(19) TZZ ¥ __T

(11) EP 2 322 187 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/7072 (2006.01) A61K 31/14 (2006.01) 14.05.2014 Bulletin 2014/20 A61K 31/685 (2006.01) A61P 25/28 (2006.01)

(21) Application number: 10075660.0

(22) Date of filing: 30.07.1999

(54) Use of in combination with choline for the treatment of memory disorders Verwendung von Uridin in Kombination mit Cholin zur Behandlung von Gedächtnisstörungen Utilisation de l’uridine en combinaison avec la choline pour le traitement des maladies de la mémoire

(84) Designated Contracting States: (56) References cited: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU WO-A-97/45127 CH-A5- 680 334 MC NL PT SE DE-A1- 2 508 474 DE-A1- 2 629 845 DE-U1- 9 412 374 US-A- 4 221 784 (30) Priority: 31.07.1998 US 95002 P US-A- 4 994 442 US-A- 5 567 689 US-A- 5 700 590 (43) Date of publication of application: 18.05.2011 Bulletin 2011/20 • CACABELOSR ET AL: "THERAPEUTIC EFFECTS OF CDP-CHOLINE IN ALZHEIMER’S DISEASE (62) Document number(s) of the earlier application(s) in COGNITION, BRAIN MAPPING, accordance with Art. 76 EPC: CEREBROVASCULAR HEMODYNAMICS, AND 09173495.4 / 2 145 627 IMMUNE FACTORS", ANNALS OF THE NEW 07116909.8 / 1 870 103 YORK ACADEMY OF SCIENCES, NEW YORK 99937631.2 / 1 140 104 ACADEMY OF SCIENCES, NEW YORK, NY, US, 1 January 1996 (1996-01-01), pages 399-403, (73) Proprietor: Massachusetts Institute of Technology XP008065562, ISSN: 0077-8923 Cambridge, Massachusetts 02142-1601 (US) • SPIERS P A ET AL: "CITICOLINE IMPROVES VERBAL MEMORY IN AGING", ARCHIVES OF (72) Inventors: NEUROLOGY, AMERICAN MEDICAL • Watkins, Carol ASSOCIATION, CHICAGO, IL, US, vol. 53, no. 5, Cambridge, MA 02142 (US) 1 May 1996 (1996-05-01), pages 441-448, • Wurtman, Richard J. XP008028412, ISSN: 0003-9942 Boston, MA 02116 (US) • WEISS G B: "Metabolism and actions of CDP- choline as an endogenous compound and (74) Representative: Korn, Richard Mervyn administered exogenously as citicoline.", LIFE Pearl Cohen Zedek Latzer Baratz UK LLP SCIENCES 1995 LNKD- PUBMED:7869846, vol. 15 Old Bailey 56, no. 9, 1995, pages 637-660, XP002640081, London EC4M 7EF (GB) ISSN: 0024-3205

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 322 187 B1

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Description ble to recover a with spectrophotometric char- acteristics of and admits that his conclusions [0001] The present invention relates to the use of uri- were based on probabilistic guessing. Thus, the alleged dine or a uridine source in combination with choline, a phenomenon observed by Dawson may have been due choline precursor, a choline salt or ester, or a mixture 5 to misinterpretation of an experimental artifact as it is thereof in the manufacture of a composition for treating now known that experimentally measurable cytidine can cognitive dysfunction associated with aging, and/or for be easily confused with tyrosine, which is chemically un- slowing down or reversing brain-aging. related amino acid compound (see Fig. 1). [0005] Thus, even though an catalyzing the DESCRIPTION OF THE RELATED ART 10 conversion of uridine to cytidine may exist in rats its ac- tivity is not sufficiently potent to raise the levels of cytidine [0002] This invention stems from unexpected discov- to a level that can be measured and ascertained beyond ery that increase in levels of uridine following the admin- any doubt. Thus, these levels may be not sufficient to istration of uridine or uridine source to certain animals warrant practical exploitation for clinical application. In- comprising human patients, leads to increased levels of 15 deed nowhere in Dawson publication is there a sugges- cytidine in a human body and particularly in the human tion or an attempt to make a suggestion that the uridine brain. Thus, administering uridine or uridine precursors to cytidine conversion process can be useful for any med- to human patients in need thereof can be as beneficial ical modality. In addition, as it is the case with many other as administration of cytidine or cytidine precursors. How- and metabolic pathways, this particular en- ever, the potential benefit of uridine or uridine source 20 zyme may have been present in rats but not in humans. administration is overwhelmingly greater than the benefit One skilled in related art knows that a discovery of a of cytidine administration. This is due to the fact that cy- biological process in one species of an animal, e.g., rat, tidine, as opposed to uridine, either cannot cross or is does not necessarily means that a similar process is much less efficient than uridine in crossing the blood- present in another animal, e.g., man. Based on that one brain barrier (Cornford et al., Independent blood-brain 25 skilled in the art will be not sufficiently motivated to exploit barrier transport systems for nucleic acid precursors. Bi- this phenomenon for any useful purposes other than an ochim. Biophys. Acta 349:211-219, 1975). experimental tool to study enzyme metabolism in rats. [0003] According to the knowledge relating to the me- Consequently, the prior art is silent in regard to the use tabolism of compounds, enzymes are known of the process of uridine to cytidine conversion for any in the art, such as cytidine deaminase (EC 3.5.4.5), which 30 meaningful application. converts cytidine into uridine. Cytidine deaminase can [0006] Uridine is a pyrimidine and is essen- be found in some prokaryotes and eukaryotes including tial in the synthesis of ribonucleic acids and tissue gly- humans, primates, and some rodents although some cogens such as UDP glucose and UTP glucose. Medical species lack this enzyme. However, according to EC (en- uses of uridine alone are limited to treatment of genetic zyme classification) list there are no known examples of 35 disorders related to deficiencies of pyrimidine synthesis aminase-like enzymes, which are capable of opposite such as orotic aciduria (Becroft DM, et al., Hereditary action, i.e., converting uridine into cytidine. orotic aciduria: longterm therapy with uridine and a trial [0004] The prior art relating to the process of uridine of . J Pediatr. 1969 Nov; 75 (5): 885-891). Other to cytidine conversion is also limited. Only one publica- less common uses of uridine alone are known such as tion, citing two earlier references, seems to exist, wherein 40 treatment of seizures and epilepsy (Roberts CA, et al., it was suggested that a soluble fraction of the rat liver Uridine anticonvulsant effects: selective control of nucl- and possibly of the brain may catalyze in vitro and in vivo eoside incorporation in experimental epilepsy. Epilepsia. the conversionof uridine nucleotide to cytidine nucleotide 1974 Dec; 15(4): 479-500). Most commonly, uridine is (Dawson. Enzymic conversion of uridine nucleotide to used in combination with cytidine (Monticone GF, et al., cytidine precursor by rat brain. J. Neurochem. 15:31-34, 45 On the therapeutic use of the , cytidine and 1968). Even though this report implicated the possibility uridine, in some neurological diseases. Minerva Med. of such an enzyme reaction in rats the activity of the en- 1966 Dec 19; 57 (101): 4348-4352). The uses of this zyme does not appear to be sufficiently potent. As com- particular dual combination range from liver and kidney pared to the initial, administered dose of uridine (consid- diseases to a number of neurological and cerebrovascu- ered as 100%), the highest levels of newly converted 50 lar diseases but such uses are irrelevant to the present cytidine in vivo were 12.4% in the liver and 9% in the invention directed at the use of uridine without concom- brain. The conversion rates in vitro were 5.4% in the liver itant use with cytidine. and 8.05% in the brain. Thus, maximum observed levels [0007] U.S. Pat. No. 4,960,759, issued to De Luca et were within 5.4-12.4 % range. From a statistical point of al., on October 2, 1990 discloses the pharmacological view all these figures are within the range of a typical 55 use of uridine in the treatment of nervous disorders such scatter in a gamma counter (15%) and practitioner in the as schizophrenia and Parkinson’s disease. De Luca et art can dismiss them either as insignificant or irreproduc- al., teach that the benefit of uridine is due to increase in ible. Moreover, Dawson himself states that he was una- cholecystokinin levels in the brain, which in turn improves

2 3 EP 2 322 187 B1 4 dopamine functioning and results in therapeutic benefit. neurological diseases associated with dopaminergic Said benefit is described as a reduction in symptoms of pathway, e.g., schizophrenia and Parkinson’s disease Parkinson’s disease, which are tremor and rigidity. As as treated by combination therapy in which uridine is one the preferred embodiment of the instant invention is treat- of constituents. ment of neurological disorders unrelated to schizophre- 5 [0011] Thus, none of the prior art patents or references nia and Parkinson’s disease it is clear that the teachings have anticipated or made the instant invention obvious. by De Luca et al., are irrelevant to this invention. The present invention is thus unique and stands out in [0008] The U.S. Pat. No. 5,470, 838, issued to von the light of the prior art. Borstel et al., on November 28, 1995 discloses the meth- od of delivering exogenous uridine or cytidine in form of 10 SUMMARY OF THE INVENTION acylated uridine or cytidine and said compounds as use- ful in treating cardiac insufficiency, myocardial infarction, [0012] This invention is based upon unexpected dis- and cirrhosis of the liver. Von Borstel et al., propose to covery that uridine administration in humans leads to in- use both forms of since it was not obvious crease in systemic and brain cytidine. Thus the present to them that uridine alone is effective. The absolute re- 15 invention relates to the use of (a) uridine or a uridine quirement of both cytidine and uridine was due to the source and (b) choline, a choline precursor, a choline salt lack of knowledge and anticipation in the prior art that or ester, or a mixture thereof, in the manufacture of a uridine might convert into cytidine, especially in humans. composition for treating cognitive dysfunction associated One skilled in the art will recognize that the disclosed with aging, and/or for slowing down or reversing brain- composition matter is different and diseases to be treated 20 aging. are not the same as in the present invention. [0013] The slowing down or reversing brain-aging may [0009] The U.S. Pat. Nos. 5,141,943; 5,567,689; and be associated with aging and age-related decline in cog- 5,723,449 disclose various methods and compositions nition functions. to raise levels of uridine in the blood as useful for reducing [0014] The choline precursor may be sphingomyelin, toxicity of pyrimidine nucleoside drugs such as AZT and 25 cytidine-diphospho-choline, acylglycerophosphocholine 5-Fluouracil for AIDS and cancer therapy respectively. It (AGP-choline), phosphatidylcholine (PC), or a combina- is apparent to anyone skilled in the art that these teach- tion thereof. The choline salt may be choline chloride, ings have nothing in common with the present invention. choline bitartrate, choline stearate or mixtures thereof. [0010] Although all of these patents and prior art ref- The uridine or uridine source may be administered in erences disclose at least one or another aspect of the 30 dosages between about 10 mg and 10 grams per day. instant invention none of them taught specifically that cy- The uridine may comprise uridine salts or a food product tidine levels can be raised in humans by administering containing uridine. uridine or uridine source as useful for the treatment of [0015] The terms" uridine precursor" or " uridine certain neurological or brain disorders. These disorders source" or" uridine prodrug" are used interchangeably comprise disorders associated with aging such as mem- 35 and as defined hereinafter mean compounds, e.g., urid- ory decline and age related decline in cognition functions. ine salts or food products containing uridine, that trans- These disorders also comprise memory decline and re- form into uridine upon administration to a host such as lated cognition dysfunction associated with pathological human. conditions like Alzheimer’s disease, Pick’s disease, Lewy [0016] Choline is involved in metabolism and lipid Body disease, and/or dementias like Huntington’s dis- 40 transport and is a component of a number of important ease and AIDS dementia. Other cognitive dysfunctions, biological compounds including the membrane phos- i.e., disorders of attention, alertness, concentration, fo- pholipids like lecithin and sphingomyelin. Choline is also cus, and dyslexia can also be treated. Other uses of uri- a precursor of acetylcholine - one of most important neu- dine therapy can be imagined such as treatment of mood rotransmitters. Although a required nutrient for several and emotional disorders, e.g., mania, depression, stress, 45 animal species, choline is not currently designated as panic, anxiety, insomnia, dysthemia, psychosis, season- essential for humans. However, recent clinical studies al effective disorders and bipolar disorders. Neurological show it to be essential for normal liver function. Addition- diseases like ataxias, including Friedreich’s ataxia and ally, a large body of evidence from the fields of molecular movement disorders like tardive dyskinesia can also be and cell biology shows that certain phospholipids play a treated. Method of treating stroke, cerebral thrombosis, 50 critical role in generating second messengers for cell ischemia, and related cerebrovascular diseases result- membrane signal transduction. This process involves a ing from hypoxia as well as behavioral and neurological cascade of reactions that translate an external cell stim- syndromes seen after brain trauma, spinal cord injury ulus such as a hormone or growth factor into a change and/or anoxia can be also imagined. Methods of treating in cell transport, metabolism, growth, function, or gene diseases of the peripheral nervous system, e.g., neu- 55 expression. Disruptions in phospholipid metabolism can romuscular disorders like myasthenia gravis, the post- interfere with this process and may underlie certain dis- polio syndrome, and muscular dystrophies are also pos- ease states such as cancer and Alzheimer’s disease. sible. It is also possible to imagine the methods of treating However, choline alone is not useful as a therapeutical

3 5 EP 2 322 187 B1 6 modality. In light of the instant invention choline or choline ified. precursors are appropriate in considering them in com- bination with uridine or uridine source. EXAMPLE 1. [0017] It is thus a further object of this invention to es- tablish a synergy between uridine and various com-5 [0021] In this example a method is established that pounds affecting cholinergic pathway and/or phospholi- overcomes the problem of the coincidence of cytidine pid metabolism. Among them are CDP-choline, choline, and tyrosine peaks when tested by a standard HPLC choline salts, and phosphatidylcholine. method for measuring various nucleosides in biological fluids (see Fig. 1). By using the standard HPLC method, BRIEF DESCRIPTION OF THE DRAWINGS 10 one can, however, easily distinguish the uridine peak from the cytidine peak. Detailed description of the HPLC [0018] method can be found for example in Lopez-Coviella et al., (Evidence that 5’-cytidinephosphocholine can affect Fig. 1 illustrates the coincidence of cytidine and ty- brain phospholipid composition by increasing choline rosinepeaks (6. 59) whentested bya standard HPLC 15 and cytidine plasma levels. J. Neurochemistry 65: method. 889-894, 1995). Modified HPLC is carried out in a same Fig. 2 illustrates distinct cytidine (3. 25) and tyrosine way as standard HPLC except that elution buffer contains (2. 92) peaks when tested by a modified HPLC meth- low amount of methanol (0.1%) instead of formic acid od, which utilizes elution buffer with low methanol. and as a result cytidine can be distinguished from unre- Fig. 3 shows the ratio of uridine (100%) to cytidine 20 lated compound tyrosine (Fig. 2). This method is useful in plasma after oral administration of 250 milligram in distinguishing cytidine from masking effect of amino per kg of body weight (mg/kg) of uridine. acid tyrosine, which may concomitantly be present in Fig. 4 shows the ratio of uridine (100%) to cytidine tested biological fluid, e.g., plasma or cerebrospinal fluid in the brain after oral administration of 250 milligram (CSF). Due to the overlap between cytidine and tyrosine per kg of body weight (mg/kg) of uridine. 25 it is very likely that the results of all the prior art studies dealing with cytidine measurement, including present in- DESCRIPTION OF THE PREFFERED EMBODIMENTS ventors’ own studies supra, were interpreted incorrectly.

[0019] The compositions prepared according to the EXAMPLE 2. present invention increase systemic and brain levels of 30 cytidine in a human patient via administration of uridine [0022] Gerbils rather than rats or other rodents are se- or a uridine source in combination with choline, a choline lected for this example, as the pyrimidine metabolism of precursor, a choline salt, a choline ester, or mixture there- said gerbils is closer to humans. For practical and ethical of. The compositions may thus be for use in treating cog- reasons humans cannot always be used for certain ex- nitive dysfunction associated with aging, and/or for slow- 35 perimental studies and those skilled in the art generally ing down or reversing brain-aging. The compositions op- recognize that the gerbil model is equivalent to a human tionally additionally encompass drugs that increase uri- model. Indeed, gerbils are the choice model for certain dine availability. Among such drugs are drugs that act as human diseases and brain disorders such as cerebral uridine phosphorylase inhibitors like benzyl ischemia (Ginsburg et al., Rodent models of cerebral or derivatives thereof. Among such drugs are also drugs 40 ischemia. Stroke 20: 1627-1642, 1989). Gerbils are given that act as uridine secretion inhibiting compounds like orally uridine and 60 minutes later plasma and brain lev- or . Among such drugs are drugs els of cytidine and uridine are measured by modified that act as uridine renal transport competitors like L-uri- HPLC method described in Example 1. The Fig. 3 shows dine, L-2’, 3’-dideoxyuridine, and D-2’, 3’-dideoxyuridine. the relative ratio between uridine and cytidine levels in The compositions are beneficial to a human patient in 45 plasma after oral administration of 250 milligram per kg need thereof and act in synergy with uridine in generation of body weight (mg/kg) of uridine. The Fig. 4 shows the of phospholipids involved in brain cell membrane forma- relative ratio between uridine and cytidine levels in the tion and repair. More specifically choline-based com- brain after oral administration of 250 mg/kg of uridine. pounds are contemplated as compounds acting in syn- These results indicate that the metabolic processing of ergy with uridine or uridine source. Among them are50 uridine in the brain is different than systemic processing choline, choline salts or esters, such as choline bitartrate of uridine in plasma. The results also indicate that uridine, or stearate or the like, or compound that dissociate to when transported into the brain, is readily converted to choline, such as sphingomyelin, cytidine-diphospho- cytidine and this conversion is more efficient in the brain choline or citicoline or CDP-choline, acylglycerophos- than in plasma. Similar experiments are also carried out phocholines, e.g., lecithin, lysolecithin, glycerophos-55 in humans wherein instead of measuring brain levels of phatidylcholine, mixtures thereof or the like. nucleosides the CSF levels are measured. The finding [0020] The following examples illustrate the invention that uridine is readily converted to cytidine especially in and are not intended to be limiting unless otherwise spec- the brain is totally unexpected and constitutes the basis

4 7 EP 2 322 187 B1 8 for the present invention. nous, intramuscular or subcutaneous injection. [0029] When necessary and as required by the exigen- EXAMPLE 3 cy of the therapy uridine is administered in combination with other compounds that act either synergistically or in [0023] In Example 3 a clinical study is carried out with 5 additive manner. This reduces the therapeutic dose of the goal of treating memory disorders and cognitive dys- administered drugs, thereby reducing potential undesir- functions associated with aging as well as memory de- able side effects and frequency of drug administration. cline and cognitive dysfunction associated with patho- Compounds that act in such a manner are chemical sub- logical conditions like Alzheimer’s disease, Pick’s dis- stances participating in cholinergic metabolism. For ex- ease, Lewy Body disease, and/or dementias like Hunt- 10 ample, compounds administered along with uridine are ington’s disease and AIDS dementia. Patients with non- following choline-based compounds: choline, choline pathological dementia associated with aging are also in- salts or esters, such as choline bitartrate or stearate or cluded. Oral doses of uridine alone ranging from 5 mg to the like, or compound that dissociate to choline, such as 50,000 mg are administered daily to five male and five sphingomyelin, cytidine-diphospho-choline or citicoline female patients suffering from one of the diseases listed 15 or CDP-choline, acylglycerophosphocholines, e.g., leci- above. The adjustment in dosage to select optimally ef- thin, lysolecithin, glycerophosphatidylcholine, mixtures fective pharmaceutical dose is a routine procedure well thereof or the like. The choline or compound that disso- known to the practitioner skilled in the relevant art. The ciates into choline is administered so that a choline level terms"therapeutically" or "pharmaceutically" or "pharma- of at least about 20-30 nanomoles and usually between cologically effective dose" of a drug as used hereinafter 20 10 and 50 nanomoles is attained in a patient’s blood or means the amount (dosage) of the drug that provides brain. desired clinical effect in at least 10% of treated[0030] The pharmacologically effective doses are with- patients" population. in about 20 mg and 50 g/day range, preferably between [0024] Various other uridine-based compounds other about 100 mg and 10 g/day. Doses are administered ei- than uridine itself serve as uridine source or uridine pre- 25 ther as a single dose or divided in several doses, e.g., cursors. These are uridine-rich food or dietary products 10 mg to 1 g/cap or tab. The minimal duration of the like algae; salts of uridine like uridine phosphates, acylat- therapy is at least one day but longer periods of time are ed uridine or the like. usually required according to the exigency of the therapy. [0025] If required by the exigency of the therapy, ther- If needed, the usual time period spans from one day to apeutically or pharmacologically effective doses of acyl 30 the period of lifetime. When these compounds are not derivatives of uridine or mixtures thereof like those dis- available in pure form the active ingredient comprises at closed in U.S. Pat. No. 5,470,838 are also administered. leastabout 20-30 percent of theweight of the preparation. [0026] If required by the exigency of the therapy, ther- The clinical study is continued for at least 1 day or longer apeutically or pharmacologically effective doses of urid- as required by the exigencies of the therapy. In general, ine phosphorylase inhibitors like 5-benzyl barbiturate de- 35 the dose administered, the frequency of administration rivatives or mixtures thereof as disclosed in U.S. Pat. No. and the duration of the treatment will vary as a function 5, 141, 943 are also administered. ofthe condition of the patient and isdetermined according [0027] If required by the exigency of the therapy, ther- to standard clinical procedures known to the practitioner apeutically or pharmacologically effective doses of urid- skilled in the relevant art. ine secretion inhibiting compounds like dilazep, hex-40 [0031] When possible clinical studies as disclosed in obendine, or mixtures thereof as disclosed in U.S. PAT. any preceding examples are preceded by in vivo studies No. 5,567, 689 are also administered. in animal models, e.g., gerbil model, according to proce- [0028] If required by the exigency of the therapy, ther- dures established in the art. apeutically or pharmacologically effective doses of com- pounds which compete with uridine in kidney clearance 45 like L-uridine, L-2’,3’-dideoxyuridine, and D-2’,3’-dideox- Claims yuridine or mixtures thereof as disclosed in U.S. Pat. Nos. 5,723,449 and 5,567,689 are also administered. Thera- 1. Use of (a) uridine or a uridine source and (b) choline, peutically or pharmacologically effective doses of uridine a choline precursor, a choline salt or ester, or a mix- as defined herein are also doses that produce blood or 50 ture thereof, in the manufacture of a composition for brain levels of cytidine ranging between 0.1 micromole treating cognitive dysfunction associated with aging (mM) and 1 m illimole (mM). In general, therapeutically or and/or for slowing down or reversing brain-aging. pharmacologically effective doses as defined herein are also doses of drugs combination, which produce desired 2. The use according to claim 1, wherein the choline effect in at least 10% of treated patients population. Dos- 55 precursor is sphingomyelin, cytidine-diphospho- es are administered either as a single dose or divided in choline, acylglycerophosphocholine (AGP-choline), several doses. Drugs are administered orally such as in phosphatidylcholine (PC), or a combination thereof. tablet, capsule or liquid form or parenterally by intrave-

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3. The use according to any of claims 1 or 2, wherein 3. L’utilisation selon l’une quelconque des Revendica- the choline salt is choline chloride, choline bitartrate, tions 1 ou 2, où le sel de choline est chlorure de choline stearate or mixtures thereof. choline, bitartrate de choline, stéarate de choline, ou des mélanges de ceux-ci. 4. The use according to any of claims 1-3, wherein the 5 uridine or uridine source is administered in dosages 4. L’utilisation selon l’une quelconque des Revendica- between about 10 mg and 10 grams per day. tions 1 à 3, où l’uridine ou la source d’uridine est administrée dans des dosages entre environ 10 mg 5. The use according to any of claims 1-4, wherein the et 10 grammes par jour. uridine source comprises uridine salts or a food prod- 10 uct containing uridine. 5. L’utilisation selon l’une quelconque des Revendica- tions 1 à 4, où la source d’uridine comprend des sels d’uridine ou un produit alimentaire contenant de l’uri- Patentansprüche dine. 15 1. Verwendung (a) von Uridin oder einer Uridinquelle und (b) von Cholin, einem Cholinvorläufer, einem Cholinsalz oder -ester oder einer Mischung davon für die Herstellung einer Zusammensetzung zur Be- handlung von altersbedingter kognitiver Dysfunktion 20 und/oder zur Verlangsamung oder Umkehrung von Hirnalterung.

2. Verwendung nach Anspruch 1, wobei der Cholinvor- läufer Sphingomyelin, Cytidin-Diphospho-Cholin, 25 Acylglycerophosphocholin (AGP-Cholin), Phospha- tidylcholin (PC) oder eine Kombination davon ist.

3. Verwendung nach einem der Ansprüche 1 oder 2, wobei das Cholinsalz Cholinchlorid, Cholinbitartrat, 30 Cholinstearat oder eine Mischung davon ist.

4. Verwendung nach einem der Ansprüche 1 bis 3, wo- bei das Uridin oder die Uridinquelle in Dosierungen zwischen etwa 10 mg und 10 Gramm pro Tag ver- 35 abreicht wird.

5. Verwendung nach einem der Ansprüche 1 bis 4, wo- bei die Uridinquelle Uridinsalze oder ein Nahrungs- mittelprodukt, das Uridin enthält, umfasst. 40

Revendications

1. L’utilisation de (a) uridine ou une source d’uridine et 45 (b) choline, un précurseur de choline, un sel ou ester de choline, ou un mélange de ceux-ci, dans la fabri- cation d’une composition destinée au traitement d’un dysfonctionnement cognitif associé au vieillisse- ment et/ou à ralentir ou inverser un vieillissement du 50 cerveau.

2. L’utilisation selon la Revendication 1, où le précur- seur de choline est sphingomyéline, cytidine-diphos- pho-choline, acylglycérophosphocholine (AGP-cho- 55 line), phosphatidylcholine (PC), ou une combinaison de ceux-ci.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 4960759 A, De Luca [0007] • US 5567689 A [0009] [0027] [0028] • US 5470838 A, von Borstel [0008] [0025] • US 5723449 A [0009] [0028] • US 5141943 A [0009] [0026]

Non-patent literature cited in the description

• CORNFORD et al. Independent blood-brain barrier • MONTICONE GF et al. On the therapeutic use of the transport systems for nucleic acid precursors.Bio- nucleosides, cytidine and uridine, in some neurolog- chim. Biophys. Acta, 1975, vol. 349, 211-219 [0002] ical diseases. Minerva Med., 19 December 1966, vol. • DAWSON. Enzymic conversion of uridine nucleotide 57 (101), 4348-4352 [0006] to cytidine precursor by rat brain.J. Neurochem., • LOPEZ-COVIELLA et al. Evidence that 5’-cyti- 1968, vol. 15, 31-34 [0004] dinephosphocholine can affect brain phospholipid • BECROFT DM et al. Hereditary orotic aciduria: long- composition by increasing choline and cytidine plas- term therapy with uridine and a trial of uracil. J Pedi- ma levels. J. Neurochemistry, 1995, vol. 65, 889-894 atr., November 1969, vol. 75 (5), 885-891 [0006] [0021] • ROBERTS CA et al. Uridine anticonvulsant effects: • GINSBURG et al. Rodent models of cerebral selective control of nucleoside incorporation in exper- ischemia. Stroke, 1989, vol. 20, 1627-1642 [0022] imental epilepsy. Epilepsia, December 1974, vol. 15 (4), 479-500 [0006]

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