United States Patent (19) 11 Patent Number: 5,872,108 Sandage, Jr

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United States Patent (19) 11 Patent Number: 5,872,108 Sandage, Jr USOO5872.108A United States Patent (19) 11 Patent Number: 5,872,108 Sandage, Jr. et al. (45) Date of Patent: *Feb. 16, 1999 54 REDUCTION OF INFARCT VOLUME USING D’Orlando, K.J. et al. Neurological Research (1995) CITICOLINE 17:281-284. Abstract: “Effects of Citicoline on infarct volume, mortality 75 Inventors: Bobby W. Sandage, Jr.; Marc Fisher; and behavioral outcome after temporary local ischemia' by: Kenneth W. Locke, all of Lexington, Johannes Weber et al., dated: Jan. 9, 1995, European Stroke Mass. Conference, Bordeaux, France Jun. 1-3, 1995. Kogure, K., et al., Annals of Neurology, Vol. 8, No. 3, Sep. 73 Assignee: Interneuron Pharmaceuticals, Inc., 1980, pp. 278-290. Lexington, Mass. Grosset, D.G., et al., Journal of Cardiovascular Pharma cology, vol. 25, No. 5, 1995, pp. 705–709. * Notice: The term of this patent shall not extend Lo, Eng H., Neuroscience Letters, 131, (1991), pp. 17-20. beyond the expiration date of Pat. No. McCulloch, J., et al., Acta Neurochii, (1993)Suppl 5,801,160. 57: 73-79. Tuor, U.I., et al., Stroke, vol. 24, No. 3, Mar. 1993, pp. 21 Appl. No.: 603,102 452-457. 22 Filed: Feb. 20, 1996 Grotta, James, Stroke, Vo. 18, No. 1, Jan.-Feb. 1987, pp. 264-267. Related U.S. Application Data Ochiai, Chikayuki, et al., Stroke, Vo. 13, No. 6, Nov.-Dec. 1982, pp. 788–796. 63 Continuation-in-part of Ser. No. 399.262, Mar. 6, 1995, Barinaga, Science, vol. 272, May 3, 1996, pp. 664-666. abandoned. Demeurisse, G., et al., Stroke, Vol. 14, No. 1, Jan.-Feb. 1983, (51) Int. Cl. ............................................... A61K 31/70 pp. 77-81. 52 U.S. Cl. ................................................................ 514/49 Windholtz et al. (eds.), The Merck Index, 19" Ed., Merck & 58 Field of Search ................................................. 514/49 Co., Inc. Rahway, NJ, 1983, entry 2290 at p. 329. Makishima et al., “Treatment of Sensory-Neural Deafness 56) References Cited and Tinnitus with a Nucleic Acid Derivative, Arzeneimittel Forsch. Dish., 21.(9),1343-1349 (1971). U.S. PATENT DOCUMENTS Nilsson, “CDP-Choline-A Short Review.” Clin. Pharma 4,386,078 5/1983 Horrocks et al. ....................... 424/180 col. Drug Epidemiol. 2, 273-277 (1979). Phuong et al., “Nouvell Méthode de Préparation de al OTHER PUBLICATIONS Cytidine Diphosphate Choline (CDP Choline)", Bull. Soc. HCAPLUS abstract, AN 1988: 143195, Kakihana, M. et al. Chim. Fr. Pt. II., 1979(9–10), 518–519. (1988). Gannaro et al. (eds.), Remmington's Pharmaceutical Sci Longa, Zea et al., Stroke (1989) 20:84-91. ences, 18" ed., Mack Publishing Co., Easton, PA, 1990, see The Ancrod Study Investigators, Stroke (1994) pp. 867, 1014 and 1026 as marked. 25:1755-1759. Sanchez et al., “CDP-Choline:Physico-Chemical Charac Budavari et al., The Merck Index (11th Ed.) pp. 361-362, teristics,” Arzneimittel Forschung-Drug Research, 33(II), 1995. 1011-1012(1983). Rossi, M. et al., Medline Abstract 93230870 (Feb. 1993). Algate et al., “Study of the Effects of Oral Administration of Canino, V. et al., Medline Abstract 80188636 (1980). CDP-Choline on EEG Changes and Lethality Induced by Girafto, T. et al., Embasse Abstract 71026199 (1980). Epidural Compressions in the Anaethestized Cat.” Arznei Kaste, M. et al. Stroke (1994) 25:1348–1353. mittel Forschung-Drug Research, 33(II), Olney, J.W. et al. Science (1991) 254:1515–1518. 1013–1016(1983). Kinouchi, H. et al. Proc. Natl. Acad. Sci. USA (1991) 88:11158-11162. (List continued on next page.) Diener, H.C. et al. Stroke (1995) 26:30. Bell, R.D. et al. Stroke (1991) 22:80–83. Primary Examiner Marianne M. Cintins del Zoppo, G.J. et al. Seminars in Neurology (1991) 11(4): ASSistant Examiner M. Moezie 368-384. Attorney, Agent, or Firm-Gilberto M. Villacorta, Pepper The Ancrod Stroke Study Investigators, Stroke (1994) Hamilton LLP 25:1755-1759. 57 ABSTRACT Hacke, W. et al. Stroke (1995) 26:167. Ulus, I.H. et al. Brain Research (1989) 484:217-227. The invention is directed to a method of reducing the extent Altman R. et al. British Medical Journal (1994) of infarction, particularly cerebral infarction Subsequent to 3O8:81-106. cerebral ischemia, by the administration of citicoline shortly The Canadian Cooperative Study Group, New England after an ischemic episode and continuing daily treatment for Journal of Medicine (1978) 299:53–59. up to about 30 days, preferably for at least about 6 weeks. The ESPS Group, “The European Stroke Prevention Study.” The method is useful in the treatment of stroke and severe (1990) Stroke 21:1122–1130. head trauma patients and maximizes the chances for a full or Minematsu, K. et al. Cerebrovasc. Dis. (1993) 3:99-104. substantially full recovery of the patient. Schabitz, W. et al. Journal of the Neurological Sciences (1996) 138:21–25. 17 Claims, 1 Drawing Sheet 5,872,108 Page 2 OTHER PUBLICATIONS Romero et al. (V), “CDP-Choline: 6-Month Study on Toxicity in Dogs,” Arzneimiittle Forschung-Drug Agut et al.(I), “Dissimilar Effects in Acute Toxicity Studies of CDP-Choline and Choline, Arzneimittel Forschung Research, 33(II), 1038-1042(1983). Drug Research, 33(II), 1016–1018(1983). Dinsdale et al. (II), “Pharmacokinetics of ''C CDP-Cho Braso et al., “Action of CDP-Choline by Intraduodenal line.” Arzneimittel Forschung-Drug Research, 33(II), Route on Rat Cardiorespitory System.” Arzneimittel Fors 1066–1070(1983). chung-Drug Research, 33(II), 1043–1045(1983). Fernandez, “Efficacy and Safety of Oral CDP-Choline,” Agut et al. (III), “Radioactivity Incorporation into Different Arzneimittel Forschung-Drug Research, 33(II), Cerebral Phospholipids after Oral Administration of 'C 1073-1080(1983). Methyl CDP-Choline, Arzneimittel Forschung-Drug Table of Contents, Key Word Index and Preface (J.A. Ortiz) Research, 33(II), 1048–1050(1983). Introducing the Series of Papers on Cytidine Diphosphate Agut et al.(II, “Bioavailability of Methyl-'C CDP-Cho Choline, Arzneimittel Forschung-Drug Research, 33(II), line and Choline by Oral Route.” Arzneimittel Forschung 1009-1010 (1983) and preceding pages. Drug Research, 33(II), 1045-1047(1983). Cohen et al., “Decreased Brain Choline Uptake in Older Aguilar et al., “Cerebral Subcellular Distribution of Adults-An In Vivo Proton Magnetic Resonance Spectros CDP-Choline and/or its Metabolites after Oral Administra copy Study,” J. Am. Medical Association, tion of Methyl-'C CDP-Choline.” Arzneimittel Fors 274(11).902-907(1995). chung-Drug Research, 33(II), 1051–1053(1983). Fukunaga et al. (I). “Hypotensive Effects of Adenosine and Romero et al.(I), “Low-Resolution Autoradiography in Rat Adenosine Triphosphate Compared with Sodium Nitroprus Brain after Administering Labeled CDP-Choline Adminis side.” Anesthesia and Analgesia, 61(3), 273-278 (1982). tration.” Arzneimittel Forschung-Drug Research, 33(II), 1054–1056(1983). Trovarelli, G. et al., “Effect of Cytidine on the Modification Romero et al.(II), “High-Resolution Autoradiography in of Phospholipid Metabolism Induced by Ischemia', Neuro Mouse Brain 24 h after Radiolabelled CDP-Choline Admin chemical Research, vol. 12, No. 3, 1987, pp. 227-235. istration.” Arzneimittel Forschung-Drug Research, 33(II), Trovarelli, G. et al., “The Influence of Cytidine on the 1056–1058(1983). Endogenous Pool of CDP-Choline, CDP-Ethanolamine, Romero et al. (III), “High-Resolution Autoradiography in and CMP of the Rat Brain”, Neurochemical Research, vol. Mouse Brain and Cerebellum 10 days after Radiolabelled 9, No. 1, 1984, pp. 73–79. CDP-Choline Administration,” Arzneimittel Forschung Trovarelli, G. et al., “The Transport of Cytidine into Rat Drug Research, 33(II), 1058–1060(1983). Brain. In Vivo, and its Conversion into Cytidine Metabo Dinsdale et al. (I), “CDP-Choline Repeated Oral Dose lites”, Neurochemical Research, vol. 7, No. 10, 1982, pp. Tolerance Studies in Adult Healthy Volunteers,” Arzneimit 1199-12O7. tel Forschung-Drug Research, 33(II), 1061-1065 (1983). De Medio, G.E. et al., “The Effect of Cytidine-Diphosphate Arrannz et al. “Treatment of Chronic Dyskinesia with Choline (CDP-Choline) on Brain Lipid Changes During CDP-Choline, Arzneimittel Forschung-Drug Research, Aging”, Journal of Neuroscience Research, 11:49-58 33(II), 1071-1073(1983). (1984). Tornos et al. (I), “Effect of Oral CDP-Choline on Experi Petkov, V.D. et al., “Effects of Cytidine Diphosphate Cho mental Withdrawal Syndrome, Arzneimittel Forschung line on Rats with Memory Deficits”, Institute of Phisiology, Drug Research, 33(II), 1018–1021 (1983). Bulgarian Academy of Science, Sofia, Bulgaria, pp. Tornos et al. (II), “Pharmacological Study of CDP-Cho 822–828, (1993). line.” Arzneimittel Forschung-Drug Research, 33(II), Kottler, P.D. et al., “RNA Metabolism in the Rat Brain 1022–1024(1983). During Learning Following Intravenous and Intraventricular Grau et al.(I), “Study on the Protection of CDP-Choline Injections of 3H-Cytidine”, Physiology and Behavior, vol. against Nicotine Intoxification,” Arzneimittel Forschung Drug Research, 33(II), 1025-1026(1983). 8, pp. 219–297 (1992). Tornos et al. (III), “Pharmacological Study of Oral Wurtman, R.J. et al., “The Autocannibalism of CDP-Choline, Arzneimittel Forschung-Drug Research, Choline-Containing Membrane Phospholipids in the Patho 33(II), 1026–1029(1983). genesis of Alzheimer's Disease', Dept. of Applied Biologi Agut et al. (IV), “Effect of Oral CDP-Choline on Acryla cal Sciences, Cambridge, MA, USA and Pharmacology mide-induced Lesion.” Arzneimittel Forschung-Drug Department, Universite, Suisse Neurochem. Intl., pp. Research, 33(II), 1029-1033(1983). 369-372 (1985). Grau et al. (II), “CDP-Choline: Acute Toxicity Study,” Buyukuysal, R.L. et al., “4-Aminopyridine Increases Ace Arzneimittel Forschung-Drug Research, 33(II), tylcholine Release Without Diminishing Membrane Phos 1033–1034(1983). phatidylcholine”, Journal of Neurochemistry, vol. 54, No. 4, Romero et al. (IV), “Study of Subacute Toxicity of 1990, pp. 1302–1309. CDP-Choline after 30 days of Oral Administration to Savei, V. et al., “Effect of Cytidine on Membrane Phospho Rates.” Arzneimittel Forschung-Drug Research, 33(II), lipid Synthesis in Rat Striatal Slices”, Journal of Neuro 1035–1038 (1983).
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