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Vanoxerine

Description of Vanoxerine:  Vanoxerine (GBR-12909) is a high-affinity dopamine reuptake inhibitor that was synthesized in the late 1970s and was initially tested in Europe as a potential antidepressant. In 1989, it was suggested that GBR-12909 might be useful in the treatment of cocaine addiction.  GBR-12909 binds to the target site on the DAT ~ 500 times more strongly than cocaine, but simultaneously inhibits the release of dopamine. This combined effect only slightly elevates dopamine levels, giving vanoxerine only mild stimulant effects. Vanoxerine has been researched for use in treating cocaine dependence both as a substitute for cocaine and to block the rewarding effects. This strategy of using a competing agonist with a longer half-life has been successfully used to treat addiction to opiates such as heroin by substituting with methadone. It was hoped that vanoxerine would be of similar use in treating cocaine addiction. (source: http://en.wikipedia.org/wiki/Vanoxerine).

Vanoxerine is a drug currently in phase IIb human trials for its use as an antiarrhythmic .  It was previously indicated as a treatment for Parkinson’s Disease and depression, however it had no significant benefit with these diseases. Vanoxerine is now being investigated for its potential benefits in treating cardiac arrhythmias.

Vanoxerine is a potentially effective treatment for cardiac arrhythmias. A significant cause of cardiac arrhythmias is reentry, an electrophysiologic event in which the proliferating signal that refuses to terminate, and endures to reexcite the heart after the refractory period. It is likely that vanoxerine acts to prevent reentrant circuits. Vanoxerine terminates atrial flutters and atrial fibrillations (both cardiac arrhythmias) by blocking the recirculating electrical signal, and preventing the reformation of the reentrant circuit.  Vanoxerine has also shown a tendency to reduce the recurrence of cardiac arrhythmias, as it was exceedingly difficult to reproduce an atrial flutter or fibrillation in a subject that had been taking vanoxerine.  Experiments have successfully been performed on cell cultures, canine hosts, and testing has moved towards human trials.

In clinical human trials with increasing dosages, vanoxerine has shown to have a highly favourable therapeutic index, showing no side effects at concentrations much higher than the therapeutic dose. In canines, the effective therapeutic dose was between 76ng/ml and 99ng/ml, however the drug reached plasma concentrations of 550ng/ml without harmful side effects, presenting a desirable therapeutic index.  One of the major benefits of vanoxerine is that it does not appear to cause the same harmful side effects as its most comparable contender: amiodarone.  (source: http://en.wikipedia.org/wiki/Vanoxerine).

1: Cakulev I, Lacerda AE, Khrestian CM, Ryu K, Brown AM, Waldo AL. Oral vanoxerine prevents reinduction of atrial tachyarrhythmias: preliminary results. J Cardiovasc Electrophysiol. 2011 Nov;22(11):1266-73. doi: 10.1111/j.1540-8167.2011.02098.x. Epub 2011 May 26. PubMed PMID: 21615815; PubMed Central PMCID: PMC3172341.

2: Matsumoto N, Khrestian CM, Ryu K, Lacerda AE, Brown AM, Waldo AL. Vanoxerine, a new drug for terminating atrial fibrillation and flutter. J Cardiovasc Electrophysiol. 2010 Mar;21(3):311-9. Epub 2009 Oct 8. PubMed PMID: 19817929.

3: Lacerda AE, Kuryshev YA, Yan GX, Waldo AL, Brown AM. Vanoxerine: cellular mechanism of a new antiarrhythmic. J Cardiovasc Electrophysiol. 2010 Mar;21(3):301-10. Epub 2009 Oct 8. PubMed PMID: 19817928; PubMed Central PMCID: PMC3107714.

4: Cherstniakova SA, Bi D, Fuller DR, Mojsiak JZ, Collins JM, Cantilena LR. Metabolism of vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, by human cytochrome P450 enzymes. Drug Metab Dispos. 2001 Sep;29(9):1216-20. PubMed PMID: 11502731.

5: Preti A. Vanoxerine National Institute on Drug Abuse. Curr Opin Investig Drugs. 2000 Oct;1(2):241-51. PubMed PMID: 11249581.

6: Ingwersen SH, Snel S, Mant TG, Edwards D. Nonlinear multiple-dose pharmacokinetics of the dopamine reuptake inhibitor vanoxerine. J Pharm Sci. 1993 Nov;82(11):1164-6. PubMed PMID: 8289134.

7: Ingwersen SH, Mant TG, Larsen JJ. Food intake increases the relative oral bioavailability of vanoxerine. Br J Clin Pharmacol. 1993 Mar;35(3):308-10. PubMed PMID: 8471409; PubMed Central PMCID: PMC1381581.

8: Ingwersen SH. Column liquid chromatographic assay of the dopamine reuptake inhibitor vanoxerine (GBR 12909) in human serum. J Chromatogr. 1991 Nov 15;571(1-2):305-11. PubMed PMID: 1839795.