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Peter Svensson - One of the best experts on this subject based on the ideXlab platform.
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effect of muscle relaxants on experimental jaw muscle pain and jaw stretch reflexes a double blind and placebo controlled trial
European Journal of Pain, 2003Co-Authors: Kelun Wang, Peter Svensson, Lars ArendtnielsenAbstract:A randomised, double-blind, placebo-controlled three-way cross-over study was performed to investigate the effect of two muscle relaxants (Tolperisone hydrochloride and pridinol mesilate) on experimental jaw-muscle pain and jaw-stretch reflexes. Fifteen healthy men participated in three randomised sessions separated by at least 1 week. In each session 300 mg Tolperisone, 8 mg pridinol mesilate or placebo was administered orally as a single dose. One hour after drug administration 0.3 ml hypertonic saline (5.8%) was injected into the right masseter to produce muscle pain. Subjects continuously rated their perceived pain intensity on an electronic 10-cm visual analogue scale (VAS). The pressure pain threshold (PPT) was measured and short-latency reflex responses were evoked in the pre-contracted (15% maximal voluntary contraction) masseter and temporalis muscles by a standardised stretch device (1 mm displacement, 10 ms ramp time) before (baseline), 1 h after medication (post-drug), during ongoing experimental muscle pain (pain-post-drug), and 15 min after pain had vanished (post-pain). Analysis of variance demonstrated significantly lower VAS peak pain scores (5.9±0.4 cm) after administration of Tolperisone hydrochloride compared with pridinol mesilate (6.8±0.4 cm) and placebo (6.6±0.4 cm) (P=0.020). Administration of pridinol mesilate was associated with a significant decrease in PPTs compared with Tolperisone hydrochloride and placebo (P=0.002) after medication, but not after experimental jaw-muscle pain. The normalised peak-to-peak amplitude of the stretch reflexes were not significantly influenced by the test medication (P=0.762), but were in all sessions significantly facilitated during ongoing experimental jaw-muscle pain (P=0.034). In conclusion, Tolperisone hydrochloride provides a small, albeit significant reduction in the perceived intensity of experimental jaw-muscle pain whereas the present dose had no effect on the short-latency jaw-stretch reflex.
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prophylactic Tolperisone for post exercise muscle soreness causes reduced isometric force a double blind randomized crossover control study
European Journal of Pain, 2003Co-Authors: Prem Bajaj, Lars Arendtnielsen, Peter Svensson, Pascal MadeleineAbstract:The role of Tolperisone hydrochloride, a centrally acting muscle relaxant in relieving painful muscle spasm is recently being discussed. The present study hypothesizes that the prophylactic use of Tolperisone hydrochloride may effectively relieve post-exercise muscle soreness, based on the spasm theory of exercise pain. Twenty male volunteers, aged 25.2 +/- 0.82 years (mean +/- SEM) participated in 10 sessions in which they received oral treatment with placebo or the centrally acting muscle relaxant Tolperisone hydrochloride (150 mg) three times daily for 8 days, in randomized crossover double-blind design. Time course assessments were made for pressure pain threshold, Likert's pain score (0-5), pain areas, range of abduction, isometric force, and electromyography (EMG) root mean square (RMS) during maximum voluntary isometric force on day 1 and 6, immediately after an eccentric exercise of first dorsal interosseous muscle, and 24 and 48 h after the exercise. Treatment with placebo or Tolperisone hydrochloride was initiated immediately after the assessments on the first day baseline assessments. On the sixth day baseline investigations were repeated and then the subjects performed six bouts of standardized intense eccentric exercise of first dorsal interosseous muscle for provocation of post-exercise muscle soreness (PEMS). Perceived intensity of warmth, tiredness, soreness and pain during the exercise bouts were recorded on a 10 cm visual analogue pain scale. VAS scores and pressure pain thresholds did not differ between Tolperisone and placebo treatment. All VAS scores increased during the exercise bouts 2, 3, 4, 5 and 6 as compared to bout 1. Increased pain scores and pain areas were reported immediately after, 24 and 48 h after exercise. Pressure pain thresholds were reduced at 24 and 48 h after the exercise in the exercised hand. Range of abduction of the index finger was reduced immediately after the exercise and was still reduced at 24 h as compared to the non-exercised hand. The EMG RMS amplitude was also reduced immediately after the exercise, but was increased at 24 and 48 h. Isometric force was reduced immediately after the exercise as compared to days 1, 6, and the 24 and 48 h post-exercise assessments with a greater reduction following the Tolperisone hydrochloride treatment and the reduction was more in Tolperisone group as compared to the placebo group. The results suggest, that the prophylactic intake of Tolperisone hydrochloride provides no relief to pain in course of post-exercise muscle soreness but results in reduction in isometric force.
Mónika Csejtei - One of the best experts on this subject based on the ideXlab platform.
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JPET #89805 1 Title
2016Co-Authors: Pál Kocsis, Norbert Bielik, Márta Thán, Sándor Kolok, Mónika Csejtei, László Fodor, Sandor Farkas, István TarnawaAbstract:Tolperisone-type drugs inhibit spinal reflexes via blockade of voltage gated sodium and calcium channel
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Tolperisone-Type Drugs Inhibit Spinal Reflexes via Blockade of Voltage-Gated Sodium and Calcium Channels
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Pál Kocsis, Norbert Bielik, Márta Thán, Sándor Kolok, Anikó Gere, László Fodor, Sandor Farkas, Mónika CsejteiAbstract:The spinal reflex depressant mechanism of Tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50–400 μM), eperisone, lanperisone, inaperisone, and silperisone (25–200 μM) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100–800 μM) produced qualitatively similar depression of spinal functions in the hemicord preparation, whereas its blocking effect on afferent nerve conduction was clearly stronger. In vivo, Tolperisone and silperisone as well as lidocaine (10 mg/kg intravenously) depressed ventral root reflexes and excitability of motoneurons. However, in contrast with lidocaine, the muscle relaxant drugs seemed to have a more pronounced action on the synaptic responses than on the excitability of motoneurons. Whole-cell measurements in dorsal root ganglion cells revealed that Tolperisone and silperisone depressed voltage-gated sodium channel conductance at concentrations that inhibited spinal reflexes. Results obtained with Tolperisone and its analogs in the [H]batrachotoxinin A 20-α-benzoate binding in cortical neurons and in a fluorimetric membrane potential assay in cerebellar neurons further supported the view that blockade of sodium channels may be a major component of the action of Tolperisone-type centrally acting muscle relaxant drugs. Furthermore, Tolperisone, eperisone, and especially silperisone had a marked effect on voltagegated calcium channels, whereas calcium currents were hardly influenced by lidocaine. These data suggest that Tolperisone-type muscle relaxants exert their spinal reflex inhibitory action predominantly via a presynaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels.
Sandor Farkas - One of the best experts on this subject based on the ideXlab platform.
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JPET #89805 1 Title
2016Co-Authors: Pál Kocsis, Norbert Bielik, Márta Thán, Sándor Kolok, Mónika Csejtei, László Fodor, Sandor Farkas, István TarnawaAbstract:Tolperisone-type drugs inhibit spinal reflexes via blockade of voltage gated sodium and calcium channel
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Tolperisone-Type Drugs Inhibit Spinal Reflexes via Blockade of Voltage-Gated Sodium and Calcium Channels
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Pál Kocsis, Norbert Bielik, Márta Thán, Sándor Kolok, Anikó Gere, László Fodor, Sandor Farkas, Mónika CsejteiAbstract:The spinal reflex depressant mechanism of Tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50–400 μM), eperisone, lanperisone, inaperisone, and silperisone (25–200 μM) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100–800 μM) produced qualitatively similar depression of spinal functions in the hemicord preparation, whereas its blocking effect on afferent nerve conduction was clearly stronger. In vivo, Tolperisone and silperisone as well as lidocaine (10 mg/kg intravenously) depressed ventral root reflexes and excitability of motoneurons. However, in contrast with lidocaine, the muscle relaxant drugs seemed to have a more pronounced action on the synaptic responses than on the excitability of motoneurons. Whole-cell measurements in dorsal root ganglion cells revealed that Tolperisone and silperisone depressed voltage-gated sodium channel conductance at concentrations that inhibited spinal reflexes. Results obtained with Tolperisone and its analogs in the [H]batrachotoxinin A 20-α-benzoate binding in cortical neurons and in a fluorimetric membrane potential assay in cerebellar neurons further supported the view that blockade of sodium channels may be a major component of the action of Tolperisone-type centrally acting muscle relaxant drugs. Furthermore, Tolperisone, eperisone, and especially silperisone had a marked effect on voltagegated calcium channels, whereas calcium currents were hardly influenced by lidocaine. These data suggest that Tolperisone-type muscle relaxants exert their spinal reflex inhibitory action predominantly via a presynaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels.
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identification of metabolic pathways involved in the biotransformation of Tolperisone by human microsomal enzymes
Drug Metabolism and Disposition, 2003Co-Authors: Balazs Dalmadi, Sandor Farkas, Janos Leibinger, Szabolcs Szeberenyi, Timea Borbas, Zsolt Szombathelyi, Karoly TihanyiAbstract:The in vitro metabolism of Tolperisone, 1-(4-methyl-phenyl)-2-methyl-3-(1-piperidino)-1-propanone-hydrochloride, a centrally acting muscle relaxant, was examined in human liver microsomes (HLM) and recombinant enzymes. Liquid chromatography-mass spectrometry measurements revealed methyl-hydroxylation (metabolite at m/z 261; M1) as the main metabolic route in HLM, however, metabolites of two mass units greater than the parent compound and the hydroxy-metabolite were also detected ( m/z 247 and m/z 263, respectively). The latter was identified as carbonyl-reduced M1, the former was assumed to be the carbonyl-reduced parent compound. Isoform-specific cytochrome P450 (P450) inhibitors, inhibitory antibodies, and experiments with recombinant P450s pointed to CYP2D6 as the prominent enzyme in Tolperisone metabolism. CYP2C19, CYP2B6, and CYP1A2 are also involved to a smaller extent. Hydroxymethyl-Tolperisone formation was mediated by CYP2D6, CYP2C19, CYP1A2, but not by CYP2B6. Tolperisone competitively inhibited dextromethorphan O -demethylation and bufuralol hydroxylation ( K i = 17 and 30 μM, respectively). Tolperisone inhibited methyl p -tolyl sulfide oxidation ( K i = 1200 μM) in recombinant flavin-containing monooxygenase 3 (FMO3) and resulted in a 3-fold ( p
László Fodor - One of the best experts on this subject based on the ideXlab platform.
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JPET #89805 1 Title
2016Co-Authors: Pál Kocsis, Norbert Bielik, Márta Thán, Sándor Kolok, Mónika Csejtei, László Fodor, Sandor Farkas, István TarnawaAbstract:Tolperisone-type drugs inhibit spinal reflexes via blockade of voltage gated sodium and calcium channel
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Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway
Frontiers in Pharmacology, 2015Co-Authors: Alexandra Lazar, Krisztina Pesti, Nora Lenkey, László Fodor, Arpad MikeAbstract:The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand-protein interactions. One-way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3, and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, Tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone, and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa) of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule), which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel). Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively.
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Tolperisone-Type Drugs Inhibit Spinal Reflexes via Blockade of Voltage-Gated Sodium and Calcium Channels
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Pál Kocsis, Norbert Bielik, Márta Thán, Sándor Kolok, Anikó Gere, László Fodor, Sandor Farkas, Mónika CsejteiAbstract:The spinal reflex depressant mechanism of Tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50–400 μM), eperisone, lanperisone, inaperisone, and silperisone (25–200 μM) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100–800 μM) produced qualitatively similar depression of spinal functions in the hemicord preparation, whereas its blocking effect on afferent nerve conduction was clearly stronger. In vivo, Tolperisone and silperisone as well as lidocaine (10 mg/kg intravenously) depressed ventral root reflexes and excitability of motoneurons. However, in contrast with lidocaine, the muscle relaxant drugs seemed to have a more pronounced action on the synaptic responses than on the excitability of motoneurons. Whole-cell measurements in dorsal root ganglion cells revealed that Tolperisone and silperisone depressed voltage-gated sodium channel conductance at concentrations that inhibited spinal reflexes. Results obtained with Tolperisone and its analogs in the [H]batrachotoxinin A 20-α-benzoate binding in cortical neurons and in a fluorimetric membrane potential assay in cerebellar neurons further supported the view that blockade of sodium channels may be a major component of the action of Tolperisone-type centrally acting muscle relaxant drugs. Furthermore, Tolperisone, eperisone, and especially silperisone had a marked effect on voltagegated calcium channels, whereas calcium currents were hardly influenced by lidocaine. These data suggest that Tolperisone-type muscle relaxants exert their spinal reflex inhibitory action predominantly via a presynaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels.
Lars Arendtnielsen - One of the best experts on this subject based on the ideXlab platform.
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effect of muscle relaxants on experimental jaw muscle pain and jaw stretch reflexes a double blind and placebo controlled trial
European Journal of Pain, 2003Co-Authors: Kelun Wang, Peter Svensson, Lars ArendtnielsenAbstract:A randomised, double-blind, placebo-controlled three-way cross-over study was performed to investigate the effect of two muscle relaxants (Tolperisone hydrochloride and pridinol mesilate) on experimental jaw-muscle pain and jaw-stretch reflexes. Fifteen healthy men participated in three randomised sessions separated by at least 1 week. In each session 300 mg Tolperisone, 8 mg pridinol mesilate or placebo was administered orally as a single dose. One hour after drug administration 0.3 ml hypertonic saline (5.8%) was injected into the right masseter to produce muscle pain. Subjects continuously rated their perceived pain intensity on an electronic 10-cm visual analogue scale (VAS). The pressure pain threshold (PPT) was measured and short-latency reflex responses were evoked in the pre-contracted (15% maximal voluntary contraction) masseter and temporalis muscles by a standardised stretch device (1 mm displacement, 10 ms ramp time) before (baseline), 1 h after medication (post-drug), during ongoing experimental muscle pain (pain-post-drug), and 15 min after pain had vanished (post-pain). Analysis of variance demonstrated significantly lower VAS peak pain scores (5.9±0.4 cm) after administration of Tolperisone hydrochloride compared with pridinol mesilate (6.8±0.4 cm) and placebo (6.6±0.4 cm) (P=0.020). Administration of pridinol mesilate was associated with a significant decrease in PPTs compared with Tolperisone hydrochloride and placebo (P=0.002) after medication, but not after experimental jaw-muscle pain. The normalised peak-to-peak amplitude of the stretch reflexes were not significantly influenced by the test medication (P=0.762), but were in all sessions significantly facilitated during ongoing experimental jaw-muscle pain (P=0.034). In conclusion, Tolperisone hydrochloride provides a small, albeit significant reduction in the perceived intensity of experimental jaw-muscle pain whereas the present dose had no effect on the short-latency jaw-stretch reflex.
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prophylactic Tolperisone for post exercise muscle soreness causes reduced isometric force a double blind randomized crossover control study
European Journal of Pain, 2003Co-Authors: Prem Bajaj, Lars Arendtnielsen, Peter Svensson, Pascal MadeleineAbstract:The role of Tolperisone hydrochloride, a centrally acting muscle relaxant in relieving painful muscle spasm is recently being discussed. The present study hypothesizes that the prophylactic use of Tolperisone hydrochloride may effectively relieve post-exercise muscle soreness, based on the spasm theory of exercise pain. Twenty male volunteers, aged 25.2 +/- 0.82 years (mean +/- SEM) participated in 10 sessions in which they received oral treatment with placebo or the centrally acting muscle relaxant Tolperisone hydrochloride (150 mg) three times daily for 8 days, in randomized crossover double-blind design. Time course assessments were made for pressure pain threshold, Likert's pain score (0-5), pain areas, range of abduction, isometric force, and electromyography (EMG) root mean square (RMS) during maximum voluntary isometric force on day 1 and 6, immediately after an eccentric exercise of first dorsal interosseous muscle, and 24 and 48 h after the exercise. Treatment with placebo or Tolperisone hydrochloride was initiated immediately after the assessments on the first day baseline assessments. On the sixth day baseline investigations were repeated and then the subjects performed six bouts of standardized intense eccentric exercise of first dorsal interosseous muscle for provocation of post-exercise muscle soreness (PEMS). Perceived intensity of warmth, tiredness, soreness and pain during the exercise bouts were recorded on a 10 cm visual analogue pain scale. VAS scores and pressure pain thresholds did not differ between Tolperisone and placebo treatment. All VAS scores increased during the exercise bouts 2, 3, 4, 5 and 6 as compared to bout 1. Increased pain scores and pain areas were reported immediately after, 24 and 48 h after exercise. Pressure pain thresholds were reduced at 24 and 48 h after the exercise in the exercised hand. Range of abduction of the index finger was reduced immediately after the exercise and was still reduced at 24 h as compared to the non-exercised hand. The EMG RMS amplitude was also reduced immediately after the exercise, but was increased at 24 and 48 h. Isometric force was reduced immediately after the exercise as compared to days 1, 6, and the 24 and 48 h post-exercise assessments with a greater reduction following the Tolperisone hydrochloride treatment and the reduction was more in Tolperisone group as compared to the placebo group. The results suggest, that the prophylactic intake of Tolperisone hydrochloride provides no relief to pain in course of post-exercise muscle soreness but results in reduction in isometric force.
