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Carlo Franchini - One of the best experts on this subject based on the ideXlab platform.
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A Focus on the Synthesis and Pharmacokinetics of Tocainide and its Analogues.
Current medicinal chemistry, 2019Co-Authors: Alessia Carocci, Filomena Corbo, Giovanni Lentini, Maria Maddalena Cavalluzzi, Carlo Franchini, Alessia CatalanoAbstract:Tocainide is an antiarrhythmic agent belonging to class IB that was primarily used for suppression of symptomatic ventricular arrhythmias. Tocainide was also reported to relieve pain such as tic douloureux, trigemina neuralgia in humans and tinnitus. Significant antinociception, as assayed on the hot-plate test, was observed after intraperitoneal injection of Tocainide, too. By the mid-1980s Tocainide was emerging as a more consistently effective treatment for myotonic disorders. Numerous reports of serious adverse reactions led to the use of Tocainide being discontinued, even though research on Tocainide and its analogues, endowed with a better pharmacological profile, is still in progress for their potential usefulness in the treatment of myotonias. This review is focused on the description of the different synthetic routes to racemic and optically active Tocainide developed in the last decades, as well as analytical studies regarding enantioseparation methods. Finally, some analogues of Tocainide reported in the literature, most of which with pharmacological studies, have been mentioned.
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Stereoselectivity in central analgesic action of Tocainide and its analogs.
Chirality, 1993Co-Authors: Carlo Franchini, Filomena Corbo, Giovanni Lentini, Francesca Chiaia Noja, V. Tortorella, Alessandro Bartolini, Carla Ghelardini, Rosanna Matucci, Alberto GiottiAbstract:The antiarrhythmic drug Tocainide (5a) and some related chiral α-amino and α-imino anilides (5b–e) were synthesized in optically active form. The antinociceptive effects of the different stereoisomers of these compounds were examined and it was found that the analgesic effect of Tocainide is due only to its (−)-(R)-enantiomer. Benzyl replacement for methyl group at the stereogenic centre of Tocainide causes loss of activity while both enantiomers of the αiminoxilidide 5e and of the strictly related Tocainide analog 5d produce an analgesic effect without any stereoselectivity. Pharmacological tests and [3H] quinuclidinyl benzilate ([3H]QNB) binding assay, taken together, seem to show that the antinociceptive effect of (−)-(R)-Tocainide, like the analgesia induced by lidocaine, procaine, and mexiletine, is due to a central presynaptic cholinergic mechanism of action. © 1993 Wiley-Liss, Inc.
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stereoselective interaction of Tocainide and its chiral analogs with the sodium channels in human myoballs
Pflügers Archiv: European Journal of Physiology, 1991Co-Authors: D Tricarico, Carlo Franchini, B Fakler, W Spittelmeister, J P Ruppersberg, R Stutzel, Vincenzo Tortorella, D Contecamerino, Reinhardt RüdelAbstract:The effects of both enantiomers of Tocainide and of some of its chiral analogs on the inactivation of the sodium current in human myoballs were investigated with the whole-cell recording technique. Structure and electron densities of the applied compounds were calculated and compared to the results. Both the R(−) and the S(+) enantiomers had little effect on fast inactivation determined with short prepulses according to Hodgkin and Huxley (1952; h∞ curve). When the inactivating prepulses used in this pulse protocol were prolonged to 1024 ms, both Tocainide enantiomers increased inactivation severely, suggesting that the drug binds to the channel when it is in the state of intermediate inactivation (Fakler et al. 1990). Tetrodotoxin-resistant “juvenile” sodium channels were more affected than tetrodotoxin-sensitive “adult” channels. The R form was four times as effective as the S form. The compound obtained by substitution of the methyl group on the chiral centre of Tocainide with a benzyl group, although in the less potent S form, affected inactivation of the juvenile sodium channels much more than the potent (R)-Tocainide. Two additional substitutions, performed on the aromatic ring of Tocainide, gave a compound that was most potent in shifting the inactivation curves, but without any selectivity for juvenile or adult channels.
S. H. Bryant - One of the best experts on this subject based on the ideXlab platform.
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Antimyotonic effects of Tocainide enantiomers on skeletal muscle fibers of congenitally myotonic goats
Neuromuscular disorders : NMD, 2000Co-Authors: Diana Conte Camerino, Sabata Pierno, A. De Luca, S. H. BryantAbstract:Abstract Tocainide is effective in the symptomatic treatment of myotonic syndromes for its ability to reduce the high frequency discharges of action potentials typical of the disease, by blocking voltage-gated sodium channels. However, its use is restricted by serious side effects. In spite of its chiral structure, Tocainide is clinically used as a racemic mixture. Since the optical isomers may differ in their efficacy and toxicity, the present study was aimed at evaluating the antimyotonic activity of the pure R (−) and S (+) enantiomers of Tocainide, on the abnormal membrane hyperexcitability of external intercostal muscle fibers of congenitally myotonic goats. The excitability parameters were recorded in vitro by means of the standard two-microelectrode current-clamp technique before and after the addition of the compounds. The R (−) enantiomer of Tocainide at concentrations as low as 10 μM potently counteracted the abnormal excitability of myotonic fibers, by increasing the threshold current, and decreasing the latency of the action potential and firing capability. Also, this concentration of R −(−) Tocainide almost completely abolished the abnormal spontaneous electrical activity occurring in about 70–80% of the myotonic fiber. The S (+) enantiomer was remarkably less potent since up to 100 μM did not restore the normal excitability pattern. The results show that most of the antimyotonic activity of Tocainide resides in the R (−) enantiomer suggesting that its clinical use may allow a significant reduction of the doses and possibly of the side effects.
Alessia Catalano - One of the best experts on this subject based on the ideXlab platform.
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A Focus on the Synthesis and Pharmacokinetics of Tocainide and its Analogues.
Current medicinal chemistry, 2019Co-Authors: Alessia Carocci, Filomena Corbo, Giovanni Lentini, Maria Maddalena Cavalluzzi, Carlo Franchini, Alessia CatalanoAbstract:Tocainide is an antiarrhythmic agent belonging to class IB that was primarily used for suppression of symptomatic ventricular arrhythmias. Tocainide was also reported to relieve pain such as tic douloureux, trigemina neuralgia in humans and tinnitus. Significant antinociception, as assayed on the hot-plate test, was observed after intraperitoneal injection of Tocainide, too. By the mid-1980s Tocainide was emerging as a more consistently effective treatment for myotonic disorders. Numerous reports of serious adverse reactions led to the use of Tocainide being discontinued, even though research on Tocainide and its analogues, endowed with a better pharmacological profile, is still in progress for their potential usefulness in the treatment of myotonias. This review is focused on the description of the different synthetic routes to racemic and optically active Tocainide developed in the last decades, as well as analytical studies regarding enantioseparation methods. Finally, some analogues of Tocainide reported in the literature, most of which with pharmacological studies, have been mentioned.
Robert E. Vestal - One of the best experts on this subject based on the ideXlab platform.
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inhibition of human liver cytochrome p 450 1a2 by the class ib antiarrhythmics mexiletine lidocaine and Tocainide
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Xiaoxiong Wei, Renke Dai, Suoping Zhai, Kenneth E Thummel, Fred K Friedman, Robert E. VestalAbstract:Mexiletine, lidocaine, and Tocainide are class IB antiarrhythmic drugs that are used for the treatment of ventricular arrhythmias and are known to inhibit drug metabolism. The objectives of this study were to characterize the inhibitory effects of mexiletine, lidocaine, and Tocainide on cytochrome P-450 1A2 (CYP1A2) activity in human liver microsomes and to evaluate their relative inhibitory potencies by using a molecular model of this P-450 isozyme. The inhibitory effect of mexiletine, lidocaine, and Tocainide on cytochrome CYP1A2 in human liver microsomes was examined with methoxyresorufin O -demethylase activity as an index of the catalytic activity of this P-450 isozyme. The kinetic inhibition types and K i values were determined by Lineweaver-Burk plots and Dixon plots, respectively. Molecular modeling was used to assess the interaction of these agents with the CYP1A2 active site. Methoxyresorufin O -demethylase activity was inhibited 67 ± 8%, 20 ± 5%, and 7 ± 4% by 2 mM mexiletine, lidocaine, and Tocainide, respectively. Mexiletine and lidocaine exhibited competitive inhibition with K i values of 0.28 ± 0.12 mM and 1.54 ± 0.74 mM, respectively, whereas the inhibition type of Tocainide could not be determined because of its weak potency. A charge interaction between mexiletine and the Asp313 side chain in the CYP1A2 active site was found, and varying degrees of hydrogen bond formation between these three compounds and the CYP1A2 active site were observed. The in vitro inhibitory potencies in human liver microsomes (mexiletine > lidocaine > Tocainide) are consistent with the structural interactions found in a molecular model of the active site of CYP1A2.
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Relative potency of mexiletine, lidocaine, and Tocainide as inhibitors of rat liver CYP1A1 activity.
Drug metabolism and disposition: the biological fate of chemicals, 1995Co-Authors: Xiaoxiong Wei, Cho-ming Loi, E. J. Jarvi, Robert E. VestalAbstract:Mexiletine and Tocainide are lidocaine congeners that share similar chemical structures. Clinical studies suggest that the in vivo inhibitory effect of mexiletine on the CYP1A family of isoforms is substantially greater than that of Tocainide. We investigated the inhibitory property of mexiletine, lidocaine, and Tocainide on the in vitro activity of the cytochrome P4501A1 (CYP1A1) isozyme in the rat. Hepatic microsomes were prepared from rat livers induced with 3-methylcholanthrene. The rate of ethoxyresorufin-O-dealkylation (EROD) was used as an index of CYP1A1 activity. Vmax and KM of the reactions were determined from Lineweaver-Burk plots. The Ki values for the inhibitors were derived from Dixon plots. Results showed that mexiletine is a competitive inhibitor, lidocaine is a mixed inhibitor, and Tocainide is a noncompetitive inhibitor of EROD. The Ki values for mexiletine and Tocainide were 0.30 +/- 0.02 mM and 12.4 +/- 0.7 mM, respectively. Two Ki values for lidocaine were determined. They were 0.65 +/- 0.07 mM and 4.1 +/- 1.3 mM, respectively. The relative inhibitory potency of these agents on rat CYP1A1 activity is mexiletine > lidocaine > Tocainide. This difference in potency, which is most likely attributable to the change in the chemical composition in the aliphatic chain among the compounds, suggests that these compounds may be useful probes for studying the mechanism of the interaction with the active site of CYP1A1.
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The effect of Tocainide on theophylline metabolism.
British journal of clinical pharmacology, 1993Co-Authors: Cm Loi, X Wei, B. M. Parker, Korrapati, Robert E. VestalAbstract:The effect of 5 days of oral Tocainide (400 mg every 8 h) on the kinetics of theophylline given as a single 5 mg kg-1 i.v. infusion over 30 min was investigated in eight healthy male nonsmokers. Treatment with Tocainide decreased the plasma clearance of theophylline from 37.5 +/- 6.9 (mean +/- s.d.) to 33.7 +/- 5.0 ml kg-1 h-1 (difference -3.8, 95% CI, -1.7 to -5.9; P = 0.004) and increased its terminal elimination half-life from 9.7 +/- 2.5 to 10.4 +/- 2.1 h (difference 0.7, 95% CI, 0.2 to 1.2; P = 0.011). Tocainide decreased the formation clearances of 3-methylxanthine and 1-methyluric acid, but the formation clearance of 1,3-dimethyluric acid was unaltered. These data indicate that Tocainide exerts a modest inhibitory effect on theophylline metabolism. The magnitude of this change is substantially smaller than that reported to be produced by mexiletine.
Giovanni Lentini - One of the best experts on this subject based on the ideXlab platform.
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A Focus on the Synthesis and Pharmacokinetics of Tocainide and its Analogues.
Current medicinal chemistry, 2019Co-Authors: Alessia Carocci, Filomena Corbo, Giovanni Lentini, Maria Maddalena Cavalluzzi, Carlo Franchini, Alessia CatalanoAbstract:Tocainide is an antiarrhythmic agent belonging to class IB that was primarily used for suppression of symptomatic ventricular arrhythmias. Tocainide was also reported to relieve pain such as tic douloureux, trigemina neuralgia in humans and tinnitus. Significant antinociception, as assayed on the hot-plate test, was observed after intraperitoneal injection of Tocainide, too. By the mid-1980s Tocainide was emerging as a more consistently effective treatment for myotonic disorders. Numerous reports of serious adverse reactions led to the use of Tocainide being discontinued, even though research on Tocainide and its analogues, endowed with a better pharmacological profile, is still in progress for their potential usefulness in the treatment of myotonias. This review is focused on the description of the different synthetic routes to racemic and optically active Tocainide developed in the last decades, as well as analytical studies regarding enantioseparation methods. Finally, some analogues of Tocainide reported in the literature, most of which with pharmacological studies, have been mentioned.
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Stereoselectivity in central analgesic action of Tocainide and its analogs.
Chirality, 1993Co-Authors: Carlo Franchini, Filomena Corbo, Giovanni Lentini, Francesca Chiaia Noja, V. Tortorella, Alessandro Bartolini, Carla Ghelardini, Rosanna Matucci, Alberto GiottiAbstract:The antiarrhythmic drug Tocainide (5a) and some related chiral α-amino and α-imino anilides (5b–e) were synthesized in optically active form. The antinociceptive effects of the different stereoisomers of these compounds were examined and it was found that the analgesic effect of Tocainide is due only to its (−)-(R)-enantiomer. Benzyl replacement for methyl group at the stereogenic centre of Tocainide causes loss of activity while both enantiomers of the αiminoxilidide 5e and of the strictly related Tocainide analog 5d produce an analgesic effect without any stereoselectivity. Pharmacological tests and [3H] quinuclidinyl benzilate ([3H]QNB) binding assay, taken together, seem to show that the antinociceptive effect of (−)-(R)-Tocainide, like the analgesia induced by lidocaine, procaine, and mexiletine, is due to a central presynaptic cholinergic mechanism of action. © 1993 Wiley-Liss, Inc.