Details of the Drug Combination

General Information of Drug Combination (ID: DCLYRM7)

• Drug Combination Name: Heparin + Methylprednisolone
• Indication: COVID-19; Status: Phase 3 [1]
• Component Drugs:
  Heparin (DM4ZP3W): Small molecular drug
  Methylprednisolone (DM4BDON): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Heparin

Disease Entry	ICD 11	Status	REF
Aplastic anemia	3A70	Approved	[2]
Bacteremia	1A73	Approved	[2]
Burns	N.A.	Approved	[2]
Coronary heart disease	BA80.Z	Approved	[2]
Deep vein thrombosis	BD71	Approved	[2]
Disseminated intravascular coagulation	3B20	Approved	[2]
Metabolic disorder	5C50-5D2Z	Approved	[2]
Pneumonia	CA40	Approved	[2]
Pulmonary embolism	BB00	Approved	[2]
Venous thrombosis	BA43	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[4]
Diabetic angiopathy	BD53.Y	Investigative	[2]

Indication(s) of Methylprednisolone

Disease Entry	ICD 11	Status	REF
Acute adrenal insufficiency	N.A.	Approved	[5]
Acute asthma	CA23	Approved	[5]
Addison disease	5A74.0	Approved	[5]
Allergic rhinitis	CA08.0	Approved	[5]
Angioedema	4A00.15	Approved	[5]
Aspiration pneumonitis	N.A.	Approved	[5]
Autoimmune haemolytic anaemia	3A20	Approved	[5]
Bursitis	N.A.	Approved	[5]
Cerebral edema	8D60.1	Approved	[5]
Chronic graft versus host disease	N.A.	Approved	[5]
Congenital adrenal hyperplasia	5A71.01	Approved	[5]
Crohn disease	DD70	Approved	[5]
Dermatitis herpetiformis	EB44	Approved	[5]
Diamond-Blackfan anemia	N.A.	Approved	[5]
Disorder of orbital region	N.A.	Approved	[5]
Epicondylitis	N.A.	Approved	[5]
Erythema multiforme	N.A.	Approved	[5]
Exanthem	N.A.	Approved	[5]
Fever	MG26	Approved	[5]
Granuloma annulare	N.A.	Approved	[5]
Inflammatory bowel disease	DD72	Approved	[5]
Ischemia-reperfusion injury	DB98.B	Approved	[5]
Leukemia	N.A.	Approved	[5]
Lupus nephritis	4A40.0Y	Approved	[5]
Microscopic polyangiitis	N.A.	Approved	[5]
Miliary tuberculosis	N.A.	Approved	[5]
Multiple sclerosis	8A40	Approved	[5]
Mycosis fungoides	2B01	Approved	[5]
Myeloproliferative neoplasm	2A20	Approved	[5]
Pneumocystis pneumonia	CA40.20	Approved	[5]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[5]
Psoriasis	EA90	Approved	[5]
Psoriatic arthritis	FA21	Approved	[5]
Rheumatic heart disease	N.A.	Approved	[5]
Rheumatoid arthritis	FA20	Approved	[6]
Sarcoidosis	4B20.5	Approved	[5]
Seasonal allergic rhinitis	CA08.01	Approved	[5]
Serum sickness	N.A.	Approved	[5]
Severe asthma	CA23	Approved	[5]
Skin disease	EA00-EM0Z	Approved	[5]
Solid tumour/cancer	2A00-2F9Z	Approved	[6]
Systemic lupus erythematosus	4A40.0	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[7]
Acquired thrombocytopenia	N.A.	Investigative	[5]
Asthma	CA23	Investigative	[5]
Beta-thalassemia major	N.A.	Investigative	[5]
Classic Hodgkin lymphoma	N.A.	Investigative	[5]
Follicular lymphoma	2A80	Investigative	[5]
Perennial allergic rhinitis	CA08.03	Investigative	[5]
Spinal cord injury	ND51.2	Investigative	[8]
Synovitis	N.A.	Investigative	[5]
Trichinellosis	N.A.	Investigative	[5]

Methylprednisolone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glucocorticoid receptor (NR3C1)	TTYRL6O	GCR_HUMAN	Modulator	[11]

Methylprednisolone Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[12]

Methylprednisolone Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]

Methylprednisolone Interacts with 87 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Expression	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[15]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[9]
CCN family member 1 (CCN1)	OTKJBEMD	CCN1_HUMAN	Increases Expression	[9]
Phospholipid phosphatase 3 (PLPP3)	OTSSF7BK	PLPP3_HUMAN	Decreases Expression	[9]
Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3)	OTPGHZB9	IFIT3_HUMAN	Decreases Expression	[9]
Calmegin (CLGN)	OTEWVFQV	CLGN_HUMAN	Decreases Expression	[9]
D-3-phosphoglycerate dehydrogenase (PHGDH)	OT1LMRTG	SERA_HUMAN	Decreases Expression	[9]
Receptor-interacting serine/threonine-protein kinase 2 (RIPK2)	OT0KMIYQ	RIPK2_HUMAN	Decreases Expression	[9]
Gasdermin-E (GSDME)	OT1ZWY32	GSDME_HUMAN	Decreases Expression	[9]
Toll-like receptor 2 (TLR2)	OTGO5P4R	TLR2_HUMAN	Decreases Expression	[9]
CCN family member 5 (CCN5)	OTADU8JJ	CCN5_HUMAN	Increases Expression	[9]
Antiviral innate immune response receptor RIG-I (RIGI)	OTFIIC43	RIGI_HUMAN	Decreases Expression	[9]
2'-5'-oligoadenylate synthase 1 (OAS1)	OT8ZLOCY	OAS1_HUMAN	Decreases Expression	[9]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Increases Expression	[9]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Decreases Expression	[9]
Ubiquitin-like protein ISG15 (ISG15)	OT53QQ7N	ISG15_HUMAN	Decreases Expression	[9]
Thrombospondin-1 (THBS1)	OT0ECWK3	TSP1_HUMAN	Increases Expression	[9]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Decreases Expression	[9]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Decreases Expression	[9]
Steryl-sulfatase (STS)	OTXTJQPC	STS_HUMAN	Increases Expression	[9]
Neuromedin-B (NMB)	OT4NLN6H	NMB_HUMAN	Decreases Expression	[9]
Stromelysin-2 (MMP10)	OTJDWW8Q	MMP10_HUMAN	Decreases Expression	[9]
Growth-regulated alpha protein (CXCL1)	OT3WCTZV	GROA_HUMAN	Decreases Expression	[9]
Interferon alpha-inducible protein 6 (IFI6)	OTWOOAM4	IFI6_HUMAN	Decreases Expression	[9]
Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)	OTXOQDSG	IFIT1_HUMAN	Decreases Expression	[9]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[9]
Interleukin-1 receptor antagonist protein (IL1RN)	OT308CBE	IL1RA_HUMAN	Decreases Expression	[9]
C-X-C motif chemokine 2 (CXCL2)	OTEJCYMY	CXCL2_HUMAN	Decreases Expression	[9]
C-X-C motif chemokine 3 (CXCL3)	OTSL94KH	CXCL3_HUMAN	Decreases Expression	[9]
Interferon-induced GTP-binding protein Mx1 (MX1)	OT6X8G5T	MX1_HUMAN	Decreases Expression	[9]
Fibulin-1 (FBLN1)	OT5MHHOP	FBLN1_HUMAN	Increases Expression	[9]
Atypical chemokine receptor 3 (ACKR3)	OTA6GA4F	ACKR3_HUMAN	Decreases Expression	[9]
11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1)	OTO7FJA9	DHI1_HUMAN	Decreases Expression	[9]
Adenosine receptor A2a (ADORA2A)	OTVRBZ0I	AA2AR_HUMAN	Decreases Expression	[9]
CCN family member 2 (CCN2)	OTC39NSU	CCN2_HUMAN	Increases Expression	[9]
Myristoylated alanine-rich C-kinase substrate (MARCKS)	OT7N056G	MARCS_HUMAN	Decreases Expression	[9]
Guanylate-binding protein 1 (GBP1)	OTUM7RPJ	GBP1_HUMAN	Decreases Expression	[9]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[9]
Macrophage metalloelastase (MMP12)	OT9Z7LHM	MMP12_HUMAN	Decreases Expression	[9]
Interferon alpha-inducible protein 27, mitochondrial (IFI27)	OTI2XGIT	IFI27_HUMAN	Decreases Expression	[9]
Signal transducer and activator of transcription 1-alpha/beta (STAT1)	OTLMBUZ6	STAT1_HUMAN	Decreases Expression	[9]
Regulator of G-protein signaling 4 (RGS4)	OTG94HHL	RGS4_HUMAN	Decreases Expression	[9]
Prolargin (PRELP)	OT9EEBUJ	PRELP_HUMAN	Increases Expression	[9]
Spermine synthase (SMS)	OT8JYKNH	SPSY_HUMAN	Decreases Expression	[9]
C-X-C chemokine receptor type 4 (CXCR4)	OTUFSBX2	CXCR4_HUMAN	Decreases Expression	[9]
C-C motif chemokine 20 (CCL20)	OTUCJY4N	CCL20_HUMAN	Decreases Expression	[9]
Interferon-induced 35 kDa protein (IFI35)	OTV9RZ53	IN35_HUMAN	Decreases Expression	[9]
DNA-binding protein inhibitor ID-3 (ID3)	OTUULW5Z	ID3_HUMAN	Increases Expression	[9]
Tumor necrosis factor alpha-induced protein 2 (TNFAIP2)	OTRZH80H	TNAP2_HUMAN	Decreases Expression	[9]
Aldehyde oxidase (AOX1)	OT2FZP6H	AOXA_HUMAN	Increases Expression	[9]
Bone marrow stromal antigen 2 (BST2)	OTU4LCJV	BST2_HUMAN	Decreases Expression	[9]
EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1)	OTZVUOOB	FBLN3_HUMAN	Increases Expression	[9]
Neuronal membrane glycoprotein M6-b (GPM6B)	OT8Q1582	GPM6B_HUMAN	Increases Expression	[9]
Laminin subunit beta-3 (LAMB3)	OTFPU6W8	LAMB3_HUMAN	Decreases Expression	[9]
Nidogen-2 (NID2)	OTHC33FF	NID2_HUMAN	Increases Expression	[9]
Signal transducer and activator of transcription 4 (STAT4)	OTAK3VFR	STAT4_HUMAN	Decreases Expression	[9]
2'-5'-oligoadenylate synthase-like protein (OASL)	OTZ05YRP	OASL_HUMAN	Decreases Expression	[9]
Bcl-2-related protein A1 (BCL2A1)	OTWRYSNA	B2LA1_HUMAN	Decreases Expression	[9]
Lymphocyte antigen 6E (LY6E)	OTMG16BZ	LY6E_HUMAN	Decreases Expression	[9]
Interferon-induced protein 44-like (IFI44L)	OTXKORJP	IF44L_HUMAN	Decreases Expression	[9]
E3 ubiquitin-protein ligase RNF19B (RNF19B)	OTYCWKBP	RN19B_HUMAN	Decreases Expression	[9]
Amphoterin-induced protein 2 (AMIGO2)	OTPAIT1O	AMGO2_HUMAN	Decreases Expression	[9]
Probable E3 ubiquitin-protein ligase HERC6 (HERC6)	OT7G9PQE	HERC6_HUMAN	Decreases Expression	[9]
Equilibrative nucleobase transporter 1 (SLC43A3)	OTR60ZLA	S43A3_HUMAN	Decreases Expression	[9]
Interferon-induced protein 44 (IFI44)	OTOKSZVA	IFI44_HUMAN	Decreases Expression	[9]
S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2)	OTCA9WCM	RSAD2_HUMAN	Decreases Expression	[9]
Nuclear receptor subfamily 4 group A member 3 (NR4A3)	OTPBE9R1	NR4A3_HUMAN	Decreases Expression	[9]
Type II iodothyronine deiodinase (DIO2)	OTGPNSLH	IOD2_HUMAN	Increases Expression	[9]
Interferon regulatory factor 7 (IRF7)	OTC1A2PQ	IRF7_HUMAN	Decreases Expression	[9]
Interferon-stimulated gene 20 kDa protein (ISG20)	OTCWRJJW	ISG20_HUMAN	Decreases Expression	[9]
Interferon-induced helicase C domain-containing protein 1 (IFIH1)	OTZA2AHA	IFIH1_HUMAN	Decreases Expression	[9]
Anthrax toxin receptor 1 (ANTXR1)	OT5W1GPC	ANTR1_HUMAN	Increases Expression	[9]
Interleukin-23 subunit alpha (IL23A)	OTYO99HC	IL23A_HUMAN	Decreases Expression	[9]
NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2)	OTK0PG7R	NUA4L_HUMAN	Decreases Expression	[9]
E3 ISG15--protein ligase HERC5 (HERC5)	OTZ5PR39	HERC5_HUMAN	Decreases Expression	[9]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[9]
Hypoxia-inducible lipid droplet-associated protein (HILPDA)	OTEID3ZM	HLPDA_HUMAN	Decreases Expression	[9]
2'-5'-oligoadenylate synthase 3 (OAS3)	OT6E5FYS	OAS3_HUMAN	Decreases Expression	[9]
Coagulation factor VIII (F8)	OTH6XHDU	FA8_HUMAN	Increases Expression	[10]
Myelin basic protein (MBP)	OTFZCEDB	MBP_HUMAN	Decreases Expression	[16]
Glial fibrillary acidic protein (GFAP)	OTQ01ZAS	GFAP_HUMAN	Decreases Expression	[16]
5-hydroxytryptamine receptor 3A (HTR3A)	OTAIV1AK	5HT3A_HUMAN	Decreases Activity	[17]
Tyrosine aminotransferase (TAT)	OT2CJ91O	ATTY_HUMAN	Increases ADR	[18]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Increases ADR	[18]
Thrombopoietin (THPO)	OTO73DZ2	TPO_HUMAN	Increases ADR	[18]
P-selectin (SELP)	OTWR90PK	LYAM3_HUMAN	Increases ADR	[18]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Covid19	DC1BSGA	N. A.	Phase 3	[19]

References

• [1] ClinicalTrials.gov (NCT04485429) Efficacy Assessment of Methylprednisolone and Heparin in Patients With COVID-19 Pneumonia
• [2] Heparin FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 090809.
• [4] Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020 Dec;9(1):727-732.
• [5] Methylprednisolone FDA Label
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] ClinicalTrials.gov (NCT04341038) Clinical Trial to Evaluate Methylprednisolone Pulses and Tacrolimus in Patients With COVID-19 Lung Injury
• [8] 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: 7088).
• [9] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [10] von Willebrand factor and thrombin activation in children with newly diagnosed acute lymphoblastic leukemia: an impact of peripheral blasts. Pediatr Blood Cancer. 2010 Jul 1;54(7):963-9. doi: 10.1002/pbc.22466.
• [11] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [12] Secretory transport of methylprednisolone possibly mediated by P-glycoprotein in Caco-2 cells. Biol Pharm Bull. 2002 Mar;25(3):393-6.
• [13] Cytochrome P450 enzyme regulation by glucocorticoids and consequences in terms of drug interaction. Expert Opin Drug Metab Toxicol. 2014 Mar;10(3):425-35.
• [14] Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos. 2006 Oct;34(10):1742-8.
• [15] Protective effect of methylprednisolone on paraquat-induced A549 cell cytotoxicity via induction of efflux transporter, P-glycoprotein expression. Toxicol Lett. 2012 Jan 25;208(2):101-7. doi: 10.1016/j.toxlet.2011.10.019. Epub 2011 Oct 31.
• [16] A prominent elevation of glial fibrillary acidic protein in the cerebrospinal fluid during relapse in neuromyelitis optica. Tohoku J Exp Med. 2008 May;215(1):55-9. doi: 10.1620/tjem.215.55.
• [17] Inhibitory effect of glucocorticoids on human-cloned 5-hydroxytryptamine3A receptor expressed in xenopus oocytes. Anesthesiology. 2004 Sep;101(3):660-5. doi: 10.1097/00000542-200409000-00014.
• [18] 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.
• [19] ClinicalTrials.gov (NCT04528888) Steroids and Unfractionated Heparin in Critically Ill Patients With Pneumonia From COVID-19 Infection