Details of the Drug Combination

General Information of Drug Combination (ID: DCQEDDL)

• Drug Combination Name: Furosemide + Mannitol
• Indication: Brain Tumors; Status: Phase 1 [1]
• Component Drugs:
  Furosemide (DMMQ8ZG): Small molecular drug
  Mannitol (DMSCDY9): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Furosemide

Disease Entry	ICD 11	Status	REF
Congestive heart failure	BD10	Approved	[2]
Edema	MG29	Approved	[3]
Renal hypoplasia	N.A.	Approved	[3]

Furosemide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Solute carrier family 12 member 1 (SLC12A1)	TTS087L	S12A1_HUMAN	Blocker	[9]

Furosemide Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[10]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[11]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[11]

Furosemide Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[12]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[13]

Furosemide Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Thiopurine S-methyltransferase (TPMT)	OTFOX70W	TPMT_HUMAN	Decreases Activity	[14]
Carbonic anhydrase 2 (CA2)	OTJRMUAG	CAH2_HUMAN	Decreases Activity	[15]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[16]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[17]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[18]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[19]
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Expression	[20]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[21]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[19]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Decreases Secretion	[19]
Solute carrier family 12 member 2 (SLC12A2)	OT3ZJ3LH	S12A2_HUMAN	Decreases Activity	[22]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[23]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Transport	[24]
Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R)	OTQF5ZAK	PTH1R_HUMAN	Increases ADR	[8]
Lipoprotein lipase (LPL)	OTTW0267	LIPL_HUMAN	Increases ADR	[8]

Indication(s) of Mannitol

Disease Entry	ICD 11	Status	REF
Bronchiectasis	CA24	Approved	[4]
Cerebral edema	8D60.1	Approved	[5]
Cystic fibrosis	CA25	Approved	[5]
Edema	MG29	Approved	[5]
Ocular hypertension	9C61.01	Approved	[5]
Pseudotumor cerebri	N.A.	Approved	[5]
Renal failure	GB60-GB6Z	Approved	[4]

Mannitol Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aspergillus Mannitol 2-dehydrogenase (Asperg M2DH)	TTTX5M8	M2DH_ASPFU	Activator	[25]
Aspergillus Mannitol-1-phosphate 5-dehydrogenase (Asperg mpdA)	TTV0PE2	MTLD_ASPFU	Activator	[25]

Mannitol Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[26]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[27]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Increases Expression	[28]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Increases Expression	[29]
Tumor protein D52 (TPD52)	OTPKSK43	TPD52_HUMAN	Decreases Expression	[29]
Programmed cell death protein 4 (PDCD4)	OTZ6NXUX	PDCD4_HUMAN	Decreases Expression	[29]
Focal adhesion kinase 1 (PTK2)	OT3Q1JDY	FAK1_HUMAN	Increases ADR	[8]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases ADR	[8]
H(+)/Cl(-) exchange transporter 3 (CLCN3)	OTEEXNMU	CLCN3_HUMAN	Affects Response To Substance	[30]

References

• [1] ClinicalTrials.gov (NCT02712476) Brain Relaxation With Mannitol and Furosemide
• [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: 4839).
• [3] Furosemide FDA Label
• [4] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 016080.
• [5] Mannitol FDA Label
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• [20] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [21] Bucolome, a potent binding inhibitor for furosemide, alters the pharmacokinetics and diuretic effect of furosemide: potential for use of bucolome to restore diuretic response in nephrotic syndrome. Drug Metab Dispos. 2005 Apr;33(4):596-602. doi: 10.1124/dmd.104.002782. Epub 2005 Jan 7.
• [22] Azosemide is more potent than bumetanide and various other loop diuretics to inhibit the sodium-potassium-chloride-cotransporter human variants hNKCC1A and hNKCC1B. Sci Rep. 2018 Jun 29;8(1):9877. doi: 10.1038/s41598-018-27995-w.
• [23] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [24] Multichannel liquid chromatography-tandem mass spectrometry cocktail method for comprehensive substrate characterization of multidrug resistance-associated protein 4 transporter. Pharm Res. 2007 Dec;24(12):2281-96.
• [25] Polyol-specific long-chain dehydrogenases/reductases of mannitol metabolism in Aspergillus fumigatus: biochemical characterization and pH studies o... Chem Biol Interact. 2009 Mar 16;178(1-3):274-82.
• [26] Insulin-like growth factor I is the key growth factor in serum that protects neuroblastoma cells from hyperosmotic-induced apoptosis. J Cell Physiol. 2000 Jan;182(1):24-32. doi: 10.1002/(SICI)1097-4652(200001)182:1<24::AID-JCP3>3.0.CO;2-6.
• [27] Insulin-like growth factor I prevents mannitol-induced degradation of focal adhesion kinase and Akt. J Biol Chem. 2002 Jul 26;277(30):27393-400. doi: 10.1074/jbc.M201963200. Epub 2002 May 14.
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• [30] Differential expression and roles of volume-activated chloride channels in control of growth of normal and cancerous nasopharyngeal epithelial cells. Biochem Pharmacol. 2012 Feb 1;83(3):324-34. doi: 10.1016/j.bcp.2011.11.007. Epub 2011 Nov 18.