USOO6989376B2 (12) United States Patent (10) Patent No.: US 6,989,376 B2 Watkins et al. (45) Date of Patent: Jan. 24, 2006 (54) METHODS FOR INCREASING BLOOD 2003/0114415 A1 6/2003 Wurtman et al. ............. 514/51 CYTIDINE AND/OR URIDINE LEVELS AND TREATING CYTIDNE-DEPENDENT HUMAN FOREIGN PATENT DOCUMENTS DISEASES EP O178267 * 4/1986 EP O178267 A2 * 4/1986 (75) Inventors: Carol Watkins, Cambridge, MA (US); JP 07/215879 A * 8/1995 Richard J. Wurtman, Boston, MA JP T215879 * 8/1995 (US) JP 09/30976 A2 * 2/1997 JP 2001/233776 A2 * 8/2001 (73) Assignee: Massachusetts Institute of 2003. A. : is: Technology, Cambridge, MA (US) WO WO 89/03837 A1 * 5/1989 (*) Notice: Subject to any disclaimer, the term of this W woo. S. A1 *: E. patent is extended or adjusted under 35 WO 974.3899 * 11/1997 U.S.C. 154(b) by 0 days. WO WO 97/43899 A1 * 11/1997 WO WO97/43899 A1 * 11/1997 (21) Appl. No.: 09/363,748 WO WO97/45127 A1 * 12/1997 WO 974.5127 * 12/1997 (22) Filed: Jul. 30, 1999 WO WO 97/45127 A1 * 12/1997 O O WO WO OO/5.0043 A1 * 8/2000 (65) Prior Publication Data WO WOOO/5.0043 A1 * 8/2000 US 2002/0028787 A1 Mar. 7, 2002 OTHER PUBLICATIONS Related U.S. Application Data Page et al., “Developmental Disorder Associated with (60) Provisional application No. 60/095,002, filed on Jul. 31, Increased Cellular Nucleotidase Activity,” Proc. National 1998. Academy of Sciences USA, 94(21), 11601-11606 (Oct. 14, (51) Int. Cl. 1997).* A6 IK3I/70 (2006.01) (Continued) (52) U.S. Cl. .............................. 514/50; 514/49; 514/51 Primary Examiner Thomas C. McKenzie (58) Field of Classification Search ................... 514/49, ASSistant Examiner-L. E. Crane 514/50, 51 (74) Attorney, Agent, or Firm-Pearl Cohen Zedek Latzer See application file for complete Search history. LLP; Mark Cohen (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Methods of treating certain neurological diseases using exogenous uridine or a uridine Source alone as a precursor 4,960,759 A 10/1990 De Luca et al. .............. 514/50 of endogenous cytidine, particularly in the human brain, are 5,141,943 A 8/1992 Naguib et al. ......... ... 514/270 disclosed. Methods are also disclosed wherein exogenous 3. A 8. E. SO etc. a - - - - - - - - - - 5. uridine or a uridine Source is combined either with drugs 2- Y- OaCOSS C a increasing uridine availability or with compounds that Serve 5. A : 3.19. SAGE - - - - - - - - - - 5. as a Source of choline in phospholipid synthesis. 5.962,459 A * 10/1999 Piazza et al. ............... 514/269 6,472.378 B2 * 10/2002 von Borstel et al. .......... 514/50 8 Claims, 3 Drawing Sheets 0.2000 -0.2000 - 0.1000 - 0.1000 w 11.99 0.00-- ---, -, -----a-0.0000 5.00 0.00 1100 US 6,989,376 B2 Page 2 OTHER PUBLICATIONS Ott et al. (I), “Effects of RNA Precursors on Development and Maintenance of Long-Term Memory,” Psychopharma Coirault et al., “Uridine 5-Triphosphate in Therapy. I. Cure cologia, 28(2), 195-204 (1973); Chemical Abstracts, of Neurogenic Muscular Atrophy.” La Presse Medicale(Fr.), 78(19), p. 77, Abstr. No. 119731q, (May 14, 1973).* 68(29), 1127–1129 (Jun. 11, 1960); Chemical Abstracts, Ott et al. (II), “Influence of 6-AZauridine on Facilitation of 57(7), p. 73, Abstract No. 10485f (Oct. 1, 1962).* Relearning by Precursors of Ribonucleic Acid.” Psychop Merlini et al., “Effects of Large Doses of Pyrimidine harmacologia, 23(3), 272-278 (1972); Chemical Abstracts, Nucleosides Cytidine and Uridine in Elderly Patients with 76(25), p. 103, Abstr. No. 149588z, (Jun. 19, 1972).* Neuropsychological Disturbances Caused by Vascular and A. Lehninger, Biochemistry, Second Edition, Worth Publish Cerebral Metabolic Insufficiency,” Gazzetta Medica Italiana ers, Inc., New York, NY, Jul., 1978, only pp. 735-737 Archivio Scienze Mediche, 145(6), 379–390 (Jun., 1966); Supplied.* Biological Abtracts, 83, Abstract No. 27367 (1987).* Gallai et al. (I), “Effects of Uridine in the Treatment of Gibbons et al., Biochemistry of Cholesterol, Elsevier Bio Diabetic Neuropathy: An Electrophysiological Study,” Acta medical Press, New York, NY, 1982, only pp. 258 and 259 Neurol. Scand., 86(1), 3–7 (1992); Biological Abtracts, 94, Supplied.* Abstract No. 112030 (1992).* Lodish et al., Molecular Cell Biology, W. H. Freeman & Co., Gallai et al. (II), “Multi-Infarct Dementia: Modification of New York, NY, 2000, only pp. 68–78 supplied, see espe the P300 Cognitive Event-Related Potential in Patients cially pp. 75–76.* Treated with the Association of Cytidine and Uridine,” Zaffaroni et al., “Adrenal Conversion of C. Labeled Cho Rivista di Neuropsichiatria e Science Afini, 41(1), 1-9 lesterol and Acetate to Adrenal Cortical Hormones,” Journal (1995); BIOSIS, 1996, Abstract Citation No. 466219; only of the American Chemical Society, 73, 1390–1391 (Mar. Abstract supplied.* 1951).* Drago et al., “Memory Deficits of Aged Male Rats Can Be Kato et al., “Determinants of Sex Hormone Levels in Men Improved by Pyrimidine Nucleosides and N-Acetyl as Useful Indices in Hormone-Related Disorders,” Journal glutamine,” Clinical Neuropharmacology, 13(4), 290–296 of Clinical Epidemiology, 45(12), 1417–1421 (Dec., 1992).* (1990); Biological Abstracts, 90, Abstract No. 91117 (YA) Gibbons et al., Biochemistry of Cholesterol, Elsevier (1990).* Biomedical Press, New York, NY, 1982, only pp. 258 and Manna et al., “Effects of Short-Term Administration of 259 Supplied.* Cytidine, Uridine and L-Glutamine Alone or in Combina (ZA) Lodish et al., Molecular Cell Biology, W. H. Freeman tion on the Cerebral Electrical Activity of Patients with & Co., New York, NY, 2000, only pp. 68-78 supplied, see Chronic Cerebrovascular Disease.” Intl. Journal Clinical especially pp. 75-76.* Pharmacology Research, 8(3), 199–210 (1988); Biological Abstracts, 86, Abstract No. 51989 (1988).* (RB) Zaffaroni et al., “Adrenal Conversion of C14 Labeled Keilbaugh et al., “Anti-Human Immunodeficiency Virus Cholesterol and Acetate to Adrenal Cortical Hormones,” Type 1 Therapy and Peripheral Neuropathy: Prevention of Journal of the American Chemical Society, 73, 1390-1391 2',3'-Dideoxycytidine Toxicity in PC12 Cells, a Neuronal (Mar, 1951).* Model, by Uridine and Pyruvate,” Molecular Pharmacol (SB) Kato et al., “Determinants of Sex Hormone Levels in ogy, 44(4), 702–706 (Oct. 1, 1993); BIOSIS, 1994, Abstract Men as Useful Indices in Hormone-Related Disorders,” Citation No. 413648. Journal of Clinical Epidemiology, 45(12), 1417–1421 (Dec., Popov et al., “Protective Effect of Uridine on D-Galac 1992).* tosamine-Induced Deficiency in Brain Uridine Phosphates.” R. Page et al., “Developmental Disorder Associated with Biomedica Biochimica Acta, 43(12), 1399–1404 (1984); Increased Cellular Nucleotidase Activity,” Proc. National Biological Abstracts, 80, Abstract No. 34525 (1985).* Academy of Sciences USA, 94(21), 11601-11606 (Oct. 14, Ingraham et al., “Nucleoside Diphosphokinase from Salmo 1997).* nella typhimurium,” Chapter 48 in Methods in Enzymology, (S) Coirault et al., “Uridine 5-Triphosphate in Therapy. I. LI(vol. 51), Hoffee et al. (eds.), New York, NY, 1978, Cure of Neurogenic Muscular Atrophy,” La Presse Medi Academic Press, only pp. 371 and 375 Supplied; assorted cale(Fr.), 68(29), 1127–1129 (Jun. 11, 1960); Chemical portions of other chapters were also Supplied including pp. Abstracts, 57(7), p. 73, Abstract No. 10485f (Oct. 1, 1962).* 305, 306, 318, 327, 329 and 330.* (T) Merlini et al., “Effects of Large Doses of Pyrimidine Miyazaki et al., “Effects of Nucleotides on Learning and Nucleosides Cytidine and Uridine in Elderly Patients with Memory in a Morris Water Maze Test in Normal and Basal Neuropsychological Disturbances Caused by Vascular and Forebrain-Lesioned Rats,” Life Sciences, 64(1), 45-52 Cerebral Metabolic Insufficiency,” Gazzetta Medica Italiana (Nov. 27, 1998).* Archivio Scienze Medic. Entingh et al., “Brain Uridine Monophosphate: Reduced (U) Gallai et al. (I), “Effects of Uridine in the Treatment of Incorporation of Uridine During Avoidance Learning.” Diabetic Neuropathy: An Electrophysiological Study,” Acta Brain Research, 70(1), 131-138 (Apr. 12, 1974); only Neurol. Scand., 86(1), 3-7 (1992); Biological Abtracts, 94, abstract Supplied.* Abstract No. 112030 (1992).* Rithrich et al., “Increase of Guanosine Incorporation into (V) Gallai et al. (II), “Multi-Infarct Dementia: Modification RNA of Hippocampal Neurons by Application of Uridine of the P300 Cognitive Event-Related Potential in Patients Monophosphate During a Learning Experiments, Brain Treated with the Association of Cytidine and Uridine,” Research, 69(1), 49-55 (Mar. 29, 1974); only abstract Sup Rivista di Neuropsichiatria e Science Affini, 41(1), 1-9 plied.* (1995); BIOSIS, 1996, Ab.* US 6,989,376 B2 Page 3 (W) Drago et al., “Memory Deficits of Aged Male Rats Can Gallai et al.(I), “Effects of Uridine in the Treatment of Be Improved by Pyrimidine Nucleosides and N-Acetyl Diabetic Neuropathy An Electrophysiological Study,” Acta glutamine,” Clinical Neuropharmacology, 13(4), 290–296 Neurol. Scand., 86(1), 3-7 (1992); Biological Abstracts, 94, (1990); Biological Abstracts, 90, Abstract No. 91117 Abstract No. 112030 (1992); only Abstract supplied.* (1990).* Gallai et al.(II), “Multi-Infarct Dementia: Modification of (X) Manna et al., “Effects of Short-Term Administration of the P300 Cognitive Event-Related Potential in Patients Cytidine, Uridine and L-Glutamine Alone or in Combina Treated with the Association of Cytidine and Uridine,” tion on the Cerebral Electrical Activity of Patients with Rivista di Neuropsichiatria e Science Afini, 41(1), 1-9 Chronic Cerebrovascular Disease.” Intl. Journal Clinical (1995); BIOSIS, 1996, Abstract Citation No. 466219; only Pharmacology Research, 8(3).* Abstract supplied.* (Y)Keilbaugh et al., “Anti-Human Immunodeficiency Virus Drago et al., “Memory Deficits of Aged Male Rats Can Be Type 1 Therapy and Peripheral Neuropathy: Prevention of 2 Improved by Pyrimidine Nucleosides and N-Acetyl 3"Dideoxycytidine Toxicity in PC12 Cells, a Neuronal glutamine,” Clinical Neuropharmacology, 13(4), 290–296 Model, by Uridine and Pyruvate,” Molecular Pharamcology, (1990); Biological Abstracts, 90, Abstract No.