Barbexaclone

Identification

Name
Barbexaclone
Accession Number
DB09001
Type
Small Molecule
Groups
Experimental
Description

Barbexaclone, a salt compound of propylhexedrine and phenobarbital, is a potent antiepileptic. By weight, barbexaclone is 40% propylhexedrine and 60% phenobarbital. While barbexaclone has sedative properties, propylhexedrine has psychostimulant properties intended to offset these sedative effects. Pharmacokinetic studies have demonstrated that the pharmacokinetics of phenobarbital given as barbexaclone are not affected by propylhexedrine. Several reports from Spanish and Italian literature suggest that barbexaclone is at least as effective as phenobarbital in adults and children, while being better tolerated and having less sedative properties. These reports were conducted in a small series of patients in the 1970s and 1980s, and have yet to be confirmed by larger controlled trials. Despite the lack of controlled trials, barbexaclone was used widely in Turkey until it was discontinued in 2009.

Barbexaclone exists in 25mg and 100mg tablets. 100mg of barbexaclone is equivalent to 60mg of phenobarbital. With this difference in potency in mind, other pharmacokinetic considerations such as dose titration, daily dosing, and optimal plasma concentration can be considered the same as for the equivalent amount of phenobarbital.

There has been a case of barbexaclone abuse due to the amphetamine like properties of propylhexedrine, although the comparative abuse potential is much lower than amphetamine.

Structure
Thumb
Synonyms
  • Barbexaclon
  • Barbexaclona
  • Barbexaclone
  • Barbexaclonum
International/Other Brands
Maliasin (Abbott)
Categories
UNII
291GX1YB65
CAS number
4388-82-3
Weight
Average: 387.524
Monoisotopic: 387.252191935
Chemical Formula
C22H33N3O3
InChI Key
MJCBWPMBFCUHBP-NPULLEENSA-N
InChI
InChI=1S/C12H12N2O3.C10H21N/c1-2-12(8-6-4-3-5-7-8)9(15)13-11(17)14-10(12)16;1-9(11-2)8-10-6-4-3-5-7-10/h3-7H,2H2,1H3,(H2,13,14,15,16,17);9-11H,3-8H2,1-2H3/t;9-/m.0/s1
IUPAC Name
5-ethyl-4,6-dihydroxy-5-phenyl-2,5-dihydropyrimidin-2-one; [(2S)-1-cyclohexylpropan-2-yl](methyl)amine
SMILES
[H][C@](C)(CC1CCCCC1)NC.CCC1(C(O)=NC(=O)N=C1O)C1=CC=CC=C1

Pharmacology

Indication

Created for the treatment for epilepsy, with the intent of creating an antiepileptic with less sedative properties than phenobarbital.

Pharmacodynamics
Not Available
Mechanism of action

Phenobarbitol targets GABA receptors in the CNS. Propylhexedrine is a TAAR1 agonist.

Absorption

After oral administration of barbexaclone in mice the maximum plasma levels of prophylhexedrine appeared after 4 minutes, and propylhexedrine was seen to penetrate the blood brain barrier rapidly. Bioavailability (AUC oral / AUC iv) = 0.37. [3] Phenobarbital was observed to reach the blood more slowly, and brain uptake was a slow process. Equilibrium concentrations with plasma reached after 30 minutes after i.v injection. [3]

Volume of distribution

In mice, the volume of distribution was 0.78L/kg of phenobarbital, and 19.3L/kg for propylhexedrine, after i.v. administration. [3] High but unequal tissue accumulation of propylhexedrine was observed in mice: lung = kidney > liver = brain > spleen > heart > skeletal muscle. [3]

Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

After IV administration in mice, levels of phenobarbital declined exponentially with a half life of 7.5h. [3] For propylhexedrine t0.5a = 0.31h and t0.5b = 2.5h.

Clearance
Not Available
Toxicity

Barbiturates are associated with congenital heart malformations, facial clefts, and other malformations. [5] There is no available data on the use of barbexaclone in pregnancy. One case of a 36 year old women who used barbexaclone 300mg/day and oxcarbezine 600mg/day for 2 years before the pregnancy and 10 weeks into pregnancy resulted in an uncomplicated delivery and normal physical, motor, and mental development at 24 months of age. [5]

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololBarbexaclone may increase the hypotensive activities of Acebutolol.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Barbexaclone.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Barbexaclone.
AgmatineThe metabolism of Agmatine can be increased when combined with Barbexaclone.
AldesleukinBarbexaclone may increase the hypotensive activities of Aldesleukin.
AlimemazineThe risk or severity of adverse effects can be increased when Barbexaclone is combined with Alimemazine.
AliskirenBarbexaclone may increase the hypotensive activities of Aliskiren.
AlprazolamThe risk or severity of adverse effects can be increased when Alprazolam is combined with Barbexaclone.
AlprenololThe serum concentration of Alprenolol can be decreased when it is combined with Barbexaclone.
Ambroxol acefyllinateThe serum concentration of Ambroxol acefyllinate can be decreased when it is combined with Barbexaclone.
Food Interactions
Not Available

References

General References
  1. Bolukbasi F, Delil S, Bulus E, Senturk A, Yeni N, Karaagac N: End of the barbexaclone era: an experience of treatment withdrawal. Epileptic Disord. 2013 Sep;15(3):311-3. doi: 10.1684/epd.2013.0605. [PubMed:23981808]
  2. Iven H, Feldbusch E: Pharmacokinetics of phenobarbital and propylhexedrine after administration of barbexaclone in the mouse. Naunyn Schmiedebergs Arch Pharmacol. 1983 Sep;324(2):153-9. [PubMed:6139756]
  3. Yaris F, Kadioglu M, Kesim M, Ulku C, Yaris E, Kalyoncu NI: Barbexaclone use in pregnancy. Saudi Med J. 2004 Feb;25(2):245-6. [PubMed:14968233]
  4. Shorvon, Simon D.;Dodson, W. E.;Fish, David;Perucca, Emilio;Aminoff, Michael J. (2004). The Treatment of Epilepsy (2nd ed.). John Wiley & Sons. [ISBN:0-632-06046-8]
External Links
PubChem Compound
71196
PubChem Substance
347827816
ChemSpider
64332
Drugs.com
Drugs.com Drug Page
Wikipedia
Barbexaclone
ATC Codes
N03AA04 — Barbexaclone

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
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.272 mg/mLALOGPS
logP1.44ALOGPS
logP2.14ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)0.97ChemAxon
pKa (Strongest Basic)-4.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area82.25 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity60.39 m3·mol-1ChemAxon
Polarizability22.47 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 barbituric acid derivatives. These are compounds containing a perhydropyrimidine ring substituted at C-2, -4 and -6 by oxo groups.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazines
Sub Class
Pyrimidines and pyrimidine derivatives
Direct Parent
Barbituric acid derivatives
Alternative Parents
N-acyl ureas / Diazinanes / Benzene and substituted derivatives / Dicarboximides / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Barbiturate / Ureide / N-acyl urea / Monocyclic benzene moiety / 1,3-diazinane / Benzenoid / Dicarboximide / Urea / Carbonic acid derivative / Carboxylic acid derivative
Molecular Framework
Not Available
External Descriptors
Not Available

Drug created on June 17, 2014 10:50 / Updated on August 18, 2018 14:57