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||||||IIII USO05506231A United States Patent (19) 11 Patent Number: 5,506,231 Lipton 45 Date of Patent: Apr ||||||IIII USO05506231A United States Patent (19) 11 Patent Number: 5,506,231 Lipton 45 Date of Patent: Apr. 9, 1996 (54) TREATMENT OF AIDS DEMENTIA, Davenport et al., Eur. J. Pharm. 154:73-78 (1988). MYELOPATHY AND BLNDNESS Goldenberg et al., J. Pharm. and Exp. Therapeutics 245:1081-1087 (1988). 75 Inventor: Stuart A. Lipton, Newton, Mass. Hahn et al., Proc. Natl. Acad. Sci. USA 85:6556-6560 (1988). 73) Assignee: The Children's Medical Center Ho et al., Annals of Internal Med. 111:400-410 (1989). Corporation, Boston, Mass. Turski et al., Nature 349:414-418 (1989). Kornhuber et al., European J. Pharm. 166:589-590 (1989). (21) Appl. No.: 6,326 Borman, European J. Pharm. 166:591-592 (1989). Aizenman et al., Neuron 2:1257-1263 (1989). 22 Filed: Jan. 21, 1993 Sernagor et al., Neuron 2:1221-1227 (1989). Seubert et al., Brain Research 492:366-370 (1989). Related U.S. Application Data Turski Arzneim-Forsch/Drug Res. 40 (I) Nr. 5 (1990). 63 Continuation-in-part of Ser. No. 571,949, Aug. 23, 1990, Müller SCRIP 1515 p. 28 (1990). abandoned, Ser. No. 939,824, Sep. 3, 1992, Pat. No. 5,334, Asanaka et al. 112 Chem. Abstract 232458q (1990). 618, and Ser. No. 949,342, Sep. 22, 1992, Pat. No. 5,234, Krieglstein et al., 112 Chem. Abstract 112:522c (1990). 956, which is a continuation of Ser. No. 688,965, Apr. 19, Nuglisch et al., 113 Chem. Abstract 113: 224453q (1990). 1991, abandoned, said Ser. No. 571,949, is a continuation in-part of Ser. No. 502,296, Mar. 30, 1990, Pat. No. 5,053, Lipton et al., Neurosci. Abstracts 18:757, No. 321.11, 1992. 419, which is a continuation-in-part of Ser. No. 331,872, Lipton et al. Trends in Neurosci. 15:75-79 (1992). Mar. 31, 1989, said Ser. No. 939,824, is a continuation-in Lipton et al. Nature 367: 113-114 (1994). part of Ser. No. 680,201, Apr. 4, 1991, abandoned. Dreyer et al., “HIV-1 Coat Protein Neurotoxicity Prevented (51 Int. Cl. ....................... A61K 31/44; A61K 31/135; by Calcium Channel Antagonists', Science 248:364-367, A61K 31/13 Apr. 20, 1990. Lipton et al., Neuron, vol. 7: 111-118, 1991. 52 U.S. Cl. .......................... 514/289; 514/284; 514/647; Lo et al., Brain Research, “HIV-1 envelope protein evokes 514/661; 514/662 intracellular calcium oscillations in rat hippocampal neu 58) Field of Search ..................................... 514/661, 662, rons', Brain Research, 594:189-196 (1992). 514/284, 289,647 Perovic et al., “The triaminopyridine flupirtine prevents cell death in rat cortical cells induced by N-Methyl-D-aspartate 56 References Cited and gp120 of HIV-1”, Eur. J. of Pharmacol., 228:27-33 U.S. PATENT DOCUMENTS (1994). 3,328,251 6/1967 Smith. Miller et al., "gp 120 of HIV-1 induces apoptosid in rat 3,391,142 7/1968 Mills et al.. cortical cell cultures: prevention by memantine', Eur, J. of 3,456,057 7/1969 Cairns et al. Pharmac., 226:209-214 (1992). 4,122,193 10/1978 Scherm et al.. Giulian et al., “The envelope glycoprotein of human immu 4,148,896 4/1979 Smith et al.. nodeficiency virus type 1 stimulates release of neurotoxins 4,273,774 6/1981 Scherm. from monocytes', Proc. Natl. Acad. Sci. USA, 4,351,847 9/1982 Griffith et al.. 90:2769-2773 (1993). 4,806,543 2/1989 Choi. Rytik et al., “Susceptibility of Primary Human Glial Fibril 4,812,458 3/1989 Honore et al.. lary Acidic Protein-Positive Brain Cells to Human Immu 4,837,218 6/1989 Olney . nodeficiency Virus Infection. In Vitro ... ', Aids Res. and 5,053,419 10/1991 Lipton ..................................... 514,356 Human Retroviruses 7:89-95 (1991). 5,061,703 10/1991 Bormann et al. Brightbart et al., The Lancet 2(8626):1488-1489 (1988). FOREIGN PATENT DOCUMENTS Meldrum et al., "Excitatory amino acid neurotoxicity and 0002065 5/1979 European Pat. Off.. neurodegenerative disease”, Trends in Pharmac. Sciences, WO/90/11761 10/1990 WIPO. 11:379-387 (1990). WO/91/0280 3/1991 WIPO. Primary Examiner-Marianne M. Cintins OTHER PUBLICATIONS Assistant Examiner-William R. A. Jarvis Attorney, Agent, or Firm-Fish & Richardson Merk Index 10th Ed. No. A7, 1983. Merk Index 10th Ed. No. 8116, 1983. 57) ABSTRACT Merk Index 10th Ed. No. 373, 1983. Choi et al., J. Pharm. and Exp. Therapeutics 242:713-720 Damage to CNS neurons of a human patient infected with a (1987). human immunodeficiency virus is reduced by administering Pomerantz et al., New Eng. Med. 317:1643-1647 (1987). an antagonist of the NMDA receptor complex. Brenneman et al., Nature 335:639-642 (1988). Price et al., Science 239:586-590 (1988). 17 Claims, 8 Drawing Sheets U.S. Patent Apr. 9, 1996 Sheet 1 of 8 5,506,231 SURVIVING RETINAL GANGLION CELLS (% OF CONTROL) FIG. 1 100 N to4. gp120-RF2rgp 120-3B 80 60 40 20 O O -13 - 12 - 11 - O -9 -8 log concentration (M) SURVIVING RETINAL FIG. 2 GANGLION CELS 40 E3 Solitary 2O Z clustered 100 % % 80 W. % 60 2 % 2040% 2 W% O s2 RS A 4 2 s 2 & A N E ON U.S. Patent Apr. 9, 1996 Sheet 2 of 8 5,506,231 N 3.0- o 200 pM gp2O O 20 pm gp120 2.5 2 pV gp2O 2.0 ca?"), (AM) 1.5 O O.5 O 2 4. 6 8 10 FIG. 3a TIME (MN) 2.5 2.0 (Ca2), (AM) 1.5 1.0 0.5 O.O O 2OO 400 600 FIG. 3b CONCENTRATION (pM) U.S. Patent Apr. 9, 1996 Sheet 3 of 8 5,506,231 1.5 O 0.5 FIG 4 0.0 NCONTROL. gp120 gp120 t gp120 + PRE-- POST -- MMUNE IMMUNE N 3.0 -o 20O pM gpl2O a 200 pMgpi2O+ OO nM NIMODPINE 2.5 2.0 (Ca2), (AM) 1.5 1.0 0.5 0.0 FIG. 7 0 2 TIME4 (MIN)6 8 10 U.S. Patent Apr. 9, 1996 Sheet 4 of 8 5,506,231 SURVIVING RETNAL GANGLON CELLS 140 Solitary F G 5a 120 2 clustered 1 OO 80 3. / CONTROL" gp12O-3BNIFEDIPINE gp120 + (OAM) NIFEDIPINE SURVIVING RETNAL GANGLON CELLS 100 Solitary FIG. 5b 80 7 clustered 60 40 20-3, v. V. contropia orf2 NFE refereof (IOM) NIFEDIPINE U.S. Patent Apr. 9, 1996 Sheet 5 of 8 5,506,231 SURVIVING RETINAL GANGLION CELLS 18O solitary 160 Z clustered FIG. 6a 140 120 OO 80 60 CONTROL gp12O-3B NIFEDIPINE gp120 + (IAM) NIFEDIPINE SURVIVING RETNAL GANGLION CELLS 140 Solitary FIG. 6b 120 7 Z clustered 100 80 60 40 20 r O. E.4 1. A. CONTROL g pia O-3BN MODIPINE gp12O+ (IAM) NIMODIPINE U.S. Patent Apr. 9, 1996 Sheet 6 of 8 5,506,231 EN|d|CJE–INST]Tid A1 HA OA OG|SUu U.S. Patent Apr. 9, 1996 Sheet 7 of 8 5,506,231 d aC "H st Y d C % SN O t C 4. O O 3 3 S. S O C3. s U.S. Patent Apr. 9, 1996 Sheet 8 of 8 5,506,231 Ca'), (uM) 2 Control gp120 gp120 gp120 -- APV -- MK801 FIG. 1 O 5,506,231 1 2 TREATMENT OF AIDS DEMENTIA, acting at the agonist binding site; un-competitive NMDA MYELOPATHY AND BLNDNESS antagonists, blocking the NMDA channel; NMDA antago nists operating at the glycine site of the NMDA receptor; This application is a continuation-in-part of the following NMDA antagonists operating at the polyamine site of the commonly owned U.S. patent applications: NMDA receptor; NMDA antagonists operating at the redox 1. U.S. Ser. No. 07/571,949, filed Aug. 23, 1990 (now site of the NMDA receptor; and non-competitive NMDA abandoned), which was a continuation in part of U.S. antagonists; inhibitors of NMDA receptor-stimulated pro Ser. No. 071502,296, filed Mar. 30, 1990, now issued as tein kinase C activation. U.S. Pat. No. 5,053,419, which in turn was a continu In a second aspect, the invention features methods of ation in part of U.S. Ser. No. 07/331,872, filed Mar. 31, O reducing damage to CNS neurons in a human patient 1989; infected with a human immunodeficiency virus by admin 2. U.S. Ser. No. 07/939,824, filed Sep. 3, 1992, now istering to said patient atherapeutic composition comprising issued as U.S. Pat. No. 5,334,68, which was a con compound which is capable of reducing the gp120-respon tinuation in part of U.S. Ser. No. 07/680,201, filed Apr. sive rise in free Cation concentration in said CNS neurons 15 of said patient, in a concentration effective to cause such 4, 1991 (now abandoned); and reduction. In addition to the NMDA receptor complex 4. U.S. Ser. No. 07/949,342, filed Sep. 22, 1992, now antagonists mentioned above, and antagonists of the volt issued as U.S. Pat. No. 5,234,956, which in turn was a age-dependent Ca-H ion channel, e.g., those described in continuation of U.S. Ser. No. 07/688,965 Apr. 19, 1991 U.S. Pat. No. 5,053,419, hereby incorporated by reference, (abandoned). 20 the invention also features administering other compounds U.S. Ser. No. 07/677,365 is hereby incorporated by refer capable of reducing the gp120-responsive rise in free Ca C. ion concentration in the patient's CNS neurons, in a con BACKGROUND OF THE INVENTION centration effective to cause such a reduction.
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