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WO1999034675A1 - Procede favorisant la mobilisation et le catabolisme des lipides - Google Patents

Procede favorisant la mobilisation et le catabolisme des lipides Download PDF

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Publication number
WO1999034675A1
WO1999034675A1 PCT/US1999/000423 US9900423W WO9934675A1 WO 1999034675 A1 WO1999034675 A1 WO 1999034675A1 US 9900423 W US9900423 W US 9900423W WO 9934675 A1 WO9934675 A1 WO 9934675A1
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composition
lipids
add
amount
adipose tissue
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PCT/US1999/000423
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English (en)
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William E. Shell
Mark E. Jarmel
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Nutracorp Scientific, Inc.
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Priority to AU22173/99A priority Critical patent/AU2217399A/en
Publication of WO1999034675A1 publication Critical patent/WO1999034675A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

  • This invention relates generally to agents for releasing and burning fats (lipids) stored in the body in order to reduce percentage of body fat and decrease weight.
  • fats lipids
  • Pharmaceutical agents used for weight reduction have known undesirable side effects. Additionally, appetite suppressing agents have had limited success in weight management since overweight individuals tend to eat when they are not hungry. Accordingly, there is a need for an agent that promotes weight loss by a means other than suppressing feelings of hunger. There is a need for an effective means of releasing fat from storage and stimulating burning of the released fat.
  • Lipolysis is the release of fat from fatty tissue (adipose tissue) into the blood stream in the form of fatty acids. It is known that lipolysis can be induced in humans by injection of norepinephrine (Millet L, et al. Catecholamine effects on lipolysis and blood flow in human abdominal and femoral adipose tissue. J.Appl.Physiol. 1998;85:181-188). However, Applicants are not aware of any prior art suggesting that lipolysis can be induced in humans through oral administration of a norepinephrine precursor. Xanthines have been characterized as having the ability to stimulate lipolysis and to augment the lipolytic effect of norepinephrine.
  • Histamine has also been identified in the literature as having a lipolytic effect when injected in test subjects.
  • Amphetamines and related appetite-suppressing agents such as phentermine are known to produce weight loss in humans (Valle-Jones JC, et al. A comparative study of phentermine and diethylpropion in the treatment of obese patients in general practice. Pharmatherapeutica. 1983;3:300-304 and Wellman PJ. Overview of adrenergic anorectic agents. Am.J.Clin.Nutr. 1992;55:193S-198S). There is no disclosure in these references that these agents cause weight loss by promoting lipolysis, at least in the absence of a concomitant exercise regimen.
  • U.S. Patent No 5,229,390 to Moriyama et al. relates to a beverage or food product containing additives for mobilizing body fats so that the fats may be utilized more efficiently, particularly for consumption during exercise. In fact, simply stimulating the release of fats from adipose tissue, at absent such exercise, is unlikely to result in a reduction in body fat. Mobilized fats would circulate for a time in the bloodstream and would then be returned to storage as body fat.
  • U.S. Patent No 5,229,390 relates to a beverage or food product containing an additive for mobilizing body fats so that the fats may be utilized more efficiently, particularly for consumption during an exercise program.
  • the additive includes certain amino acids, and particularly arginine, alanine, an leucine, that accelerate the release of glucagon and xanthines. Both glucagon and xanthines are lipolytic agents and are used in these products for mobilizing fats. These products are reported to increase metabolism of fatty acids when taken during an exercise program. However, it is not apparent that the additive would appreciably reduce body fat, absent the exercise program. In fact, simply stimulating the release of fats from adipose tissue is unlikely to result in a reduction in body fat. Mobilized fats would circulate for a time in the bloodstream and then be returned to storage as body fat.
  • substrate cycling reactions also known as futile shuttles
  • substrate cycling reactions also known as futile shuttles
  • Applicants are not aware of any prior art suggesting how these substrate cycling reactions might be clinically activated or, if activated, how they can result in a reduction of percentage body fat and/ or weight loss. Simply activating energy consuming reactions would not be expected to reduce body fat, since circulating blood sugar would tend to be used for energy production rather than circulating fat.
  • Energy-consuming reactions particularly suitable for this invention are the glutamine-glutamate cycle and /or the urea cycle.
  • the glutamine-glutamate cycle and the urea cycle comprise a class of substrate cycling chemical reactions endogenous to the body that consume energy.
  • the substrates that may be employed in this invention include any of the constituents or intermediates of the metabolic pathways of these cycles. Substrates used by other energy- consuming cycles that are endogenous to the body, may also be used as a substitute for, or together with, substrates for the glutamine-glutamate cycle and/ or the urea cycle.
  • Norepinephrine promotes release of fats stored in adipose tissue.
  • methods and compositions are provided for promoting release of stored fat by administering a norepinephrine precursor.
  • Tyrosine and phenylalanine each are precursors for both norepinephrine and dopamine.
  • histidine (the precursor for histamine), may be orally administered with a norepinephrine precursor.
  • Administering histidine with a norepinephrine precursor preferentially promotes conversion of the precursor to norepinephrine instead of dopamine.
  • Histamine promotes norepinephrine release and inhibits dopamine release. Additionally, histamine may augment release of fat from adipose tissues.
  • the precursors for norepinephrine may be orally administered simultaneously with one or more xanthines, and particularly caffeine, theobromine, and/ or theophylline, in order to increase activity of norepinephrine. Additionally the xanthine may augment mobilization of fat from adipose tissue.
  • histidine and xanthines may be employed together with the norepinephrine precursors for a further enhanced effect. Histidine and xanthines operate through different mechanisms in enhancing norepinephrine release and are thus complementary.
  • a norepinephrine agonist or indirect sympathomimetic agent particularly epinephrine, ephedrine, pseudoephedrine, isoproterenol HC1, or metaproterenol sulfate, may be administered, as the lipolytic agent.
  • adrenergic agents may be administered simultaneously with a substrate used by the glutamine-glutamate cycle or urea cycle in order to increase fat burning.
  • a xanthine may be used as the fat-releasing agent.
  • One may simultaneously administer a xanthine with a substrate used by an energy-consuming reaction in order to stimulate release and burning of stored fat.
  • Theobromine has been found to be surprisingly useful. Theobromine may promote release of fat from storage without central nervous system stimulation, thereby avoiding undesired side effects.
  • Glutamine, glycine, histidine and glutamic acid are metabolized to form ammonia.
  • glutamine, glycine, histidine or glutamic acid may be administered to promote formation of ammonia within the body.
  • the conversion of ammonia to urea consumes ATP, which creates a relative energy deficit.
  • the relative energy deficit caused by processing ammonia promotes burning of fats that have been released from storage by the lipolytic agent.
  • glutamine is converted into glutamate in the cytoplasm and glutamate is transported into the mitochondria by the malate- aspartate shuttle. Aspartate is transported out of the mitochondria into the cytoplasm in exchange for glutamate.
  • glutamate is transported out of the mitochondria into the cytoplasm in exchange for glutamate.
  • arginine may be simultaneously administered with glutamine and/ or glutamic acid. Arginine promotes transport of glutamine from the bloodstream into metabolically active cells of the various body systems. Thus, arginine potentiates the effects of glutamine used by this invention.
  • Arginine additionally acts as a substrate for the urea cycle, which consumes ATP. Processing arginine through the urea cycle thus consumes energy, which stimulates burning of fatty acids released by this invention for energy production.
  • Amino acids such as arginine, citrulline, ornithine, aspartic acid, glutamine, and glutamic acid comprise a class of substrates for the urea cycle and may be administered simultaneously with a lipolytic agent in accordance with this invention. These substrates for the urea cycle may be administered simultaneously with a lipolytic agent to promote catabolism of mobilized lipids. Ornithine, arginine and glutamine are preferred due to their synergistic action in promoting the use of mobilized fats for fuel.
  • Ornithine is known to stimulate secretion of glucagon and may be utilized in this invention for this purpose. Thus, it may perform the dual role of being a substrate for the urea cycle and for additionally promoting secretion of glucagon. Ornithine stimulates secretion of glucagon without appreciably promoting secretion of insulin. Ornithine may thus be utilized in a dual role, without dosage restriction, both as a urea cycle substrate in this invention and as promoter of lipolysis. For this invention, excessive release of insulin is undesirable since insulin is anti-lipolytic and inhibits glucagon secretion. For this reason, the amount of carbohydrate and /or insulin secretogogues (substances that promote insulin secretion) is desirably limited in some embodiments of this invention, as will be discussed.
  • Arginine also stimulates glucagon.
  • arginine can also be used advantageously in the dual role of an energy cycle substrate and additionally as a promoter of glucagon secretion for lipolysis.
  • arginine is an insulin.
  • higher doses of arginine are appropriately limited to avoid excessive release of insulin that would inhibit glucagon secretion.
  • arginine is administered in this invention in a limited dosage, desirably at least 25 mg., but less than about 1 gram and preferably less than about 600 mg.
  • a carbohydrate and particularly a mono- and /or disaccharide, is concomitantly administered to the subject.
  • the secretion of glucagon can be stimulated by a relative drop in blood sugar. It has been found that a relatively minor release of insulin will stimulate a blood sugar decrease.
  • a limited amount of carbohydrate is concomitantly administered to cause release of a relative small amount of insulin. This, in turn, causes drop in blood sugar that will stimulate glucagon secretion to act as a lipolytic agent.
  • the carbohydrate is administered in an amount too low to cause the excessive insulin release that would result in an antiUpolytic effect and suppression of glucagon release.
  • the dosage amount of such carbohydrates is at least about 250 mg. but desirably less than about 6 grams and preferably less than about 3 grams, as dextrose equivalent.
  • Formulations of this invention using the foregoing ingredients for promoting glucagon may produce an additional benefit by affecting eating-related satiation.
  • subjects ingesting such formulations reported experiencing early onset of satiation during a meal and /or prolonged satiety after completion of a meal.
  • favorable effect on appetite may result from the use of the pharmaceutical adrenergic lipolytic agents used in this invention.
  • compositions of this invention are desirably administered to the subject on an empty stomach and concomitant intake by the subject of carbohydrates and insulin secretagogue amino acids is restricted, desirably to a combined dosage amount of less than about 6 grams.
  • the concomitant intake by he subject of foodstuffs is desirably restricted. Such intake may adversely affect absorption by the subject of the active agent.
  • the concomitant intake by the subject of amino acids, other than the energy cycle substrates and lipolytic agents administered is desirably restricted to an amount less than about 50% by weight of the substrate amino acids administered.
  • concomitant intake of such other amino acids is completely excluded.
  • concomitant intake of fiber is desirably limited to about 10% by weight of the substrate amino acids administered and is preferably excluded completely.
  • a lipolytic agent and particularly a precursor and /or agonist for norepinephrine, may be administered concomitantly with a substrate of an energy-consuming reaction in the body and particularly a substrate used by the glutamine-glutamate cycle and /or the urea cycle, to enhance release and burning of stored body fat. It has been discovered that such co-administration promotes a reduction of percentage of body fat and a decrease in scale weight.
  • FIGURE 1 illustrates their current theoretical understanding of how the present invention may operate in one preferred embodiment.
  • This embodiment utilizes two energy-consuming cycles.
  • glutamine is converted to glutamate, releasing ammonia, and then glutamate is converted back to glutamine (box 1).
  • glutamate is converted back to glutamine (box 1).
  • ammonia is converted to urea (box 6).
  • glutamine the substrate for the glutamine-glutamate cycle, is ingested (box 5) causing production of glutamate and ammonia (NH 4 + ) and then conversion of the glutamate back to glutamine (box 1). Both of these reactions consume energy in the form of ATP.
  • compositions produce their effects by either activating or inhibiting mechanisms that are already present in the body. They therefore, attempt to emulate actions normally produced by the body's intrinsic homeostatic mechanisms. All pharmaceuticals that are foreign to the body have associated undesirable side effects since synthetic drugs imperfectly interact with the body's regulatory mechanisms. Side effects are further promoted by the nonselective distribution of drugs throughout the bloodstream. These pharmaceuticals thus may affect each organ and body system in unknown and potentially undesirable ways.
  • This invention has the advantage of permitting the administration of naturally occurring agents, namely neurotransmitter precursors and substrates that are normally used by the body's intrinsic homeostatic mechanisms. Administering precursors normally used by the body to synthesize neurotransmitters along with substrates that are endogenous to the body desirably decreases the occurrence of side effects.
  • this invention advantageously emulates effects produced by synthetic pharmaceutical agents on various mechanisms regulated by neurotransmitters, with reduced risk of side effects.
  • norepinephrine precursors and agonists and utilized in this invention function by promoting the activity of norepinephrine.
  • the neurotransmitter norepinephrine is active in the central nervous system and peripherally.
  • precursors for norepinephrine, and particularly tyrosine and phenylalanine are administered for the purpose of promoting the production and release of norepinephrine to optimize lipolysis.
  • the norepinephrine precursors may be administered concomitantly with one or more xanthines.
  • Xanthines are not only lipolytic and are useful as an lipolytic agent in this invention, but they have also been found by Applicants to enhance the production and release of norepinephrine, thus synergistically enhancing its effect.
  • the norepinephrine agonists employed in this invention for lipolysis include the indirect-acting sympathomimetic amines which are known to function as appetite suppressants. They include drugs with both indirect-acting and direct-acting norepinephrine-releasing components.
  • This class of agents includes epinephrine, ephedrine, pseudoephedrine, isoproterenol, metaproterenol, phentermine, phenylpropanola ine, amphetamine, pseudephedrine, norpseudoephedrine, diethylpropion, benzphetamine, phendimetrazine, phenmetrazine, chlorphentermine, and aminorex and their physiologically acceptable salts, hydrates, acid adducts, mineral chelates and their other active derivitives.
  • histidine the precursor for the neurotransmitter histamine may be administered as a lipolytic agent in this invention.
  • administration of the precursor enhances the production of histamine, which is also lipolytic.
  • histidine may be administered together with one or more of the other precursors above, in place of or together with a xanthine. It has been discovered that histidine is also capable of effectively increasing synthesis and release of norepinephrine, mediated through the increased production of histamine. Histidine and xanthines are desirably used together to increase synthesis and release of norepinephrine to achieve yet further enhanced effect.
  • Glutamine and glutamic acid are substrates used by the glutamine-glutamate cycle and form ammonia, which is processed by the urea cycle. Additionally, glycine and histidine are metabolized in the body to form ammonia. It has been found that these ammonia- generating substrates will enhance catabolism of lipids released from adipose tissue when administered together with a lipolytic agent and preferably a precursor and/ or agonist for norepinephrine.
  • amino acids arginine, citrulline, ornithine, aspartic acid, glutamine and glutamic acid comprise a class of substrates for the urea cycle.
  • One or more of these amino acids may be administered concomitantly with a lipolytic agent in accordance with this invention to enhance catabolism of lipids mobilized by the lipolytic agent.
  • Ornithine and arginine are also preferred due to their synergistic action in promoting the catabolism of lipids.
  • arginine When concomitantly administered with glutamine and /or glutamic acid, arginine promotes transport of glutamine from the bloodstream into metabolically active cells of the various body systems, thus potentiating the effects of glutamine. Ornithine additionally promotes the release of glucagon which promotes lipolysis, as will be discussed.
  • the neurotransmitter precursors and the substrates of this invention may be employed in this invention in pure form, e.g. exogenous material synthesized or derived from animal or vegetable protein, particularly purified extracts isolated from the amino acid residues in enzyme hydrolyzed proteins. It is to be understood that these agents may also be in the form of their physiologically acceptable derivitives, including their salts, hydrates, acid adducts (e.g. hydrochloric acid) and mineral chelates (e.g. salts bound to the precursor by chelation bonding).
  • physiologically acceptable derivitives including their salts, hydrates, acid adducts (e.g. hydrochloric acid) and mineral chelates (e.g. salts bound to the precursor by chelation bonding).
  • the xanthines may be used in the form of their free compounds or as their salts, adducts or other derivatives, for example citrated caffeine, theophylline ethylenediamine, theophylline sodium acetate, sodium glycinate, the choline salt, the theophylline derivatives theophylline megumine and dyphylline, theobromine calcium salicylate, sodium acetate or sodium salicylate.
  • a particularly suitable form of xanthines for use in this invention are those that are derived from natural sources. Cocoa provides a unique combination of the xanthines theobromine and caffeine in a form that is normally easily ingested and tolerated by the subject. Cocoa powder was originally included in preliminary formulations with neurotransmitter precursors to improve flavor and because its mood enhancing effects have appealed to people for centuries. An unexpected result was that the cocoa powder significantly potentiated the effects of the neurotransmitter precursors. This potentiating effect was determined by us to be produced by the naturally occurring xanthines present in cocoa powder.
  • Infusions of caffeine from coffee beans and of caffeine and theophylline from tea leaves may be employed as a natural source of these xanthines, either in liquid form as coffee and tea, or in dried extract form, alone or, more conveniently, in composition with the neurotransmitter precursor.
  • Caffeinated soft drinks, chocolate, guarana, ephedra, mate' and other food or herb sources may be employed.
  • Xanthines may be employed in this invention in dosage ranges appropriate to promote release of neurotransmitters and to avoid undesired side effects.
  • Theobromine may be administered in a dosage of preferably from about 1 mg. to about 2 grams or higher.
  • Caffeine may be administered preferably in a dose of from about 1 mg. to about 200 mg. or higher if tolerated by the subject.
  • Theophylline may be administered in a dose preferably of from about 1 to about 200 mg or higher if tolerated by the subject.
  • Cocoa may be administered in a dose preferably of about 1 mg. to about 10 grams or higher for an appropriate dose of xanthines, with a preferred dose being about 500 to about 800 milligrams. Somewhat higher doses of these xanthines may be employed with some subjects without undue discomfort.
  • the desired dosage is an amount which will increase the mobilization of lipids in the subject.
  • the appropriate dosage for lipolytic effect will depend on the particular class of agent.
  • the desired dosage range for norepinephrine precursors, and particularly tyrosine or phenylalanine is from about 50 to about 2,000 milligrams, with a typical dose of about 500 to 1,000 milligrams. However, doses up to 2,000 milligrams and even higher, e.g. up to 3 grams may be administered without undue risk of side effects.
  • the desired single dose range for a sympathomimetic agent utilized as the lipolytic agent in this invention desirably is typical for that agent where it is used as an appetite suppressant in the treatment of obesity.
  • Appropriate dosage ranges for these agents are found in the literature, including in U.S. Patent 5,019,594 to Wurtman et al.
  • an appropriate single dose for phenylpropanolamine is from 5 to 25 mg., for amphetamine from 1.25 to 10 mg. and ephedrine 5 to 50 mg. More generally, as a class, these agents are administered in dosages as low as 3 mg, and as high as 50 mg.
  • a sympathomimetic agent is utilized in this invention along with another lipolytic agent, such as a norepinephrine precursor and/ or a xanthine
  • the dosage amount of sympathomimetic agent may be reduced, proportionally.
  • the dosage of histidine is an amount sufficient to enhance synthesis and release of histamine in the body.
  • Histidine may be administered in accordance with this invention to enhance thereby lipolysis, for which norepinephrine precursors, and /or sympathomimetic agents are simultaneously administered.
  • the desired single dose range for this purpose for histidine is typically from about 1 to about 500 milligrams and may be up to about 1,000 milligrams, with a typical dose preferably being about 30 to about 200 milligrams.
  • the desired single dose range for glycine administered in accordance with this invention is preferably from about 1 to about 500 milligrams and may be up to about 1,000 milligrams, with a typical dose preferably being about 30 to about 200 milligrams.
  • the desired dosage for the purposes of this invention is an amount which will enhance the catabolization of lipids in the subject.
  • the desired single dose range for each of the energy cycle substrates, other than arginine, i.e. citrulline, ornithine, glycine, aspartic acid glutamic acid and glutamine is from about 100 to 2,000 milligrams, with a typical dose of between 500 and 1,000 milligrams.
  • the desired single dose range for arginine administered as a urea cycle substrate in accordance with this invention is from about 25 to 1,000 milligrams, with a typical dose of 25 to 600 milligrams. As arginine is a strong insulin secretagogue, higher doses may lead to excessive insulin secretion that suppression lipolysis, as will be discussed.
  • glucagon it is further desirable in this invention to stimulate secretion of glucagon as glucagon will further promote lipolysis.
  • the first is employment as a energy- consuming cycle substrate of an amino acid that additionally promotes secretion of glucagon.
  • Ornithine additionally promotes secretion of glucagon.
  • ornithine may be utilized in a dual role both as a urea cycle substrate in this invention and as promoter of lipolysis.
  • As ornithine does not appreciably promote secretion of insulin, it may be employed without restriction as dosage.
  • the same dosage range indicated above for use of ornithine as a urea cycle substrate in this invention may apply for this dual use.
  • arginine another substrate of the urea cycle, may be used in the dual role, as an energy cycle substrate and additionally as a promoter of glucagon for lipolysis.
  • Arginine does promote insulin secretion and at limited dosage will release a relatively small amount of insulin that will be sufficient to cause a relative blood sugar drop. The blood sugar drop will then stimulate secretion of glucagon.
  • a dose of from about 25 mg. up to about 1 gram and preferably less than about 600 mg. may be desirable.
  • a relatively small amount of insulin is released by arginine causing a relative blood sugar drop that will stimulate glucagon secretion to promote lipolysis.
  • a carbohydrate and particularly a mono- and /or disaccharide, is concomitantly administered to the subject in an appropriate limited dose.
  • This dose will cause a relative blood sugar drop.
  • the blood sugar drop will, in turn, cause release of a relatively small amount of insulin that will stimulate glucagon secretion.
  • the appropriate carbohydrate dose is insufficient to cause insulin release in an amount that would result in an antiUpolytic effect and suppression of glucagon release.
  • Dextrose is the preferred carbohydrate, because it is a relatively strong insulin secretagogue and for volume considerations, a lesser quantity may be required.
  • other mono- or di-saccharides may be employed in amounts that provide a corresponding insulin secretory effect.
  • the dosage amount of such carbohydrates is at least about 250 mg. but desirably less than about 6 grams and preferably less than about 3 grams, as dextrose equivalent.
  • dextrose equivalent is meant an amount of any particular mono- or di-saccharide to be employed that will produce an equivalent secretory effect as would the amount of dextrose specified.
  • compositions in the form of powders or Uquids may be packaged in multiple dosage quantities with instructions to the user to extract therefrom for ingestion appropriate individual dosage amounts, e.g. a teaspoonful.
  • the compositions are desirably prepared in discreet units, e.g. prepackaged beverages, capsules, wafers, etc., which each contain the appropriate dosage amounts of neurotransmitter precursors with xanthines and/ or histidine, for a single dose as discussed above.
  • the compositions may include the usual carriers, in fiUers, excipients, flavorings and adjuvants in addition to neurotransmitter precursors, and other active agents.
  • compositions of this invention are administered when the subject has an empty stomach, typically at least an hour after the subject has eaten.
  • Administering the compositions on an empty stomach is preferred in order to avoid undesirably slow uptake of precursors into the bloodstream. Uptake of administered neurotransmitter precursors would be inhibited by competition for absorption by other amino acids from the ingested food. It is a particular advantage of this invention that exercise is not a requirement for its effectiveness. However, further benefit may be seen by having the subject engage in exercise concomitantly with adminstration of the compositions of this invention.
  • the effects of the formulations of this invention normally should be sufficiently potent that their effects can be evaluated after two or three weeks.
  • Objective measures of body fat may advantageously be used to assess the effectiveness of this invention. Examples of such objective measures are bioelectrical impedance, dual energy X-ray absorptiometry, underwater weighing, abdominal girth measurement, deuterium dilution in body fluids and determination of total body potassium.
  • a formulation was prepared in the proportions of about 80 parts of cocoa with about 50 parts glutamine, about 50 parts tyrosine, about 10 parts glycine, about 5 parts histidine, about 40 parts arginine, and about 300 parts dextrose.
  • Gelatin capsules are filled with the powder blend so that 6 gelatin capsules contain cocoa about 800 mg, glutamine about 500 mg, tyrosine about 500 mg, glycine about 100 mg, arginine about 400 mg, histidine about 50 mg, and sucrose about 3,000 mg.
  • This formulation is preferably administered_when the subject has an empty stomach, preferably about 30-60 minutes after eating.
  • the average reduction in percent body fat was 4 (+/- 2) percent.
  • Norepinephrine is known to decrease heart rate. Change in heart rate was used to assess the formulation's abiUty to increase norepinephrine levels sufficiently to produce significant physiologic alterations. Heart rate was measured using an ECG event recorder (King of Hearts) and a Pace Art receiving center. Following ingestion of the formulation, heart rate decreased by 16.7% at 30 minutes as compared to baseline, where placebo did not significantly change heart rate (Table 1).
  • Example 1 the formulation in Example 1 was able to reduce heart rate consistent with increased norepinephrine production.
  • a formulation was prepared in the proportions of about 100 parts of cocoa with about 50 parts glutamine, about 50 parts tyrosine, about 10 parts glycine, about 5 parts histidine, about 5 parts arginine, and about 400 parts sucrose.
  • Gelatin capsules are filled with the powder blend so that 6 gelatin capsules contain cocoa about 1,000 mg, glutamine about 500 mg, tyrosine about 500 mg, glycine about 100 mg, arginine about 50 mg, histidine about 50 mg, and sucrose about 4,000 mg.
  • This formulation is preferably administered as in Example 1.
  • the formulation was administered to an adult male who experienced early onset of satiation and greatly reduced meal size.
  • a formulation was prepared in the proportions of about 80 parts of cocoa with about 50 parts glutamine, about 50 parts tyrosine, about 10 parts glycine, about 2.55 parts histidine, about 40 parts arginine, and about 400 parts sucrose.
  • Gelatin capsules are filled with the powder blend so that 6 gelatin capsules contain cocoa about 800 mg, glutamine about 500 mg, tyrosine about 500 mg, glycine about 100 mg, arginine about 400 mg, histidine about 25 mg, and sucrose about 2,500 mg.
  • This formulation is preferably administered as in Example 1.
  • the formulation was administered to eight adults who each experienced early onset of satiation, prolonged post-meal satiety, and greatly reduced meal size (Table 2).
  • a formulation was prepared using aspartic acid and ornithine as substrates for the energy-consuming urea cycle.
  • the formulation was prepared in the proportions of about 70 parts of cocoa with about 50 parts ornithine, about 50 parts tyrosine, about 50 parts histidine, about 25 parts aspartic acid, and about 25 parts dexcrose.
  • Gelatin capsules are filled with the powder blend so that 4 gelatin capsules contain cocoa about 700 mg, ornithine about 500 mg, tyrosine about 500 mg, aspartic acid about 250 mg, histidine about 500 mg, and dextrose about 250 mg.
  • This formulation is preferably administered as in Example 1.
  • the formulation was administered to an adult male and an adult female who both experienced increased duration of post-meal satiation.
  • Example 5 Example 5
  • This example illustrates the use of formulations of this invention such as those described in Examples 1 through 4 in combination with a sympathomimetic agent as an additional lipolytic agent along with a norepinephrine precursor.
  • a sympathomimetic agent as an additional lipolytic agent along with a norepinephrine precursor.
  • Phentermine about 7.5 mg may be advantageously administered with each of the formulation of Examples 1 through 4 to effectively promote appetite suppression and augment catabolism of lipids stored in adipose tissue. This dosage of phentermine is reduced by about 50% or more from the amount typically used in the treatment of obesity.
  • This dosage of phentermine is reduced by about 50% or more from the amount typically used in the treatment of obesity.
  • other sympathomimetic agents such as ephedrine may be substituted for phentermine and administered in amounts similarly reduced by about 50% or more compared to the doses of these agents typically used in the treatment of obesity.
  • the sympathomimetic agent promotes appetite suppression.
  • the formulation was given to an adult male who experienced an increase in fat mobilization as measured by triglyceride levels in plasma (Table 3). The subject also experienced an associated increase in oxygen consumption, reflected in an increase in nitric oxide production. As fatty acids are metabolized, oxygen consumption and the production of resulting oxygen radicals increases. Nitric oxide has anti-oxidant effects and is released in order to scavenge oxygen radicals produced by fatty acid oxidation. Thus, ingestion of the formulation induced increased oxygen consumption as reflected by an increase in nitric oxide production.
  • Example 7 increased fat liberation by 17% as measured by changes in plasma triglycerides and increased fat catabolism by 18.5% as measured by increased oxygen consumption.
  • a formulation may be prepared comprising tyrosine about 1,000 mg, glutamine about 1,000 mg, arginine about 500 mg , histidine about 100 mg, cocoa about 800 mg, and sugar about 1,600 mg. These ingredients may be administered as a single dose in the form of a chocolate candy by combining them with melted semi-sweet chocolate with sufficient heavy cream and additional sugar to form an acceptable texture and taste of the resulting chocolate candy. This formulation is preferably administered as in Example 1.
  • Example 9 A formulation may be prepared comprising tyrosine about 1,000 mg, glutamine about 500 mg, arginine about 500 mg, histidine about 100 mg, cocoa about 800 mg, and dextrose about 1,600 mg. These ingredients may be administered as a single dose in the form of a chocolate candy by combining them with melted semi-sweet chocolate with sufficient heavy cream and additional sugar to form an acceptable texture and taste of the resulting chocolate candy. This formulation is preferably administered as in Example 1.
  • the synergistic combinations of the invention allow reduced doses of the individual components, particularly of the neurotransmitter precursors and sympathomimetic agents, to be used to achieve the desired effects.
  • the reduced doses decrease side effects caused by the large doses heretofore necessary to achieve the desired effects.
  • Our invention allows mobilization and catabolism of stored fats to be achieved without requiring the use of pharmaceuticals.
  • Our invention allows these desired effects to be achieved at dosage levels of neurotransmitter precursors that are considered safe by regulatory authorities. Previous attempts to use certain of the components in isolation were either ineffective or required dosages which caused side effects.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur des procédés et des compositions favorisant la mobilisation et le catabolisme des lipides. Un agent lipolytique est administré de façon à mobiliser des lipides avec un substrat afin d'obtenir une réaction chimique énergivore dans le corps, ce qui active la réaction énergivore pour favoriser la catabolyse des lipides mobilisés. Les agents lipolytiques comprennent des xanthines, des amines sympathomimétiques indirectes et des précurseurs de noradrénaline et d'histamine. Le substrats comprennent des acides aminés qui sont métabolisés de façon à former de l'ammoniaque et des acides aminés impliqués dans l'un ou l'autre ou dans les deux cycles réactionnels glutamine-glutamate et urée tels que glutamine, acide glutamique, acide aspartique, glycine, histidine, arginine, citruline, ornithine. La sécrétion de glucagon est, de plus, favorisée, de sorte que s'effectue ensuite la lipolyse, par administration d'ornithine et d'arginine qui jouent également le rôle de substrats. La sécrétion de glucagon est également favorisée par l'administration de quantités limitées de mono- et disaccharides.
PCT/US1999/000423 1998-01-07 1999-01-07 Procede favorisant la mobilisation et le catabolisme des lipides WO1999034675A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22173/99A AU2217399A (en) 1998-01-07 1999-01-07 Promoting mobilization and catabolism of lipids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7062498P 1998-01-07 1998-01-07
US60/070,624 1998-01-07

Publications (1)

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WO1999034675A1 true WO1999034675A1 (fr) 1999-07-15

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PCT/US1999/000423 WO1999034675A1 (fr) 1998-01-07 1999-01-07 Procede favorisant la mobilisation et le catabolisme des lipides

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AU (1) AU2217399A (fr)
WO (1) WO1999034675A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
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WO2006061992A1 (fr) * 2004-12-10 2006-06-15 Ajinomoto Co., Inc. Preparation prophylactique/therapeutique contre une maladie du foie
WO2007142297A1 (fr) * 2006-06-09 2007-12-13 Ajinomoto Co., Inc. Composition pour prévention/traitement d'une maladie hépatique
EP1605764A4 (fr) * 2003-03-14 2008-07-23 Eurark Llc Composition et procede destines a supprimer l'appetit et l'etat de besoin et a ameliorer l'humeur
US8597692B2 (en) 2007-04-26 2013-12-03 Barry Callebaut Ag Cocoa extract and use thereof
US8603547B2 (en) 2007-04-26 2013-12-10 Barry Callebaut Ag Use of cocoa extract
US8709503B2 (en) 2007-04-26 2014-04-29 Barry Callebaut Ag Use of cocoa extract

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US5728678A (en) * 1995-06-06 1998-03-17 Nestec Ltd. Method and composition for providing nutrition to a renal failure patient

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Title
DATABASE HCAPLUS ON STN, (Columbus, Ohio, USA), 120:307528, ABE T. et al., "Amino Acid Compositions for Infusion Solutions Regulating Metabolism of Sugar and Lipid"; & JP 06024976 A (01 February 1994). *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1605764A4 (fr) * 2003-03-14 2008-07-23 Eurark Llc Composition et procede destines a supprimer l'appetit et l'etat de besoin et a ameliorer l'humeur
WO2006061992A1 (fr) * 2004-12-10 2006-06-15 Ajinomoto Co., Inc. Preparation prophylactique/therapeutique contre une maladie du foie
JPWO2006061992A1 (ja) * 2004-12-10 2008-06-05 味の素株式会社 肝疾患予防・治療用組成物
WO2007142297A1 (fr) * 2006-06-09 2007-12-13 Ajinomoto Co., Inc. Composition pour prévention/traitement d'une maladie hépatique
US8597692B2 (en) 2007-04-26 2013-12-03 Barry Callebaut Ag Cocoa extract and use thereof
US8603547B2 (en) 2007-04-26 2013-12-10 Barry Callebaut Ag Use of cocoa extract
US8709503B2 (en) 2007-04-26 2014-04-29 Barry Callebaut Ag Use of cocoa extract

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