WO2013089689A1 - Constituent of desmodium elegans and methods of use - Google Patents

Abstract

Disclosed are compositions and formulations comprising or consisting of, for example, N, N' -dimethyl 3, 4-dimethoxy-beta-phenylethylamine and/or a pharmacologically acceptable salt thereof, and methods use of said compositions and formulations, e.g., to reduce caloric intake in a mammal.

Description

Inventor: Bruce W. Kneller

CONSTITUENT OF DESMODIUM ELEGANS AND METHODS OF USE

BACKGROUND OF THE INVENTION

Obesity is a chronic medical condition characterized by too much body fat. Obesity is diagnosed by a number known as the Body Mass Index (BMI) , which calculates the amount of body fat based on height and weight. The higher the BMI, the more body fat a person has.

It is well documented that overweight or obese individuals are more susceptible to serious diseases, including but not limited to diabetes, high blood

pressure, heart disease, stroke, gallstones, high

cholesterol, gout, and many types of cancer, often leading, ultimately, to premature death. It is also widely known that being overweight or obese can also make other medical conditions far more difficult to treat .

Obesity is very complex and multi- factorial in terms of causation; contrary to popular belief it is not a simple problem of willpower or self-control. Scientific understanding of obesity is growing rapidly. For example, it is now known that fat cells produce many hormones that play an important role in how much food a human eats, how much energy a human expends , and how much a human will weigh . It is well noted in the literature that obesity cuts across all socioeconomic strata. While there are some differences in obesity rates between sex, race,

ethnicity, educational level and economic status, the overall rate of obesity for all people in the United

States is far too high. Many of the pharmacotherapeutic agents that have been used to ameliorate symptoms of obesity have undesirable and prevalent side effects associated with their usage. Better pharmacotherapeutic agents are needed to help ameliorate the symptoms of obesity and assist, directly or indirectly with fat and weight loss.

SUMMARY OF THE INVENTION

In some aspects the invention relates to an oral formulation consisting of one or more compositions selected from the group consisting of N-alkylated-3 , 4 - dimethoxy-beta-phenylethylamine , Ν,Ν' -dialkylated-3 , 4 - dimethoxy-beta-phenylethylamine , a pharmacologically acceptable salt of N-alkylated-3 , 4 -dimethoxy-beta- phenylethylamine , and a pharmacologically acceptable salt of Ν,Ν' -dialkylated-3 , 4 -dimethoxy-beta-phenylethylamine . In some embodiments the N, ' -dialkylated- 3 , 4 -dimethoxy- beta-phenylethylamine is N, N' -dimethyl-3 , 4 -dimethoxy- beta-phenylethylamine .

The invention also relates to an oral formulation comprising one or more compositions selected from the group consisting of N-alkylated-3 , 4 -dimethoxy-beta- phenylethylamine , Ν,Ν' -dialkylated-3 , 4 -dimethoxy-beta- phenylethylamine , a pharmacologically acceptable salt of

N-alkylated-3 , 4 -dimethoxy-beta-phenylethylamine , and a pharmacologically acceptable salt of Ν,Ν' -dialkylated- 3 , 4 -dimethoxy-beta-phenylethylamine ; and an additional ingredient not found in a natural source of Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine . In some embodiments the N, N' -dialkylated- 3 , 4 -dimethoxy-beta- phenylethylamine is N, N' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine .

The invention further relates to an oral formulation comprising one or more compositions selected from the group consisting of a pharmacologically acceptable salt of N-alkylated-3 , 4 -dimethoxy-beta-phenylethylamine and a pharmacologically acceptable salt of Ν,Ν' -dialkylated- 3 , 4 -dimethoxy-beta-phenylethylamine . In some embodiments the Ν,Ν' -dialkylated-3 , 4 -dimethoxy-beta-phenylethylamine is Ν,Ν' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine .

In certain aspects the oral formulation further comprises an additional ingredient not found in a natural source of N, N' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine . In some aspects the additional

ingredient is an active ingredient.

In some embodiments the oral formulation delivers between about 1.208 mg and 200 mg, preferably between about 1.208 mg and about 20.1 mg, and more preferably between about 1.208 mg and 1.608 mg of said composition per kg of bodyweight of a mammal to whom it is

administered per 24 hour period.

In certain aspects the formulation is a solid dosage form or a liquid dosage form. In some embodiments the formulation is selected from the group consisting of a tablet, a capsule, a lozenge, a chewing gum, a

transdermal patch and a topical. In some aspects the formulation is a controlled release, extended release, or time release formulation. In some embodiments of the oral formulation the composition is an extract and/or concentrate of Dssmodiuw. elegans .

In some embodiments the formulation comprises from about 0.01% to about 100% by weight, from about 0.1% to about 100% by weight, from about 0.5% to about 100% by weight, from about 1% to about 100% by weight, or from about 10% to about 100% by weight of said composition.

The invention also relates to a method for reducing caloric intake in a mammal comprising administering to a mammal an effective amount of a formulation described herein. In some aspects the formulation is administered orally. In some aspects the mammal is a human.

The invention encompasses a method for reducing caloric intake in a mammal comprising orally

administering to a mammal an effective amount of one or more compositions selected from the group consisting of N-alkylated-3 , 4 -dimethoxy-beta-phenylethylamine , Ν,Ν' - dialkylated-3 , 4 -dimethoxy-beta-phenylethylamine , a pharmacologically acceptable salt of N-alkylated- 3 , 4 - dimethoxy-beta-phenylethylamine , and a pharmacologically acceptable salt of N, N' -dialkylated-3 , -dimethoxy-beta- phenylethylamine .

The invention also encompasses a method for reducing caloric intake in a mammal comprising orally

administering to a mammal an effective amount of Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine or a

pharmacologically acceptable salt thereof, wherein said effective amount is between about 1.208 mg and 200 mg per kg of bodyweight per 24 hour period.

In some embodiments the invention relates to a method for reducing caloric intake in a mammal comprising orally administering to a mammal an effective amount of N-alkylated-3 , 4 -dimethoxy-beta-phenylethyla ine or Ν,Ν'- dialkylated-3 , 4 -dimethoxy-beta-phenylethylamine (e.g. , Ν,Ν' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine) and/or a pharmacologically acceptable salt thereof. The

invention is described in detail with specific reference to N, N' -dimethyl -3 , 4 -dimethoxy-beta-phenylethylamine , but it should be understood that the invention applies equally in all aspects to N-alkylated-3 , 4 -dimethoxy-beta- phenylethylamine or N, ' -dialkylated- 3 , 4 -dimethoxy-beta- phenylethylamine unless otherwise indicated.

In some embodiments N, N' -dimethyl- 3 , 4 -dimethoxy- beta-phenylethylamine is administered in the form of an extract and/or concentrate of Desmodium elegans . In other embodiments the N, N' -dimethyl-3 , 4 -di ethoxy-beta- phenylethylamine is chemically synthesized. In certain embodiments the administered dosage comprises from about 0.5% to about 99% N, N' -dimethyl- 3 , 4 -dimethoxy-beta- phenylethylamine or a pharmacologically acceptable salt thereof .

In certain embodiments the effective amount of Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine and/or a pharmacologically acceptable salt thereof is between about 1.208 mg per kg of bodyweight per day and about 20.1 mg per kg of bodyweight per day; between about 1.208 mg per kg of bodyweight per day and about 1.608 mg per kg of bodyweight per day; or between about 15.1 mg per kg of bodyweight per day and about 20.1 mg per kg of bodyweight per day.

In preferred embodiments the mammal's net bodyweight is reduced. In particular embodiments the mammal is a human .

Also disclosed are oral formulations comprising, consisting essentially of or consisting of N, N' -dimethyl- 3 , 4 -dimethoxy-beta-phenylethylamine and/or a pharmaceutically acceptable salt thereof , In certain embodiments the formulation comprises an additional ingredient not found in a natural source of N, N' - dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine . In some aspects the additional ingredient is an active

ingredient. In certain embodiments the formulation is not the intact Desmodium elegans plant or root. In certain embodiments the formulation is an extract or concentrate obtained from the Desmodium elegans plant or root .

In some embodiments the oral formulation delivers between about 1.208 mg N, N' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine and/or a pharmaceutically acceptable salt thereof per kg of bodyweight of a mammal to whom it is administered per 24 hour period and about 200 mg Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine and/or a pharmaceutically acceptable salt thereof per kg of bodyweight of the mammal per 24 hour period. In some embodiments the formulation delivers between about 1.208 mg Ν,Ν' -dimethyl - 3 , 4 -dimethoxy-beta-phenylethylamine and/or a pharmaceutically acceptable salt thereof per kg of bodyweight of a mammal to whom it is administered per 24 hour period and about 20.1 mg N, ' -dimethyl- 3 , 4 - dimethoxy-beta-phenylethylamine and/or a pharmaceutically acceptable salt thereof per kg of bodyweight of the mammal per 24 hour period. In some embodiments the formulation delivers between about 1.208 mg N, N' - dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine and/or a pharmaceutically acceptable salt thereof per kg of bodyweight of a mammal to whom it is administered per 24 hour period and about 1.608 mg N, ' -dimethyl-3 , 4- dimethoxy-beta-phenylethylamine and/or a pharmaceutically acceptable salt thereof per kg of bodyweight of the mammal per 24 hour period.

In some embodiments the formulation is selected from the group consisting of a tablet, a capsule, a lozenge, and a chewing gum. The formulation can be, for example, a solid or liquid/fluid dosage form. In some aspects the formulation is a tablet or a capsule wherein said tablet or capsule utilizes a pharmaceutically acceptable

controlled release, extended release, or time release technology. In other aspects the formulation is a topical or transdermal formulation.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the structure of N, ' -dimethyl- 3 , 4 -dimethoxy-beta-phenylethylamine (alternatively called "Desadrine" ) .

DETAILED DESCRIPTION OF THE INVENTION

Desmodium is a genus in the flowering, herbal plant family Fabaceae sometimes called "tick- trefoil , " "tick clover" or "beggar lice." There are dozens of species, and the delimitation of the genus has shifted much over time. Most are inconspicuous legumes; a few have bright or large flowers. Though some can become sizable plants, most are herbs valued for their flavor, scent, medicinal, or other commercial qualities or small shrubs. Their fruit are loments, meaning each seed is dispersed

individually enclosed in its segment. This makes them tenacious plants, and some species are considered weeds in some geographies. The plants do have a variety of uses though, which are not readily apparent from their modest looks . Several Desmodium species contain potent secondary metabolites, which are organic in nature and are not directly involved in the normal growth, development or reproduction of the herb. These secondary metabolites probably play an important role in the plant's defense against herbivory. Humans have been known to use these secondary metabolites as medicines, flavorings, and recreational drugs. They are used aggressively in

agriculture as part of the "push-pull technology." Some species of Desmodium produce extremely high amounts of antixenotic allomones - chemicals which repel many insect pests - and allelopthic compounds which can kill weeds.

For example, Desmodium intortum and Desmodium uncinatum are employed in some parts of the world as ground cover in maize and sorghum fields to repel Chilo partellus stem-borer grass moths. They also suppress witchweeds such as Asiatic Witchweed (Striga asiatica) and Purple Witchweed (Striga hermonthica) . Some species of Desmodium are quite useful as living mulch and as green manure, as they are able to replenish soil

fertility due to their ability to fix nitrogen. Most also provide good animal fodder.

Some Desmodium species were shown to contain

elevated amounts of tryptamine alkaloids. This phenomenon is widespread in this genus. Ν,Ν' -Dimethyltryptamine (DMT) and 5 -Methoxy-DMT have been shown to occur in all green parts of Desmodium gangeticum as well as in the roots. Desmodium triflorum roots are known to contain contain DMT-N-oxide .

Desmodium elegans (also known as "Desmodium

tiliaefolium" or "Hedysarum tiliifolium" or "Desmodium tiliifolium" ) is a species in the Desmodium genus. It is a deciduous herbal plant growing to up to 1.5 meters tall by 1.5 meters wide. It is in flower from August to

October, and the seeds ripen from September to November. The flowers are hermaphroditic (have both male and female organs) and are pollinated by a variety of insects. This plant is an arching trifoliate herb with terminal

panicles of lilac-pink pea flowers which can be observed from mid-summer into autumn.

This herbal plant readily grows in light (sandy) , medium (loamy) and heavy (clay) soils as well as in acid, neutral and basic (alkaline) soils. It typically requires moist soil. This herbal plant is most commonly found on dry grassy slopes and in glades in deodar forests to 2700 meters in elevation as well as forest margins, forests, thickets, mountain slopes, rocky places, roadsides and ditches at elevations of 1000 - 4000 meters. This herbal plant is endogenous to East Asia, being ubiquitous from the Himalayas throughout most of Southwestern China as well as being endogenous to Pakistan, Afganistan,

Kashmir, India (Punjab, Kumaon, Bombay, & Madras

regions) , Nepal, and Bhutan. This herb has also been found growing in Korea. Various parts of the herb are used in traditional Chinese Herbal Medicine, Ayurvedic Medicine in India and Nepal, as well as in Bhutanese and Arabic natural herbology.

The roots of this herb are often used as as a carminative, diuretic and tonic and sometimes used by Asian herbalists to treat epileptic conditions. Parts of the plant are used in the treatment of bilious

complaints. The juice of the root, sometimes combined with the bark juice of Bauhinia malabarica, has been used in the treatment of cholera. The juice of the bark is also well known to be used in the treatment of peptic ulcers. A fiber from the bark is used for making ropes and paper. The leaves are often crushed and applied to cuts and wounds to avoid infection and to stimulate healing. The bark is known to be used for cleaning teeth. Dried root, stem and leaves are readily found for sale in traditional Chinese Herbal Medicine Pharmacies and

Apothecaries in the Southwest Chinese provinces of Gansu, Guizhou, Shaanxi, Sichuan, Yunnan and parts of Hunan. An herbal decoction using the roots of the Desmodium elegans is often used in these areas of China to treat a variety of digestive and intestinal maladies. Additionally, in certain areas of India, the whole plant is known by the name of "Atakka Choki" and used to cure stomach aches and hemmorhoids (Indian Journal of Natural Products and

Resources, Vol. 1(2), June 2010, pp. 249-253). Desmodium elegans is also known by a variety of other vernacular names throughout Asia, such as Bre, Chamkat, Chamlai, Chamra, Chamyar, Chamyat, Dudshambar, Gurkats, Gurshagel, Kalanchi, Kalimort, Kathi, Laber, Marara, Marfan, Martoi, Matoi Motha, Murt, Mushkzamin, Muss, Nagarmotha, Pirhi, Pri, Sadkoofi, Sambar and Shamru.

Prior scientific analysis of the roots and stems of Desmodium elegans has shown that the herb contains various alkaloids including beta-phenylethylamines , tetrahydroisoquinolines and indole-3 -alkylamines

{Phytoche istry 12: 193 to 197 (1973)), including

tyramine, hordenine, 3 , 4 -dimethoxy-beta-phenylethylamine , Ν,Ν'- dimethyl - 3 , 4 -dimethoxy-beta-phenylethylamine , N- methyl-3 , - dimethoxy-beta-hydroxyphenylethylamine , salsoline, salsolidine, tryptamine, abrine, and

hyaphorine.

As exemplified below, it has been discovered as a result of the work described herein that administration of N, ' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine to a mammal can reduce the caloric intake of the mammal . The present invention relates, in one embodiment, to

compositions and formulations comprising, consisting essentially of, or consisting of N, N' -dimethyl-3,4- dimethoxy-beta-phenylethylamine and/or a

pharmacologically acceptable salt thereof, as well as to methods for making said compositions and formulations. Additionally, the invention relates to administration of the compounds, compositions or formulations to an animal (e.g., a human) as a means for reducing caloric intake

(e.g., daily caloric intake) of the mammal and,

correspondingly, reducing the body mass, body mass index, or percent of body fat of the mammal .

N, N' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine may be administered to subjects (e.g., humans) with or without a specific diet and/or exercise regimen, e.g., a high protein diet (about 1.25 to 2.0 grams

protein/kilogram of body mass) in order to increase the variables associated with loss of body fat. The preferred oral, daily dose of a N, N' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine can be from about 1.208 mg/kg of

bodyweight of the mammal to whom it is administered to about 200 mg/kg bodyweight per day. A preferred daily dosing schedule is a dose of from about 15.1 mg/kg bodyweight to about 20.1 mg/kg bodyweight per day, and a particularly preferred daily dosing schedule is a dose of from about 1.208 mg/kg bodyweight to about 1.608 mg/kg bodyweight for a human. As used herein, the term "about" refers to a +/-10% variation from the nominal value.

In order to effectuate delivery of the preferred daily dose, compositions of the present invention will preferably comprise from about 0.01% to about 100% of N, ' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine . Preferably the composition or formulation comprises from about 0.1% to about 100% (by weight) , N' -dimethyl -3 , 4 - dimethoxy-beta-phenylethylamine , more preferably about 1% to about 100% N, ' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine, and even more preferably about 10% to about 100% N, N' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine .

N, N' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine can be administered before, concurrent with, or after other optional components such as other active

ingredients. In some embodiments the composition or formulation comprises one or more of the following ingredients, preferably as an active ingredient:

•Carbohydrates including, but not limited to, isomaltulose , trehalose, maltodextrin, glucose, sucrose, fructose, lactose, amylose, rice oligodextrins , waxy maize starch, waxy rice starch, waxy potato starch and/or ribose ;

•Water soluble vitamins including, but not limited to, Vitamin C, Vitamin Bl, Vitamin B2 , Vitamin

B3 , Vitamin B5, Vitamin B6, Vitamin B12, and/or Vitamin K, or the salt or chelate form of any of these water soluble vitamins;

•Minerals including, but not limited to, calcium, sodium, potassium, chromium, vanadium,

magnesium, and/or iron or the salt or chelate form of any of these minerals (preferably in amounts less than the RDA) ;

•Amino acids including, but not limited to arginine, ornithine, citrulline, glutamine, tyrosine, taurine, phenylalanine, creatine, creatinol, leucine, isoleucine, and/or valine or the salt or chelate form of any of these amino acids as well as any optical isomer of any of these amino acids;

•Dipeptides and tripeptides including, but not limited to, Carnitine, Carnosine, Anserine, Balenine, Kyotorphin, and/or Glutathione;

•Nutraceutically acceptable stimulants including, but not limited to, methylxanthines (e.g., caffeine, theobromine) and/or glucuronolactone ;

•Nutraceutically acceptable hypoglycemic agents including, but not limited to, alpha-lipoic acid and its salts, cinnamon bark, bitter melon extracts, Gymnema sylvestre extracts, 4 -hydroxy- isoleucine , corosolic acid, pterostilbene and/or D-pinitol;

•glycocyamine , guanidinopropionic acid, and cyclocreatine ;

•Adenosine triphosphates and its disodium salt; •Glycerol and glycerol monostearate ; •Mannitol ;

•Sorbitol; and

*Dextrin.

In some embodiments of the invention the formulation comprises at least one additional ingredient not found in a natural source of N, ' -dimethyl - 3 , 4 -dimethoxy-beta- phenylethylamine .

The compositions and formulations of the invention can be nutraceuticals or comprise nutraceutically

acceptable ingredients. As used herein, the terms

"nutraceutical" and nutraceutically acceptable" are used herein to refer to any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease. Hence, compositions falling under the label "nutraceutical" or "nutraceutically acceptable" may range from isolated nutrients, nutritional or dietary supplements, and specific diets to genetically engineered designer foods, herbal products, and processed foods such as cereals, soups, and beverages. In a more technical sense, the term has been used to refer to a product isolated or purified from foods, and generally sold in medicinal forms not usually associated with foods and demonstrated to have a physiological benefit or provide protection against In certain embodiments the invention may include derivatives of N, N' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine . As used herein, the term "derivative" can include salts, esters, ethers, amides, chelates, lactone forms, hydrates, or complexes of Ν,Ν' -dimethyl- 3 , 4 -dimethoxy-beta-phenylethylamine . Such derivatives can also include stereoisomers or structural isomers, so long as the derivative operates similarly and produces the desired effect. Alternatively, the derivative can be a precursor to N, N' -dimethyl -3 , 4 -dimethoxy-beta- phenylethylamine , which subsequently undergoes a reaction in vivo to yield N, N' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine .

Also useful in the invention are physiologically acceptable salts of N, N' -dimethyl-3 , -dimethoxy-beta- phenylethylamine. Some non- limiting examples include

Ν,Ν' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine

hydrochloride , N, N' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine phosphate, Ν,Ν' -dimethyl-3 , 4 -dimethoxy- beta-phenylethylamine sulfate, N, ' -dimethyl-3 , 4- dimethoxy-beta-phenylethylamine nitrate, Ν,Ν' -dimethyl-

3 , 4 -dimethoxy-beta-phenylethylamine citrate, and Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine

hydrobromide . The compositions and formulations of the invention may contain pharmaceutically, e.g., nutraceutically, acceptable excipients, according to methods and

procedures well known in the art. As used herein,

"excipient" refers to substances that are typically of little or no therapeutic value, but are useful in the manufacture and compounding of various pharmaceutical preparations and which generally form the medium of the composition . These substances include , but are not limited to, coloring, flavoring, and diluting agents; emulsifying, dispersing and suspending agents, ointments, bases, pharmaceutical solvents; antioxidants and

preservatives; and miscellaneous agents. Suitable

excipients are described, for example, in Remington's Pharmaceutical Sciences.

The compositions and formulations according to the present invention can further comprise one or more acceptable carriers . A wide number of acceptable carriers are known in the art. The carrier need only be suitable for administration to a mammal, including a human, and be able to act as a carrier without substantially affecting the desired activity of the composition. Also, the carrier (s) may be selected based upon the desired

administration route and dosage form of the composition. For example, the compositions according to the present invention are suitable for use in a variety of dosage forms, such as liquid form and solid form (e.g., a chewable bar or wafer). In desirable embodiments, as discussed below, the compositions comprise a solid dosage form, such as a tablet or capsule, lozenges, chewing gums, transdermal formulations (e.g., patches), and topical formulations (e.g., creams and ointments).

Examples of suitable carriers for use in tablet and capsule compositions include, but are not limited to, organic and inorganic inert carrier materials such as gelatin, starch, magnesium stearate, talc, gums, silicon dioxide, stearic acid, cellulose, and the like.

Desirably, the carrier is substantially inert. In other aspects the formulation is a fluid dosage form. In certain embodiments the formulation is a tablet or a capsule which utilizes a pharmaceutically acceptable controlled release, extended release, or time release technology; suitable technologies are known in the art.

Advantageously, Ν,Ν' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine can be used as a composition, either alone or as part of a more complex composition containing any number of additional ingredients. It will be apparent to those skilled in the art which specific ingredients may be beneficially included in such compositions.

Furthermore, Ν,Ν' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine , as a compositional ingredient, may be administered in any form common in the art. For example, the compositional ingredient may be administered in the form of a powder to be mixed in liquid or in a solid dosage form such as a tablet, capsule or caplet .

Additionally, Ν,Ν' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine may be suspended or dissolved in any pharmaceutically acceptable carrier or vehicle medium for injection. As such, it may be combined with any number of commonly accepted excipients, as is regularly practiced in the art .

Any individual may beneficially use the compositions and methods of the invention, and particularly those who would benefit from a reduction in caloric intake and/or loss of body fat. Indeed, the disclosed compositions and methods have application to all mammals (e.g., dogs, horses, cows, mules) and more preferably humans.

The compositions and formulations according to the present invention may be employed in methods for reducing the caloric intake of an individual and/or methods of reducing body mass, body fat and/or Body Mass Index of an individual. Accordingly, the present invention provides methods comprising administering to the individual an effective amount of a composition (e.g., Ν,Ν' -dimethyl- 3 , 4 -dimethoxy-beta-phenylethylamine or a formulation comprising Ν,Ν' -dimethyl -3 , 4 -dimethoxy-beta- phenylethylamine) to reduce the caloric intake of said individual .

As used herein, an "effective amount" of

compositions and formulations of the present invention is defined as an amount effective, at dosages and for periods of time necessary, to achieve the desired result. The effective amount of compositions of the invention may vary according to factors such as age, sex, and weight of the individual. Dosage regime may be adjusted to provide the optimum response. Several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of an individual's situation. As will be readily appreciated, a composition in accordance with the present invention may be

administered in a single serving or in multiple servings spaced throughout the day. As will be understood by those skilled in the art, servings need not be limited to daily administration, and may be on an every second or third day or other convenient effective basis. The

administration on a given day may be in a single serving or in multiple servings spaced throughout the day

depending on the exigencies of the situation. The administration of compositions and formulations of the invention results in a reduction in caloric intake in a mammal to whom they are administered. For example, daily caloric intake can be reduced by about 1% to about 30%, more preferably by about 1% to about 15%. This result is produced without a concerted effort on the part of the mammal to reduce caloric intake that is, the compositions and formulations have an appetite

suppressant effect. As a result, the body weight, body mass, Body Mass Index and/or percent body fat of the mammal are expected to be reduced over time.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the present invention is not intended to be limited to the

Description or the details set forth therein. Articles such as "a" , "an" and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are

considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention also includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, it is to be understood that the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the claims (whethe original or subsequently added claims) is introduced into another claim (whether original or subsequently added) . In particular, any claim that is dependent on another claim can be modified to include one or more elements or limitations found in any other claim that is dependent on the same base claim. Furthermore, where the claims recite a product (e.g., a formulation) or composition, the invention provides methods of making the product composition, e.g., according to methods disclosed herein, and methods of using the product composition, e.g., for purposes disclosed herein. Also, where the claims recite a method of making a product or composition, the invention provides products or

compositions made according to the inventive methods and methods of using the composition, unless otherwise indicated or unless one of ordinary skill in the art would recognize that a contradiction or inconsistency would arise. It is contemplated that any one or more embodiments or aspects of the invention can be freely combined with one or more other embodiments or aspects whenever appropriate.

Where elements are presented as lists, e.g., in

Markush group format, each subgroup of the elements is also disclosed, and any element (s) can be removed from the group. For purposes of conciseness only some of these embodiments have been specifically recited herein, but the invention includes all such embodiments. It should also be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements, features, etc., certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements, features, etc.

Where numerical ranges are mentioned herein, the invention includes embodiments in which the endpoints are included, embodiments in which both endpoints are

excluded, and embodiments in which one endpoint is included and the other is excluded. It should be assumed that both endpoints are included unless indicated

otherwise. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are

expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. Where phrases such as "less than X", "greater than X" , or "at least X" is used (where X is a number or percentage} , it should be understood that any reasonable value can be selected as the lower or upper limit of the range. It is also understood that where a list of numerical values is stated herein (whether or not

prefaced by "at least"), the invention includes

embodiments that relate to any intervening value or range defined by any two values in the list, and that the lowest value may be taken as a minimum and the greatest value may be taken as a maximum. Furthermore, where a list of numbers, e.g., percentages, is prefaced by "at least", the term applies to each number in the list. For any embodiment of the invention in which a numerical value is prefaced by "about" or "approximately" , the invention includes an embodiment in which the exact value is recited. For any embodiment of the invention in which a numerical value is not prefaced by "about" or

"approximately" , the invention includes an embodiment in which the value is prefaced by "about" or

"approximately" . "Approximately" or "about" generally includes numbers that fall within a range of 1% or in some embodiments 5% or in some embodiments 10% of a number in either direction (greater than or less than the number) unless otherwise stated or otherwise evident from the context (e.g., where such number would impermissibly exceed 100% of a possible value) . Any particular

embodiment ( s ) , aspect (s), or element (s) of the present invention may be explicitly excluded from any one or more of the claims.

In this description, for the purposes of

explanation, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one skilled in the art that the present invention is not so limited. The invention will be further illustrated by the

following non-limiting examples.

EXAMPLES

A total of 22.24 kilograms of dried Desmodium elegans stems and roots was obtained from several

traditional Chinese pharmacies located in the Sichuan and

Hunan Provinces of The People's Republic of China. The material was collected and pulverized and extracted per the procedures of Ghosal and Srivastav ( Phytochemistry 12:193- 197 (1973)). A total of 0.443 grams of Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine (as the hydrochloride salt) was recovered and identified, which is similar to the yield noted by Ghosal and Srivastav (who recovered 0.041 grams and 0.009 grams, respectively. (total recovered = 0.050 grams) from 2.3 kilograms of dried root material in their experiment) . One quarter (approximately 0.111 grams) of resultant salt was

solvated with distilled and deionized water to a

concentration of 1.00 milligrams per 10.00 milliliters of distilled/deionized water and the solution stored in clean, amber glass, screw-top bottles ("Desmodium elegans Extract Test Solution").

Two cohorts of six (6) mice each (N = 12 total mice in experiment) of male common mice (Mus usculus) 50 days of age were allowed to ingest either the Desmodium elegans Extract Test Solution described above ad libitum in lieu of their drinking water (Cohort One) or were allowed to ingest plain tap water as their drinking water ad libitum (Cohort Two) over a period of seven days. The mice were observed for behavioral changes initially every hour for the first twelve hours and then once every four hours for the duration of the experiment, as other species in the genus Desmodium as well as Desmodium elegans have been shown to contain other psychoactive alkaloids. However, a close homolog of N, N' -dimethyl-3 , 4- dimethoxy-beta- phenylethylamine , known as 'DMPEA' (3,4- dimethoxy-beta- phenylethylamine) and also found

naturally in Desmodium elegans and other Desmodium species, has been shown to have no effects when tested even with very high doses, such as 1,000 mg orally or 10 mg via intravenous injection in humans (PiHKAL: A

Chemical Love Story, 1991, p.614-615).

The present inventor wished to determine if

alkylation at the amine terminal of 3 , 4 -dimethoxy-beta- phenylethylamine (e.g., in the form of a salt of Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine ) could induce any dopaminergic effects in mammals, as both Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine and 3,4- dimethoxy-beta-phenylethylamine are both structurally homologous to dopamine ( 3 , 4 -dihydroxy-beta- phenylethylamine) .

At the onset of the experiment the mice in Cohort

One weighed an average of 21.20 grams and the mice in Cohort Two weighed an 20.98 grams. Mice in both cohorts had free and unfettered access to food (Harlan

Laboratories, Teklad Global 14% Protein Rodent

Maintenance Diet Block) .

During the seven day experiment, the mice in Cohort One ingested between a low of 3.02 milliliters and a high 4.04 milliliters of Desmodium elegans Extract Test

Solution per day (equating to a low of 0.302 milligrams to a high of 0.404 milligrams of N, N ' -dimethyl -3,4- dimethoxy-beta-phenylethylamine hydrochloride or

approximately 15.1 milligrams/kilogram of mouse

bodyweight/24 hours to 20.1 milligrams/kilogram of mouse bodyweight/24 hours), while the mice in Cohort Two ingested a low of 3.32 milliliters to a high 3.88 milliliters of tap water per day.

The mice in Cohort One consumed between 2.93 grams of food per day to 2.98 grams of food per day (Median = 2.96 grams of food per day), while the mice in Cohort Two consumed between 3.15 grams of food per day to 3.36 grams of food per day (Median = 3.26 grams of food per day) . Thus the mice in Cohort One consumed approximately 13.96% of their bodyweight in food per day while the mice in Cohort Two consumed approximately 15.53% of their

bodyweight in food per day. The mice in Cohort One ingested approximately 10.11% less food expressed as a percentage of bodyweight per day (9.2% absolute food material) than the mice in Cohort Two. While the inventor had hoped to observe effects similar to traditional, anti-Parkinsonian

pharmacotherapuetic agents (e.g., those inducing

dopaminergic effects) , no such effects were observed or noted in either cohort. The sole observable effect was that the mice in Cohort One consumed substantially less food than the mice in Cohort Two over a one week period. This effect was not anticipated or expected, as there is no published data in the literature demonstrating that the consumption of Desmodium elegans, concentrates or extracts derived of or from Desmodium elegans, or Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine

hydrochloride induces an anorectic effect in humans or animals. No other significant results were observed.

An effort to determine a murine oral LD50 for Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine

hydrochloride was undertaken. Additional 50 day old male mice were obtained and gavaged by small, plastic tubes. These mice were dosed with increasingly higher absolute amounts of N, N ' -dimethyl- 3 , 4 -dimethoxy-beta- phenylethylamine hydrochloride solvated into distilled and deionized water. However, it became impossible to dose mice with more than approxiately 200

milligrams/kilogram of mouse bodyweight of Ν,Ν' -dimethyl - 3 , 4 -dimethoxy-beta-phenylethylamine Hydrochloride

solution, as the volume of the solution became too high to administer to the mice via the plastic gavage tube.

Thus, while an exact murine LD50 could not be ascertained, it was determined that the oral LD50 for Ν,Ν' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine

hydrochloride in mice is >200 milligrams/kilogram of bodyweight/24 hours . Morbidity and Mortality Weekly Report notes that the average American male between the ages of 20-39,

inclusive, consumes an average of approximately 2,828 kilocalories per day of food (MMWR, 53(4) :80—2). For comparative notation, the reduction of 9.2%- 10.11% of daily food intake unexpectedly observed in the above experiment in a murine model would equate to

approximately a 260 to 286 kilocalorxe per day reduction in food intake in an American male between the ages of 20-39 years. As a pound of bodyfat equates to

approximately 3,500 kilocalories, a daily reduction of 260-286 kilocalories in food intake in an adult male human could theoretically yield a weight loss, in the form of bodyfat loss, of 2.228 pounds to 2.451 pounds per month: a substantial and significant loss.

Human Equivalent Dose (HED) modeling equations and algorithms published by U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) in July 2005 suggest that the estimated, maximum safe starting dose in initial clinical trials for therapeutics in adult healthy

volunteers expressed in milligrams per kilograms is roughly 8% of that found to be acceptable in murine models . That is to say that to convert a murine dose in milligrams per kilograms to a HED, one should multiply the murine dose by 0.08. The established murine dose in the experiment described herein yielded a murine dose for oral N, ' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine hydrochloride of between 15.1 milligrams/kilogram of mouse bodyweight to 20.1 milligrams/ki logram of mouse bodyweight. Thus, an acceptable HED range would be from between about 1.208 milligrams/kilogram of human bodyweight and about 1.608 milligrams/ kilogram of human bodyweigh .

Although the relative and absolute amounts of Ν,Ν'- dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine needed to be consumed orally would require exceedingly high amounts of the herbal plant Desmodium elegans, it is well known by those skilled in the art that various and somewhat common, commercially viable technologies exist and are well characterized in the literature that would allow for the extraction of Ν,Ν' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine from Desmodium elegans and/or the concentration of the absolute and relative quantity of N, N ' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine within the herbal biomass in order to reduce the amount of biomass that needs to be consumed. Some non- limiting examples include aquaeous extraction, ethanolic

extraction, chloroform extraction, petroleum extraction, concentration and purification by dry columnar

chromatography, and liquid or gel columnar

chromatography.

It has now been unexpectedly discovered by the inventor that Desmodium elegans, and/or an extract and/or concentrate derived of or from Desmodium elegans

containing N, N ' -dimethyl-3 , 4 - dimethoxy-beta- phenylethylamine and/or a pharmacologically acceptable salt of N, N ' -dimethyl-3 , 4 -dimethoxy-beta-phenylethylamine are potentially useful as oral anorectic agents for reducing the daily caloric intake of a mammal. By extension, it may be a useful adjuvant in the treatment of obesity in humans. A list of FDA approved

pharmacologically acceptable salts is given in Int. J. of Phar . 33:201-217 (1986) (incorporated herein in its entirety by reference) .

Claims

CLAIMS is claimed is:

An oral formulation consisting of one or more compositions selected from the group consisting of N-alkylated-3 , 4 -dimethoxy-beta-phenylethylamine , N, ' -dialkylated-3 , 4 -diraethoxy-beta- phenylethylamine , a pharmacologically acceptable salt of N-alkylated-3 , 4 -dimethoxy-beta- phenylethylamine , and a pharmacologically acceptable salt of N, N' -dialkylated-3 , -dimethoxy-beta- phenylethylamine .

An oral formulation according to claim 1 wherein the N, ' -dialkylated-3 , 4 -dimethoxy-beta-phenylethylamine is Ν,Ν' -dimethyl-3 , -dimethoxy-beta- phenylethylamine .

An oral formulation comprising one or more

compositions selected from the group consisting of N-alkylated-3 , 4 -dimethoxy-beta-phenylethylamine , Ν,Ν' -dialkylated-3 , 4 -dimethoxy-beta- phenylethylamine , a pharmacologically acceptable salt of N-alkylated-3 , 4 -dimethoxy-beta- phenylethylamine , and a pharmacologically acceptable salt of N, ' -dialkylated-3 , -dimethoxy-beta- phenylethylamine ; and an additional ingredient not found in a natural source of N, ' -dimethyl-3 , 4 - dimethoxy-beta-phenylethylamine . . An oral formulation according to claim 3 wherein the N, N' -dialkylated-3 , 4 -dimethoxy-beta-phenylethylamine is N, N' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine .

An oral formulation comprising one or more

compositions selected from the group consisting of a pharmacologically acceptable salt of N-alkylated- 3 , 4 -dimethoxy-beta-phenylethylamine and a

pharmacologically acceptable salt of Ν,Ν'- dialkylated-3 , 4 -dimethoxy-beta-phenylethylamine .

An oral formulation according to claim 5 wherein the N, ' -dialkylated-3 , -dimethoxy-beta-phenylethylamine is N, N' -dimethyl- 3 , 4 -dimethoxy-beta- phenylethylamine .

An oral formulation according to claim 5 further comprising an additional ingredient not found in a natural source of Ν,Ν' -dimethyl-3 , 4 -dimethoxy-beta- phenylethylamine .

An oral formulation according to claim 3 or claim 7 wherein the additional ingredient is an active ingredient .

An oral formulation according to any of claims 1-8 which delivers between about 1.208 mg and 200 mg of said composition per kg of bodyweight of a mammal to whom it is administered per 24 hour period. 10. An oral formulation according to any of claims 1 which delivers between about 1.208 mg and about mg of said composition per kg of bodyweight of a mammal to whom it is administered per 24 hour period .

An oral formulation according to any of claims 1- which delivers between about 1.208 mg and about 1.608 mg of said composition per kg of bodyweight a mammal to whom it is administered per 24 hour period. 12. An oral formulation according to any of claims 1-11 wherein the formulation is selected from the group consisting of a tablet, a capsule, a lozenge, a chewing gum, a transdermal patch and a topical. 13. An oral formulation according to any of claims 1-11 wherein the formulation is a fluid dosage form.

14. An oral formulation according to any of claims 1-11 wherein the formulation is a solid dosage form.

15. An oral formulation according to any of claims 1-14 wherein the formulation is a controlled release, extended release, or time release formulation. 16. An oral formulation according to any of claims 1-11 wherein the composition is an extract and/or concentrate of Desmodium elegans .

17. An oral formulation according to any of claims 1-11 wherein the formulation comprises from about 0.01% to about 100% by weight of said composition.

18. An oral formulation according to any of claims 1-11 wherein the formulation comprises from about 0.1% to about 100% by weight of said composition. 19. An oral formulation according to any of claims 1-11 wherein the formulation comprises from about 0.5% to about 100% by weight of said composition.

20. An oral formulation according to any of claims 1-11 wherein the formulation comprises from about 1% to about 100% by weight of said composition.

21. An oral formulation according to any of claims 1-11 wherein the formulation comprises from about 10% to about 100% by weight of said composition.

22. A method for reducing caloric intake in a mammal comprising administering to a mammal an effective amount of a formulation of any of claims 1-21.

23. A method according to claim 22 wherein the

formulation is administered orally.

24. A method according to claim 22 wherein the mammal is a human .

25. A method for reducing caloric intake in a mammal comprising orally administering to a mammal an effective amount of one or more compositions

selected from the group consisting of N-alkylated-

3 , 4 -dimethoxy-beta-phenylethylamine , N, N' - dialkylated- 3 , 4 -dimethoxy-beta-phenylethylamine , a pharmacologically acceptable salt of N-alkylated- 3 , 4 -dimethox -beta -phenylethylamine , and a pharmacologically acceptable salt of Ν,Ν'- dialkylated-3 , 4 -dimethoxy-beta-phenylethylamine . 26. A method for reducing caloric intake in a mammal comprising orally administering to a mammal an effective amount of N, ' -dimethyl-3 , 4 -dimethoxy- beta-phenylethylamine or a pharmacologically acceptable salt thereof, wherein said effective amount is between about 1.208 mg and 200 mg per kg of bodyweight per 24 hour period.