been shown to be effective for reversing hypothermia or hypokinesia in mice depleted of presynaptic endogenous monoamines by pretreatment with reserpine, .alpha.-methyl-p-tyrosine and p-chlorophenylalanine, when the forskolin is co-administered† with cyclic nucleotide analogs dibutyryl cAMP (dBcAMP), 8-bromo cAMP (8-BrcAMP) and dibutyryl cGMP (dBcGMP). (Psychopharmacology 90 (1986), pp. 430-435) Forskolin increases the lean body mass by stimulating the enzyme adenylate cyclase (AC), with a resulting increase in the levels of cAMP. The mechanism of Forskohlin & subsequently the cAMP agonist Sclareolide has been shown to work as follows: 1.) stimulating noradrenaline released from the sympathetic nerves to interact with beta-adrenergic receptors; this results in an increase in AC (adenylate cyclase) enzyme, with a subsequent rise in cAMP levels; cAMP stimulates the activity of a protein kinase which phosphorylates a hormone-sensitive lipase (HSL) to produce the active form of this enzyme; the lipase stimulates the release of fatty acids from body adipose depots; the released fatty acids stimulate the uncoupling process in the mitochondria, resulting in thermogenesis and provision of fuel to increase thermogenesis; there is an increase in T4 5' deiodinase, which activates the thermogenic thyroid hormone T3; there is an increase in the beta-adrenergic dependent metabolic functions, which leads to an increase in the lean body mass, i.e., activation of phosphorylase in skeletal muscles, insulin secretion, and the synthesis and secretion of anabolic steroid hormones.

YOHIMBINE

Yohimbe is a small evergreen tree native to Africa, and the scientific name is Pausinystalia yohimbe. Chemically, Yohimbe bark contains a substance called yohimbine, plus additional similar compounds, known as indole alkaloids. Yohimbine is synthesized, and has been used as a drug for many decades.

Yohimbine is a potent naturally-occurring alpha-2 receptor antagonist. Adrenergic lipolysis in human adipose tissue is regulated in a dual nature by adrenoceptors. Most notably, activation of the beta-2 or beta-3 subtype increases the process of lipolysis; while activation of alpha-2 receptors diminishes it (fat cells appear to be the only type of cells in the human body that exhibit such dual regulation by adrenoceptors). Yohimbine blocks the messaging system that negatively regulates lipolysis in human fat cells. It also strongly stimulates the synaptic release of norepinephrine, an endogenous beta-agonist extremely important to lipolysis. As such it serves a dual purpose, both by blocking alpha-2 activation and increasing the level of norepinephrine available to fat cells. Studies have furthermore shown that in reasonable doses it does not act as a strong central nervous system stimulant, so when used in direct accordance to this invention it should not be a strong instigator of stimulant-related side effects.

Studies with yohimbine†, in the form of yohimbine HCl, have shown that it is capable of increasing lipolysis in humans after oral dosing, likely via both alpha-2 receptor antagonism and increases in synaptic norephinephrine release (Eur J Clin Invest 1988;18:587-94). In effect, it serves both beta stimulating and alpha blocking properties, an ideal combination to stimulate fat loss. Of note, when single doses as high as 21.6 mg (J Clin Pharmacol 1996;36:814-22), or daily cumulative doses as high as 43.2 mg (J Urol 1995;141:1360-63), were taken, the agent was well tolerated, and had no significant impact on blood pressure or heart rate as would be expected of a beta-agonist like ephedrine.

VINPOCETINE

Vincamine is an alkaloid extracted from the Periwinkle plant. Vinpocetine is produced by slightly altering the Vincamine molecule. Vinpocetine is more technically referred to as "ethyl apovincaminate."Vincamine and Vinpocetine have been widely researched and used clinically for over 25 years†, in disorders ranging from cerebral arteriosclerosis and senile dementia, to Meniere ’s disease, tinnitus, and diabetic retinopathy. Research has gradually shown Vinpocetine to be the superior Vinca alkaloid.

Some of the metabolic roles of Vinpocetine’s, also refereed to as Apovincaminic acid ethyl ester, is disclosed in U.S. Patent No. 4,035,370, issued July 12, 1977. This active agent, designated by its generic name vinpocetine, previously has been reported to have cerebral vasodilator activity and to have a desirable influence on the cerebral vascular flow, a desirable influence on the heart functions and to stimulate the metabolism of the cerebral tissues (U.S. Patent No. 4,035,370).

Vinpocetine has been shown to enhance oxygen and glucose uptake from blood by brain neurons, and to increase neuronal ATP bio-energy production, even under hypoxic (low oxygen) conditions. (Szobor A, Klein M. Arzneimittelforschung 1976;26(10a):1984-9).

Both animal experimental and human clinical research† have shown ethyl apovincaminate (“vinpocetine”) to restore impaired brain carbohydrate/ energy metabolism. (Comparative study of the effect of ethyl apovincaminate and xantinol nicotinate in cerebrovascular diseases. Immediate drug effects on the concentrations of carbohydrate metabolites and electrolytes in blood and CSF.Vamosi B, Molnar L, Demeter J, Tury F.Arzneimittelforschung 1976;26(10a):1980-4). This report illustrated the favorable use of vinpocetine to increase carbohydrate metabolism, thus increasing levels of available energy.

The study† measured a large number of blood and cerebrospinal fluid variables before and after treatment, such as glucose, lactate, pyruvate, oxygen, pH, electrolyte levels, etc. The study concluded that vinpocetine enhances both glycolytic and oxidative reactions of glucose breakdown in the central nervous system (“CNS”). The study further indicated that changes in the concentration of K [potassium] and Mg [magnesium] may be considered a sign of recovery of the energy metabolism of the nerve cells. The study also demonstrated a superior clinical efficacy of vinpocetine over Xanthinol Nicotinate.

Another study reaffirmed the potential use of vinca alkaloids, namely vinpocetine to increase metabolic rate. (Psychopharmacology (Berl) 1990;101(2):147-59). Specifically the study demonstrated that vinpocetine increases mitochondria respiratory rate in mitochondria suspensions, indicating that vinca alkaloids can increase the rate of ATP synthesis. In addition, elevation of cortical cyclic AMP levels may increase ATP availability and this may contribute to the metabolic activity of vinpocetine

As such, in one of the preferred embodiments of this formula, one of the components used in the composition is a optimal amount of vinpocetine.

BIOPERINE

Piper nigrum extract may be produced by the method of isolation of piperine and the compound obtained in such manner is commercially available as "Bioperine.”

Documents† describing ayurvedic medicine, which is well understood in the art as containing piperine and piperine like substances, date back to the seventh century B.C. Trikatu is a sanskrit word meaning three acrids, and refers to a combination of black pepper (Piper nigrum Linn.), long pepper (Piper longum Linn.) and ginger (Zingiber officinale Rosc.). In traditional ayurvedic medicine these compounds are essential ingredients of many prescriptions and formulations used for a wide range of diseases. Experimental evidence shows that the use of "trikatu", and its constituents individually as well as collectively, enhance the bioavailability of a number of drugs. In those studies carried out in animals as well as human volunteers, it was noted that the active component is piperine. Piperine, or mixtures containing piperine, have been shown to increase the efficacy, blood levels, and bioavailability of a number of substances including ingredients of vasaka leaves (Bose, K. G., (1928) Pharmacopeia India, Bose Laboratories, Calcutta), vasicine (Atal et al., Journal of Ethnopharmacology, 4, 229-233 (1981)), spartein (Atal et al., ibid), sulfadiazine (Atal et al., ibid), rifampicin (Zutshi, U. et al. (1984) Journal of the Association of Physicians of India, 33, 223-224), phenytoin (Bano et al., Planta Medica, 1987, pp. 568-569), pentobarbitone (Majumdar, A. N. et al. (1990), Indian Journal of Experimental Biology, 28, 486-487), theophylline (Bano et al., Eur. J. Clin. Pharmacol. (1991) 41:615-617) and propranolol (ibid). Bioavailability enhancement helps to lower dosage levels and shorten cycle lengths.

The effect of piperine on the bioavailability of various other substances has also been studied†. The chronic oral administration of the agent propranolol is frequently rendered difficult due to the fact that steady therapeutic levels of this substance are not achieved or maintained. In addition, large doses are needed to be administered for efficacy and this frequently causes side-effects. Piperine has been shown to enhance the bioavailability of this substance. Propranolol administered with piperine shows a significant increase in plasma levels of the substance, presumably due to decrease in metabolism by the liver.

Similar results† have been obtained with piperine and vasicine, theophylline, and phenytoin. Anyone of piperine and vasicine, theophylline, and phenytoin are suitable for use in the composition of the present invention. In one preferred embodiment, piperine is utilized in the composition of the present invention. Piperine has clearly been shown to play a role as a substance bioavailability enhancer. The combination of piperine with tested medicines is effective primarily due to higher plasma concentration and a longer stay of the substances in the body.

Several studies† indicate that piperine may act primarily by non-specifically inhibiting the mixed function oxidases systems. This slows down the process of metabolic biodegradation and enhances the bioavailability of the substances it is taken with. In a detailed study of the interaction of piperine with enzymatic drug biotransforming reactions in jejunal epithelial cells and liver hepatocytes in vitro and in vivo, piperine appears to be a non-specific inhibitor of drug metabolism. Such results led the authors to speculate that piperine may find useful applications in successful substance delivery (Atal et al., The Journal of Pharmacology and Experimental Therapeutics, Vol. 232, pp. 258-262, 1985).

Piperine allows the extraction of additional nutritional value from less and fewer foods, enhances systemic bioavailability of the essential nutrients, which is applicable to increase absorption of nutrients and increase their metabolic utilization. Piperine is believed to act by affecting various active and passive transport mechanisms and by causing the increase for the substrate demand due to enhanced metabolism at the cellular level. This latter mechanism is triggered when piperine acts on the thermoregulation of the body, acting directly or indirectly through activation of thermoreceptors, which results in increased thermogenesis, or metabolic heat energy production and release. **

**Consult your physician before starting this or any weight loss regimen. Read the label and follow directions. Do not use Tight! if pregnant or nursing. Not for use by or sale to persons under 18 years of age. Must be combined with diet and exercise. These statements have not been evaluated by the Food and Drug Administration. This Product is not intended to diagnose, treat, cure or prevent any disease.

† These studies were performed at a different dosage than that in our product. The efficacy of this ingredient at the dosage level in our product has not been established in a clinical study and may not be equivalent.. Some of these studies were performed on animals and not humans. Because of differences between humans and animals and the difficulty in determining the equivalence of dosages administered to animals and humans, the results of animal studies may not be transferable to humans.