Details of the Drug Combination

General Information of Drug Combination (ID: DCTFQ3X)

• Drug Combination Name: Ketamine + Morphine
• Indication: Progressive Infantile Idiopathic Scoliosis; Status: Phase 2 [1]
• Component Drugs:
  Ketamine (DMT5HA4): Small molecular drug
  Morphine (DMRMS0L): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ketamine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[2]
Anxiety	N.A.	Approved	[3]
Bipolar disorder	6A60	Approved	[3]
Depression	6A70-6A7Z	Approved	[3]
Traumatic brain injury	NA07.Z	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]
Chronic pain	MG30	Investigative	[3]

Ketamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
N-methyl-D-aspartate receptor (NMDAR)	TT9IK2Z	NOUNIPROTAC	Antagonist	[8]

Ketamine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[9]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[9]

Ketamine Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Zinc finger protein SNAI2 (SNAI2)	OT7Y8EJ2	SNAI2_HUMAN	Increases Expression	[7]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Increases Expression	[7]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[10]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[7]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[11]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[7]
Protein S100-A4 (S100A4)	OTLRGFSQ	S10A4_HUMAN	Increases Expression	[7]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[12]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Increases Expression	[7]
Sodium/hydrogen exchanger 6 (SLC9A6)	OT5N47TC	SL9A6_HUMAN	Decreases Expression	[11]

Indication(s) of Morphine

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[5]
Chronic pain	MG30	Approved	[6]
Pain	MG30-MG3Z	Approved	[5]
Diarrhea	ME05.1	Investigative	[5]

Morphine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Modulator	[16]

Morphine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[17]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[18]

Morphine Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[19]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[20]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[21]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[22]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[23]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[24]

Morphine Interacts with 22 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Response	[25]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Response	[25]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[26]
LIM homeobox transcription factor 1-beta (LMX1B)	OTM8145D	LMX1B_HUMAN	Increases Expression	[27]
Krueppel-like factor 7 (KLF7)	OTS3YVA0	KLF7_HUMAN	Increases Expression	[28]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[29]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Increases Expression	[30]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[31]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Expression	[32]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[33]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[33]
Kappa-type opioid receptor (OPRK1)	OTXCZF4L	OPRK_HUMAN	Increases Activity	[34]
C-C motif chemokine 8 (CCL8)	OTCTWYN8	CCL8_HUMAN	Increases Secretion	[31]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Increases Secretion	[26]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Increases Phosphorylation	[29]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[35]
DNA damage-binding protein 2 (DDB2)	OTO8HVVB	DDB2_HUMAN	Increases Expression	[27]
Ninjurin-1 (NINJ1)	OTLRZ1EU	NINJ1_HUMAN	Increases Expression	[27]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[27]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Increases Chemical Synthesis	[36]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases ADR	[37]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases ADR	[37]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Acute Pain	DC0BTFI	N. A.	Phase 1	[38]

References

• [1] ClinicalTrials.gov (NCT02571491) Comparison of the Efficacy of Ketamine in Pediatric Patients With Idiopathic Scoliosis After Surgery
• [2] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 076092.
• [3] Ketamine FDA Label
• [4] ClinicalTrials.gov (NCT04365985) Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19. U.S. National Institutes of Health.
• [5] Morphine FDA Label
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-1. Am J Physiol Renal Physiol. 2017 Oct 1;313(4):F961-F972. doi: 10.1152/ajprenal.00686.2016. Epub 2017 Mar 22.
• [8] Ketamine modulates theta and gamma oscillations. J Cogn Neurosci. 2010 Jul;22(7):1452-64.
• [9] Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos. 2002 Jul;30(7):853-8.
• [10] Ketamine hypertension and the renin-angiotensin system. Clin Exp Hypertens A. 1983;5(6):875-83. doi: 10.3109/10641968309081814.
• [11] Ketamine promotes the amyloidogenic pathway by regulating endosomal pH. Toxicology. 2022 Apr 15;471:153163. doi: 10.1016/j.tox.2022.153163. Epub 2022 Apr 1.
• [12] Lipoxin A4 methyl ester attenuated ketamine-induced neurotoxicity in SH-SY5Y cells via regulating leptin pathway. Toxicol In Vitro. 2023 Jun;89:105581. doi: 10.1016/j.tiv.2023.105581. Epub 2023 Mar 11.
• [13] Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Pharmacogenetics. 2000 Nov;10(8):679-85. doi: 10.1097/00008571-200011000-00002.
• [14] Isoform selectivity and kinetics of morphine 3- and 6-glucuronidation by human udp-glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7. Drug Metab Dispos. 2003 Sep;31(9):1086-9. doi: 10.1124/dmd.31.9.1086.
• [15] Inhibition of NF-B by opioids in T cells. J Immunol. 2013 Nov 1;191(9):4640-7. doi: 10.4049/jimmunol.1300320. Epub 2013 Sep 25.
• [16] Antianalgesia: stereoselective action of dextro-morphine over levo-morphine on glia in the mouse spinal cord.J Pharmacol Exp Ther.2005 Sep;314(3):1101-8.
• [17] Genetic variability and clinical efficacy of morphine. Acta Anaesthesiol Scand. 2005 Aug;49(7):902-8.
• [18] Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 2007 Feb;453(5):661-73.
• [19] Modulation of UDP-glucuronosyltransferase 2B7 function by cytochrome P450s in vitro: differential effects of CYP1A2, CYP2C9 and CYP3A4. Biol Pharm Bull. 2005 Oct;28(10):2026-7.
• [20] Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties. Drug Metab Dispos. 2008 Apr;36(4):688-94.
• [21] Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors. J Pharmacol Exp Ther. 2004 Feb;308(2):547-54.
• [22] In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos. 2005 May;33(5):689-95.
• [23] Molecular cloning of the baboon UDP-glucuronosyltransferase 2B gene family and their activity in conjugating morphine. Drug Metab Dispos. 2010 Apr;38(4):545-53.
• [24] Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug Metab Dispos. 1998 Jun;26(6):507-12.
• [25] Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008 Apr;83(4):559-66.
• [26] Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway. FEBS J. 2009 Apr;276(7):2022-36. doi: 10.1111/j.1742-4658.2009.06938.x.
• [27] Morphine induces DNA damage and P53 activation in CD3+ T cells. Biochim Biophys Acta. 2009 Aug;1790(8):793-9. doi: 10.1016/j.bbagen.2009.04.011. Epub 2009 May 3.
• [28] Identification of opioid-regulated genes in human lymphocytic cells by differential display: upregulation of Krppel-like factor 7 by morphine. Exp Cell Res. 2003 Dec 10;291(2):340-51. doi: 10.1016/s0014-4827(03)00408-7.
• [29] Mechanisms of the inhibition of nuclear factor-B by morphine in neuronal cells. Mol Pharmacol. 2012 Apr;81(4):587-97. doi: 10.1124/mol.111.076620. Epub 2012 Jan 18.
• [30] Effect of opium addiction on new and traditional cardiovascular risk factors: do duration of addiction and route of administration matter?. Lipids Health Dis. 2008 Nov 3;7:42. doi: 10.1186/1476-511X-7-42.
• [31] Morphine treatment of human monocyte-derived macrophages induces differential miRNA and protein expression: impact on inflammation and oxidative stress in the central nervous system. J Cell Biochem. 2010 Jul 1;110(4):834-45. doi: 10.1002/jcb.22592.
• [32] Morphine inhibits human microglial cell production of, and migration towards, RANTES. J Psychopharmacol. 2000;14(3):238-43. doi: 10.1177/026988110001400307.
• [33] opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes. J Neuroimmunol. 2013 Oct 15;263(1-2):35-42. doi: 10.1016/j.jneuroim.2013.07.012. Epub 2013 Jul 25.
• [34] In vivo and in vitro evaluation of novel -opioid receptor agonist compounds. Eur J Pharmacol. 2015 Nov 15;767:193-200. doi: 10.1016/j.ejphar.2015.10.025. Epub 2015 Oct 20.
• [35] Morphine induces apoptosis of human endothelial cells through nitric oxide and reactive oxygen species pathways. Toxicology. 2009 Feb 4;256(1-2):83-91. doi: 10.1016/j.tox.2008.11.015. Epub 2008 Nov 25.
• [36] Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases. J Pharmacol Exp Ther. 1996 Nov;279(2):713-7.
• [37] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [38] ClinicalTrials.gov (NCT01900847) Ketamine and Morphine Versus Morphine Alone for the Treatment of Acute Pain in the Emergency Department