EP1221945A1 - Procedes, compositions pharmaceutiques et therapeutiques destines a l'administration d'adenosine - Google Patents

Procedes, compositions pharmaceutiques et therapeutiques destines a l'administration d'adenosine

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Publication number
EP1221945A1
EP1221945A1 EP00970984A EP00970984A EP1221945A1 EP 1221945 A1 EP1221945 A1 EP 1221945A1 EP 00970984 A EP00970984 A EP 00970984A EP 00970984 A EP00970984 A EP 00970984A EP 1221945 A1 EP1221945 A1 EP 1221945A1
Authority
EP
European Patent Office
Prior art keywords
adenosine
triphosphate
tablet
human
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00970984A
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German (de)
English (en)
Other versions
EP1221945A4 (fr
Inventor
Eliezer Rapaport
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Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP1221945A1 publication Critical patent/EP1221945A1/fr
Publication of EP1221945A4 publication Critical patent/EP1221945A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the invention relates to the chronic elevation of endogenous adenosine levels by the use of stable adenosine 5'- triphosphate (ATP) compositions, which are taken orally over a period of time.
  • ATP adenosine 5'- triphosphate
  • the decrease in sensitivity can materialize through a decrease in numbers of receptors (density) or through a reduction in the receptor's coupling activity (intracellular signal transduction).
  • adenosine receptors can be useful by itself or in combination with adenosine antagonists, which are much more active towards desensitized adenosine receptors.
  • adenosine antagonists which are much more active towards desensitized adenosine receptors. Examples for utilization of these methods are in the treatment of disorders or diseases, which are controlled by biochemical mechanisms regulated by adenosine receptors.
  • One such case is in the treatment of obesity, which can be treated by the metabolic stimulation of weight loss.
  • Lipolysis the degradation of fat (triglycerides) in adipose tissue to free fatty acids and glycerol, is known to be inhibited by the interaction of adenosine with Ai adenosine receptors of the adipocyte (fat cell).
  • Ai adenosine receptors The interaction of adenosine with adipose tissue Ai adenosine receptors was shown to stimulate lipogenesis- the buildup of triglycerides (fat) in fat cells.
  • Methods for desensitization of Ai adenosine receptors in a human in vivo thus significantly diminishing the activity of endogenous adenosine, are disclosed and taught and are utilized for the effective reduction of weight in humans.
  • Effective weigh loss in humans can be achieved either by the desensitization of the adipose tissue adenosine Ai receptors by themselves, or by desensitization in combination with adenosine antagonists such as caffeine or theophylline, which are much more effective in blocking the action of adenosine once its receptors became desensitized.
  • adenosine antagonists such as caffeine or theophylline
  • Obesity in terms of a disease is defined if body weight is 20% or more above the desirable weight (Council on Scientific Affairs, J. Amer. Med. Assoc. 1988). Overweight is defined if body weight exceeds the desirable weight by less than 20%. Desirable weight in humans has been well-defined (council on scientific affairs, JAMA 1988). Weight loss in overweight or obese humans can be achieved by diet, physical activity and behavior modification or by treatment with drugs. There are three main ways for the pharmaceutical treatment of overweight or obesity: 1. Inhibition of absorption of nutrients in the intestine; 2.
  • Adenosine triphosphate and adenosine were first discovered in 1929 (for a review, see Williams and Burnstock 1997). It is now known that adenosine exerts its physiological effects by interacting with specific receptors, several subtypes of which (Ai, A 2 A, A 2 B and A 3 ) have been characterized and shown to regulate specific physiological processes. Adenosine triphosphate in turn, exerts its physiological activities by interacting with another family of receptors termed P 2 receptors (Burnstock 1990).
  • P 2 receptors P 2 receptors
  • Ai adenosine receptors were shown to regulate significant brain (Williams and Burnstock 1997), heart and adipose tissue functions (van der Graaf et al. 1999) by their in vivo interactions with endogenous, extracellular adenosine in animals and humans.
  • the function of these Ai adenosine receptors is to transmit regulatory signals from adenosine, which is the product of extracellular metabolism, to the inside of the cells. This signal transduction is in turn achieved by a family of G proteins-linked to cell membrane Ai adenosine receptors (Linden 1991).
  • the G, protein which interacts with the Ai adenosine receptors, acts in inhibiting the intracellular activity of adenyl cyclase, the enzyme catalyzing the synthesis of cyclic AMP (cAMP) inside the cell.
  • cAMP cyclic AMP
  • the G, proteins coupled to this receptor inhibit the synthesis of c AMP, resulting in lower cellular levels of cAMP and in the case of adipose Ai adenosine receptors, overall inhibition of lipolysis (LaNoue and Martin 1994).
  • Ai adenosine receptor antagonists such as caffeine (1,3,7- trimethylxanthine), theophylline (1 ,3-dimethylxanthine) or synthetic Ai adenosine receptor antagonists, did not produce weight loss in genetically obese experimental animals (Xu et al. 1998).
  • Caffeine which is an established nonspecific Ai adenosine receptor antagonist (Jacobson and van Rhee 1997), was shown effective in inducing weight loss in humans as part of a variety of regimens discussed in several issued U.S. patents.
  • U.S. Patent No. 5,422,352 discloses a combination of caffeine and ephedrine in a ratio of about 12:1 as a composition for reducing weight in humans.
  • U.S. Patent No. 5,480,657 discloses a composition of caffeine, chromium and fructose for the treatment of obesity.
  • U.S. Patent No. 5,679,358 discloses compositions containing caffeine, theophylline or their derivatives along with other ingredients for the purpose of reduction of superfluous fat of any origin by topical application. For example, this patent refers to caffeine, theophylline or pentoxifylline as lipolytic agents, though no mechanism is discussed in the specifications.
  • 5,798,101 discloses compositions and methods for reducing weight consisting of St. John's Wart herbal extracts with or without caffeine.
  • Caffeine and theophilline have been established as non-specific antagonists of adenosine receptors, namely, they interact with both Ai and A 2A adenosine receptors with moderate affinity (Jacobson and van Rhee 1997). All of the issued U.S. Patents discussed above refer to caffeine as a "stimulator of metabolism" or in one case a "lipolytic agent".
  • a published placebo-controlled double blind human clinical study has demonstrated that caffeine ingestion increased the levels of free fatty acids (the products of lipolysis) in young men in a statistically significant manner. The increase in free fatty acids after caffeine challenge was not related to alterations in norepinephrine kinetics or fat oxidation (Arciero et al. 1995).
  • Ai adenosine receptors Several physiological sites are regulated to a significant degree by Ai adenosine receptors. These are the brain (Williams and Burnstock 1997), the heart (Kollias-Baker et al. 1995), adipose tissue (van der Graaf et al. 1999) and the coordination of glucose and lipid metabolism (van Schaick et al. 1998). Attempts to affect the function of specific organs or tissues by the use of adenosine or synthetic adenosine analogues acting as agonists or antagonists would seemingly produce global effects leading to intolerable side effects.
  • Adipose tissue-metabolic Ai adenosine receptors are therefore a good therapeutic target, taking into account their sensitivity towards adenosine in comparison to other potential therapeutic targets, which is expected to yield significant efficacy with a manageable spectrum of side effects.
  • One condition is that the agonist for the adipose tissue-metabolic Ai adenosine receptors has to be a relatively low affinity agonist, since a high affinity agonist is expected to interact with low affinity Ai adenosine receptors on other organs and produce significant side effects (van der Graaf et al. 1999). Adenosine itself is known to be such an agonist (Jacobson and van Rhee 1997).
  • the reason that it has not been used for these therapeutic targets is its extremely short blood plasma half- life, limiting any efficacy and potential usefulness (Williams and Burnstock 1997).
  • the present invention discloses and teaches a method for consistently and chronically elevating blood plasma adenosine levels for achieving adipose tissue-metabolic therapeutic targets without any side-effects.
  • Desensitization of receptors is a general phenomenon, whereby chronic exposure of sensitive receptors to their agonists can produce a marked reduction in the capacity of the receptors to respond to the same or related agonists.
  • the same phenomena have also been termed refractoriness, tolerance or tachyphylaxis (Hoppe and Lohse 1995).
  • the Ai adenosine receptors, both in cardiac and adipose tissues have been demonstrated to undergo desensitization after chronic exposure to adenosine analogues that are proven agonists for the Ai adenosine receptors.
  • Desensitization of the Ai adenosine receptors in both tissues was demonstrated to be mediated by both a reduction in receptor density
  • the Ai adenosine receptors desensitization is used as a therapeutic target as disclosed and taught by the present invention.
  • the effectiveness of adenosine as an endogenous anti- lipolytic agent is significantly diminished.
  • antagonism of adenosine at these sites, by common Ai adenosine receptor antagonists such as caffeine or theophylline, is markedly enhanced.
  • Desensitization of adipose tissue-metabolic Ai adenosine receptors does not affect heart or brain Ai adenosine receptors because of the heart's receptors much lower sensitivity (van der Graaf 1999) and the brain's effective barrier against systemic adenosine (Williams and Burnstock 1997).
  • the present invention discloses and teaches:
  • adenosine 5'- triphosphate adenosine 5'- triphosphate (ATP) or physiologically acceptable salt thereof suitable for oral delivery.
  • the invention provides for a stable oral dosage form such as a pill of ATP or physiologically acceptable salt thereof along with fillers, binders, stabilizers and enteric coating materials.
  • the objective of the oral delivery of ATP is to achieve systemic absorption of adenosine.
  • Extracellular adenosine interacts with a variety of adenosine receptors regulating functions of organs and tissues.
  • a method for the chronic administration of adenosine for the purpose of desensitizing adipose tissue-metabolic Ai adenosine receptors The utility of this method is in decreasing the sensitivities of these receptors towards adenosine and at the same time increasing the sensitivities of these receptors towards adenosine antagonists such as caffeine or theophilline.
  • This method is used for the purpose of inducing weight loss in humans or in the treatment of obesity in humans. Since the adipose tissue-metabolic
  • Al adenosine receptors act in inhibiting lipolysis (degradation of fats), reductions in their activities as a result of chronic exposure to adenosine is suffecient to induce lipolysis and effective weight loss.
  • Chronic exposure to adenosine can be supplemented by caffeine or theophilline, both commonly used drugs in order to further reduce the activities of adipose tissue-metabolic Al adenosine receptors, thus achieving a more enhanced weight loss.
  • the term "chronic administration" and similar terms used herein refer to prolonged or substantially sustained release over an extended period of time, typically at least about 96 hours.
  • Pharmacologically active substances such as ATP, which undergo rapid degradation inside parts of the gastrointestinal tract or inside the vascular bed, are coated with an enteric polymer that dissolves at a specific pH.
  • enteric polymer that dissolves at a specific pH.
  • the catabolic enzymes that catalyze the degradation of purines are present in the stomach and the proximal small intestines (Mohamedali et al. 1993).
  • a pH- sensitive enteric coating can be designed to release ATP as the therapeutically active agent in the distal part of the small intestine, the ileum, where catabolic activities that catalyze the degradation of ATP are minimal (Mohamedi et al. 1993).
  • the human stomach has a variable acidic pH of about 1 to 2 and the transit time of a pill through the stomach is between 20 minutes and 2 hours, depending on the prandial state.
  • An ATP pill passing through the stomach intact would enter the small intestine, which consists of the duodenum, jejunum and ileum.
  • Transit time of a pill throughout the small intestine is relatively steady at approximately 3 hours.
  • an enteric stable pill then passes through the large intestine, which consists of the caceum, the ascending colon, the transverse colon, the descending colon and the sigmoid colon. Total transit time through the large intestine is about 30-35 hours.
  • Suitable tablets of adenosine 5'-triphosphate-disodium salt were prepared containing binders, fillers and stabilizers. The mixtures were granulated and condensed into 250 milligrams of ATP and 500 milligrams of ATP tablets using an oval-shaped punch. The tablets had to provide smooth surfaces, free from edges or sharp curves preferably with concave surfaces, all are properties desirable for the stability and mechanical strength of the enteric coating.
  • Stabilizers suitable for ATP disodium tablets are magnesium stearate, silica (Si0 2 )(Sylox), which are suitable stabilizers in small well-established amounts, sodium bicarbonate, ascorbic acid, tocopherols, and maltodextrin, which is especially effective in protecting hygroscopic compositions such as ATP.
  • Suitable fillers for use with ATP in a tablet include microcrystalline cellulose, carboxymefhyl cellulose, mannitol or calcium phosphate- dibasic.
  • Binders that are suitable for the ATP therapeutic composition include gum arabic, gelatin, polyvinylpyrrolidone (PVP), hydroxypropylcellulose (HPC) or methylcellulose.
  • a preparation of ATP together with selected stabilizers, fillers and/or binders are then compressed into tablets of optimal size and shape to provide good mechanical strength and surface suitable for enteric coating.
  • the blended preparations may be used to form capsules, microtablets or micropellets all of which may, or may not be enteric coated depending on the state of the art.
  • the function of the pH-dependent enteric coating is to prevent release of the therapeutically active pro-drug- ATP, until it reaches the targeted or desired location of the small intestine such as the distal portion of the small intestine, the section of the ileum where the pH rises to 7.2.
  • the coating thickness is dependent upon the size and shape of the tablets and ranges from 20 to 80 .mu.m. Whereas the traditional enteric polymer coating materials were designed to protect the pharmaceutically active preparation in transit through the stomach, newer coating materials allow for the pH-dependent pills to dissolve only at higher pH's, with a great degree of accuracy.
  • the older enteric polymer coating materials include cellulose acetate phthalate, polyvinylacctate phthalate, cellulose acetate trimclliate, polyvinyl acetate phthalate and hydroxypropyl methylcellulose phthalate.
  • the preferred materials for enteric coating of ATP therapeutic compositions are methacrylic acid/methyl mcthacrylate copolymers, which arc commercially available from Rhom Pharma under the name Eudragit S and Eudragit L.
  • Eudragit S is a poly(metacrylic acid, methylmetacrylate) 1 :2
  • Eudragit L is a poly(metacrylic acid, mefhylmetacrylate) 1 : 1.
  • Both are anionic copolymers where the ratios refer to the ratios of free carboxyl groups to methyl ester groups. Both copolymers have a mean molecular weight of 135,000. These two copolymers can be mixed in a variety of ratios to achieve a mechanically stable coating of pH sensitivity of between pH's 6 and 7, with Eudragit S being the preferred ingredient.
  • the overall established mechanism thus provides for the slow, continuous release of adenosine in the blood plasma after the release of ATP at a preferred position along the distal part of the small intestine.
  • compositions consisting of 250 milligrams and 500 milligrams ATP tablets were formulated.
  • Formulation Material 250 mg ATP Tablet 500 mg ATP Tablet
  • ATP tablets formulation materials were compressed into tablets utilizing an oval punch. The tablets were without prominent edges and exhibited smooth concave surfaces. The tablets exhibited excellent mechanical strength and proved to be suitable for enteric coating. Six volunteer subjects ingested 1000 mg per day of the 250 mg or 500 mg ATP tablets, for a period of one month. No noticeable side effects were reported.
  • Each of the ATP-formulation tablets was coated with four different types of coating. The primary considerations in selecting these coating materials were that they should be of sufficient mechanical strength, provide good protection in acidic media and release the therapeutic composition of ATP at pH 6.8 or higher.
  • the following enteric formulations were used:
  • Eudragit FS30D which is an acqueous version of Eudragit S, coated to 8% coating.
  • Eudragit SI 00 coated from acetone/methanol to a 6% coating.
  • Eudragit S100 coated from acetone/methanol to a 8% coating. All of the above coatings release ATP at a pH of 7.0-7.2.
  • enteric coating formulations were stable and completely resisted simulated gastric fluid (no enzymes) test for over 2 hours.
  • Six human volunteers ingested a total of 1000 milligrams of each of the four types of enteric coated ATP pills per day (two 500 mg pills per day, one in the morning and one in the evening) for a period of two weeks per type of enteric coating. No side effects or discomfort of any type were reported.
  • the ATP pills were completely safe over the short term.
  • a safe, stable, ingestable therapeutic composition of adenosine 5 '-triphosphate disodium (ATP) in a form of a tablet containing more than 100 milligrams of ATP can be prepared using binders, fillers and stabilizers well-known to the skilled artisan.
  • a safe, stable ingestable therapeutic composition of ATP in a form of an enteric coated pill designed to dissolve in the distal part of the small intestine can be prepared containing more than 100 milligrams of ATP per pill.
  • the distal portion of the small intestine, the ileum contains the lowest levels of catabolic enzymes catalyzing the degradation of ATP and adenosine.
  • a method for the chronic continuous administration of adenosine, which is the major catabolic product of its pro-drug ATP, has been unexpectedly produced utilizing the oral therapeutic compositions outlined in 1 and 2 above.
  • adenosine or any of its pro-drugs by injection or infusion results in the acutely elevated levels of adenosine.
  • a method for the desensitization of adenosine receptors in a human by exposing adenosine receptors to chronically elevated levels of their natural agonist, adenosine.
  • a method for achieving weight loss in an overweight or obese human by desensitization of adipose tissue Ai adenosine receptors The interaction of endogenous adenosine with the Ai adenosine receptors of adipose tissue is known to the skilled artisan to inhibit lipolysis or the degradation of fat.
  • the unexpected finding is of a method for exposing these receptors to chronically elevated levels of adenosine, which desensitize these receptors towards the action of adenosine, endogenous or exogenous, resulting in the stimulation of lipolysis in humans.
  • Caffeine is a known antagonist of adenosine for the Ai adenosine receptors of adipose tissue. Exposure of the desensitized receptors to caffeine during or after the chronic administration of adenosine, results in further stimulation of lipolysis and weight loss in humans.
  • Ai adenosine receptors are desensitized towards adenosine, their sensitivity towards caffeine, an adenosine antagonist, is increased yielding additional inhibition of the activities of endogenous or exogenous adenosine at these receptors.
  • Cited Arciero P.J. ct al. Effects of caffeine ingestion on kinetics, fat oxidation, and energy expenditure in younger and older men. Am. J. Physiol. 268: El 192-E1 198, 1995.
  • Jacobson K.A. and van Rhee A.M. Development of selective purinoceptor agonists and antagonists, in Purinergic Approaches in Experimental Therapeutics, Jacobson K.A. and Jarvis M.F., Editors, Wiley-Liss, 1997, pp 101-128.
  • Rapaport E. and Fontaine J. Generation of extracellular ATP in blood and its mediated inhibition of host weight loss in tumor-bearing mice. Biochem. Pharmacol. 38: 4261 - 4266, 1989.
  • Rapaport E. and Fontaine J. Anticancer activities of adenine nucleotides in mice are mediated through expansion of erythrocyte ATP pools. Proc. Natl. Acad. Sci. USA 86: 1662-1666, 1989.
  • Rapaport E. Mechanisms of anticancer activities of adenine nucleotides in tumor-bearing hosts, in Ann. N.Y. Acad. Sci., vol. 603, Biological Actions of Extracellular ATP, 1990, pp 142-150.
  • Van der Graaf P. H. et al. Mechanism-based pharmacokinetic-pharmacodynamic modeling of antilipolytic effects of adenosine Ai receptor agonists in rats: prediction of tissue-dependent efficacy in vivo. J. Pharmacol. Exp. Ther. 290: 702-709, 1999.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Obesity (AREA)
  • General Chemical & Material Sciences (AREA)
  • Child & Adolescent Psychology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes destinées à l'administration chronique d'adénosine, qui contrairement à l'administration précise du médicament par injection ou infusion, agissent par désensibilisation des récepteurs d'adénosine vis-à-vis de l'action de l'adénosine. On peut utiliser les méthodes et les compositions orales d'adénosine triphosphate (ATP) qui est dégradée en adénosine in vivo, dans le cadre de traitement de troubles et de maladies qui sont ciblés thérapeutiquement par des agonistes ou antagonistes de récepteurs d'adénosine. Un exemple est la stimulation de la lipolyse utilisée dans le traitement de l'obésité et dans le but de parvenir à une perte de poids chez les humains.
EP00970984A 1999-10-20 2000-10-18 Procedes, compositions pharmaceutiques et therapeutiques destines a l'administration d'adenosine Withdrawn EP1221945A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US16063499P 1999-10-20 1999-10-20
US160634P 1999-10-20
PCT/US2000/028769 WO2001028528A1 (fr) 1999-10-20 2000-10-18 Procedes, compositions pharmaceutiques et therapeutiques destines a l'administration d'adenosine

Publications (2)

Publication Number Publication Date
EP1221945A1 true EP1221945A1 (fr) 2002-07-17
EP1221945A4 EP1221945A4 (fr) 2005-06-15

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EP00970984A Withdrawn EP1221945A4 (fr) 1999-10-20 2000-10-18 Procedes, compositions pharmaceutiques et therapeutiques destines a l'administration d'adenosine

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EP (1) EP1221945A4 (fr)
AU (1) AU8028600A (fr)
WO (1) WO2001028528A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068104A1 (fr) 2000-03-16 2001-09-20 The Mclean Hospital Corporation Composes servant a traiter des troubles psychiatriques ou des troubles provoques par la consommation abusive de substances psychoactives
US7629329B2 (en) * 2001-06-04 2009-12-08 Tsi Health Sciences, Inc. Method for increasing muscle mass and strength through administration of adenosine triphosphate
US20030069203A1 (en) * 2001-06-04 2003-04-10 Lee Steve S. Method for increasing human performance by reducing muscle fatigue and recovery time through oral administration of adenosine triphosphate
WO2006020703A1 (fr) 2004-08-11 2006-02-23 The Mclean Hospital Corporation Compose pour le traitement de la dependance, de la suppression et de l'usage de la marijuana

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0344795A1 (fr) * 1988-06-03 1989-12-06 Senju Pharmaceutical Co., Ltd. Composition pharmaceutique stabilisée et procédé pour la préparer
EP0348688A1 (fr) * 1988-06-03 1990-01-03 Senju Pharmaceutical Co., Ltd. Préparation pharmaceutique solide et procédé d'obtention de celle-ci
EP0352477A2 (fr) * 1988-07-25 1990-01-31 Eliezer Rapaport Utilisation de l'adénosine-5'-phosphate dans le traitement de cancer cachexia
WO1993021783A1 (fr) * 1992-05-06 1993-11-11 The Penn State Research Foundation Procedes de traitement de l'obesite au moyen de composes apparentes a la purine
US5547942A (en) * 1994-01-04 1996-08-20 Rapaport; Eliezer Method of treatment of diabetes mellitus by administration of adenosine 5'-t

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
US5900407A (en) * 1997-02-06 1999-05-04 Inspire Pharmaceuticals, Inc. Method of treating dry eye disease with uridine triphosphates and related compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0344795A1 (fr) * 1988-06-03 1989-12-06 Senju Pharmaceutical Co., Ltd. Composition pharmaceutique stabilisée et procédé pour la préparer
EP0348688A1 (fr) * 1988-06-03 1990-01-03 Senju Pharmaceutical Co., Ltd. Préparation pharmaceutique solide et procédé d'obtention de celle-ci
EP0352477A2 (fr) * 1988-07-25 1990-01-31 Eliezer Rapaport Utilisation de l'adénosine-5'-phosphate dans le traitement de cancer cachexia
WO1993021783A1 (fr) * 1992-05-06 1993-11-11 The Penn State Research Foundation Procedes de traitement de l'obesite au moyen de composes apparentes a la purine
US5547942A (en) * 1994-01-04 1996-08-20 Rapaport; Eliezer Method of treatment of diabetes mellitus by administration of adenosine 5'-t

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KAARTINEN J M ET AL: "ATTENUATED ADENOSINE-SENSITIVITY AND DECREASED ADENOSINE-RECEPTOR NUMBER IN ADIPOCYTE PLASMA MEMBRANES IN HUMAN OBESITY" BIOCHEMICAL JOURNAL, vol. 279, no. 1, 1991, pages 17-22, XP009046533 ISSN: 0264-6021 *
See also references of WO0128528A1 *

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EP1221945A4 (fr) 2005-06-15
WO2001028528A1 (fr) 2001-04-26
AU8028600A (en) 2001-04-30

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