Details of the Drug Combination

General Information of Drug Combination (ID: DCLHFWX)

• Drug Combination Name: Carvedilol + Pentoxifylline
• Indication: Liver Cirrhosis; Status: Phase 1 [1]
• Component Drugs:
  Carvedilol (DMHTEAO): Small molecular drug
  Pentoxifylline (DMU3DNC): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Carvedilol

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[2]
Congestive heart failure	BD10	Approved	[3]
Pulmonary hypertension	BB01	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[4]

Carvedilol Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUAMN alpha-1 adrenergic receptor (ADRA1)	TTDBOI7	ADA1A_HUMAN; ADA1B_HUMAN; ADA1D_HUMAN	Inhibitor	[8]
Adrenergic receptor Alpha-1 (ADRA1)	TTG28O6	NOUNIPROTAC	Antagonist	[9]
HUMAN beta adrenergic receptor (BAR)	TTJB8UY	ADRB1_HUMAN; ADRB2_HUMAN; ADRB3_HUMAN	Antagonist	[4]

Carvedilol Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

Carvedilol Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[13]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[14]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[15]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[16]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[13]

Carvedilol Interacts with 28 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Affects Glucuronidation	[17]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[18]
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Increases Activity	[19]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[20]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Phosphorylation	[21]
Potassium channel subfamily K member 3 (KCNK3)	OTWMAV6G	KCNK3_HUMAN	Decreases Activity	[22]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Expression	[23]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[24]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[25]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[26]
Vasopressin-neurophysin 2-copeptin (AVP)	OTAVZ76K	NEU2_HUMAN	Decreases Expression	[27]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[28]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[29]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[30]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Expression	[31]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Phosphorylation	[20]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[25]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Affects Activity	[32]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[33]
Gap junction alpha-1 protein (GJA1)	OTT94MKL	CXA1_HUMAN	Increases Expression	[34]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Expression	[35]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[20]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[36]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[33]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[30]
Ryanodine receptor 2 (RYR2)	OT0PF19E	RYR2_HUMAN	Increases Activity	[37]
Vascular endothelial growth factor receptor 2 (KDR)	OT15797V	VGFR2_HUMAN	Increases ADR	[38]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Increases ADR	[38]

Indication(s) of Pentoxifylline

Disease Entry	ICD 11	Status	REF
Alcoholic hepatitis	DB94.1	Approved	[5]
Intermittent claudication	BD40.00	Approved	[6]
Type-1 diabetes	5A10	Approved	[5]
Peripheral vascular disease	BD4Z	Investigative	[5]

Pentoxifylline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	TTF8CQI	TNFA_HUMAN	.	[39]

Pentoxifylline Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[40]

Pentoxifylline Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Increases ADR	[38]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases ADR	[38]
Thrombomodulin (THBD)	OT8VHLKY	TRBM_HUMAN	Increases ADR	[38]
Matrix metalloproteinase-14 (MMP14)	OT9C197Z	MMP14_HUMAN	Increases ADR	[38]
Perforin-1 (PRF1)	OTFVXD7H	PERF_HUMAN	Increases ADR	[38]
Granzyme B (GZMB)	OTPPVIRS	GRAB_HUMAN	Increases ADR	[38]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases ADR	[38]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases ADR	[38]

References

• [1] ClinicalTrials.gov (NCT06041932) Pentoxifylline Plus Carvedilol vs Carvedilol Monotherapy in Preventing New Decompensation in Stable Cirrhotic Patients With Prior Decompensation
• [2] Carvedilol 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: 551).
• [4] Can beta-adrenergic blockers be used in the treatment of COVID-19 Med Hypotheses. 2020 May 5;142:109809.
• [5] Pentoxifylline FDA Label
• [6] 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: 7095).
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• [9] Beta-blockers in the treatment of hypertension: are there clinically relevant differences Postgrad Med. 2009 May;121(3):90-8.
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• [28] After myocardial infarction carvedilol improves insulin resistance compared to metoprolol. Clin Res Cardiol. 2006 Feb;95(2):99-104. doi: 10.1007/s00392-006-0336-4. Epub 2006 Feb 6.
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