Details of the Drug Combination

General Information of Drug Combination (ID: DC62OSK)

• Drug Combination Name: Terbutaline + Danazol
• Indication: Immune Thrombocytopenia; Status: Phase 2 [1]
• Component Drugs:
  Terbutaline (DMD4381): Small molecular drug
  Danazol (DML8KTN): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Terbutaline

Disease Entry	ICD 11	Status	REF
Asthma	CA23	Approved	[2]
Bronchitis	CA20	Approved	[3]
Pulmonary emphysema	CA21.Z	Approved	[3]
Severe asthma	CA23	Approved	[3]
Pruritus	EC90	Investigative	[3]

Terbutaline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-2 (ADRB2)	TT2CJVK	ADRB2_HUMAN	Agonist	[6]

Terbutaline Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[7]

Terbutaline Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Response To Substance	[8]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Increases Expression	[9]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[10]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Increases Expression	[11]
Gastrin (GAST)	OTD0IP9N	GAST_HUMAN	Increases Secretion	[12]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[13]
Corticoliberin (CRH)	OT2MOC4T	CRF_HUMAN	Decreases Expression	[14]
Pulmonary surfactant-associated protein B (SFTPB)	OTOHS07E	PSPB_HUMAN	Increases Expression	[15]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Activity	[13]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Expression	[16]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Increases Expression	[17]
Alpha-1B adrenergic receptor (ADRA1B)	OTSAYAFD	ADA1B_HUMAN	Increases Expression	[17]
Alpha-2-HS-glycoprotein (AHSG)	OTUG0LEA	FETUA_HUMAN	Increases Response To Substance	[18]

Indication(s) of Danazol

Disease Entry	ICD 11	Status	REF
Menorrhagia	GA20.50	Approved	[4]
Breast cancer	2C60-2C65	Phase 2	[4]
Breast fibrocystic disease	N.A.	Investigative	[5]
Endometriosis	GA10	Investigative	[5]

Danazol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Antagonist	[19]

Danazol Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Decreases Activity	[20]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[21]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Decreases Activity	[22]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[23]
Complement factor B (CFB)	OTZITNEJ	CFAB_HUMAN	Increases Expression	[24]
Complement C3 (C3)	OTCH5GS0	CO3_HUMAN	Increases Expression	[24]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[25]
Plasma protease C1 inhibitor (SERPING1)	OT6CVN45	IC1_HUMAN	Increases Expression	[24]
Steryl-sulfatase (STS)	OTXTJQPC	STS_HUMAN	Decreases Activity	[26]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[27]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[28]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[23]

References

• [1] ClinicalTrials.gov (NCT04481282) The Combination of Terbutaline and Danazol as the Treatment of Steroid-resistant/Relapse Immune Thrombocytopenia
• [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: 560).
• [3] Terbutaline FDA Label
• [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: 6942).
• [5] Danazol FDA Label
• [6] Evaluation of a new oral beta2-adrenoceptor stimulant bronchodilator, terbutaline. Pharmacology. 1975;13(3):201-11.
• [7] Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem. 2013 Sep 26;56(18):7232-42.
• [8] Beta2-adrenergic receptor polymorphisms in African American children with status asthmaticus. Pediatr Crit Care Med. 2006 Jan;7(1):15-8. doi: 10.1097/01.pcc.0000194010.63115.a2.
• [9] Interaction between glucocorticoids and beta2-agonists: alpha and beta glucocorticoid-receptor mRNA expression in human bronchial epithelial cells. Biochem Pharmacol. 1998 Dec 15;56(12):1561-9.
• [10] Beta-adrenoceptor activation-induced placental prorenin secretion is mediated by increased renin messenger RNA and protein synthesis. Mol Pharmacol. 1997 Feb;51(2):201-8. doi: 10.1124/mol.51.2.201.
• [11] A comparison of the beta1-selectivity of three beta1-selective beta-blockers. J Clin Pharm Ther. 2003 Jun;28(3):179-86. doi: 10.1046/j.1365-2710.2003.00477.x.
• [12] L-type calcium channels regulate gastrin release from human antral G cells. Am J Physiol. 1997 Aug;273(2 Pt 1):G281-8. doi: 10.1152/ajpgi.1997.273.2.G281.
• [13] Activation of beta(2)-adrenoceptor prevents shiga toxin 2-induced TNF-alpha gene transcription. J Am Soc Nephrol. 2001 Nov;12(11):2288-2299. doi: 10.1681/ASN.V12112288.
• [14] Terbutaline inhibits corticotropin-releasing hormone (CRH) expression in human trophoblast cells. J Matern Fetal Neonatal Med. 2006 Nov;19(11):735-9. doi: 10.1080/14767050600886724.
• [15] Regulation of messenger RNAs for the hydrophobic surfactant proteins in human lung. J Clin Invest. 1989 Apr;83(4):1191-7. doi: 10.1172/JCI114000.
• [16] Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome. J Clin Endocrinol Metab. 2000 Feb;85(2):692-6. doi: 10.1210/jcem.85.2.6379.
• [17] Neuroendocrine mediators up-regulate alpha1b- and alpha1d-adrenergic receptor subtypes in human monocytes. J Neuroimmunol. 1999 Mar 1;95(1-2):165-73. doi: 10.1016/s0165-5728(99)00011-9.
• [18] Polymorphism of the AHSG gene is associated with increased adipocyte beta2-adrenoceptor function. J Lipid Res. 2005 Oct;46(10):2278-81. doi: 10.1194/jlr.M500201-JLR200. Epub 2005 Jul 16.
• [19] Danazol suppression of luteinizing hormone in the rat: evidence for mediation by both androgen and estrogen receptors. Proc Soc Exp Biol Med. 1990 May;194(1):54-7.
• [20] The anabolic androgenic steroid fluoxymesterone inhibits 11beta-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation. Toxicol Sci. 2012 Apr;126(2):353-61.
• [21] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [22] Inhibitory effects of Danshen components on CYP2C8 and CYP2J2. Chem Biol Interact. 2018 Jun 1;289:15-22.
• [23] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [24] Guillain-Barr syndrome following danazol and corticosteroid therapy for hereditary angioedema. Am J Med. 1985 Jul;79(1):111-4. doi: 10.1016/0002-9343(85)90553-4.
• [25] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [26] Synthesis and steroid sulphatase inhibitory activity of C19- and C21-steroidal derivatives bearing a benzyl-inhibiting group. Eur J Med Chem. 2001 Jul-Aug;36(7-8):659-71. doi: 10.1016/s0223-5234(01)01262-4.
• [27] Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. Environ Health Perspect. 2011 Aug;119(8):1142-8. doi: 10.1289/ehp.1002952. Epub 2011 May 4.
• [28] High-content imaging-based BAC-GFP toxicity pathway reporters to assess chemical adversity liabilities. Arch Toxicol. 2017 Mar;91(3):1367-1383. doi: 10.1007/s00204-016-1781-0. Epub 2016 Jun 29.