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(12) United States Patent (10) Patent No.: US 6,780,871 B2 Glick Et Al

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(12) United States Patent (10) Patent No.: US 6,780,871 B2 Glick Et Al USOO6780871B2 (12) United States Patent (10) Patent No.: US 6,780,871 B2 Glick et al. (45) Date of Patent: Aug. 24, 2004 (54) METHODS AND COMPOSITIONS FOR OTHER PUBLICATIONS TREATING ADDICTION DISORDERS Murray et al., “Interaction of Dextrorotary Opioids with (75) Inventors: Stanley D. Glick, Delmar, NY (US); Phencyclidine Recognition Sites in Rat Brain Membranes,” Isabelle M. Maisonneuve, Delmar, NY Life Sci., 34:1899–1911 (1984). (US) Nishikawa et al., “Evidence for, and Nature of, the Tonic Inhibitory Influence of Habenulointerpeduncular Pathways (73) Assignee: Albany Medical College, Albany, NY upon Cerebral Dopaminergic Transmission in the Rat,” (US) Brain Res., 373:324–336 (1986). Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (List continued on next page.) U.S.C. 154(b) by 0 days. Primary Examiner Marianne C. Seidel Assistant Examiner Brian-Yong S. Kwon (21) Appl. No.: 10/051,770 (74) Attorney, Agent, or Firm-Rogalskyi & Weyand, LLP (22) Filed: Jan. 18, 2002 (57) ABSTRACT (65) Prior Publication Data A method for treating an addiction disorder (Such as an US 2002/0103109 A1 Aug. 1, 2002 addiction to or dependency on Stimulants, nicotine, morphine, heroin, other opiates, amphetamines, cocaine, Related U.S. Application Data and/or alcohol) in a patient is disclosed. The method (60) Provisional application No. 60/264,742, filed on Jan. 29, includes administering to the patient a first C.B. nicotinic 2001. receptor antagonist and administering to the patient a Second (51) Int. Cl........................... A61K 31/44; A61 K9/70; Cla?s nicotinic receptor antagonist. The Second O?3 nico A61K 31/55; A61K 3.1/542 tinic receptor antagonist is different than the first CB nicotinic receptor antagonist, and the first CBA nicotinic (52) U.S. Cl. .................. 514/282; 514/343; 514/214.03; receptor antagonist and the Second O?3 nicotinic receptor 514/226.2 antagonist are administered simultaneously or non (58) Field of Search ................................. 514/343,282, Simultaneously. Compositions which include a first CB 514/214.03, 226.2 nicotinic receptor antagonist and a Second C.B. nicotinic References Cited receptor antagonist are also described. Examples of Suitable (56) CB nicotinic receptor antagonists for use in the present U.S. PATENT DOCUMENTS inventions methods and compositions include mecamylamine, 18-methoxycoronaridine, bupropion, 5,654,281 A 8/1997 Mayer et al. 5,863,927 A 1/1999 Smith et al. dextromethorphan, dextrorphan, and phamaceutically 5,965,567 A 10/1999 Archer et al. acceptable Salts and Solvates thereof. A method of evaluating 6.211,360 B1 4/2001 Glick et al. a compound for its effectiveness in treating addiction dis orders is also described. FOREIGN PATENT DOCUMENTS WO WO 99/17803 4/1999 56 Claims, 7 Drawing Sheets . 1. 100 drug M) US 6,780.871 B2 Page 2 OTHER PUBLICATIONS Fryer et al., “Noncompetitive Functional Inhibition at Diverse , Human Nicotinic Acetylcholine Receptor Sub Koyuncuoglu et al., “The Treatment of Heroin Addicts with types by Bupropion, Phencyclidine, and Ibogaine,” J. Phar Dextromethorphan: A Double-blind Comparison of Dex tromethrophan with Chlorpromazine,” Int. J. Clin. Pharma macol. Exp. Ther, 288:88-92 (1999). col. Ther, 28:147–152 (1990). Lukas et al., “International Union of Pharmacology, XX, Glick et al., “Effects and Aftereffects of Ibogaine on Mor Current Status of the Nomenclature for Nicotinic Acetyl phine Self-administration in Rats,” Europ. J. Pharmacol., choline Receptors and Their Subunits.” Pharmacol. Rev., 195:341–345 (1991). 51:397–401 (1999). Flores et al., “A Subtype of Nicotinic Cholinergic Receptor Maisonneuve et al., “Attenuation of the Reinforcing Efficacy in Rat Brain Is Comprised of 4 and 2 Subunits and Is of Morphine by 18-Methoxycoronaridine,” Euro. J. Phar Up-regulated by Chronic Nicotine Treatment,” Mol. Phar macol., 383:15–21 (1999). macol., 41:31-37 (1992). Quick et al., “3 4. Subunit-containing Nicotinic Receptors Koyuncuoglu, “The Combination of Tizanidine Markedly Dominate Function in Rat Medial Habenula Neurons.” Improves the Treatment with Dextromethorphan of Heroin Neuropharmacology, 38:769–783 (1999). Addicted Outpatients.” Int. J. Clin. Pharmacol. Ther., Reid et al., “A Nicotinic Antagonist, Mecamylamine, 33:13-19 (1995). Reduces Cue-induced Craving in Cocaine-dependent Sub Popik et al., “NMDA Antagonist Properties of the Putative jects.” Neuropsychopharmacology, 20:297-307 (1999). Antiaddictive Drug, Ibogaine,” J. Pharmacol. Exp. Ther., Glicket al., “18-MC Reduces Methamphetamine and Nico 275–753–760 (1995). Sweetnam et al., “Receptor Binding Profile Siggest Multiple tine Self-Administration in Rats,” NeuroReport, Mechanisms of Action Are Responsible for Ibogaine's Puta 11:2013–2015 (2000). tive Anti-addictive Activity,” Psychopharmacology, Glick et al., “18-Methoxycoronaridine (18-MC) and 118:369-376 (1995). Ibogaine: Comparison of Anti-addictive Efficacy, Toxicity Chen et al., “Ibogaine Block of the Nmda Receptor: in Vitro and Mechanisms of Action,” Ann. N.Y. Acad. Sci., and in Vivo Studies,” Neuropharmacology, 35:423-431 914:369-387 (2000). (1996). Glick et al., “Development of Novel Medication for Drug Glick et al., “18-Methoxycoronaridine, a Non-toxic Iboga Addicition: The Legacy of an African Shrub,” Ann. N.Y. Alkaloid Congener: Effects of Morphine and Cocaine Self Acad. Sci., 909:88-103 (2000). administration and on Mesolimbic Dopamine Release in Hernandez et al., “Dextromethorphan and its Metabolite Rats.” Brain Res., 719:29-35 (1996). Dextrorphan Block 3 4 Neuronal Nicotinic Receptors,” J. Badio et al., “Ibagaine: A Potent Noncompetitive Blocker of Pharmacol. Exp. Ther, 293:962–967 (2000). Ganglionic/Neuronal Nicotinic Receptors.” Molec. Pharma Jun et al., “Dextromethorphan Alters Methamphetamine col., 51:1–5 (1997). Self-Administration in the Rat, Pharmacol. Biochem. Pulvirenti et al., “Dextromethorphan Reduces Intravenous Behav, 67:405-409 (2000). Cocaine Self-administration in the Rat, Eur: J. Pharmacol., Levin et al., “Mecamylamine Preferentially Inhibits Cocaine 321:279-283 (1997). Rezvani et al., “Attenuation of Alcohol Consumption by a Versus Food Self-administration in Rats.” Soc. Neurosci. Novel Non-toxic Ibogaine Analog (18-Methoxycoronari Abstr., 26:1821 (2000). dine) in Alcohol Preferring Rats.” Pharmacol. Biochem. Glicket al., “Comparative Effects of Dextromethorphan and Behav, 58:615–619 (1997). Dextrorphan on Morphine, Methamphetamine, and Nicotine Ebert et al., “Opioid Analgesics as Noncompetitive N-meth Self-administration in Rats,” Europ. J. Pharmacol., yl-d-aspartate (NMDA) Antagonists,” Biochem. Pharma 422:87–90 (2001). col., 56:533–559 (1998). Klink et al., “Molecular and Physiological Diversity of Glick et al., “Mechanisms of Anti-addictive Actions of Nicotinic Acetylcholine Receptors in the Midbrain Dopam Ibogaine,” Ann. N.Y. Acad. Sci., 844, 214-226 (1998). inergic Nuclei,” J. Neurosci., 21:1452–1463 (2001). Mah et al., “Ibogaine Acts at the Nicotinic Acetylcholine Papke et al., “Analysis of Mecamylamine Steroisomers on Receptor to Inhibit Catecholamine Release,” Brain Res., Human Nicotinic Receptor Subtypes,” J. Pharmacol. Exp. 797:173–180 (1998). Ther, 297:646–656 (2001). U.S. Patent Aug. 24, 2004 Sheet 1 of 7 US 6,780,871 B2 ACh FIGURE 1B O. O 1 OO drug (prM) U.S. Patent Aug. 24, 2004 Sheet 2 of 7 US 6,780,871 B2 FIGURE 2 18MC ACh as FIGURE 3A 18MC GLU FIGURE 3B U.S. Patent Aug. 24, 2004 Sheet 3 of 7 US 6,780,871 B2 FIGURE 4 SHT BO 5HT 18MC Occa Recr-P A saw Control Control toolpa 10 Sec FIGURE 5 Baseline Treatment Mec 1 18MC 1 DM 5 Mec 1 Mec 1 DM 5 18MC 1 DM 5 18MC 1 Treatment U.S. Patent Aug. 24, 2004 Sheet 4 of 7 US 6,780,871 B2 FIGURE 6 Treatment Mec 1 18MC 2 DM5 Mec 1 Mec 1 DM 5 18MC 2 DM 5 18MC 2 Treatment FIGURE 7 1200 Treatment 1000 Mec 1 18MC 2 DM 5 Mec 1 Mec 1 DM 5 18MC 2 DM 5 18MC 2 Treatment U.S. Patent Aug. 24, 2004 Sheet 5 of 7 US 6,780,871 B2 FIGURE 8 45 Baseline 40 Treatment 2 Mec 18Mc1 DM52. Bup5 Mec1 DM5 18Mc1 Bup5 Bup5 Bup5 Treatment FIGURE 9 - 35 Baseline Treatment 5 30 E 25 S 20 E 15 2- 10 E. : e O Mec 1 18MC5 DM10 Bup 10 Mec1 DM10 18MC5 Bup 10 Bup 10 Bup10 Treatment U.S. Patent Aug. 24, 2004 Sheet 6 of 7 US 6,780,871 B2 FIGURE 10 Baseline 1 2O O Treatment 1000 800 600 400 S. 200 g Mec 1 18MC5 DM10 Bup 10 Mec1 DM10 18MC5 Bup 10 Bup 10 Bup10 Treatment 20 Mec. 1 18MC5 DM5 Mec. 18MC5 Treatment U.S. Patent Aug. 24, 2004 Sheet 7 of 7 US 6,780,871 B2 FIGURE 2 35 Baseline ha Treatment R 30 s 25 O 5 20 C P . au G 15 SS 10 : 5 : 2. S. Mec. 1 18MC5 DM 5 Bup5 Mec. 1 DM.5 18MC.5 Bup5 Bup5 Bup5 Treatment US 6,780,871 B2 1 2 METHODS AND COMPOSITIONS FOR is a graph showing inhibition of 1 mM ACh-evoked whole TREATING ADDICTION DISORDERS cell currents by various concentrations of various drugs. FIG. 2 is a graph of whole-cell current VS. time showing The present invention claims the benefit of U.S. Provi sional Patent Application Serial No. 60/264,742, filed Jan. the effect of various drugs on whole-cell currents in cells 29, 2001, which is hereby incorporated by reference. expressing recombinant CB nicotinic receptors. The present invention was made with the Support of the FIGS. 3A and 3B are graphs of whole-cell current vs. time National Institute on Drug Abuse Grant No. DAO3817. The showing the effect of various drugs on whole-cell currents in Federal Government may have certain rights in this inven cells expressing recombinant NR1/2A (FIG. 3A) and NR1/ tion.
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