Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases

11980,595

16/969713

February 14, 2019

This preventive or therapeutic agent for inflammatory diseases or bone diseases, and this pharmaceutical composition for preventing or treating inflammatory diseases or bone diseases include, as effective components, a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. [chemical expression included] [In formula (1), X is a hydrogen atom, a halogen atom, or a C1-C10 alkyl group that may be substituted; R1 is a C1-C10 alkyl group that may be substituted, a C1-C10 alkenyl group that may be substituted, or a C6-C14 aryl group that may be substituted; and one or more hydrogen atoms may be substituted with deuterium atoms.]

National University Corporation Chiba University (Chiba, JP)

National University Corporation Chiba University (Chiba, JP)

1. A method of preventing or treating ulcerative colitis or Crohn's disease in a subject in need thereof, comprising administering to the subject a composition comprising a compound of formula (1) or a pharmacologically acceptable salt thereof: [chemical expression included] wherein the composition comprises less than 0.15 mol % of a compound of formula (3) compared to an amount of the compound of formula (1): [chemical expression included] wherein in formula (1) and formula (3), X represents a hydrogen atom, a halogen atom, or a C 1 -C 10 alkyl group that may be substituted; R 1 represents a C 1 -C 10 alkyl group that may be substituted, a C 1 -C 10 alkenyl group that may be substituted, or a C 6 -C 14 aryl group that may be substituted; and one or more hydrogen atoms may be substituted for deuterium atoms.

2. The method according to claim 1 , wherein the compound of formula (1) is represented by formula (2) or a pharmacologically acceptable salt thereof: [chemical expression included] and wherein the compound of formula (3) is represented by formula (4) or a pharmacologically acceptable salt thereof: [chemical expression included]

3. The method of claim 1 , wherein the composition is a pharmaceutical composition comprising a pharmacologically acceptable carrier.

4. The method of claim 1 , wherein the composition does not contain the compound of formula (3).

5. The method of claim 2 , wherein the composition does not contain the compound of formula (4).

6. The method of claim 1 , wherein the composition is formulated for oral, nasal, intravenous, subcutaneous or intramuscular administration.

7. The method of claim 1 , wherein the composition is in the form of a liquid, solution, suspension, powder, tablet, coated tablet, capsule, troche, cream, suppository, gel, patch, liniment or aerosol.

8. The method of claim 1 , comprising administering a therapeutically effective amount of the composition to the subject.

9. The method of claim 8 , wherein the therapeutically effective amount is about 0.01 mg/day to about 1,000 mg/day.

10. The method of claim 8 , wherein the therapeutically effective amount is about 0.1 mg/day to about 500 mg/day.

11. The method of claim 8 , wherein the therapeutically effective amount is about 0.1 mg/day to about 100 mg/day.

12. The method of claim 1 , wherein the compound of formula (1) or a pharmacologically acceptable salt thereof is R-ketamine.

13. The method of claim 1 , wherein the compound of formula (3) or a pharmacologically acceptable salt thereof is S-ketamine.

14. The method of claim 4 , wherein one or more hydrogen atoms in formula (1) are substituted for deuterium atoms.

3254124 May 1966 Stevens
4670459 June 1987 Sjoerdsma
5543434 August 1996 Weg
5679714 October 1997 Weg
5989582 November 1999 Weg
6040479 March 2000 Steiner et al.
6248789 June 2001 Weg
6743949 June 2004 Russo et al.
6962151 November 2005 Knoch et al.
7001609 February 2006 Matson et al.
7044125 May 2006 Vedrine et al.
7090830 August 2006 Hale et al.
7273889 September 2007 Mermelstein et al.
7713440 May 2010 Anderson
7973043 July 2011 Migaly
8785500 July 2014 Charney et al.
9539220 January 2017 Charney et al.
9592207 March 2017 Charney et al.
9610259 April 2017 Erickson et al.
9872841 January 2018 Hashimoto
9918993 March 2018 Berdahl et al.
10232117 March 2019 Halseth
10252982 April 2019 Nivorozhkin et al.
10406121 September 2019 Hashimoto
10441544 October 2019 Glue et al.
10478405 November 2019 Charney et al.
10683262 June 2020 Xiang et al.
10744094 August 2020 Glue et al.
10815196 October 2020 Chen et al.
10836714 November 2020 Xiang et al.
10869838 December 2020 Glue et al.
10881665 January 2021 Javitt
10973780 April 2021 Becker et al.
11007200 May 2021 Godek et al.
11045424 June 2021 Glue et al.
11103499 August 2021 Vepachedu et al.
11191734 December 2021 Tang et al.
11207279 December 2021 Hashimoto
11253487 February 2022 Kagan et al.
11286230 March 2022 Toupy et al.
11426367 August 2022 Witkin et al.
20040248964 December 2004 Crooks et al.
20080268071 October 2008 Gant et al.
20120225949 September 2012 Papalos
20130236573 September 2013 Singh et al.
20140057988 February 2014 Weg
20140093592 April 2014 Singh et al.
20140274981 September 2014 Basstanie et al.
20140275276 September 2014 Basstanie et al.
20140275277 September 2014 Basstanie et al.
20140275278 September 2014 Basstanie et al.
20150056308 February 2015 Charney et al.
20150057306 February 2015 Fava et al.
20150196501 July 2015 Erickson et al.
20160045455 February 2016 Drevets et al.
20160067196 March 2016 Charney et al.
20160175266 June 2016 Mermelstein et al.
20160220513 August 2016 Hashimoto
20190060254 February 2019 Sherman et al.
20190083420 March 2019 Wainer et al.
20190117591 April 2019 Basstanie et al.
20190343781 November 2019 Hashimoto
20190350879 November 2019 Jay
20200000748 January 2020 Kagan et al.
20200069674 March 2020 Vepachedu et al.
20200121619 April 2020 Rey
20200147005 May 2020 Kagan et al.
20200261442 August 2020 Vepachedu
20200297734 September 2020 Saadeh
20200360307 November 2020 Denny et al.
20200360308 November 2020 Becker et al.
20200405663 December 2020 Hashimoto
20210032194 February 2021 Kandula
20210196654 July 2021 Gershon et al.
20210251969 August 2021 Abdallah et al.
20210259993 August 2021 Witkin et al.
20210378989 December 2021 Kagan
20220041540 February 2022 Kruegel
20220071929 March 2022 Hashimoto
20220110889 April 2022 Hashimoto
20220119338 April 2022 Lin et al.
20220151955 May 2022 Wolfson et al.
20220347124 November 2022 Witkin et al.
2062 620 July 1971
3085366 October 2016
3130582 February 2017
3263108 January 2018
3689340 August 2020
1 330 878 September 1973
2008509137 March 2008
4401613 January 2010
2010525081 July 2010
2017519723 July 2017
WO 01/062932 August 2001
WO 01/098265 December 2001
WO 2004/028522 April 2004
WO-2006019962 February 2006
WO 2007/038949 April 2007
WO 2007/111880 October 2007
WO-2008134525 November 2008
WO 2011/020061 February 2011
WO 2013/138322 September 2013
WO-2015037248 March 2015
WO 2015/051259 April 2015
WO 2016/073653 May 2016
WO 2016/170124 October 2016
WO 2016/180984 November 2016
WO 2016/186968 November 2016
WO 2017/087691 May 2017
WO-2017180589 October 2017
WO 2019/065900 April 2019
WO 2019/160057 August 2019
WO 2019/169165 September 2019
WO 2019/213551 November 2019
WO 2019/243791 December 2019
WO 2020/0138491 July 2020
WO 2020/198039 October 2020
WO 2020/212510 October 2020
WO 2021/121366 June 2021
WO 2021/134086 July 2021
WO 2021/137147 July 2021
WO 2021/150985 July 2021
WO 2021/195627 September 2021
WO 2021/207359 October 2021
WO 2021/231905 November 2021
WO 2021/252971 December 2021
WO 2021/255737 December 2021

Rodan et al. Science 2000, 289 (5484), 1508-1514. cited by examiner
Webb Biochemical Pharmacology 2014, 87, 121-130. cited by examiner
Carroll, K. M. & Onken, L. S., “Behavioral Therapies for Drug Abuse,” Am J Psychiatry; 162:1452-1460 (2005). cited by applicant
Kawasaki, C. et al., “Ketamine isomers suppress superantigen-induced proinflammatory cytokine production in human whole blood,” Can J Anesth, 48(8):819-823 (2001). cited by applicant
Xiong, Z. et al., “Beneficial effects of (R)-ketamine, but not its metabolite (2R,6R)-hydroxynorketamine, in the depression-like phenotype, inflammatory bone markers, and bone mineral density in a chronic social defeat stress model,” Behavioural Brain Research, 368:111904 (2019), 7 pages; https://doi.org/10.1016/j.bbr.2019.111904. cited by applicant
Abbott, A. & Dolgin, E., “Leading Alzheimer's theory survives drug failure,” Nature, 540(7631):15-16 (2016). cited by applicant
Abi-Saab, W. M. et al., “The NMDA Antagonist Model for Schizophrenia: Promise and Pitfalls,” Pharmacopsychiat. 31(Suppl):104-109 (1998). cited by applicant
Ashry, E. E. et al., “Protective Effect of Ketamine against Acetic Acid-Induced Ulcerative Colitis in Rats,” Pharmacology & Pharmacy, 7:9-18 (2016). cited by applicant
Barch, D. M. & Ceaser, A., “Cognition in schizophrenia: core psychological and neural mechanisms,” Trends in Cognitive Sciences, 16(1):27-34 (2012). cited by applicant
Bell, D. S., “The Motivation of Addiction,” Acta Neurochir (Wien), 132:185-191 (1995). cited by applicant
Berman, R. M. et al., “Antidepressant Effects of Ketamine in Depressed Patients,” Biological Psychiatry, 47:351-354 (2000). cited by applicant
Bloch, M. H. et al., “Effects of Ketamine in Treatment-Refractory Obsessive-Compulsive Disorder,” Biol Psychiatry, 72(11):964-970 (2012). cited by applicant
Carlezon, W. A. & Wise, R. A., “Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward,” Psychopharmacology, 128:413-420 (1996). cited by applicant
Carlezon, W. A. & Chartoff, E. H., “Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation,” Nature Protocols, 2(11):2987-2995 (2007). cited by applicant
Cooper, M. D. et al., “Strategies to mitigate dissociative and psychotomimetic effects of ketamine in the treatment of major depressive episodes: a narrative review,” The World Journal of Biological Psychiatry, 18(6):410-423 (2017). cited by applicant
Deneau, G. A. & Seevers, M. H., “Pharmacological Aspects of Drug Dependence,” Advances in Pharmacology, 3:267-283 (1964). cited by applicant
Diazgranados, N. et al., “A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression,” Arch Gen Psychiatry, 67(8):793-802 (2010). cited by applicant
Diazgranados, N. et al., “Rapid Resolution of Suicidal Ideation After a Single Infusion of an N-Methyl-D-Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder,” J Clin Psychiatry, 71(12):1605-1611 (2010). cited by applicant
Diniz, B. D. et al., “Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies,” The British Journal of Psychiatry, 202:329-335 (2013). cited by applicant
Domino, E. F., “Taming the ketamine tiger,” Anesthesiology, 113(3):678-686 (2010). cited by applicant
Domino, E. F. & Luby, E. D., “Phencyclidine/Schizophrenia: One View Toward the Past, The Other to the Future,” Schizophrenia Bulletin, 38(5):914-919 (2012). cited by applicant
Ebert, B. et al., “Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord,” European Journal of Pharmacology, 333:99-104 (1997). cited by applicant
Elvevåg, B. & Goldberg, T. E., “Cognitive Impairment in Schizophrenia Is the Core of the Disorder,” Critical Reviews in Neurobiology, 14(1):1-21 (2000). cited by applicant
Erami, E. et al., “Blockade of orexin receptor 1 attenuates the development of morphine tolerance and physical dependence in rats,” Pharmacology, Biochemistry and Behavior, 103:212-219 (2012). cited by applicant
Fan, J. -C. et al., “Neuron-protective effect of subanesthestic-dosage ketamine on mice of Parkinson's disease,” Asian Pacific Journal of Tropical Medicine, 10(10):1007-1010 (2017). cited by applicant
Feder, A. et al., “Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder: A Randomized Clinical Trial,” JAMA Psychiatry, 71(6):681-688 (2014). cited by applicant
Ferro, M. M. et al., “Neuroprotective effect of ketamine/xylazine on two rat models of Parkinson's disease,” Brazilian Journal of Medical and Biological Research, 40:89-96 (2007). cited by applicant
Fidecka, S., “Interactions of Ketamine, Naloxone and Morphine in the Rat,” Pol. J. Pharmacol. Pharm., 39:33-40 (1987). cited by applicant
Freo, U. & Ori, C., “Effects of Anesthesia and Recovery from Ketamine Racemate and Enantiomers on Regional Cerebral Glucose Metabolism in Rats,” Anesthesiology, 100:1172-1178 (2004). cited by applicant
Frohlich, J. & Van Horn, J. D., “Reviewing the ketamine model for schizophrenia,” Journal of Psychopharmacology, 28(4):287-302 (2014). doi: 10.1177/0269881113512909. Epub Nov. 20, 2013; 16 pages. cited by applicant
Fujita, A. et al., “MPTP-induced dopaminergic neurotoxicity in mouse brain is attenuated after subsequent intranasal administration of (R) -ketamine: a role of TrkB signaling,” Psychopharmacology, 237:83-92 (2020); doi:10.1007/S00213-019-05346-5, Aug. 15, 2019. cited by applicant
Fukumoto, K. et al., “Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine,” J Pharmacol Exp Ther, 361:9-16 (2017). cited by applicant
Gastambide, F. et al., “Temporally distinct cognitive effects following acute administration of ketamine and phencyclidine in the rat,” European Neuropsychopharmacology, 23:1414-1422 (2013). cited by applicant
Ginski, M. J. & Witkin, J. M., “Sensitive and rapid behavioral differentiation of N-methyl-D-aspartate receptor antagonists,” Psychopharmacology, 114:573-582 (1994). cited by applicant
Golden, S. A. et al., “A standardized protocol for repeated social defeat stress in mice,” Nature Protocols, 6(8):1183-1191, (2011), including 1 page corrigendum. cited by applicant
Graf, B. M., “Ketamine Has Stereospecific Effects in the Isolated Perfused Guinea Pig Heart,” Anesthesiology, 82(6):1426-1437 (1995). cited by applicant
Hachinski, V. et al., “National Institute of Neurological Disorders and Stroke—Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards,” Stroke, 37:2220-2241 (2006). cited by applicant
Han, M. et al., “Intake of 7,8-Dihydroxyflavone During Juvenile and Adolescent Stages Prevents Onset of Psychosis in Adult Offspring After Maternal Immune Activation,” Scientific Reports, 6:36087 (2016), 10 pages; doi:10.1038/srep36087. cited by applicant
Hashimoto, K., “Emerging role of glutamate in the pathophysiology of major depressive disorder,” Brain Research Reviews, 61:105-123 (2009). cited by applicant
Hashimoto, K. et al., “Reduction of dopamine D2/3 receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys,” Eur Arch Psychiatry Clin Neurosci, 267:173-176 (2017). cited by applicant
Hashimoto, K. et al., “Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of clozapine, but not haloperidol,” European Journal of Pharmacology, 519:114-117 (2005). cited by applicant
Hashimoto, K. et al., “Phencyclidine-Induced Cognitive Deficits in Mice are Improved by Subsequent Subchronic Administration of Fluvoxamine: Role of Sigma-1 Receptors,” Neuropsychopharmacology, 32:514-521 (2007). cited by applicant
Hashimoto, K. et al., “Phencyclidine-Induced Cognitive Deficits in Mice are Improved by Subsequent Subchronic Administration of the Novel Selective α7 Nicotinic Receptor Agonist SSR180711,” Biol Psychiatry, 63:92-97 (2008). cited by applicant
Hatzigiakoumis, D. S. et al., “Anhedonia and substance dependence: clinical correlates and treatment options,” Front. Psychiatry, 2(10):1-12 (2011); https://doi.org/10.3389/fpsyt.2011.00010; 12 pages. cited by applicant
Herman, B. H. et al., “The Effects of NMDA Receptor Antagonists and Nitric Oxide Synthase Inhibitors on Opioid Tolerance and Withdrawal Medication Development Issues for Opiate Addiction,” Neuropsychopharmacology, 13(4):269-293 (1995). cited by applicant
Higgins, G. A. & Sellers, E. M., “Antagonist-Precipitated Opioid Withdrawal in Rats: Evidence for Dissociations Between Physical and Motivational Signs,” Pharmacology Biochemistry and Behavior, 48(1):1-8 (1994). cited by applicant
Higgins, G. A. et al., “The NMDA Antagonist Dizocilpine (MK801) Attenuates Motivational as well as Somatic Aspects of Naloxone Precipitated Opioid Withdrawal,” Life Sciences, 50:PL-167-PL-172 (1992). cited by applicant
Hillhouse, T. M. et al., “Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats,” Psychopharmacology, 231:2705-2716 (2014). cited by applicant
Hillhouse, T. M. & Porter, J. H., “Ketamine, but not MK-801, produces antidepressant-like effects in rats responding on a differential-reinforcement-of-low- rate operant schedule,” Behavioural Pharmacology, 25:80-91 (2014). cited by applicant
Huhn, A. S. et al., Evidence of anhedonia and differential reward processing in prefrontal cortex among post-withdrawal patients with prescription opiate dependence, Brain Research Bulletin, 123:102-109 (2016). cited by applicant
Irwin, S. A. et al., “Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial,” Journal of Palliative Medicine, 16(8):958-965 (2013). cited by applicant
Jackson-Lewis, V. & Przedborski, S., “Protocol for the MPTP mouse model of Parkinson's disease,” Nature Protocols, 2(1):141-151 (2007). cited by applicant
Javitt, D. C. & Zukin, S. R., “Recent Advances in the Phencyclidine Model of Schizophrenia,” Am J Psychiatry, 148:1301-1308 (1991). cited by applicant
Ji, D. et al., “NMDA Receptor in Nucleus Accumbens is Implicated in Morphine Withdrawal in Rats,” Neorochemical Research, 29(11):2113-2120 (2004). cited by applicant
Johnson, K. M., “Phencyclidine: it ain't excitin', but it sure is toxic,” Amino Acids, 45:588-589 (2013). cited by applicant
Jovai{hacek over (s)}a, T. et al., “Effects of ketamine on precipitated opiate withdrawal,” Medicina (Kaunas), 42(8):625-634 (2006). cited by applicant
Kadriu, B. et al., “Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder,” Molecular Psychiatry, 23:1626-1631 (2018). cited by applicant
Khanna, J. M. et al., “Effect of NMDA receptor antagonists on rapid tolerance to ethanol,” European Journal of Pharmacology, 230:23-31 (1993). cited by applicant
Kolesnikov, Y. et al., “Blockade of Morphine-Induced Hindlimb Myoclonic Seizures in Mice by Ketamine,” Pharmacology Biochemistry and Behavior, 56(3): 423-425 (1997). cited by applicant
Koob, G. F. “Neural Mechanisms of Drug Reinforcement,” In P. W. Kalivas & H. H. Samson (Eds.), Annals of the New York Academy of Sciences: New York Academy of Sciences, 654:171-191 (1992). cited by applicant
Koob, G. F. & Volkow, N. D., “Neurobiological substrates for the dark side of compulsivity in addiction,” Neuropharmacology, 56:18-31 (2009). cited by applicant
Koob, G. F., “Neurobiology of addiction: a neurocircuitry analysis,” Lancet Psychiatry, 3:760-773 (2016). cited by applicant
Khorramzadeh, E. & Lofty, A. O., “The Use of Ketamine in Psychiatry,” Psychosomatics, 14(6):344-346 (1973). cited by applicant
Koyuncuo{hacek over (g)}lu, H. et al., “Suppression by Ketamine and Dextromethorphan of Precipitated Abstinence Syndrome in Rats,” Pharmacol Biochem Behav, 35(4):829-832 (1990). cited by applicant
Krystal, J. H. et al., “Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans,” Arch Gen Psychiatry, 51:199-214 (1994). cited by applicant
Krystal, J. H. et al., “Rapid-Acting Glutamatergic Antidepressants: The Path to Ketamine and Beyond,” Biol Psychiatry, 73:1133-1141 (2013). cited by applicant
Krupitsky, E. et al., “Anhedonia, depression, anxiety, and craving in opiate dependent patients stabilized on oral naltrexone or an extended release naltrexone implant,” The American Journal of Drug and Alcohol Abuse, 42(5):614-620 (2016). cited by applicant
Langdon, K. J. et al., “Comorbidity of opioid-related and anxiety-related symptoms and disorders,” Current Opinion in Psychology, 30:17-23 (2019). cited by applicant
Lapidus, K. A. et al., “A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder,” Biol Psychiatry, Published online Apr. 3, 2014, 17 pages; doi: 10.1016/j.biopsych.2014.03.026. cited by applicant
Li, F. et al., “Cannabinoid CB1 receptor antagonist rimonabant attenuates reinstatement of ketamine conditioned place preference in rats,” European Journal of Pharmacology, 589:122-126 (2008). cited by applicant
Li, S. X. et al., “Role of the NMDA receptor in cognitive deficits, anxiety and depressive-like behavior in juvenile and adult mice after neonatal dexamethasone exposure,” Neurobiology of Disease, 62:124-134 (2014). cited by applicant
Liu, Y. et al., “Ketamine abuse potential anduse disorder,” Brain Research Bulletin, 126:68-73 (2016). cited by applicant
Lopez, O. L. et al., “Risk Factors for Mild Cognitive Impairment in the Cardiovascular Health Study Cognition Study,” Part 2, Arch Neurol., 60:1394-1399 (2003). cited by applicant
Ma, M. et al., “Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation,” PNAS, 116(14):7083-7088 (2019). cited by applicant
Matsuura, A. et al., “Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation,” Scientific Reports, 8:2158 (2018); doi:10.1038/s41598-018-20538-3,12 pages. cited by applicant
Millan, M. J. et al., “Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy,” Nature Reviews Drug Discovery, 11:141-168 (2012). cited by applicant
Miller, N. S. et al., “The Relationship of Addiction, Tolerance, and Dependence to Alcohol and Drugs: A Neurochemical Approach,” Journal of Substance Abuse Treatment, 4:197-207 (1987). cited by applicant
Mohammadi, A. et al., “Dysfunction in Brain-Derived Neurotrophic Factor Signaling Pathway and Susceptibility to Schizophrenia, Parkinson's and Alzheimer's Diseases,” Current Gene Therapy, 18:45-63 (2018). cited by applicant
Muelken, P. et al., “A Two-Day Continuous Nicotine Infusion Is Sufficient to Demonstrate Nicotine Withdrawal in Rats as Measured Using Intracranial Self-Stimulation,” PLoS One, 10(12):e0144553 (2015), 18 pages; doi:10.1371/journal.pone.0144553. cited by applicant
Napier, T. C. et al., “Using conditioned place preference to identify relapse prevention medications,” Neuroscience and Biobehavioral Reviews, 37:2081-2086 (2013). cited by applicant
Negus, S. S. & Miller, L. L., “Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs,” Pharmacol Rev 66:869-917 (2014). cited by applicant
Nikiforuk, A. & Popik, P., “The effects of acute and repeated administration of ketamine on attentional performance in the five-choice serial reaction time task in rats,” Eur Neuropsychopharmacol., 24(8):1381-1393 (2014). cited by applicant
Pan, J. et al., “Blockade of the translocation and activation of c-Jun N-terminal kinase 3 (JNK3) attenuates dopaminergic neuronal damage in mouse model of Parkinson's disease,” Neurochemistry International, 54:418-425 (2009). cited by applicant
Paslakis, G. et al., “Oral Administration of the NMDA Receptor Antagonist S-Ketamine as Add-On Therapy of Depression: A Case Series,” Pharmacopsychiatry, 43:33-35 (2010). cited by applicant
Paul, R. et al., “Comparison of racemic ketamine and S-ketamine in treatment-resistant major depression: Report of two cases,” The World Journal of Biological Psychiatry, 10(3):241-244 (2009). cited by applicant
Perry, M. B., “Perceptions of Mindfulness: A Qualitative Analysis of Group Work in Addiction Recovery,” Rhode Island Medical Journal, 102:28-31 (2019). cited by applicant
Persson, J. et al., “The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans,” Acta Anaesthesiol Scand, 42:750-758 (1998). cited by applicant
Persson, J. et al., “Pharmacokinetics and non-analgesic effects of S- and R-ketamines in health volunteers with normal and reduced metabolic capacity,” Eur J Clin Pharmacol, 57:869-875 (2002). cited by applicant
Rodriguez, C. I. et al., “Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept,” Neuropsychopharmacology, 38:2475-2483 (2013). cited by applicant
Pfenninger, E. G. et al., “Cognitive Impairment after Small-dose Ketamine Isomers in Comparison to Equianalgesic Racemic Ketamine in Human Volunteers,” Anesthesiology, 96:357-366 (2002). cited by applicant
Rowland, L. M., “Subanesthetic Ketamine: How It Alters Physiology and Behavior in Humans,” Aviat Space Environ Med, 76(7, Suppl.):C52-58 (2005). cited by applicant
Sams-Dodd, F., “Phencyclidine-induced stereotyped behaviour and social isolation in rats: a possible animal model of schhizophrenia,” Behavioural Pharmacology, 7:3-23 (1996). cited by applicant
Schmidt, A. et al., “Cerebral physiological responses to bolus injection of racemic, S(+)- or R(-)-keamine in the pig,” Acta Anaesthesiol Scand, 49:1436-1442 (2005). cited by applicant
Sekine, Y. et al., “Methamphetamine-Related Psychiatric Symptoms and Reduced Brain Dopamine Transporters Studied With PET,” Am J Psychiatry, 158:1206-1214 (2001). cited by applicant
Shearman, G. T. et al., “Effectiveness of Lofexidine in Blocking Morphine-Withdrawal Signs in the Rat,” Pharmacology Biochemistry & Behavior, 12:573-575 (1980). cited by applicant
Streel, E. et al., “Effects of anaesthetic agents in interference of naloxone-induced opiate-withdrawal are dose-dependent in opiate-dependent rats,” Life Sciences, 77:650-655 (2005). cited by applicant
Suzuki, T. et al., “Effects of the non-competitive NMDA receptor antagonist ketamine on morphine-induced place preference in mice,” Life Sciences, 67:383-389 (2000). cited by applicant
Tannock, I. F. et al., “Cognitive Impairment Associated With Chemotherapy for Cancer: Report of a Workshop,” Journal of Clinical Oncology, 22(11):2233-2239 (2004). cited by applicant
Trujillo, K. A., “Effects of Noncompetitive N-Methyl-D-Aspartate Receptor Antagonists on Opiate Tolerance and Physical Dependence,” Neuropsychopharmacology, 13:301-307(1995). cited by applicant
Tsai, S. -J., “TrkB partial agonists: Potential treatment strategy for epilepsy, mania, and autism,” Medical Hypotheses, 66:173-175 (2006). cited by applicant
Tzschentke, T. M., “Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade,” Addiction Biology, 12:227-462 (2007). cited by applicant
Van Dam, F. S. A. M., et al., “Impairment of Cognitive Function in Women Receiving Adjuvant Treatment for High-Risk Breast Cancer: High-Dose Versus Standard-Dose Chemotherapy,” J. Natl Cancer Inst, 90(3):210-218 (1998). cited by applicant
Vayr, F. et al., “Barriers to seeking help for physicians with substance use disorder: A review,” Drug and Alcholol Dependence, 199:116-121 (2019). cited by applicant
Vogels, R. L. C. et al., “Cognitive impairment in heart failure: A systematic review of the literature,” European Journal of Heart Failure, 9:440-449 (2007). cited by applicant
Volkow, N. D. et al., “Association of Dopamine Transporter Reduction With Psychomotor Impairment in Methamphetamine Abusers,” Am J Psychiatry, 158:377-382 (2001). cited by applicant
Volkow, N. D. et al., “Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects,” Nature, 386:830-833 (1997). cited by applicant
Vollenweider, F. X. et al., “Differential psychopathology and patterns of cerebral glucose utilization produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET),” Eur. Neuropsychopharmacol. 7:25-38 (1997). cited by applicant
Wang, C. et al., “Brain damages in ketamine addicts as revealed by magnetic resonance imaging,” Front. Neuroanat., vol. 7, Article 23 (2013), 8 pages; doi.org/10.3389/fnana.2013.00023. cited by applicant
White, P. F. et al., “Comparative pharmacology of the ketamine isomers,” Br. J. Anaesth., 57:197-203 (1985). cited by applicant
Wink, L. K. et al., “Intranasal Ketamine Treatment in an Adult With Autism Spectrum Disorder,” J Clin Psychiatry, 75(8):835-836 (2014). cited by applicant
Womble, A. L., “Effects of Ketamine on Major Depressive Disorder in a Patient with Posttraumatic Stress Disorder,” AANA Journal, 81(2):118-119 (2013). cited by applicant
Xiaoyin, K. et al., “The profile of cognitive impairments in chronic ketamine users,” Psychiatry Research, 266:124-131 (2018). cited by applicant
Yamamoto, N. et al., “Ketamine reduces amyloid -protein degradation by suppressing neprilysin expression in primary cultured astrocytes,” Neuroscience Letters, 545:54-58 (2013). cited by applicant
Yang, C. et al., “R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects,” Transl Psychiatry, 5:e632 (2015), 11 pages; doi:10.1038/tp.2015.136. cited by applicant
Yang, C. et al., “Loss of parvalbumin-immunoreactivity in mouse brain regions after repeated intermittent administration of esketamine, but not R-ketamine,” Psychiatry Research, 239:281-283 (2016). cited by applicant
Yoon, G. et al., “Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case Series of Patients With Depression and Alcohol Use Disorder,” JAMA Psychiatry, published online Jan. 9, 2019; doi:10.1001/jamapsychiatry.2018.3990, 2 pages. cited by applicant
Zanos, P. et al., “NMDAR inhibition-independent antidepressant actions of ketamine metabolites,” Nature, 533:481-486 (2016), and Methods, 12 pages. cited by applicant
Zarate, C. A. et al., “A Randomized Trial of an N-methyl-d-aspartate Antagonist in Treatment-Resistant Major Depression,” Arch Gen Psychiatry, 63: 856-864 (2006). cited by applicant
Zhang, J. -c, Z. et al., “R(-)-ketamine shows greater potency and longer lasting antidepressant effects than S(+)-ketamine,” Pharmacology, Biochemistry and Behavior, 116:137-141 (2014). cited by applicant
Zhang, K. et al., “Role of Inflammatory Bone Markers in the Antidepressant Actions of (R)-Ketamine in a Chronic Social Defeat Stress Model,” International Journal of Neuropsychopharmacology, 21(11):1025-1030 (2018). cited by applicant
Ago, Y. et al., “(R)-ketamine induces a greater increase in prefrontal 5-HT release than (S)-ketamine and ketamine metabolites via an AMPA receptor-independent mechanism,” Int J Neuropsychopharmacol, 22(10):665-674 (2019). cited by applicant
CDC. National Violent Death Reporting System. 2015; 2 pages; Available from: www.cdc.gov/violenceprevention/nvdrs/index.html. cited by applicant
Canuso, C.M. et al., “Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study,” Am J Psychiatry, 175(7):620-630 (2018). cited by applicant
Chan, W. -H. et al., “Induction of rat hepatic cytochrome P-450 by ketamine and its toxicological implications”, J Toxicol Environ Health A, 68(17-18):1581-1597 (2005). cited by applicant
Chang, L. et al., “Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine,” Pharmacol Biochem Behav, 181:53-59 (2019). cited by applicant
Chang, L. et al., “Lack of dopamine D1 receptors in the antidepressant actions of (R)-ketamine in a chronic social defeat stress model,” Eur Arch Psychiatry Clin Neurosci, 270:271-275 (2020). cited by applicant
Ezquerra-Romano, I. I. et al., “Ketamine for the treatment of addiction: Evidence and potential mechanisms,” Neuropharmacology, 142:72-82 (2018). cited by applicant
Ide, S. et al. “Cognitive impairment that is induced by (R)-ketamine is abolished in NMDA GluN2D receptor subunit knockout mice,” Int J Neuropsychopharmacol, 22(7):449-452 (2019). cited by applicant
Ivanova, J. I. et al., “Direct and indirect costs of employees with treatment-resistant and non-treatment-resistant major depressive disorder,” Curr Med Res Opin, 26(10):2475-2484 (2010). cited by applicant
Janssen Pharmaceutical Companies. Medication Guide Spravato™ CIII (esketamine) nasal spray: prescribing information. 2020. Titusville, NJ, USA, 44 pages. cited by applicant
Klepstad, P. et al., “Evidence of a role for NMDA receptors in pain perception,” Eur J Pharmacol, 187(3):513-518 (1990). cited by applicant
Leal, G. C. et al., “Intravenous arketamine for treatment-resistant depression: open-label pilot study,” Eu Arch Psych Clin Neurosci, 271:577-582 (2021). cited by applicant
Li, J. -M. et al., “Ketamine may exert antidepressant effects via suppressing NLRP3 inflammasome to upregulate AMPA receptors,” Neuropharmacology, 146:149-153 (2019). cited by applicant
Mathisen, L.C. et al., “Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain,” Pain, 61(2):215-220 (1995). cited by applicant
Mizukami,K., “Alzheimer's Disease and Depression,” Journal of Neurology, 115(11):1122-1125 (2013). English Abstract Only. cited by applicant
Mudter, J. & Neurath, M. F., “IL-6 Signaling in Inflammatory Bowel Disease: Pathophysiological Role and Clinical Relevance,” Inflamm Bowl Dis., 13(8):1016-1023 (2007). cited by applicant
Oye, I. et al., “Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors,” J Pharmacol Exp Ther, 260(3):1209-1213 (1992). cited by applicant
Pfenninger, E. G. et al., “Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers,” Anesthesiology, 96(2):357-366 (2002). cited by applicant
Shah, S. et al., “Combination of oral ketamine and midazolam as a premedication for a severely autistic and combative patient,” J Anesth, 23:126-128 (2009). cited by applicant
Sheehan, D. V. et al., “The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10,” J Clin Psychiatry, 59 Suppl 20:22-33 (1998). cited by applicant
Shirayama, Y. & Hashimoto, K., “Effects of a single bilateral infusion of R-ketamine in the rat brain regions of a learned helplessness model of depression,” Eur Arch Psychiatry Clin Neurosci, 267(2):177-182 (2017). cited by applicant
Shirayama & Hashimoto, “Lack of antidepressant effects of (2R,6R)-hydroxynorketamine in a rat learned helplessness model: comparison with (R)-ketamine,” Int J Neuropsychopharmacol, 21(1):84-88 (2018). cited by applicant
Souery, D. et al., “Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study,” J Clin Psychiatry, 68(7):1062-1070 (2007). cited by applicant
Tian, Z. et al., “Expression of heat shock protein HSP-70 in the retrosplenial cortex of rat brain after administration of (R,S)-ketamine and (S)-ketamine, but not (R)-ketamine,” Pharmacol Biochem Behav, 172:17-21 (2018). cited by applicant
WHO. Depression. 2017; 5 pages; Available from: www.who.int/news-room/factsheets/detail/depression. cited by applicant
Yang, C. et al., “(R)-ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine,” Biol Psychiatry, 82(5):e43-e44 (2017), 2 pages. cited by applicant
Yang, C. et al., “Possible role of the gut microbiota-brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model,” Transl Psychiatry, 7(12):1294 (2017), 11 pages. cited by applicant
Yang, C. et al., “AMPA Receptor Activation-Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine,” Biol Psychiatry, 84(8):591-600 (2018). cited by applicant
Zanos, P. et al., “(R)-ketamine exerts antidepressant actions partly via conversion to (2R,6R)-hydroxynorketamine, while causing adverse effects at sub-anesthetic doses,” Br J Pharmacol, 176(14):2573-2592 (2019). cited by applicant
Zanos, P. & Gould, T. D., “Intracellular signaling pathways involved in (S)- and (R)-ketamine antidepressant actions,” Biol Psychiatry, 83(1):2-4 (2018). cited by applicant
Zanos, P. et al., “Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms,” Pharmacol Rev, 70(3):621-660 (2018). cited by applicant
Zhang, M. et al., “Effects of subanesthetic intravenous ketamine infusion on neuroplasticity-related proteins in the prefrontal cortex, amygdala, and hippocampus of Sprague-Dawley rats,” IBRO Rep, 6:87-94 (2019). cited by applicant
Coiro, P. et al., “Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders,” Brain, Behavior, and Immunity, 50:249-258 (2015). cited by applicant
Solanki, I. et al., “Neurodegenerative diseases: From available treatments to prospective herbal therapy,” Neurochemistry International, 95:100-108 (2016). 17 pages provided. cited by applicant
Zhu, W. et al., “Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant,” Neurosci. Bull., 32(6):557-564 (2016). cited by applicant
Ruda-Kucerova, J. et al., “Both ketamine and NBQX attenuate alcohol drinking in male Wistar rats,” Neuroscience Letters, 2018, 666:175-180. cited by applicant
Mion, G. & Villevieille, T., “Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings),” CNS Neurosci Ther., 19(6):370-80 (2013); doi: 10.1111/cns.12099. Epub Apr. 10, 2013. cited by applicant
Bremner, J. D. et al., “Measurement of Dissociative States with the Clinician-Administered Dissociative States Scale (CADSS),” Journal of Traumatic Stress, 11(1):125-136 (1998). cited by applicant
Daly, E. J. et al., “Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression A Randomized Clinical Trial,” JAMA Psychiatry, 2018; 75(2): 139-148. doi: 10.1001/jamapsychiatry.2017.3739; Published online Dec. 27, 2017. cited by applicant
Enarson, M. C. et al., “Clinical Experience with Oral Ketamine,” Journal of Pain and Symptom Management, 17(5):384-386 (1999). cited by applicant
Fava, M. et al., “Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD),” Molecular Psychiatry (2020) 25:1592-1603, https://doi.org/10.1038/s41380-018-0256-5. cited by applicant
Galvez, V. et al., “Long-Lasting Effects of a Single Subcutaneous Dose of Ketamine for Treating Melancholic Depression: A Case Report,” Biol. Psychiatry, 2014; 76 e1-e2, 2 pages. cited by applicant
George, D. et al., “Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression,” Am J Geriatr Psychiatry 2017; 25:1199-1209. cited by applicant
Glue, P. et al., “Safety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disorders,” Journal of Psychopharmacology 2018, vol. 32(6) 663-667. cited by applicant
Hasler, F. et al. Acute psychological and physiological effects of psilocybin in healthy humans: A double-blind, placebo-controlled dose-effect study. Psychopharmacology (2004); 172(2):145-156. cited by applicant
Kavalali, E. T. & Monteggia, L. M., “Synaptic Mechanisms Underlying Rapid Antidepressant Action of Ketamine,” Am J Psychiatry 2012; 169:1150-1156. cited by applicant
Kroenke, K. et al., “The PHQ-9 Validity of a Brief Depressive Severity Measure,” J Gen Intern Med, 16:606-613 (2001). cited by applicant
Loo, C. K. et al., “Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression,” Acta Psychiatr Scand 2016: 134: 48-56. cited by applicant
Murrough, J. W. et al., “Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression,” Biol Psychiatry 2013;74:250-256; dx.doi.org/10.1016/j.biopsych.2012.06.022. cited by applicant
Overall, J. E. & Gorham, D. R., “The Brief Psychiatric Rating Scale,” Psychological Reports, 10:799-812 (1962). cited by applicant
Pambianco, D. J. et al., “Computer-assisted personalized sedation for upper endoscopy and colonoscopy: a comparative, multicenter randomized study,” Gastrointest Endosc 2011;73:765-72. cited by applicant
Reich, D. L. & Silvay, G., “Ketamine: an update on the first twenty-five years of clinical experience,” Can J Anaesth, 1989, 36(2): 186-197. cited by applicant
Reus G.Z., et al., “A Single Dose of S-Ketamine Induces Long-Term Antidepressant Effects and Decreases Oxidative Stress in Adulthood Rats Following Maternal Deprivation,” Developmental Neurobiology, Nov. 2015, vol. 75(11), pp. 1268-1281. cited by applicant
Rugani, F. et al., “Symptomatological Features of Patients with and without Ecstasy Use during Their First Psychotic Episode,” Int. J. Environ. Res. Public Health 2012, 9: 2283-2292; doi:10.3390/ijerph9072283. cited by applicant
Sanacora, G., “New Understanding of Mechanisms of Action of Bipolar Medications,” J Clin Psychiatry 2008; 69 (suppl 5): 22-27, 6 pages. cited by applicant
Schmid, R. L. et al., “Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes,” Pain, 82:111- 125 (1999). cited by applicant
Singh, J. B. et al., “A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression,” AmJ Psychiatry 2016; 173:816-826; doi: 10.1176/appi.ajp.2016.16010037. cited by applicant
Singh, J. B. et al., “Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study,” Biological Psychiatry, 80(6):424-431 (2016). cited by applicant
Singh, V. et al., “Intranasal Ketamine and Its Potential Role in Cancer-Related Pain,” Pharmacotherapy 2018; 38(3):390-401; doi: 10.1002/phar.2090. cited by applicant
Spitzer, R. L. et al., “Validation and Utility of a Self-report Version of PRIME-MD. The PHQ Primary Care Study,” Nov. 1999, JAMA The Journal of the American Medical Association 282(18):1737-1744. cited by applicant
Spitzer, R. L. et al., “Validity and utility of the PRIME-MD Patient Health Questionnaire in assessment of 3000 obstetric-gynecologic patients: The PRIME-MD Patient Health Questionnaire Obstetrics-Gynecology Study,” Am J Obstet Gynecol 2000;183:759-769. cited by applicant
Studerus, E et al. (2010) Psychometric evaluation of the altered states of consciousness rating scale (OAV). PloS One, 5:e12412, 19 pages. cited by applicant
Tamoaka et al., “Differential Diagnosis and Current Treatment of Dementia” Divine Healing, 2016. Vol. 33 No. 2 pp. 125-130. cited by applicant
Vollenweider, F. X. et al., “Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG),” European Neuropsychopharmacology 7 (1997) 9-24. cited by applicant
Zarate, C. A. et al., “Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial,” Biol Psychiatry 2012;71:939- 946; doi:10.1016/j.biopsych.2011.12.010. cited by applicant
Zhuo, C. et al., “Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment-resistant depression: A protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans,” Brain and Behavior, 2019; 9:e01423, 11 pages; doi.org/10.1002/brb3.1423. cited by applicant
Gammaitoni, A. et al., “Topical Ketamine Gel: Possible Role in Treating Neuropathic Pain,” Pain Medicine, 1(1):97-100 (2000). cited by applicant
Krupitsky, E. et al., “Ketamine Psychotherapy for Heroin Addiction: Immediate Effects and Two-year Follow-up”, Journal of Substance Abuse Treatment, vol. 23, No. 4, pp. 273-283, 2002. cited by applicant
Krupitsky, E. M. et al., “Ketamine psychedelic therapy (KPT): A review of the results of ten years of research”, Journal of Psychoactive Drugs, vol. 29, No. 2, Jan. 1, 1997, pp. 165-183. cited by applicant
Wang, S. & Li, C., “Synthesis of anesthetic compound 2-(o-fluorophenyl)-2-methylaminocyclohexanone hydrochloride (F-ketamine),” Beijing Daxue Xuebao, Ziran Kexueban, 1987, Issue 2, pp. 116-119, with English Abstract, 4 pages. cited by applicant
Wang, S. & Li, C., “Synthesis of anesthetic compound 2-(o-fluorophenyl)-2-methylaminocyclohexanone hydrochloride (F-ketamine),” Beijing Daxue Xuebao, Ziran Kexueban, 1987, Issue 2, Abstract, 1 page. cited by applicant

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