Details of the Drug Combination

General Information of Drug Combination (ID: DC25RWD)

• Drug Combination Name: Pamidronate + Isosorbide Dinitrate
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Pamidronate (DMB4AVP): Small molecular drug
  Isosorbide Dinitrate (DMBI4JG): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 21.02
  Bliss Independence Score: 21.02
  Loewe Additivity Score: 34.66
  LHighest Single Agent (HSA) Score: 34.66

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pamidronate

Disease Entry	ICD 11	Status	REF
Bone Paget disease	N.A.	Approved	[2]
Hypercalcaemia	5B91.0	Approved	[3]

Pamidronate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Geranyltranstransferase (FDPS)	TTIKWV4	FPPS_HUMAN	Inhibitor	[6]

Pamidronate Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[7]
Osteocalcin (BGLAP)	OTK1YLWQ	OSTCN_HUMAN	Increases Expression	[7]
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL)	OTG7J4BP	PPBT_HUMAN	Increases Expression	[7]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[7]
Beta-2-microglobulin (B2M)	OTDWN6NX	B2MG_HUMAN	Decreases Expression	[7]
Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B)	OTQ4W7MT	TR11B_HUMAN	Increases Expression	[8]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[9]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Decreases Expression	[10]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[11]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[11]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Expression	[12]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[12]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[12]
Transforming protein RhoA (RHOA)	OT6YOJ9N	RHOA_HUMAN	Decreases Expression	[12]
Ras-related protein Rap-1A (RAP1A)	OT5RH6TI	RAP1A_HUMAN	Decreases Prenylation	[13]
Rho-associated protein kinase 1 (ROCK1)	OTSXYVW1	ROCK1_HUMAN	Decreases Expression	[12]
Fibroblast growth factor 23 (FGF23)	OTZT523D	FGF23_HUMAN	Decreases Expression	[14]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Response To Substance	[15]

Indication(s) of Isosorbide Dinitrate

Disease Entry	ICD 11	Status	REF
Anal fissure	DB50.0	Approved	[4]
Angina pectoris	BA40	Approved	[4]
Chronic heart failure	BD1Z	Approved	[5]

Isosorbide Dinitrate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Guanylate cyclase (GC)	TT6HPVC	NOUNIPROTAC	Stimulator	[16]

Isosorbide Dinitrate Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[17]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[18]

Isosorbide Dinitrate Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[19]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Decreases Response To Substance	[20]

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] Pamidronate 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: 7259).
• [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: 7051).
• [5] Isosorbide dinitrate FDA Label
• [6] Detection of nonsterol isoprenoids by HPLC-MS/MS. Anal Biochem. 2008 Dec 1;383(1):18-24.
• [7] Pamidronate increases markers of bone formation in patients with multiple myeloma in plateau phase under interferon-alpha treatment. Calcif Tissue Int. 2001 May;68(5):285-90.
• [8] Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Commun. 2002 Mar 1;291(3):680-6. doi: 10.1006/bbrc.2002.6510.
• [9] An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int. 1997 Nov;61(5):386-92. doi: 10.1007/s002239900353.
• [10] Expression profile and synthesis of different collagen types I, II, III, and V of human gingival fibroblasts, osteoblasts, and SaOS-2 cells after bisphosphonate treatment. Clin Oral Investig. 2010 Feb;14(1):51-8. doi: 10.1007/s00784-009-0312-2. Epub 2009 Jul 14.
• [11] Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer. 2000 Apr;82(8):1459-68. doi: 10.1054/bjoc.1999.1131.
• [12] Pamidronate induced anti-proliferative, apoptotic, and anti-migratory effects in hepatocellular carcinoma. J Hepatol. 2006 Jan;44(1):142-50. doi: 10.1016/j.jhep.2005.09.022. Epub 2005 Nov 9.
• [13] Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity. Bone. 2001 Oct;29(4):336-43. doi: 10.1016/s8756-3282(01)00589-0.
• [14] The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune-Albright syndrome. J Bone Miner Metab. 2005;23(3):231-7. doi: 10.1007/s00774-004-0589-9.
• [15] Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk / Bik. Oncogene. 2005 Nov 10;24(49):7369-80. doi: 10.1038/sj.onc.1208890.
• [16] Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart. Mol Cell Biochem. 2010 Jan;333(1-2):191-201.
• [17] Isoforms of cytochrome P450 on organic nitrate-derived nitric oxide release in human heart vessels. FEBS Lett. 1999 Jun 11;452(3):165-9.
• [18] Nitroglycerin and isosorbide dinitrate stimulation of glutathione disulfide efflux from perfused rat liver. Biochem Pharmacol. 1989 Nov 1;38(21):3807-10.
• [19] 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.
• [20] Isosorbide dinitrate-induced hemolysis in G6PD-deficient subjects. Acta Haematol. 1983;69(1):63-4. doi: 10.1159/000206844.