Details of the Drug Combination

General Information of Drug Combination (ID: DCC59YA)

• Drug Combination Name: Iloprost + Tiagabine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Iloprost (DMVPZBE): Small molecular drug
  Tiagabine (DMKSQG0): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 8.99
  Bliss Independence Score: 8.99
  Loewe Additivity Score: 10.81
  LHighest Single Agent (HSA) Score: 10.87

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Iloprost

Disease Entry	ICD 11	Status	REF
Pulmonary arterial hypertension	BB01.0	Approved	[2]
Pulmonary hypertension	BB01	Approved	[3]
Systemic sclerosis	4A42	Approved	[3]

Iloprost Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Prostaglandin E2 receptor EP2 (PTGER2)	TT1ZAVI	PE2R2_HUMAN	Agonist	[5]

Iloprost Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporting polypeptide 2A1 (SLCO2A1)	DT021JD	SO2A1_HUMAN	Substrate	[6]
Organic anion transporting polypeptide 3A1 (SLCO3A1)	DTVNRXW	SO3A1_HUMAN	Substrate	[7]

Iloprost Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Angiopoietin-2 (ANGPT2)	OTEQK65P	ANGP2_HUMAN	Increases Expression	[8]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[9]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[9]
Fibroblast growth factor 2 (FGF2)	OT7YUJ9F	FGF2_HUMAN	Increases Expression	[8]
L-selectin (SELL)	OT6RAJZR	LYAM1_HUMAN	Decreases Expression	[9]
DNA-binding protein inhibitor ID-1 (ID1)	OTKGNZN5	ID1_HUMAN	Increases Expression	[10]
Prostacyclin receptor (PTGIR)	OTWTABYM	PI2R_HUMAN	Affects Binding	[11]
Angiopoietin-1 (ANGPT1)	OTVZ1NG3	ANGP1_HUMAN	Increases Expression	[8]

Indication(s) of Tiagabine

Disease Entry	ICD 11	Status	REF
Epilepsy	8A60-8A68	Approved	[4]
Anxiety disorder	6B00-6B0Z	Phase 2	[4]

Tiagabine Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Gamma-aminobutyric acid uptake (GABAU)	TTV9MQG	NOUNIPROTAC	Inhibitor	[12]
GABA transporter GAT-1 (SLC6A1)	TTPRKM0	SC6A1_HUMAN	Inhibitor	[13]

Tiagabine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[15]

Tiagabine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[16]
Sodium- and chloride-dependent GABA transporter 1 (SLC6A1)	OTLCJJF3	SC6A1_HUMAN	Decreases Activity	[17]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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: 1966).
• [3] Iloprost 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: 4818).
• [5] Exploration of prostanoid receptor subtype regulating estradiol and prostaglandin E2 induction of spinophilin in developing preoptic area neurons. Neuroscience. 2007 May 25;146(3):1117-27.
• [6] Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA(hPGT). J Clin Invest. 1996 Sep 1;98(5):1142-9.
• [7] Molecular characterization of human and rat organic anion transporter OATP-D. Am J Physiol Renal Physiol. 2003 Dec;285(6):F1188-97.
• [8] Prostacyclin receptor up-regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1/2 pathway. Endocrinology. 2006 Apr;147(4):1697-705. doi: 10.1210/en.2005-1073. Epub 2005 Dec 22.
• [9] The response of skin perfusion and of rheological and immunological variables to intravenous prostanoid administration in Raynaud's phenomenon secondary to collagenosis. Vasa. 2005 Nov;34(4):243-9. doi: 10.1024/0301-1526.34.4.243.
• [10] Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. Circ Res. 2010 Jul 23;107(2):252-62. doi: 10.1161/CIRCRESAHA.109.209940. Epub 2010 Jun 3.
• [11] Investigation of a functional requirement for isoprenylation by the human prostacyclin receptor. Eur J Biochem. 2002 Mar;269(6):1714-25. doi: 10.1046/j.1432-1327.2002.02817.x.
• [12] Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
• [13] 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. (Target id: 929).
• [14] Enzyme induction and inhibition by new antiepileptic drugs: a review of human studies. Fundam Clin Pharmacol. 2000 Jul-Aug;14(4):301-19.
• [15] Actual and Predicted Pharmacokinetic Interactions Between Anticonvulsants and Antiretrovirals.
• [16] Inhibition of human aromatase complex (CYP19) by antiepileptic drugs. Toxicol In Vitro. 2008 Feb;22(1):146-53.
• [17] GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci. 2005 Mar 23;25(12):3234-45. doi: 10.1523/JNEUROSCI.3364-04.2005.