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Use of Uridine in Combination with Choline for the Treatment Of

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Use of Uridine in Combination with Choline for the Treatment Of (19) TZZ ¥ _T (11) EP 2 329 829 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) 16.04.2014 Bulletin 2014/16 A61K 31/685 (2006.01) A61P 25/28 (2006.01) (21) Application number: 10075661.8 (22) Date of filing: 30.07.1999 (54) Use of uridine in combination with choline for the treatment of neurological disorders Verwendung von Uridin in Kombination mit Cholin zur Behandlung neurologischer Erkrankungen Utilisation de l’uridine en combinaison avec la choline pour le traitement des maladies neurologiques (84) Designated Contracting States: • CACABELOSR ET AL: "THERAPEUTIC EFFECTS AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU OF CDP-CHOLINE IN ALZHEIMER’S DISEASE MC NL PT SE COGNITION, BRAIN MAPPING, CEREBROVASCULAR HEMODYNAMICS, AND (30) Priority: 31.07.1998 US 95002 P IMMUNE FACTORS", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, NEW YORK (43) Date of publication of application: ACADEMY OF SCIENCES, NEW YORK, NY, US, 1 08.06.2011 Bulletin 2011/23 January 1996 (1996-01-01), pages 399-403, XP008065562, ISSN: 0077-8923 (62) Document number(s) of the earlier application(s) in • SPIERS P A ET AL: "CITICOLINE IMPROVES accordance with Art. 76 EPC: VERBAL MEMORY IN AGING", ARCHIVES OF 09173495.4 / 2 145 627 NEUROLOGY, AMERICAN MEDICAL 07116909.8 / 1 870 103 ASSOCIATION, CHICAGO, IL, US, vol. 53, no. 5, 99937631.2 / 1 140 104 1 May 1996 (1996-05-01), pages 441-448, XP008028412, ISSN: 0003-9942 (73) Proprietor: Massachusetts Institute of Technology • WEISS G B: "Metabolism and actions of CDP- Cambridge, Massachusetts 02142-1601 (US) choline as an endogenous compound and administered exogenously as citicoline.", LIFE (72) Inventors: SCIENCES 1995 LNKD- PUBMED:7869846, vol. • Watkins, Carol 56, no. 9, 1995, pages 637-660, XP002640081, Cambridge, MA 02142 (US) ISSN: 0024-3205 • Wurtman, Richard J. • D’ORLANDO K J ET AL: "Citicoline (CDP- Boston, MA 02116 (US) choline): mechanisms of action and effects in ischemic brain injury.", NEUROLOGICAL (74) Representative: Pearl Cohen Zedek Latzer Baratz RESEARCH AUG 1995 LNKD- PUBMED: 7477743, UK LLP vol. 17, no. 4, August 1995 (1995-08), pages 15 Old Bailey 281-284, XP009149054, ISSN: 0161-6412 London EC4M 7EF (GB) • PICCOLI F ET AL: "CDP- choline in the treatment of chronic cerebrovasculopathies", ARCHIVES (56) References cited: OF GERONTOLOGY AND GERIATRICS, WO-A-97/45127 DE-A1- 2 508 474 ELSEVIER, AMSTERDAM, NL, vol. 18, no. 3, 1 May DE-A1- 2 629 845 US-A- 4 221 784 1994 (1994-05-01), pages 161-168, XP023512323, US-A- 4 609 647 US-A- 4 960 759 ISSN: 0167-4943, DOI: DOI: 10.1016/0167-4943(94) US-A- 5 567 689 90010-8 [retrieved on 1994-05-01] 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 2 329 829 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 329 829 B1 • KARKISHCHENKO N N; MAKLYAKOV YU S; STRADOMSKII B V: "Use of uridine as antidepressant - shows its reduced toxicity and elimination of several harmful side effects", DERWENT, 30 November 1993 (1993-11-30), XP002302971, • DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1986, MERLINI G ET AL: "EFFECTS OF LARGE DOSES OF PYRIMIDINE NUCLEOSIDES CYTIDINE AND URIDINE IN ELDERLY PATIENTS WITH NEUROPSYCHOLOGICAL DISTURBANCES CAUSED BY VASCULAR AND CEREBRAL METABOLIC INSUFFICIENCY", XP002640124, Database accession no. PREV198783027367 & GAZZETTA MEDICA ITALIANAARCHIVIO PER LE SCIENZE MEDICHE, vol. 145, no. 6, 1986, pages 379-390, ISSN: 0393-3660 2 1 EP 2 329 829 B1 2 Description ible. Moreover, Dawson himself states that he was una- ble to recover a nucleotide with spectrophotometric char- [0001] The present invention relates to uridine or a uri- acteristics of cytidine and admits that his conclusions dine source in combination with choline, a choline pre- were based on probabilistic guessing. Thus, the alleged cursor, a choline salt or ester, or a mixture thereof, for 5 phenomenon observed by Dawson may have been due use in treating neurological disorders associated with the to misinterpretation of an experimental artifact as it is dopaminergic pathway, such as schizophrenia or Parkin- now known that experimentally measurable cytidine can son’s disease, cognitive dysfunction stroke andbe easily confused with tyrosine, which is chemically un- ischemia. related amino acid compound (see Fig. 1). 10 [0005] Thus, even though an enzyme catalyzing the DESCRIPTION OF THE RELATED ART 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 15 warrant practical exploitation for clinical application. In- comprising human patients, leads to increased levels of 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- 20 enzymes and metabolic pathways, this particular en- ever, the potential benefit of uridine or uridine source 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- 25 present in another animal, e.g., man. Based on that one brain barrier (Cornford et al., independent blood-brain 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 pyrimidine compounds, enzymes are known 30 of the process of uridine to cytidine conversion for any in the art, such as cytidine deaminase (EC 3.5.4.5), which meaningful application. converts cytidine into uridine. Cytidine deaminase can [0006] Uridine is a pyrimidine nucleoside 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- 35 uses of uridine alone are limited to treatment of genetic zyme classification) list there are no known examples of 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 uracil. J Pediatr. 1969 Nov; 75 (5): 885-891). Other to cytidine conversion is also limited. Only one publica- 40 less common uses of uridine alone are known such as tion, citing two earlier references, seems to exist, wherein 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 45 used in combination with cytidine (Monticone GF, et al., cytidine precursor by rat brain. J. Neurochem. 15:31-34, On the therapeutic use of the nucleosides, 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- 50 diseases to a number of neurological and cerebrovascu- ered as 100%), the highest levels of newly converted 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.
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