Absorption, Distribution and Excretion
In patients, the mean peak plasma concentration of vinakalan hydrochloride was 3.9 μg/ml after a single 10-minute intravenous infusion of 3 mg/kg (15 minutes apart); the peak plasma concentration was 4.3 μg/ml after a second infusion of 2 mg/kg (15 minutes apart). It is primarily excreted via the kidneys. Approximately 2 L/kg. The typical systemic clearance of vinakalan is estimated to be 0.41 L/hr/kg. Metabolism/Metabolites In CYP2D6 extensive metabolizers, vinakalan is primarily metabolized via CYP2D6-mediated O-demethylation. Glucuronization is the major metabolic pathway in CYP2D6 weak metabolizers. Biological Half-Life The elimination half-life is 3 hours for CYP2D6 strong metabolizers and 5.5 hours for weak metabolizers.

Protein Binding
At concentrations ranging from 1 to 5 μg/ml, vinakalan exhibits low protein binding in human serum, with a free fraction of 53-63%.

: Dorian, Paul MD et al. The Effect of Vernakalant (RSD1235), an Investigational Antiarrhythmic Agent, on Atrial Electrophysiology in Humans. Journal of Cardiovascular Pharmacology:July 2007 - Volume 50 -Issue 1 - pp 35-40. [2]. Jodene Eldstrom et al. The Molecular Basis of High-Affinity Binding of the Antiarrhythmic Compound Vernakalant (RSD1235) to Kv1.5 Channels. Molecular Pharmacology December 2007 vol. 72 no. 6 1522-1534 [3]. Vernakalant. Too dangerous in atrial fibrillation.Prescrire Int. 2012 May;21(127):119-22. [4]. Blomstr?m-Lundqvist C, Blomstr?m P.Safety and efficacy of pharmacological cardioversion of atrial fibrillation using intravenous vernakalant, a new antiarrhythmic drug with atrial selectivity.Expert Opin Drug Saf. 2012 Jul;11(4):671-9. Epub 2012 May 26. [5]. Bash LD, Buono JL, Davies GM, Martin A, Fahrbach K, Phatak H, Avetisyan R, Mwamburi M.Systematic review and meta-analysis of the efficacy of cardioversion by vernakalant and comparators in patients with atrial fibrillation.Cardiovasc Drugs Ther. 2012 Apr;

Venakalan is an alcohol compound belonging to the phenolic class of compounds. Developed by Cardiom Pharmaceuticals, Venakalan is an antiarrhythmic drug used to rapidly convert atrial fibrillation to sinus rhythm. It is an atypical class III antiarrhythmic drug, with better efficacy at higher heart rates. The intravenous formulation was approved in Europe in September 2010 under the brand name Brinavess, and in Canada in April 2017. Currently, it is an investigational drug under regulatory review by the U.S. Food and Drug Administration (FDA). See also: Venakalan hydrochloride (note moved here). Indications: Suitable for non-surgical adult patients for the rapid conversion of recent episodes of atrial fibrillation to sinus rhythm lasting less than 7 days; also suitable for patients with atrial fibrillation lasting less than 3 days after cardiac surgery.

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Mechanism of Action
Venakarano blocks atrial voltage-gated sodium channels in a dose- and frequency-dependent manner and inhibits late sodium currents (INa), thereby affecting atrial conduction. As heart rate increases, veenakarano's affinity for INa increases, thus enhancing this current-blocking effect and accelerating the onset of action. Once the heart rate slows, its binding effect is rapidly released. It also blocks Kv1.5 channels and their early activated potassium channels (IKur), and inhibits acetylcholine-activated potassium channels (IKAch), which are specifically localized to the atria and can lead to atrial refractory period prolongation. Veenakarano also blocks Kv4.3 channels and their transient outward potassium current (Ito), which is more closely related to atrial refractory period than ventricular refractory period. Veenakarano's blocking effect on hERG channels and their rapid activated/delayed rectifier potassium current (IKr) is weaker, which can lead to mild QT interval prolongation. QRS widening caused by sodium ion channel blockade also leads to QT interval prolongation.

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Pharmacodynamics
Venacarlan blocks the currents in all phases of the atrial action potential, including atrial-specific potassium currents (ultrafast delayed rectifier potassium current and acetylcholine-dependent potassium current), and prolongs the refractory period. It dose-dependently prolongs the atrial refractory period, atrioventricular nodal conduction, and refractory period, and slightly prolongs the QRS duration, but has no significant effect on the ventricular refractory period. Venacarlan has a high affinity for ion channels involved in atrial tissue repolarization and is therefore considered to have a low risk of proarrhythmia.

C20H31NO4

349.46444

349.225

794466-70-9

Vernakalant Hydrochloride;748810-28-8;Vernakalant-d6 hydrochloride;866455-16-5

9930049

Typically exists as solid at room temperature

1.1±0.1 g/cm3

479.0±45.0 °C at 760 mmHg

243.5±28.7 °C

0.0±1.3 mmHg at 25°C

1.557

2.4

1

5

7

25

394

3

O([C@@H]1CCCC[C@H]1N1C[C@H](O)CC1)CCC1C=CC(OC)=C(OC)C=1

VBHQKCBVWWUUKN-KZNAEPCWSA-N

InChI=1S/C20H31NO4/c1-23-19-8-7-15(13-20(19)24-2)10-12-25-18-6-4-3-5-17(18)21-11-9-16(22)14-21/h7-8,13,16-18,22H,3-6,9-12,14H2,1-2H3/t16-,17-,18-/m1/s1

(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]pyrrolidin-3-ol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)