Details of the Drug Combination

General Information of Drug Combination (ID: DCJ6USG)

• Drug Combination Name: Naloxone + Flumazenil
• Indication: Brain Death; Status: Phase 1 [1]
• Component Drugs:
  Naloxone (DM3FXMA): Small molecular drug
  Flumazenil (DMPCG2L): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Naloxone

Disease Entry	ICD 11	Status	REF
Narcotic depression	6A7Z	Approved	[2]
Pain	MG30-MG3Z	Approved	[3]
Pruritus	EC90	Phase 3	[4]
Respiratory depression	MD11.5	Phase 3	[5]
Opioid dependence	6C43.2Z	Phase 1	[5]

Naloxone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Antagonist	[8]

Naloxone Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[9]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[10]
Vasopressin-neurophysin 2-copeptin (AVP)	OTAVZ76K	NEU2_HUMAN	Decreases Secretion	[11]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[12]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[13]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Affects Expression	[14]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Response To Substance	[15]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[16]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Affects Binding	[17]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Decreases Response To Substance	[18]

Indication(s) of Flumazenil

Disease Entry	ICD 11	Status	REF
Benzodiazepine overdose	PC91	Approved	[6]

Flumazenil Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
GABA(A) receptor alpha-5 (GABRA5)	TTNZPQ1	GBRA5_HUMAN	Modulator (allosteric modulator)	[19]
GABA(A) receptor gamma-3 (GABRG3)	TTEX6LM	GBRG3_HUMAN	Modulator (allosteric modulator)	[20]
GABA(A) receptor alpha-2 (GABRA2)	TTBMV1G	GBRA2_HUMAN	Modulator (allosteric modulator)	[21]
GABA(A) receptor alpha-3 (GABRA3)	TT37EDJ	GBRA3_HUMAN	Modulator (allosteric modulator)	[22]
Translocator protein (TSPO)	TTPTXIN	TSPO_HUMAN	Antagonist	[23]

Flumazenil Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2)	OTGNDWUO	GBRG2_HUMAN	Affects Binding	[24]
Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3)	OT80C3D4	GBRB3_HUMAN	Affects Binding	[24]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6)	OTX4UC3O	GBRA6_HUMAN	Affects Binding	[24]

References

• [1] ClinicalTrials.gov (NCT03743805) Rapid Reversal of CNS-Depressant Drug Effect Prior to Brain Death Determination
• [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: 1668).
• [3] Naloxone FDA Label
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] 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: 4192).
• [7] Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury. Arch Toxicol. 2018 Jan;92(1):383-399. doi: 10.1007/s00204-017-2036-4. Epub 2017 Jul 31.
• [8] OxyContin abuse and overdose. Postgrad Med. 2009 Mar;121(2):163-7.
• [9] beta-Endorphin and essential hypertension: importance of the clonidine-naloxone interaction. Acta Physiol Hung. 1985;65(2):217-26.
• [10] Opioid peptides attenuate blood pressure increase in acute respiratory failure. Peptides. 2001 Apr;22(4):631-7. doi: 10.1016/s0196-9781(01)00373-4.
• [11] Blood pressure and vasopressin in progressive autonomic failure. Response to postural stimulation, L-dopa and naloxone. Brain. 1983 Jun;106 (Pt 2):503-11. doi: 10.1093/brain/106.2.503.
• [12] Endogenous opioids modulate the cardiovascular response to mental stress. Psychoneuroendocrinology. 1990;15(3):185-92. doi: 10.1016/0306-4530(90)90029-9.
• [13] Differences in the opioid control of luteinizing hormone secretion between pathological and iatrogenic hyperprolactinemic states. J Clin Endocrinol Metab. 1987 Mar;64(3):508-12. doi: 10.1210/jcem-64-3-508.
• [14] Influence of naloxone on muscle sympathetic nerve activity, systemic and calf haemodynamics and ambulatory blood pressure after exercise in mild essential hypertension. J Hypertens. 1995 Apr;13(4):447-61.
• [15] Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone. J Neurosci. 2009 May 20;29(20):6449-60. doi: 10.1523/JNEUROSCI.0708-09.2009.
• [16] Chronic oxycodone induces integrated stress response in rat brain. BMC Neurosci. 2015 Sep 16;16:58. doi: 10.1186/s12868-015-0197-8.
• [17] Human carboxylesterase 1: from drug metabolism to drug discovery. Biochem Soc Trans. 2003 Jun;31(Pt 3):620-4. doi: 10.1042/bst0310620.
• [18] Interleukin-2-induced antinociception in morphine-insensitive rats. Acta Pharmacol Sin. 2002 Nov;23(11):981-4.
• [19] 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: 408).
• [20] 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: 415).
• [21] 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: 405).
• [22] 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: 406).
• [23] 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: 2879).
• [24] Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors. Mol Pharmacol. 1996 Feb;49(2):253-9.