Details of the Drug Combination

General Information of Drug Combination (ID: DC88V2F)

• Drug Combination Name: Sevoflurane + Remifentanil
• Indication: Haemodynamic Rebound; Status: Phase 4 [1]
• Component Drugs:
  Sevoflurane (DMC9O43): Small molecular drug
  Remifentanil (DMZTXCH): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sevoflurane

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[3]

Sevoflurane Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glutamate receptor AMPA (GRIA)	TTAN6JD	NOUNIPROTAC	Antagonist	[5]

Sevoflurane Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[7]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[8]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[9]

Sevoflurane Interacts with 60 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[10]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[11]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[11]
Glycine receptor subunit alpha-1 (GLRA1)	OT05Y9ZR	GLRA1_HUMAN	Increases ADR	[12]
Glutamate dehydrogenase 1, mitochondrial (GLUD1)	OTXKOCUH	DHE3_HUMAN	Increases Expression	[13]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[14]
GTPase HRas (HRAS)	OTWQN0DP	RASH_HUMAN	Increases Expression	[14]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Decreases Expression	[14]
Progonadoliberin-1 (GNRH1)	OTH8A44K	GON1_HUMAN	Increases Expression	[14]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[14]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Increases Expression	[14]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[10]
Insulin-like growth factor I (IGF1)	OTIIZR61	IGF1_HUMAN	Increases Expression	[14]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[15]
Integrin beta-3 (ITGB3)	OTWCK1K6	ITB3_HUMAN	Decreases Expression	[14]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[14]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Increases Expression	[13]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[14]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Increases Expression	[14]
Hepatocyte growth factor (HGF)	OTGHUA23	HGF_HUMAN	Increases Expression	[14]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Increases Expression	[14]
Cyclic AMP-dependent transcription factor ATF-2 (ATF2)	OTNIZPEA	ATF2_HUMAN	Increases Phosphorylation	[16]
Sphingomyelin phosphodiesterase (SMPD1)	OTZSMA54	ASM_HUMAN	Decreases Activity	[10]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[13]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[13]
Ephrin type-B receptor 2 (EPHB2)	OT8VZ6C5	EPHB2_HUMAN	Increases Expression	[14]
Macrosialin (CD68)	OTOYEY3J	CD68_HUMAN	Increases Expression	[14]
Merlin (NF2)	OT6E5ACG	MERL_HUMAN	Increases Expression	[14]
Pigment epithelium-derived factor (SERPINF1)	OTWZH98J	PEDF_HUMAN	Decreases Expression	[13]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[11]
Cell surface glycoprotein MUC18 (MCAM)	OTT8XKGE	MUC18_HUMAN	Decreases Expression	[14]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Increases Expression	[14]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Increases Expression	[13]
Dual specificity mitogen-activated protein kinase kinase 3 (MAP2K3)	OTI2OREX	MP2K3_HUMAN	Increases Phosphorylation	[16]
Stromal cell-derived factor 1 (CXCL12)	OT2QX5LL	SDF1_HUMAN	Increases Expression	[13]
Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6)	OTK13JKC	MP2K6_HUMAN	Increases Phosphorylation	[16]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[17]
Beta-secretase 1 (BACE1)	OTCA7B6A	BACE1_HUMAN	Increases Expression	[15]
C-X-C chemokine receptor type 4 (CXCR4)	OTUFSBX2	CXCR4_HUMAN	Increases Expression	[13]
Protein SET (SET)	OTGYYQJO	SET_HUMAN	Increases Expression	[14]
RNA-binding protein EWS (EWSR1)	OT7SRHV3	EWS_HUMAN	Increases Expression	[14]
Urokinase plasminogen activator surface receptor (PLAUR)	OTIRKKEQ	UPAR_HUMAN	Increases Expression	[14]
Alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase A (MGAT5)	OTU4DD4G	MGT5A_HUMAN	Increases Expression	[14]
Metastasis-associated protein MTA1 (MTA1)	OTBHW3S9	MTA1_HUMAN	Increases Expression	[14]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[11]
Integrin alpha-7 (ITGA7)	OTTBTAYW	ITA7_HUMAN	Decreases Expression	[14]
Interleukin-18 (IL18)	OTBB2A8O	IL18_HUMAN	Increases Expression	[14]
Metastasis-suppressor KiSS-1 (KISS1)	OT6IE3K2	KISS1_HUMAN	Decreases Expression	[14]
Mothers against decapentaplegic homolog 2 (SMAD2)	OTC6VB4K	SMAD2_HUMAN	Increases Expression	[14]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[14]
KiSS-1 receptor (KISS1R)	OTQA3J6G	KISSR_HUMAN	Decreases Expression	[14]
FXYD domain-containing ion transport regulator 5 (FXYD5)	OT81DIOD	FXYD5_HUMAN	Increases Expression	[14]
Mitogen-activated protein kinase kinase kinase 5 (MAP3K5)	OTQR6ENW	M3K5_HUMAN	Increases Phosphorylation	[16]
Oxidoreductase HTATIP2 (HTATIP2)	OT9MZ4QO	HTAI2_HUMAN	Increases Expression	[14]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[11]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Increases Expression	[11]
Pinin (PNN)	OT0HXICH	PININ_HUMAN	Increases Expression	[14]
Programmed cell death 1 ligand 1 (CD274)	OTJ0VFDL	PD1L1_HUMAN	Decreases Expression	[18]
Heparanase (HPSE)	OTPTK5VS	HPSE_HUMAN	Increases Expression	[14]
Mitochondrial pyruvate carrier 1 (MPC1)	OT6DYFUO	MPC1_HUMAN	Increases Expression	[13]

Indication(s) of Remifentanil

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[4]

Remifentanil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Agonist	[19]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Intra-abdominal and Intrapelvic Surgery	DCO1IZT	N. A.	Phase 4	[20]

References

• [1] ClinicalTrials.gov (NCT02271555) The Effects of Remifentanil on Attenuating the Hemodynamic Responses After Electroconvulsive Therapy
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7296).
• [3] Sevoflurane in COVID-19 ARDS (SevCov)
• [4] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7292).
• [5] Effects of sevoflurane on carrageenan- and fentanyl-induced pain hypersensitivity in Sprague-Dawley rats. Can J Anaesth. 2009 Feb;56(2):126-35.
• [6] Identification of cytochrome P450 2E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane, and methoxyflurane. Anesthesiology. 1993 Oct;79(4):795-807.
• [7] Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology. 1995 Mar;82(3):689-99.
• [8] Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes. Biochem Pharmacol. 2002 Oct 1;64(7):1151-6.
• [9] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [10] Different apoptosis ratios and gene expressions in two human cell lines after sevoflurane anaesthesia. Acta Anaesthesiol Scand. 2009 Oct;53(9):1192-9. doi: 10.1111/j.1399-6576.2009.02036.x. Epub 2009 Jun 30.
• [11] 4.8% sevoflurane induces activation of autophagy in human neuroblastoma SH-SY5Y cells by the AMPK/mTOR signaling pathway. Neurotoxicology. 2022 May;90:256-264. doi: 10.1016/j.neuro.2022.04.008. Epub 2022 Apr 23.
• [12] 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.
• [13] Sevoflurane but not propofol enhances ovarian cancer cell biology through regulating cellular metabolic and signaling mechanisms. Cell Biol Toxicol. 2023 Aug;39(4):1395-1411. doi: 10.1007/s10565-022-09766-6. Epub 2022 Oct 8.
• [14] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
• [15] The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels. Arch Neurol. 2009 May;66(5):620-31. doi: 10.1001/archneurol.2009.48.
• [16] Sevoflurane-mediated activation of p38-mitogen-activated stresskinase is independent of apoptosis in Jurkat T-cells. Anesth Analg. 2008 Apr;106(4):1150-60, table of contents. doi: 10.1213/ane.0b013e3181683d37.
• [17] Sevoflurane-induced oxidative stress and cellular injury in human peripheral polymorphonuclear neutrophils. Food Chem Toxicol. 2006 Aug;44(8):1399-407. doi: 10.1016/j.fct.2006.03.004. Epub 2006 Mar 29.
• [18] CircRNA VIM silence synergizes with sevoflurane to inhibit immune escape and multiple oncogenic activities of esophageal cancer by simultaneously regulating miR-124/PD-L1 axis. Cell Biol Toxicol. 2022 Oct;38(5):825-845. doi: 10.1007/s10565-021-09613-0. Epub 2021 May 20.
• [19] The pro-nociceptive effects of remifentanil or surgical injury in mice are associated with a decrease in delta-opioid receptor mRNA levels: Prevent... Pain. 2009 Jan;141(1-2):88-96.
• [20] ClinicalTrials.gov (NCT01809041) Comparison of Intravenous Anesthetics to Volatile Anesthetics on Postoperative Cognitive Dysfunction