Details of the Drug Combination

General Information of Drug Combination (ID: DCKMRGW)

• Drug Combination Name: Levobupivacaine + Phenylephrine
• Indication: Hypotension; Status: Phase 4 [1]
• Component Drugs:
  Levobupivacaine (DM783CH): Small molecular drug
  Phenylephrine (DMZHUO5): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Levobupivacaine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[2]

Levobupivacaine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sodium channel unspecific (NaC)	TTRK8B9	NOUNIPROTAC	Blocker	[6]

Levobupivacaine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[8]

Indication(s) of Phenylephrine

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[3]
Arrhythmia	BC9Z	Approved	[3]
Common cold	CA00	Approved	[3]
Cough	MD12	Approved	[3]
Fecal incontinence	ME07	Approved	[4]
Fever	MG26	Approved	[3]
Headache	8A80-8A84	Approved	[3]
Mydriasis	LA11.62	Approved	[3]
Ophthalmic graves disease	5A02.0	Approved	[5]
Proctitis	DB33.Z	Approved	[3]
Rhinitis	FA20	Approved	[3]
Seasonal allergic rhinitis	CA08.01	Approved	[3]
Vasomotor/allergic rhinitis	CA08	Approved	[3]

Phenylephrine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Agonist	[9]

Phenylephrine Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Expression	[10]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[11]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[12]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Increases Secretion	[11]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Increases Activity	[13]
Alpha-1A adrenergic receptor (ADRA1A)	OTUIWCL5	ADA1A_HUMAN	Increases Activity	[13]
Alpha-1B adrenergic receptor (ADRA1B)	OTSAYAFD	ADA1B_HUMAN	Increases Activity	[13]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[14]
Myosin regulatory light chain 2, atrial isoform (MYL7)	OT7ZNDP4	MLRA_HUMAN	Increases Phosphorylation	[15]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[10]
Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4)	OTTDCUAO	NFAC4_HUMAN	Increases Localization	[16]
Mixed lineage kinase domain-like protein (MLKL)	OTDSLC81	MLKL_HUMAN	Increases Expression	[10]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[10]
Receptor-interacting serine/threonine-protein kinase 3 (RIPK3)	OTL1D484	RIPK3_HUMAN	Increases Expression	[10]
Pro-adrenomedullin (ADM)	OT7T0TA4	ADML_HUMAN	Decreases Response To Substance	[17]
Plasma membrane calcium-transporting ATPase 4 (ATP2B4)	OTMWFDAC	AT2B4_HUMAN	Increases Response To Substance	[18]
Beta-3 adrenergic receptor (ADRB3)	OTPMG4V7	ADRB3_HUMAN	Increases Response To Substance	[19]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Response To Substance	[20]
Caveolin-3 (CAV3)	OTWSFDB4	CAV3_HUMAN	Decreases Response To Substance	[21]

References

• [1] ClinicalTrials.gov (NCT02802683) Hemodynamic Impact of Hyperbaric Versus Isobaric for Spinal Anesthesia During Cesarean Delivery
• [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: 7211).
• [3] Isoproterenol FDA Label
• [4] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019494)
• [5] 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: 485).
• [6] Block of neuronal tetrodotoxin-resistant Na+ currents by stereoisomers of piperidine local anesthetics. Anesth Analg. 2000 Dec;91(6):1499-505.
• [7] Clinical profile of levobupivacaine in regional anesthesia: A systematic review. J Anaesthesiol Clin Pharmacol. 2013 Oct;29(4):530-9.
• [8] Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age. Br J Anaesth. 2005 Oct;95(4):524-9.
• [9] MMP-2 induced vein relaxation via inhibition of [Ca2+]e-dependent mechanisms of venous smooth muscle contraction. Role of RGD peptides. J Surg Res. 2010 Apr;159(2):755-64.
• [10] Phenylephrine induces necroptosis and apoptosis in corneal epithelial cells dose- and time-dependently. Toxicology. 2019 Dec 1;428:152305. doi: 10.1016/j.tox.2019.152305. Epub 2019 Oct 9.
• [11] [Effects of phenylephrine on atrial natriuretic factor and the renin-aldosterone axis in normal patients and essential hypertensive patients]. Arch Mal Coeur Vaiss. 1988 Jun;81 Spec No:75-8.
• [12] The regulation of human vascular smooth muscle extracellular matrix protein production by alpha- and beta-adrenoceptor stimulation. J Hypertens. 2002 Feb;20(2):287-94. doi: 10.1097/00004872-200202000-00019.
• [13] Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by human alpha1D- and alpha1B-adrenergic receptors. Cardiovasc Res. 2004 Sep 1;63(4):662-72. doi: 10.1016/j.cardiores.2004.05.014.
• [14] Alpha(1) adrenergic agonist induction of p21(waf1/cip1) mRNA stability in transfected HepG2 cells correlates with the increased binding of an AU-rich element binding factor. J Biol Chem. 2000 Apr 21;275(16):11846-51. doi: 10.1074/jbc.275.16.11846.
• [15] Key role of myosin light chain (MLC) kinase-mediated MLC2a phosphorylation in the alpha 1-adrenergic positive inotropic effect in human atrium. Cardiovasc Res. 2005 Jan 1;65(1):211-20. doi: 10.1016/j.cardiores.2004.09.019.
• [16] Constrictor-induced translocation of NFAT3 in human and rat pulmonary artery smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L1061-74. doi: 10.1152/ajplung.00096.2005. Epub 2005 Jul 29.
• [17] Adrenomedullin contributes to vascular hyporeactivity in cirrhotic rats with ascites via a release of nitric oxide. Scand J Gastroenterol. 2004 Jul;39(7):686-93. doi: 10.1080/00365520410005306.
• [18] Plasma membrane calcium ATPase overexpression in arterial smooth muscle increases vasomotor responsiveness and blood pressure. Circ Res. 2003 Oct 3;93(7):614-21. doi: 10.1161/01.RES.0000092142.19896.D9. Epub 2003 Aug 21.
• [19] Characterization of beta3-adrenoceptors in human internal mammary artery and putative involvement in coronary artery bypass management. J Am Coll Cardiol. 2005 Jul 19;46(2):351-9. doi: 10.1016/j.jacc.2005.03.061.
• [20] Effect of sodium depletion on pressor responsiveness in ACTH-induced hypertension in man. Clin Exp Pharmacol Physiol. 1987 Mar;14(3):237-42. doi: 10.1111/j.1440-1681.1987.tb00382.x.
• [21] Adenovirus-mediated overexpression of caveolin-3 inhibits rat cardiomyocyte hypertrophy. Hypertension. 2003 Aug;42(2):213-9. doi: 10.1161/01.HYP.0000082926.08268.5D. Epub 2003 Jul 7.