Details of the Drug

General Information of Drug (ID: DM2N0TO)

• Drug Name: Physostigmine
• Synonyms: Xalieve; Acetylcholinesterase inhibitor (dry mouth), Calabar; Physostigmine (local acting gel, xerostomia); Physostigmine (buccal, xerostomia), Calabar; Physostigmine (local acting gel, xerostomia), Calabar

Indication

Disease Entry	ICD 11	Status	REF
Xerostomia	DA02.1	Discontinued in Phase 2	[1], [2]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 275.35
  Topological Polar Surface Area (xlogp); 0.7
  Rotatable Bond Count (rotbonds); 2
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 4
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [3]
  Clearance: The drug present in the plasma can be removed from the body at the rate of 72 mL/min/kg [4]
  Half-life: The concentration or amount of drug in body reduced by one-half in 1 hour [4]
  Metabolism: The drug is metabolized via the cholinesterases [5]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.06065 micromolar/kg/day [6]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.64% [4]
  Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 3.9 L/kg [4]
• Chemical Identifiers:
  Formula: C15H21N3O2
  IUPAC Name: [(3aR,8bS)-3,4,8b-trimethyl-2,3a-dihydro-1H-pyrrolo[2,3-b]indol-7-yl] N-methylcarbamate
  Canonical SMILES: C[C@@]12CCN([C@@H]1N(C3=C2C=C(C=C3)OC(=O)NC)C)C
  InChI: InChI=1S/C15H21N3O2/c1-15-7-8-17(3)13(15)18(4)12-6-5-10(9-11(12)15)20-14(19)16-2/h5-6,9,13H,7-8H2,1-4H3,(H,16,19)/t13-,15+/m1/s1
  InChIKey: PIJVFDBKTWXHHD-HIFRSBDPSA-N
• Cross-matching ID:
  PubChem CID: 5983
  ChEBI ID: CHEBI:27953
  CAS Number: 57-47-6
  DrugBank ID: DB00981
  TTD ID: D09JVV

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Acetylcholinesterase (AChE)	TT1RS9F	ACES_HUMAN	Inhibitor	[7]

Molecular Expression Atlas of This Drug

• The Studied Disease: Xerostomia
• ICD Disease Classification: DA02.1

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Acetylcholinesterase (AChE)	DTT	ACHE	6.39E-02	-1.07	-1.15

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Physostigmine (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Bethanechol	DMCLHO0	Moderate	Additive cholinergic effects by the combination of Physostigmine and Bethanechol.	Abnormal micturition [MF50]	[18]
Mepyramine	DMB4SFH	Moderate	Antagonize the effect of Physostigmine when combined with Mepyramine.	Allergic/hypersensitivity disorder [4A80-4A8Z]	[19]
Phenyltoloxamine	DMKAEQW	Moderate	Antagonize the effect of Physostigmine when combined with Phenyltoloxamine.	Allergic/hypersensitivity disorder [4A80-4A8Z]	[19]
Rivastigmine	DMG629M	Moderate	Additive cholinergic effects by the combination of Physostigmine and Rivastigmine.	Alzheimer disease [8A20]	[18]
Desipramine	DMT2FDC	Moderate	Antagonize the effect of Physostigmine when combined with Desipramine.	Attention deficit hyperactivity disorder [6A05]	[20]
Umeclidinium	DM4E8O9	Moderate	Antagonize the effect of Physostigmine when combined with Umeclidinium.	Chronic obstructive pulmonary disease [CA22]	[21]
Tiotropium	DMFDC0Q	Moderate	Antagonize the effect of Physostigmine when combined with Tiotropium.	Chronic obstructive pulmonary disease [CA22]	[21]
Revefenacin	DMMP5SI	Moderate	Antagonize the effect of Physostigmine when combined with Revefenacin.	Chronic obstructive pulmonary disease [CA22]	[21]
OPC-34712	DMHG57U	Moderate	Antagonize the effect of Physostigmine when combined with OPC-34712.	Depression [6A70-6A7Z]	[20]
Clomipramine	DMINRKW	Moderate	Antagonize the effect of Physostigmine when combined with Clomipramine.	Depression [6A70-6A7Z]	[20]
Doxepin	DMPI98T	Moderate	Antagonize the effect of Physostigmine when combined with Doxepin.	Depression [6A70-6A7Z]	[20]
Mepenzolate	DM8YU2F	Moderate	Antagonize the effect of Physostigmine when combined with Mepenzolate.	Digestive system disease [DE2Z]	[20]
Oxybutynine	DMJPBAX	Moderate	Antagonize the effect of Physostigmine when combined with Oxybutynine.	Discovery agent [N.A.]	[20]
Diphenhydramine	DMKQTBA	Moderate	Antagonize the effect of Physostigmine when combined with Diphenhydramine.	Episodic vestibular syndrome [AB31]	[20]
Solifenacin	DMG592Q	Moderate	Antagonize the effect of Physostigmine when combined with Solifenacin.	Functional bladder disorder [GC50]	[20]
Tolterodine	DMSHPW8	Moderate	Antagonize the effect of Physostigmine when combined with Tolterodine.	Functional bladder disorder [GC50]	[20]
Belladonna	DM2RBWK	Moderate	Antagonize the effect of Physostigmine when combined with Belladonna.	Infectious gastroenteritis/colitis [1A40]	[20]
ITI-007	DMUQ1DO	Moderate	Antagonize the effect of Physostigmine when combined with ITI-007.	Insomnia [7A00-7A0Z]	[20]
Polyethylene glycol	DM4I1JP	Moderate	Increased risk of lowers seizure threshold by the combination of Physostigmine and Polyethylene glycol.	Irritable bowel syndrome [DD91]	[22]
Thalidomide	DM70BU5	Moderate	Increased risk of ventricular arrhythmias by the combination of Physostigmine and Thalidomide.	Multiple myeloma [2A83]	[23]
Siponimod	DM2R86O	Major	Increased risk of bradycardia by the combination of Physostigmine and Siponimod.	Multiple sclerosis [8A40]	[23]
Fingolimod	DM5JVAN	Moderate	Increased risk of atrioventricular block by the combination of Physostigmine and Fingolimod.	Multiple sclerosis [8A40]	[24]
Ozanimod	DMT6AM2	Moderate	Increased risk of atrioventricular block by the combination of Physostigmine and Ozanimod.	Multiple sclerosis [8A40]	[25]
Neostigmine	DM6T2J3	Moderate	Additive cholinergic effects by the combination of Physostigmine and Neostigmine.	Myasthenia gravis [8C6Y]	[18]
Edrophonium	DMCRQHB	Moderate	Additive cholinergic effects by the combination of Physostigmine and Edrophonium.	Myasthenia gravis [8C6Y]	[18]
Ambenonium	DMOP0BL	Moderate	Additive cholinergic effects by the combination of Physostigmine and Ambenonium.	Myasthenia gravis [8C6Y]	[18]
Phenindamine	DMDTC7R	Moderate	Antagonize the effect of Physostigmine when combined with Phenindamine.	Nasopharyngitis [CA00]	[20]
Dimenhydrinate	DM264B3	Moderate	Antagonize the effect of Physostigmine when combined with Dimenhydrinate.	Nausea/vomiting [MD90]	[20]
Promethazine	DM6I5GR	Moderate	Antagonize the effect of Physostigmine when combined with Promethazine.	Nausea/vomiting [MD90]	[20]
Cyclizine	DM9G7BS	Moderate	Antagonize the effect of Physostigmine when combined with Cyclizine.	Nausea/vomiting [MD90]	[20]
Bupropion	DM5PCS7	Major	Increased risk of lowers seizure threshold by the combination of Physostigmine and Bupropion.	Nicotine use disorder [6C4A]	[26]
Flavoxate	DMKV4NL	Moderate	Antagonize the effect of Physostigmine when combined with Flavoxate.	Pain [MG30-MG3Z]	[20]
Orphenadrine	DMW542E	Moderate	Antagonize the effect of Physostigmine when combined with Orphenadrine.	Parkinsonism [8A00]	[20]
Methylscopolamine	DM5VWOB	Moderate	Antagonize the effect of Physostigmine when combined with Methylscopolamine.	Peptic ulcer [DA61]	[20]
Levomepromazine	DMIKFEL	Moderate	Antagonize the effect of Physostigmine when combined with Levomepromazine.	Psychotic disorder [6A20-6A25]	[20]
Quetiapine	DM1N62C	Moderate	Antagonize the effect of Physostigmine when combined with Quetiapine.	Schizophrenia [6A20]	[20]
Aripiprazole	DM3NUMH	Moderate	Antagonize the effect of Physostigmine when combined with Aripiprazole.	Schizophrenia [6A20]	[20]
Molindone	DMAH70G	Moderate	Antagonize the effect of Physostigmine when combined with Molindone.	Schizophrenia [6A20]	[20]
Thiothixene	DMDINC4	Moderate	Antagonize the effect of Physostigmine when combined with Thiothixene.	Schizophrenia [6A20]	[20]
Pimozide	DMW83TP	Moderate	Antagonize the effect of Physostigmine when combined with Pimozide.	Schizophrenia [6A20]	[20]
Chlorpheniramine	DM5URA2	Moderate	Antagonize the effect of Physostigmine when combined with Chlorpheniramine.	Vasomotor/allergic rhinitis [CA08]	[20]
Trimeprazine	DMEMV9D	Moderate	Antagonize the effect of Physostigmine when combined with Trimeprazine.	Vasomotor/allergic rhinitis [CA08]	[19]
Acrivastine	DMTIGA0	Moderate	Antagonize the effect of Physostigmine when combined with Acrivastine.	Vasomotor/allergic rhinitis [CA08]	[20]
Procainamide	DMNMXR8	Moderate	Antagonize the effect of Physostigmine when combined with Procainamide.	Ventricular tachyarrhythmia [BC71]	[20]

References

• [1] 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: 6598).
• [2] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028816)
• [3] BDDCS predictions, self-correcting aspects of BDDCS assignments, BDDCS assignment corrections, and classification for more than 175 additional drugs
• [4] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [5] FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
• [6] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [7] The effects of physostigmine on acetylcholinesterase activity of CSF plasma and brain. A comparison of intravenous and intraventricular administration in beagle dogs. Neuropharmacology. 1986 Oct;25(10):1167-77.
• [8] Evidence that the clinical effects of cholinesterase inhibitors are related to potency and targeting of action. Int J Clin Pract Suppl. 2002 Jun;(127):6-19.
• [9] 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: 2465).
• [10] Acetylcholinesterase activity in Corbicula fluminea Mull., as a biomarker of organophosphate pesticide pollution in Pinacanauan River, Philippines. Environ Monit Assess. 2010 Jun;165(1-4):331-40.
• [11] [From symptomatic to disease modifying therapy Recent developments in the pharmacotherapy of Alzheimer's disease]. Fortschr Neurol Psychiatr. 2009 Jun;77(6):326-33.
• [12] Huperzine A attenuates cognitive deficits and brain injury in neonatal rats after hypoxia-ischemia. Brain Res. 2002 Sep 13;949(1-2):162-70.
• [13] Screening of acetylcholinesterase inhibitors by CE after enzymatic reaction at capillary inlet. J Sep Sci. 2009 May;32(10):1748-56.
• [14] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [15] Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens. Neuropsychopharmacology. 2008 Aug;33(9):2158-66.
• [16] The effects of topical ocular application of 0.25% demecarium bromide on serum acetylcholinesterase levels in normal dogs. Vet Ophthalmol. 2003 Mar;6(1):23-5.
• [17] Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators. Chem Biol. 2003 Jun;10(6):491-502.
• [18] Product Information. Aricept (donepezil). Pfizer US Pharmaceuticals, New York, NY.
• [19] Carnahan RM, Lund BC, Perry PJ, Chrischilles EA "The concurrent use of anticholinergics and cholinesterase inhibitors: rare event or common practice?" J Am Geriatr Soc 52 (2004): 2082-7. [PMID: 15571547]
• [20] Beers MH, Ouslander JG, Rollingher I, Reuben DB, Brooks J, Beck JC "Explicit criteria for determining inappropriate medication use in nursing home residents." Arch Intern Med 151 (1991): 1825-32. [PMID: 1888249]
• [21] Multum Information Services, Inc. Expert Review Panel.
• [22] Product Information. Suprep Bowel Prep Kit (magnesium/potassium/sodium sulfates). Braintree Laboratories, Braintree, MA.
• [23] Cerner Multum, Inc. "Australian Product Information.".
• [24] Product Information. Gilenya (fingolimod). Novartis Pharmaceuticals, East Hanover, NJ.
• [25] Product Information. Zeposia (ozanimod). Celgene Corporation, Summit, NJ.
• [26] Product Information. Wellbutrin XL (buPROPion). GlaxoSmithKline, Philadelphia, PA.