Details of the Drug Combination

General Information of Drug Combination (ID: DCE22ZE)

• Drug Combination Name: Norepinephrine + Terlipressin
• Indication: Safety and Efficacy of Terlipressin and Noradrenaline and Predictive Factors of Response in Type 2 HRS; Status: Phase 1 [1]
• Component Drugs:
  Norepinephrine (DMOUC09): Small molecular drug
  Terlipressin (DMT9FH3): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Norepinephrine

Disease Entry	ICD 11	Status	REF
Alopecia	ED70	Approved	[2]
Bronchiectasis	CA24	Approved	[2]
Bronchitis	CA20	Approved	[2]
Chronic fatigue syndrome	8E49	Approved	[2]
Depression	6A70-6A7Z	Approved	[2]
Psychosexual disorder	N.A.	Approved	[2]
Pulmonary emphysema	CA21.Z	Approved	[2]
Pure autonomic failure	N.A.	Approved	[2]
Radiodermatitis	N.A.	Approved	[2]
Sepsis	1G40-1G41	Approved	[3]
Severe asthma	CA23	Approved	[2]
Asthma	CA23	Investigative	[2]

Norepinephrine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Stimulator	[6]

Norepinephrine Interacts with 7 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[7]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[7]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[8]
Vesicular amine transporter 2 (SLC18A2)	DTT7VPB	VMAT2_HUMAN	Substrate	[9]
Vesicular amine transporter 1 (SLC18A1)	DTM953D	VMAT1_HUMAN	Substrate	[9]
Sodium-dependent noradrenaline transporter (SLC6A2)	DT9JBVI	SC6A2_HUMAN	Substrate	[10]
Sodium- and chloride-dependent glycine transporter 2 (SLC6A5)	DTE8R17	SC6A5_HUMAN	Substrate	[11]

Norepinephrine Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Synaptic vesicular amine transporter (SLC18A2)	OTUOMMM6	VMAT2_HUMAN	Decreases Activity	[12]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[13]
Sodium-dependent noradrenaline transporter (SLC6A2)	OTMHQJMP	SC6A2_HUMAN	Decreases Uptake	[14]
Protein phosphatase 1 regulatory subunit 12A (PPP1R12A)	OT4AVU95	MYPT1_HUMAN	Increases Phosphorylation	[15]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[16]
Protein S100-B (S100B)	OTHHDS33	S100B_HUMAN	Increases Expression	[17]
Protein S100-A8 (S100A8)	OTVMOB3F	S10A8_HUMAN	Increases Expression	[18]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Increases Expression	[16]
Myosin light chain 1/3, skeletal muscle isoform (MYL1)	OTDUYR4U	MYL1_HUMAN	Increases Phosphorylation	[15]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[18]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Affects Binding	[19]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Increases Expression	[19]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[19]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Increases Secretion	[20]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[16]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Increases Expression	[19]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Affects Localization	[16]
Cannabinoid receptor 1 (CNR1)	OTEALO6G	CNR1_HUMAN	Affects Expression	[21]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Affects Binding	[22]
Alpha-1A adrenergic receptor (ADRA1A)	OTUIWCL5	ADA1A_HUMAN	Affects Binding	[23]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Affects Localization	[16]
Proto-oncogene c-Rel (REL)	OTTCKMAC	REL_HUMAN	Affects Localization	[16]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Increases Uptake	[24]
Pro-neuropeptide Y (NPY)	OT4ICV3P	NPY_HUMAN	Affects Response To Substance	[25]
Amine oxidase A (MAOA)	OT8NIWMQ	AOFA_HUMAN	Increases Metabolism	[26]
Sulfotransferase 1A3 (SULT1A4)	OTHJ8WWV	ST1A3_HUMAN	Increases Sulfation	[27]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Increases Methylation	[28]
Neuron-specific vesicular protein calcyon (CALY)	OTQ7EMPU	CALY_HUMAN	Increases Secretion	[29]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Abundance	[30]
Equilibrative nucleoside transporter 4 (SLC29A4)	OTWTZXMX	S29A4_HUMAN	Increases Uptake	[13]

Indication(s) of Terlipressin

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[4]

Terlipressin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Vasopressin V1a receptor (V1AR)	TT4TFGN	V1AR_HUMAN	Stimulator	[31]

References

• [1] ClinicalTrials.gov (NCT01637454) TYPE 2 HEPATORENAL SYNDROME
• [2] Norepinephrine FDA Label
• [3] 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: 505).
• [4] Pharmacology, clinical efficacy and safety of terlipressin in esophageal varices bleeding, septic shock and hepatorenal syndrome. Expert Rev Gastroenterol Hepatol. 2007 Dec;1(2):207-17.
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• [15] Role of protein kinase D1 in vasoconstriction and haemodynamics in rats. Microvasc Res. 2024 Mar;152:104627. doi: 10.1016/j.mvr.2023.104627. Epub 2023 Nov 12.
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• [18] Norepinephrine stimulates calprotectin expression in human monocytic cells. J Periodontal Res. 2006 Jun;41(3):159-64. doi: 10.1111/j.1600-0765.2005.00845.x.
• [19] Quercetin-3-O-glucuronide inhibits noradrenaline-promoted invasion of MDA-MB-231 human breast cancer cells by blocking ?-adrenergic signaling. Arch Biochem Biophys. 2014 Sep 1;557:18-27. doi: 10.1016/j.abb.2014.05.030. Epub 2014 Jun 11.
• [20] Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2006 Nov;291(5):G877-84. doi: 10.1152/ajpgi.00537.2005. Epub 2006 Jun 15.
• [21] Cannabinoid Type 1 Receptors Are Upregulated During Acute Activation of Brown Adipose Tissue. Diabetes. 2018 Jul;67(7):1226-1236. doi: 10.2337/db17-1366. Epub 2018 Apr 12.
• [22] Chromatography studies on bio-affinity of nine ligands of alpha1-adrenoceptor to alpha1D subtypes overexpressed in cell membrane. Sci China C Life Sci. 2004 Aug;47(4):376-81. doi: 10.1360/03yc0109.
• [23] The alpha 1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha 1c subtype. Mol Pharmacol. 1994 Apr;45(4):703-8.
• [24] Substrates and inhibitors display different sensitivity to expression level of the dopamine transporter in heterologously expressing cells. J Neurochem. 2007 Apr;101(2):377-88. doi: 10.1111/j.1471-4159.2006.04384.x. Epub 2007 Jan 22.
• [25] Release and functional role of neuropeptide Y as a sympathetic modulator in human saphenous vein biopsies. Peptides. 2004 Jan;25(1):53-64. doi: 10.1016/j.peptides.2003.11.001.
• [26] Association between monoamine oxidase A activity in human male skin fibroblasts and genotype of the MAOA promoter-associated variable number tandem repeat. Hum Genet. 1999 Dec;105(6):542-51. doi: 10.1007/s004399900183.
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• [28] Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase. Mol Pharmacol. 2001 Feb;59(2):393-402. doi: 10.1124/mol.59.2.393.
• [29] Increased arterial pressure in mice with overexpression of the ADHD candidate gene calcyon in forebrain. PLoS One. 2019 Feb 12;14(2):e0211903. doi: 10.1371/journal.pone.0211903. eCollection 2019.
• [30] Nesiritide: past, present, and future. Minerva Cardioangiol. 2005 Dec;53(6):509-22.
• [31] Investigational vasopressin receptor modulators in the pipeline. Expert Opin Investig Drugs. 2009 Aug;18(8):1119-31.