Electrophysiological effects of flecainide enantiomers in canine Purkinje fibres

Smallwood, Jeffrey K.; Robertson, David W.; Steinberg, Mitchell I.

doi:10.1007/bf00168654

Cited by 20 publications

(6 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a relatively small number of instances, both enantiomers are desired products such as mandelic acid where the (S)‐form is used as an intermediate in pharmaceutical synthesis and the (R)‐form is utilized in skin treatment . Other examples of chiral drugs with bioequivalent enantiomers are fluoxetine (antidepressant) and flecainide (anti‐arrhythmic) …”

Section: Introductionmentioning

confidence: 99%

Diastereomeric salt crystallization of chiral moleculesvia sequential coupled‐Batch operation

et al. 2018

View full text Add to dashboard Cite

A novel process, sequential coupled‐batch diastereomeric crystallization is presented for the resolution of racemic mixtures. This strategy utilized a preferential crystallization of diastereomeric salt followed by sequential coupled diastereomeric salt resolution of racemic ibuprofen with the resolving agent (S)‐lysine utilizing a novel small scale pneumatic liquid exchange design to couple two batch crystallizers. Results were compared to conventional sequential resolution via seeded isothermal batch crystallization. Diastereomeric salt resolution was developed using the ternary phase diagram of the isolated (R)‐ibuprofen‐(S)‐lysine and (S)‐ibuprofen‐(S)‐lysine salts and optimized empirically with the aid of process analytical technology. Sequential coupled‐batch crystallization was found to be capable of increasing the yield of both salts while maintaining purity. This gave an increase in both the productivity and yield (20.5% for (S)‐ibuprofen‐(S)‐lysine) compared to the equivalent sequential batch (17.7% for (S)‐ibuprofen‐(S)‐lysine) crystallization methodology. Single crystals of the (S)‐ibuprofen‐(S)‐lysine were isolated, and its single crystal structure determined. © 2018 American Institute of Chemical Engineers AIChE J, 65: 604–616, 2019

show abstract

Section: Introductionmentioning

confidence: 99%

Diastereomeric salt crystallization of chiral moleculesvia sequential coupled‐Batch operation

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Similar eudismic ratios have been described for tocainide and some related compounds on sodium currents of human myoballs (Tricarico et al 1991), as well as for cocaine and bupivacaine on sodium channels of GH3 cells (Wang and Wang 1992). However, biochemical and electrophysiological studies on nervous and cardiac tissues evidenced that drugs such as RAC 109 have higher eudismic ratios (up to 10 during use-dependent block) (Yeh 1980;Postma and Catterall 1984;Hill et al 1988) whereas other drugs such as flecainide are almost devoid of stereoselectivity (Hill et al 1988;Smallwood et al 1989). These findings suggest that the structural part of the receptor accounting for stereospecificity is relatively conserved among tissues and that the degree of stereoselectivity mainly depends upon the physico-chemical characteristics of the drug.…”

Section: Discussionmentioning

confidence: 99%

Stereoselective effects of mexiletine enantiomers on sodium currents and excitability characteristics of adult skeletal muscle fibers

A¹,

Natuzzi²,

Lentini³

et al. 1995

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

The effects of the enantiomers of mexiletine were tested on sodium currents of frog skeletal muscle fibers recorded by means of the three vaseline gap voltage clamp method and compared with the effects produced by tocainide enantiomers. The R-(-) mexiletine produced a tonic block of the sodium current, elicited by single depolarizing test pulses from the holding potential of -100 mV to -20 mV, with an IC50 of 43.9 +/- 1 microM, whereas the corresponding S-(+) enantiomer produced the same effects at about twofold higher concentrations. A similar steroselectivity was observed with tocainide enantiomers, but at about 5 fold higher concentrations. Both the R-(-) and S-(+) enantiomers of mexiletine and tocainide produced a further use-dependent block of sodium currents when the test pulse was applied repetitively at a frequency of 2 Hz. The use dependent behavior led to a significant lowering of the IC50 values with respect to the tonic block but the eudismic ratios ([IC50S-(+)]/[IC50R(-)]) and the relative potency between mexiletine and tocainide were maintained. All the tested compounds produced a left shift of the steady state inactivation curves (h infinity), suggesting a high-affinity interaction with the inactivated sodium channels. Again a stronger potency of R-(-) vs. S-(+) enantiomers and of mexiletine vs. tocainide was observed. The excitability characteristics recorded from the semitendinosus muscle by the two microelectrode technique were modified by the tested drugs in agreement with their ability to block sodium current. Thus a concentration-related increase in the threshold current required to elicit an action potential as observed along with a decrease in the amplitude and a shortening of the latency of action potential and a decrease in the firing capability of the membrane. Again the R-(-) isomers were more potent than the S-(+) ones and mexiletine was more effective than tocainide. These data corroborate the presence of a stereospecific site for these drugs on adult skeletal muscle sodium channels. The constant eudismic ratios between the enantiomers during both tonic and use-dependent block suggest that the increase in the apparent affinity of the receptor during state-dependent conformational changes of the channel does not enhance its stereospecificity. The decrease in effective concentration upon high frequency stimulation supports the potential usefulness of low doses of R-(-) mexiletine in the treatment of the abnormal hyperexcitability of the myotonic muscles, with a likely reduction of unwanted side effects.

show abstract

“…However, there is little or no difference in the ability of the enantiomers of flecainide to depress disposition of the mexiletine enantiomers [72,73]. The R-enantiomer has been reported to have greater antisodium channels [86][87][88] and, consequently, it is unlikely that the relative disposition of the enantiomers is arrhythmic activity [74]. Mexilitine is generally assayed using achiral GC or h.p.l.c.…”

Section: Class Ib Drugs ( Lignocaine and Mexiletine)mentioning

confidence: 99%

Therapeutic drug monitoring: antiarrhythmic drugs

Campbell

Williams

2001

Brit J Clinical Pharma

View full text Add to dashboard Cite

Antiarrhythmic agents are traditionally classified according to Vaughan Williams into four classes of action. Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics, and have as a common action, blockade of the fast-inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class II agents are antisympathetic drugs, particularly the b-adrenoceptor blockers. These are generally safe agents which do not normally require TDM. Class III antiarrhythmic agents include sotalol and amiodarone. TDM can be useful in the case of amiodarone to monitor compliance and toxicity but is generally of little value for sotalol. Class IV antiarrhythmic drugs are the calcium channel blockers verapamil and diltiazem. These are normally monitored by haemodynamic effects, rather than using TDM. Other agents which do not fall neatly into the Vaughan Williams classification include digoxin and perhexiline. TDM is very useful for monitoring the administration (and particularly the safety) of both of these agents.

show abstract

Electrophysiological effects of flecainide enantiomers in canine Purkinje fibres

Cited by 20 publications

References 31 publications

Diastereomeric salt crystallization of chiral moleculesvia sequential coupled‐Batch operation

Diastereomeric salt crystallization of chiral moleculesvia sequential coupled‐Batch operation

Stereoselective effects of mexiletine enantiomers on sodium currents and excitability characteristics of adult skeletal muscle fibers

Therapeutic drug monitoring: antiarrhythmic drugs

Contact Info

Product

Resources

About