Details of the Drug Combination

General Information of Drug Combination (ID: DCH1826)

• Drug Combination Name: Topiramate + Amantadine
• Indication: Parkinson's Disease; Status: Phase 1 [1]
• Component Drugs:
  Topiramate (DM82Z30): Small molecular drug
  Amantadine (DMS3YE9): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Topiramate

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[2]
Epilepsy	8A60-8A68	Approved	[2]
Epilepsy with generalized tonic-clonic seizures	N.A.	Approved	[3]
Hyperlipidemia	5C80.Z	Approved	[3]
Hypertriglyceridemia	5C80.1	Approved	[3]
Obesity	5B81	Approved	[3]
Metabolic syndrome x	5C50-5D2Z	Investigative	[3]
Seizure disorder	8A6Z	Investigative	[4]

Topiramate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glutamate receptor ionotropic kainate 1 (GRIK1)	TT0MYE2	GRIK1_HUMAN	Antagonist	[8]

Topiramate Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

Topiramate Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]

Topiramate Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[10]
Glutamate receptor ionotropic, kainate 1 (GRIK1)	OTO19X5C	GRIK1_HUMAN	Affects Response To Substance	[11]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[10]
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[12]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2)	OT02MSKN	3BHS2_HUMAN	Decreases Activity	[12]
Carbonic anhydrase 12 (CA12)	OT6WNFU8	CAH12_HUMAN	Decreases Activity	[13]
Carbonic anhydrase 2 (CA2)	OTJRMUAG	CAH2_HUMAN	Decreases Activity	[13]
HLA class I histocompatibility antigen, A alpha chain (HLA-A)	OTAH14LU	HLAA_HUMAN	Affects Expression	[14]
HLA class II histocompatibility antigen, DM beta chain (HLA-DMB)	OT17HGXJ	DMB_HUMAN	Affects Expression	[14]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[15]
Pro-neuropeptide Y (NPY)	OT4ICV3P	NPY_HUMAN	Increases ADR	[16]
Galanin peptides (GAL)	OTB3VPTO	GALA_HUMAN	Increases ADR	[16]

Indication(s) of Amantadine

Disease Entry	ICD 11	Status	REF
Influenza A virus infection	1E30	Approved	[5]
Parkinsonian disorder	N.A.	Approved	[6]
Postencephalitic Parkinson disease	N.A.	Approved	[6]

Amantadine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Influenza M2 protein (Influ M)	TTXT3PU	M2_I34A1	Inhibitor	[17]

Amantadine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[18]

Amantadine Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Interferon alpha-inducible protein 6 (IFI6)	OTWOOAM4	IFI6_HUMAN	Increases Expression	[19]
Microtubule-associated protein 2 (MAP2)	OT6UYT3X	MTAP2_HUMAN	Decreases Expression	[20]
Interferon alpha/beta receptor 1 (IFNAR1)	OTD4OOFK	INAR1_HUMAN	Affects Expression	[19]
Tyrosine-protein kinase JAK1 (JAK1)	OT0X3D17	JAK1_HUMAN	Increases Expression	[19]
2'-5'-oligoadenylate synthase 2 (OAS2)	OT64CCTM	OAS2_HUMAN	Increases Expression	[19]
Interferon alpha-inducible protein 27, mitochondrial (IFI27)	OTI2XGIT	IFI27_HUMAN	Increases Expression	[19]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[21]
Tyrosyl-DNA phosphodiesterase 1 (TDP1)	OTYINMBR	TYDP1_HUMAN	Decreases Activity	[22]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Idiopathic Parkinson's Disease	DCBAE1L	N. A.	Phase 1	[23]

References

• [1] ClinicalTrials.gov (NCT00794313) Quantification of the Antidyskinetic Effect of Amantadine and Topiramate in Parkinson's Disease
• [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: 6849).
• [3] Topiramate FDA Label
• [4] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [5] 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: 4128).
• [6] Amantadine FDA Label
• [7] The association between the C802T polymorphism of the UDP-glucuronosyltransferase 2B7 gene and effective topiramate dosage. Zh Nevrol Psikhiatr Im S S Korsakova. 2007;107(5):63-4.
• [8] Development of medications for alcohol use disorders: recent advances and ongoing challenges. Expert Opin Emerg Drugs. 2005 May;10(2):323-43.
• [9] The antiepileptic drug topiramate is a substrate for human P-glycoprotein but not multidrug resistance proteins. Pharm Res. 2009 Nov;26(11):2464-70.
• [10] Dose-dependent induction of cytochrome P450 (CYP) 3A4 and activation of pregnane X receptor by topiramate. Epilepsia. 2003 Dec;44(12):1521-8.
• [11] A preliminary pharmacogenetic investigation of adverse events from topiramate in heavy drinkers. Exp Clin Psychopharmacol. 2009 Apr;17(2):122-9. doi: 10.1037/a0015700.
• [12] Effects of anticonvulsants on human p450c17 (17alpha-hydroxylase/17,20 lyase) and 3beta-hydroxysteroid dehydrogenase type 2. Epilepsia. 2005 Mar;46(3):444-8.
• [13] Design, synthesis, and biological evaluation of novel carbohydrate-based sulfamates as carbonic anhydrase inhibitors. J Med Chem. 2011 Mar 10;54(5):1481-9.
• [14] 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.
• [15] Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents. Epilepsy Res. 2005 Jan;63(1):17-25. doi: 10.1016/j.eplepsyres.2004.10.002. Epub 2004 Dec 8.
• [16] 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.
• [17] Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus. J Am Chem Soc. 2009 Jun 17;131(23):8066-76.
• [18] Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol. 1998 Aug;54(2):342-52.
• [19] Interferon signal transduction of biphenyl dimethyl dicarboxylate/amantadine and anti-HBV activity in HepG2 2.2.15. Arch Pharm Res. 2006 May;29(5):405-11. doi: 10.1007/BF02968591.
• [20] Establishment of a 13 genes-based molecular prediction score model to discriminate the neurotoxic potential of food relevant-chemicals. Toxicol Lett. 2022 Feb 1;355:1-18. doi: 10.1016/j.toxlet.2021.10.013. Epub 2021 Nov 5.
• [21] Identification of human Ether--go-go related gene modulators by three screening platforms in an academic drug-discovery setting. Assay Drug Dev Technol. 2010 Dec;8(6):727-42. doi: 10.1089/adt.2010.0331.
• [22] Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors. Bioorg Chem. 2018 Feb;76:392-399. doi: 10.1016/j.bioorg.2017.12.005. Epub 2017 Dec 9.
• [23] ClinicalTrials.gov (NCT01789047) Topiramate as an Adjunct to Amantadine in the Treatment of Dyskinesia in Parkinson's Disease