Identification

Name
Moxisylyte
Accession Number
DB09205
Type
Small Molecule
Groups
Approved, Investigational
Description

Moxisylyte, denominated as thymoxamine in the UK, is a specific and orally active α1-adrenergic antagonist.[10] According to the WHO, moxisylyte is approved since 1987[9] and in the same year, it acquired the denomination of orphan product by the FDA.[11] This drug was developed by the Japanese company Fujirebio and also by the American company Iolab in the late 80s.

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Carlytene
Categories
UNII
PW8QYA7KI0
CAS number
54-32-0
Weight
Average: 279.38
Monoisotopic: 279.183443669
Chemical Formula
C16H25NO3
InChI Key
VRYMTAVOXVTQEF-UHFFFAOYSA-N
InChI
InChI=1S/C16H25NO3/c1-11(2)14-10-15(20-13(4)18)12(3)9-16(14)19-8-7-17(5)6/h9-11H,7-8H2,1-6H3
IUPAC Name
4-[2-(dimethylamino)ethoxy]-2-methyl-5-(propan-2-yl)phenyl acetate
SMILES
CC(C)C1=C(OCCN(C)C)C=C(C)C(OC(C)=O)=C1

Pharmacology

Indication

By the WHO, moxisylyte is indicated for the symptomatic management of sequelae of cerebral infarction or hemorrhage.[9] The cerebral infarction is characterized by the blockage of the artery either by the formation of a thrombus or an embolus.[3]

On the other hand, the FDA classified moxisylyte for the reversal of phenylephrine-induced mydriasis in patients who have narrow anterior angles and are at risk of developing an acute attack of angle-closure glaucoma.[11] Closed-angle glaucoma is caused by the contact between the iris and the trabecular meshwork. This contact will damage the aqueous outflow by the meshwork thus, increasing eye pressure and producing the symptoms of glaucoma.[4] Mydriasis is referred to the dilatation of the pupils and this standard body function is known to be a trigger factor for the development of acute closed-angle glaucoma.This risk is explained by the generation of a pupillary block, which is the contact between the pupillary margins and the lens, thus preventing flow from the aqueous humor to the anterior chamber and followed by an increased pressure gradient.[12]

Moxisylyte is also approved in France as the first drug for the treatment of impotence.[5]

Pharmacodynamics

Administration of moxisylyte has shown to improve peripheral flow in occlusive arterial disease with little effect in blood pressure. There are reports of increases in cutaneous blood flow and skin temperature after local application of moxisylyte.[10]

Mechanism of action

Moxisylyte is vasodilator that works as a specific alpha-adrenergic blocking agent. Its action is known to be competitive against norepinephrine without beta-receptor blocking, anti-angiotensin or anti-serotonin activity.[1]

TargetActionsOrganism
AAlpha adrenergic receptor
antagonist
Human
Absorption

Moxisylyte is rapidly absorbed after oral administration.[13] Its pharmacokinetic profile is linear in the dose range from 10 to 30 mg for the values of Cmax and AUC.[5] After intravenous administration, the maximal plasma concentration was of 352.8 ng/ml with an AUC of 152.6 mcg h/L.[8] In preclinical trials, the bioavailability was always presented in approximately 10%.[14]

Volume of distribution

In preclinical trials, the volume of distribution presented for beagle dogs is in the range of 0.83-0.98 L/kg.[14]

Protein binding
Not Available
Metabolism

The pharmacokinetic profile of moxisylyte can make this drug to be considered as a prodrug as its biotransformation is very rapid. This drug gets rapidly hydrolyzed by pseudocholinesterase in plasma and tissues to give the major metabolite deacetyl-thymoxamine.[5, 14] This first metabolite is later demethylated by the cytochrome P450 monooxygenase system to form deacetyl-demethyl-thymoxamine.[14] Both of this major metabolites are pharmacologically active. The pharmacokinetic studies with moxisylyte in urine and feces have shown the presence of 8 different metabolites, where two of them are highly polar and resistant to enzymatic hydrolysis. From this metabolites, it has been detected the sulfate and glucuronide conjugates of the major metabolites.[2, 5]

Route of elimination

The major elimination route of moxisylyte is via the kidneys.[13] The complete elimination of all the metabolites by urine is of 75% when administered intravenously and 69% when administered orally.[7] From the elimination profile, The specific ranges of the two major metabolites of moxisylyte in the urine are of 50% and 10% for desacetyl-thymoxamine and N-monodemethyl-desacetyl-thymoxamine respectively.[6] The fecal elimination corresponded only to the 14% of the administered dose.[14]

Half life

The half-life of moxisylyte was of 1-2 hours.[13]

Clearance

In preclinical trials, the plasma clearance was of 7.17 ml min/kg for beagle dogs.[14]

Toxicity

Moxisylyte is very well accepted by the patients and it presents very few adverse effects. The side effects are usually related to a profound alpha blockade than to a toxic response.[10]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of hypertension can be increased when 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid is combined with Moxisylyte.
1-benzylimidazoleThe risk or severity of hypertension can be increased when 1-benzylimidazole is combined with Moxisylyte.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of hypertension can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Moxisylyte.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of hypertension can be increased when Moxisylyte is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of hypertension can be increased when 3,4-Methylenedioxyamphetamine is combined with Moxisylyte.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Moxisylyte.
4-MethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Methoxyamphetamine is combined with Moxisylyte.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of hypertension can be increased when Moxisylyte is combined with 5-methoxy-N,N-dimethyltryptamine.
AbacavirAbacavir may decrease the excretion rate of Moxisylyte which could result in a higher serum level.
AbediterolThe risk or severity of hypertension can be increased when Moxisylyte is combined with Abediterol.
Food Interactions
Not Available

References

General References
  1. Wand M, Grant WM: Thymoxamine hydrochloride: an alpha-adrenergic blocker. Surv Ophthalmol. 1980 Sep-Oct;25(2):75-84. [PubMed:6108620]
  2. Duchene P, Bernouillet C, Bromet-Petit M, Mosser J, Feniou C, Gaudin D, Virelizier H: Metabolism of 14C-thymoxamine in rat and man. Xenobiotica. 1988 Aug;18(8):919-28. doi: 10.3109/00498258809167515. [PubMed:2973182]
  3. Samad F, Ruf W: Inflammation, obesity, and thrombosis. Blood. 2013 Nov 14;122(20):3415-22. doi: 10.1182/blood-2013-05-427708. Epub 2013 Oct 3. [PubMed:24092932]
  4. Pandit RJ, Taylor R: Mydriasis and glaucoma: exploding the myth. A systematic review. Diabet Med. 2000 Oct;17(10):693-9. [PubMed:11110501]
  5. Bressolle F, Costa P, Rouzier-Panis R, Marquer C: Pharmacokinetics of moxisylyte in healthy volunteers after intracavernous injection of increasing doses. Eur J Clin Pharmacol. 1996;49(5):411-5. [PubMed:8866639]
  6. Costa P, Bressolle F, Jarroux E, Sarrazin B, Mosser J, Navratil H, Galtier M: Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteers. J Pharm Sci. 1993 Sep;82(9):968-71. [PubMed:8229699]
  7. Costa P, Bressolle F, Bromet-Petit M, Mosser J, Sarrazin B: Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and oral administration. J Pharm Sci. 1992 Dec;81(12):1223-6. [PubMed:1491345]
  8. Costa P, Bressolle F, Sarrazin B, Mosser J, Galtier M: Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and intracavernous administration. J Pharm Sci. 1993 Jul;82(7):729-33. [PubMed:8103112]
  9. WHO (1987). WHO drug information (4th ed.). WHO.
  10. Ellis G.P. and West G.B. (1986). Progress in Medicinal Chemistry Volume 23. Elsevier.
  11. FDA-orphan products [Link]
  12. Eye wiki [Link]
  13. Opilon monograph [Link]
  14. Jstage [Link]
External Links
KEGG Drug
D08239
PubChem Compound
4260
PubChem Substance
310265113
ChemSpider
4110
BindingDB
50452139
ChEBI
94754
ChEMBL
CHEMBL159226
Wikipedia
Moxisylyte
ATC Codes
C04AX10 — MoxisylyteG04BE06 — Moxisylyte
MSDS
Download (42 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)145ºCUnited States Environmental Protection Agency.
boiling point (°C)371ºC at 760 mmHg'MSDS'
water solubility>47.4 ug/mlBurnham Center for Chemical Genomics
logP3.17United States Environmental Protection Agency.
pKa8.71Microphysiology Database Project. University of Pittsburgh.
Predicted Properties
PropertyValueSource
Water Solubility0.406 mg/mLALOGPS
logP3.22ALOGPS
logP3.2ChemAxon
logS-2.8ALOGPS
pKa (Strongest Basic)8.79ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area38.77 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity80.9 m3·mol-1ChemAxon
Polarizability32.39 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as aromatic monoterpenoids. These are monoterpenoids containing at least one aromatic ring.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Prenol lipids
Sub Class
Monoterpenoids
Direct Parent
Aromatic monoterpenoids
Alternative Parents
Monocyclic monoterpenoids / Phenol esters / Cumenes / Phenylpropanes / Phenoxy compounds / Phenol ethers / Toluenes / Alkyl aryl ethers / Trialkylamines / Carboxylic acid esters
show 6 more
Substituents
P-cymene / Aromatic monoterpenoid / Monocyclic monoterpenoid / Phenol ester / Cumene / Phenylpropane / Phenoxy compound / Phenol ether / Alkyl aryl ether / Toluene
show 19 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...

Components:
References
  1. Wand M, Grant WM: Thymoxamine hydrochloride: an alpha-adrenergic blocker. Surv Ophthalmol. 1980 Sep-Oct;25(2):75-84. [PubMed:6108620]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Bressolle F, Costa P, Rouzier-Panis R, Marquer C: Pharmacokinetics of moxisylyte in healthy volunteers after intracavernous injection of increasing doses. Eur J Clin Pharmacol. 1996;49(5):411-5. [PubMed:8866639]
  2. Jstage [Link]
2. Cytochrome p450 3A subfamily
Kind
Protein group
Organism
Human
Pharmacological action
No
Actions
Substrate
References
  1. Jstage [Link]

Drug created on October 19, 2015 14:13 / Updated on November 02, 2018 07:00