Use of Uridine in Combination with Choline for the Treatment of Memory Disorders
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(19) & (11) EP 2 322 187 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 18.05.2011 Bulletin 2011/20 A61K 31/7072 (2006.01) A61K 31/14 (2006.01) A61K 31/685 (2006.01) A61P 25/28 (2006.01) (21) Application number: 10075660.0 (22) Date of filing: 30.07.1999 (84) Designated Contracting States: (72) Inventors: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU • Watkins, Carol MC NL PT SE Cambridge, MA 02142 (US) • Wurtman, Richard J. (30) Priority: 31.07.1998 US 95002 P Boston, MA 02116 (US) (62) Document number(s) of the earlier application(s) in (74) Representative: Maury, Richard Philip accordance with Art. 76 EPC: Marks & Clerk LLP 09173495.4 / 2 145 627 90 Long Acre 07116909.8 / 1 870 103 London 99937631.2 / 1 140 104 WC2E 9RA (GB) (71) Applicant: Massachusetts Institute of Technology Remarks: Cambridge, Massachusetts 02139 (US) This application was filed on 01-10-2010 as a divisional application to the application mentioned under INID code 62. (54) Use of uridine in combination with choline for the treatment of memory disorders (57) A preparation for use in the prevention and/or ageing, said preparation comprising (a) uridine or a uri- treatment of memory disorders, memory decline, cogni- dine source and (b) chholine, a choline precursor, a tive dysfunction, and/or slowing down or reversing brain- choline salt or ester, or a mixture thereof. EP 2 322 187 A2 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 322 187 A2 2 Description art can dismiss them either as insignificant or irreproduc- ible. Moreover, Dawson himself states that he was una- FIELD OF THE INVENTION ble to recover a nucleotide with spectrophotometric char- acteristics of cytidine and admits that his conclusions [0001] The present invention relates to methods of in- 5 were based on probabilistic guessing. Thus, the alleged creasing cytidine levels by administering an exogenous phenomenon observed by Dawson may have been due uridine source and in particular to the pharmacological to misinterpretation of an experimental artifact as it is use of said uridine or uridine source alone or in combi- now known that experimentally measurable cytidine can nation with other pharmaceutical substances in treating be easily confused with tyrosine, which is chemically un- certain neurological disorders. 10 related amino acid compound (see Fig. 1). [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- 15 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 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 20 ical modality. In addition, as it is the case with many other as administration of cytidine or cytidine precursors. How- 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 25 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 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- 30 Consequently, the prior art is silent in regard to the use tabolism of pyrimidine 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 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 35 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 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: long-term therapy with uridine and a trial [0004] The prior art relating to the process of uridine 40 of uracil. 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 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 conversion of uridine nucleotide to cytidine nucleotide 45 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, 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 par- zyme does not appear to be sufficiently potent. As com- 50 ticular dual combination range from liver and kidney dis- pared to the initial, administered dose of uridine (consid- eases to a number of neurological and cerebrovascular ered as 100%), the highest levels of newly converted diseases but such uses are irrelevant to the present in- cytidine in vivo were 12.4% in the liver and 9% in the vention directed at the use of uridine without concomitant brain. The conversion rates in vitro were 5.4% in the liver use with cytidine. and 8.05% in the brain. Thus, maximum observed levels 55 [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 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 2 3 EP 2 322 187 A2 4 al., teach that the benefit of uridine is due to increase in polio syndrome, and muscular dystrophies are also pos- cholecystokinin levels in the brain, which in turn improves sible. It is also possible to imagine the methods of treating 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 5 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- [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 von10 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 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 15 covery that uridine administration in humans leads to in- use both forms of pyrimidines since it was not obvious crease in systemic and braincytidine. While certain meth- to them that uridine alone is effective. The absolute re- ods of treatment of certain neurological diseases using quirement of both cytidine and uridine was due to the uridine are known the prior art has heretofore failed to lack of knowledge and anticipation in the prior art that provide methods of treatment of diseases which are ob- uridine might convert into cytidine, especially in humans.