Details of the Drug Combination

General Information of Drug Combination (ID: DC5XWTI)

• Drug Combination Name: Betamethasone + Ropivacaine
• Indication: Plantar Fascitis; Status: Phase 1 [1]
• Component Drugs:
  Betamethasone (DMAHJEF): Small molecular drug
  Ropivacaine (DMSPJG2): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Betamethasone

Disease Entry	ICD 11	Status	REF
Acute adrenal insufficiency	N.A.	Approved	[2]
Addison disease	5A74.0	Approved	[2]
Allergic rhinitis	CA08.0	Approved	[2]
Angioedema	4A00.15	Approved	[2]
Aspiration pneumonitis	N.A.	Approved	[2]
Autoimmune haemolytic anaemia	3A20	Approved	[2]
Bursitis	N.A.	Approved	[2]
Cerebral edema	8D60.1	Approved	[2]
Congenital adrenal hyperplasia	5A71.01	Approved	[2]
Crohn disease	DD70	Approved	[2]
Dermatitis herpetiformis	EB44	Approved	[2]
Diamond-Blackfan anemia	N.A.	Approved	[2]
Disorder of orbital region	N.A.	Approved	[2]
Epicondylitis	N.A.	Approved	[2]
Erythema multiforme	N.A.	Approved	[2]
Exanthem	N.A.	Approved	[2]
Granuloma annulare	N.A.	Approved	[2]
Inflammation	1A00-CA43.1	Approved	[3]
Inflammatory bowel disease	DD72	Approved	[2]
Miliary tuberculosis	N.A.	Approved	[2]
Multiple sclerosis	8A40	Approved	[2]
Mycosis fungoides	2B01	Approved	[2]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[2]
Psoriasis	EA90	Approved	[2]
Psoriatic arthritis	FA21	Approved	[2]
Rheumatic heart disease	N.A.	Approved	[2]
Sarcoidosis	4B20.5	Approved	[2]
Scalp dermatosis	N.A.	Approved	[2]
Serum sickness	N.A.	Approved	[2]
Severe asthma	CA23	Approved	[2]
Skin disease	EA00-EM0Z	Approved	[2]
Systemic lupus erythematosus	4A40.0	Approved	[2]
Tinea corporis	1F28.Y	Approved	[2]
Tinea cruris	1F28.3	Approved	[2]
Acquired thrombocytopenia	N.A.	Investigative	[2]
Asthma	CA23	Investigative	[2]
Beta-thalassemia major	N.A.	Investigative	[2]
Classic Hodgkin lymphoma	N.A.	Investigative	[2]
Follicular lymphoma	2A80	Investigative	[2]
Rheumatoid arthritis	FA20	Investigative	[2]
Synovitis	N.A.	Investigative	[2]
Tinea pedis	1F28.2	Investigative	[2]
Trichinellosis	N.A.	Investigative	[2]

Betamethasone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glucocorticoid receptor (NR3C1)	TTYRL6O	GCR_HUMAN	Agonist	[7]

Betamethasone Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Betamethasone Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Frataxin, mitochondrial (FXN)	OTE9U09A	FRDA_HUMAN	Increases Expression	[9]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Increases Activity	[10]
Mineralocorticoid receptor (NR3C2)	OT0F2V2Z	MCR_HUMAN	Increases Activity	[10]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[6]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[6]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[6]
Early growth response protein 1 (EGR1)	OTCP6XGZ	EGR1_HUMAN	Affects Expression	[11]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Increases Metabolism	[12]

Indication(s) of Ropivacaine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[4]
Appendicitis	DB10	Approved	[5]

Ropivacaine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated sodium channel alpha Nav1.8 (SCN10A)	TT90XZ8	SCNAA_HUMAN	Modulator	[14]

Ropivacaine Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[16]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[17]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[17]

Ropivacaine Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Expression	[18]
L-lactate dehydrogenase A chain (LDHA)	OTN7K4XB	LDHA_HUMAN	Increases Expression	[19]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[19]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[19]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[20]
Caspase-1 (CASP1)	OTZ3YQFU	CASP1_HUMAN	Increases Cleavage	[19]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[13]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[13]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Decreases Expression	[21]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[13]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Decreases Activity	[22]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Decreases Expression	[21]
Gasdermin-D (GSDMD)	OTH39BKI	GSDMD_HUMAN	Increases Cleavage	[19]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[13]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[13]
Interleukin-18 (IL18)	OTBB2A8O	IL18_HUMAN	Increases Expression	[19]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Increases Expression	[13]
NACHT, LRR and PYD domains-containing protein 3 (NLRP3)	OTZM6MHU	NLRP3_HUMAN	Increases Expression	[19]
Sulfotransferase 1A1 (SULT1A1)	OT0K7JIE	ST1A1_HUMAN	Increases Sulfation	[23]
Histamine H1 receptor (HRH1)	OT8F9FV6	HRH1_HUMAN	Affects Binding	[24]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Response To Substance	[20]
Sulfotransferase 1E1 (SULT1E1)	OTGPJ517	ST1E1_HUMAN	Increases Sulfation	[23]
Sulfotransferase 1A3 (SULT1A4)	OTHJ8WWV	ST1A3_HUMAN	Increases Sulfation	[23]
Clusterin (CLU)	OTQGG0JM	CLUS_HUMAN	Decreases Response To Substance	[20]

References

• [1] ClinicalTrials.gov (NCT03054610) Therapeutic Effect of Botulinum Toxin A for the Treatment of Plantar Fasciitis.
• [2] Betamethasone 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: 7061).
• [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: 7602).
• [5] Ropivacaine FDA Label
• [6] Cell-based and cytokine-directed chemical screen to identify potential anti-multiple myeloma agents. Leuk Res. 2010 Jul;34(7):917-24. doi: 10.1016/j.leukres.2009.12.002. Epub 2010 Feb 8.
• [7] The cannabinoid CB2 receptor inverse agonist JTE-907 suppresses spontaneous itch-associated responses of NC mice, a model of atopic dermatitis. Eur J Pharmacol. 2006 Aug 7;542(1-3):179-83.
• [8] Structural determinants of P-glycoprotein-mediated transport of glucocorticoids. Pharm Res. 2003 Nov;20(11):1794-803.
• [9] Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia. PLoS One. 2013;8(2):e55940.
• [10] Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur J Endocrinol. 2004 Sep;151(3):397-406. doi: 10.1530/eje.0.1510397.
• [11] [Steroid drugs and GM-CSF modulates activity of Egr-1 in glioma cells]. Cir Cir. 2013 Jan-Feb;81(1):3-13.
• [12] Metabolism of synthetic steroids by the human placenta. Placenta. 2007 Jan;28(1):39-46.
• [13] Ropivacaine inhibits proliferation?and invasion?and promotes apoptosis and autophagy in bladder cancer cells via inhibiting PI3K/AKT pathway. J Biochem Mol Toxicol. 2023 Jan;37(1):e23233. doi: 10.1002/jbt.23233. Epub 2022 Oct 3.
• [14] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [15] Metabolism of a new local anesthetic, ropivacaine, by human hepatic cytochrome P450. Anesthesiology. 1995 Jan;82(1):214-20.
• [16] Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors. Clin Pharmacol Ther. 1998 Nov;64(5):484-91.
• [17] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [18] Effect of parthanatos on ropivacaine-induced damage in SH-SY5Y cells. Clin Exp Pharmacol Physiol. 2017 May;44(5):586-594. doi: 10.1111/1440-1681.12730.
• [19] Dexmedetomidine protects against Ropivacaine-induced neuronal pyroptosis via the Nrf2/HO-1 pathway. J Toxicol Sci. 2023;48(3):139-148. doi: 10.2131/jts.48.139.
• [20] Ectopic expression of clusterin/apolipoprotein J or Bcl-2 decreases the sensitivity of HaCaT cells to toxic effects of ropivacaine. Cell Res. 2004 Oct;14(5):415-22. doi: 10.1038/sj.cr.7290242.
• [21] Apoptosis and mitochondrial dysfunction in human chondrocytes following exposure to lidocaine, bupivacaine, and ropivacaine. J Bone Joint Surg Am. 2010 Mar;92(3):609-18. doi: 10.2106/JBJS.H.01847.
• [22] Long QT 1 mutation KCNQ1A344V increases local anesthetic sensitivity of the slowly activating delayed rectifier potassium current. Anesthesiology. 2006 Sep;105(3):511-20. doi: 10.1097/00000542-200609000-00015.
• [23] Studies on sulfation of synthesized metabolites from the local anesthetics ropivacaine and lidocaine using human cloned sulfotransferases. Drug Metab Dispos. 1999 Sep;27(9):1057-63.
• [24] H(1)R mediates local anesthetic-induced vascular permeability in angioedema. Toxicol Appl Pharmacol. 2020 Apr 1;392:114921. doi: 10.1016/j.taap.2020.114921. Epub 2020 Feb 12.