The Acute Antiallodynic Effect of Tolperisone in Rat Neuropathic Pain and Evaluation of Its Mechanism of Action.

Current treatment approaches to manage neuropathic pain have a slow onset and their use is largely hampered by side-effects, thus there is a significant need for finding new medications. Tolperisone, a centrally acting muscle relaxant with a favorable side effect profile, has been reported to affect ion channels, which are targets for current first-line medications in neuropathic pain. Our aim was to explore its antinociceptive potency in rats developing neuropathic pain evoked by partial sciatic nerve ligation and the mechanisms involved. Acute oral tolperisone restores both the decreased paw pressure threshold and the elevated glutamate level in cerebrospinal fluid in neuropathic rats. These effects were comparable to those of pregabalin, a first-line medication in neuropathy. Tolperisone also inhibits release of glutamate from rat brain synaptosomes primarily by blockade of voltage-dependent sodium channels, although inhibition of calcium channels may also be involved at higher concentrations. However, pregabalin fails to affect glutamate release under our present conditions, indicating a different mechanism of action. These results lay the foundation of the avenue for repurposing tolperisone as an analgesic drug to relieve neuropathic pain.

[Influence of mydocalm on the degree of intra-abdominal hypertension and local blood circulation in the intestinal wall in experiment].

The effect of mydocalm (tolperison, 5 mg/kg single dose) on the dynamics of intra-abdominal hypertension (IAH), blood circulation regulation, and oxygen balance in the tissues of intestinal wall were studied in acute experiments on rabbits. Using a special stand of original design, the initial IAH level was modeled at 200 mm H2O with the subsequent stopping of further receipt of liquid during 3 hours in an elastic container in the abdominal cavity. During 3-h observation without drug administration, no changes in IAH due to the tone of muscles of the frontal abdominal wall takes place, but there is progressive deceleration of local blood flow (-35.33 + 0.99%, p < 0.01), suppressed dilation (-20.02 + 0.54%, p < 0.01) and constriction (-60.45 + 1.17%, p < 0.01) reactivity of vessels, and decreased oxygen tension (-47.18 + 0.75%, p < 0.01) in the intestinal wall at the end of experiment. The introduction of mydocalm reduces the tone of muscles of the frontal abdominal wall, which leads to a decrease in IAH (maximum effect after 1.5 hours, -20.81 + 0.84%, p < 0.01) and prevents decrease in the local blood flow (-26.77 + 0.41%, p < 0.01), suppression of dilation (-16.51 + 0.34%, p < 0.01) and constriction (-37.85 + 0.61%, p < 0.01) reactivity of vessels, and reduction in oxygen tension (-36.60 + 1.18%, p < 0.01) at the end of experiment. The administration of mydocalm can extend the limits of application of a conservative therapy for patients with IAH and to improve the results.

A phase IV observational multi-centre, open-label study on efficacy and safety of tolperisone 150 mg in patients with painful muscle spasm associated with degenerative or inflammatory diseases of the musculoskeletal system.

AIMS: To generate real world clinical data on efficacy and tolerability of tolperisone 150 mg in painful muscle spasms in Indian population. SETTINGS AND DESIGN: Prospective, open-labelled, non-comparative, multi-centre observational, Post Marketing surveillance study conducted at 174 participating orthopaedic care centres across India METHODS AND MATERIAL: Nine hundred and twenty adult patients having painful muscle spasm associated with degenerative or inflammatory conditions were enrolled who received tolperisone 150 mg thrice daily orally for 7 days. Assessment of primary efficacy (muscle spasm) was done by (0-3) Likert scale. Adverse events were monitored for safety and global efficacy assessment was done by clinicians and patients at the end of study period. RESULTS: Significant improvements from baseline (p < 0.0001) in scores for muscle tone, mobility & pain were seen on days 3 & 7. At the end of study there was a significant reduction in scores by more than 80% from baseline. A subgroup analysis revealed no statistical difference in the scores in patients receiving Non-Steroidal AntiInflammatory Drug (NSAID) as compared to those receiving Tolperisone alone suggesting that Tolperisone alone could be offered to patients with painful muscle spasm who are intolerant to NSAIDs or in whom NSAIDs are contraindicated. Tolperisone was well tolerated with no sedation reported by any patient during study period. The incidence of common adverse effects like nausea, gastric irritation was less than 2%. CONCLUSIONS: Tolperisone is a safe, effective and non sedative alternative in management of acute painful spasm conditions associated with degenerative or inflammatory diseases of the musculoskeletal system. Key Messages: Tolperisone is a skeletal muscle relaxant without concomitant sedation or withdrawal phenomena. In this open-labelled, non-comparative, prospective study tolperisone was proved to be a safe & effective alternative to skeletal muscle relaxants in the management of acute painful spasm conditions associated with degenerative or inflammatory diseases of the musculoskeletal system.

A comparative study of the action of tolperisone on seven different voltage dependent sodium channel isoforms.

The specific, acute interaction of tolperisone, an agent used as a muscle relaxant and for the treatment of chronic pain conditions, with the Na(v1.2), Na(v1.3), Na(v1.4), Na(v1.5), Na(v1.6), Na(v1.7), and Na(v1.8) isoforms of voltage dependent sodium channels was investigated and compared to that of lidocaine. Voltage dependent sodium channels were expressed in the Xenopus laevis oocyte expression system and sodium currents were recorded with the two electrode voltage clamp technique. Cumulative dose response relations revealed marked differences in IC(50) values between the two drugs on identical isoforms, as well as between isoforms. A detailed kinetic analysis uncovered that tolperisone as well as lidocaine exhibited their blocking action not only via state dependent association/dissociation with voltage dependent sodium channels, but a considerable fraction of inhibition is tonic, i.e. permanent and basic in nature. Voltage dependent activation was affected to a minor extent only. A shift in steady-state inactivation to more negative potentials could be observed for most drug/isoform combinations. The contribution of this shift to overall block was, however, small at drug concentrations resulting in considerable overall block. Recovery from inactivation was affected notably by both drugs. Lidocaine application led to a pronounced prolongation of the time constant of the fast recovery process for the Na(v1.3), Na(v1.5), and Na(v1.7) isoforms, indicating common structural properties in the local anesthetic receptor site of these three proteins. Interestingly, this characteristic drug action was not observed for tolperisone.

Simple pharmacological test battery to assess efficacy and side effect profile of centrally acting muscle relaxant drugs.

INTRODUCTION: Centrally muscle relaxants (CMRs) are used mainly for treating muscle spasticities of neurological origin, and painful muscle spasms due to rheumatologic conditions. Their use is frequently associated with dose-limiting adverse effects. New drugs with improved side-effect characteristics are badly needed. However, there is no general agreement in the pharmacological literature on what methods are adequate to assess CMR effect and side effects in behaving rodents, which may hinder the development of new drugs. Here we report on the establishment of a simple pharmacological test battery, which was used to compare efficacies and side effect profiles of 11 compounds with central muscle relaxant action, in mice (intraperitoneal application). METHODS: For measuring muscle relaxant activity, (1) a new tremor model (GYKI 20039-induced tremor) and (2) the morphine-induced Straub-tail assay were used. The former, newly developed method has advantages over harmaline- or LON-954-induced tremor. For detecting side effect liability (ataxia, sedation, impairment of voluntary motor functions), (1) the rota-rod test, (2) measurement of spontaneous motility, (3) the weight-lifting test and (4) the thiopental sleep test were used. RESULTS: Among the 11 muscle relaxant compounds tested (tolperisone, eperisone, silperisone, diazepam, baclofen, tizanidine, afloqualon, mephenesin, zoxazolamine, memantine and carisoprodol), the calculated safety ratios (i.e. ID50 for side effect/ID50 for muscle relaxant effect) varied in a wide range. Silperisone seems to have the most advantageous profile (safety ratios range between 1.7 and 3.3 in the different pairs of assays) compared to the other tested drugs with lower (one or more ratios below 1.5, and often far below 1) and more varying ratios. DISCUSSION: Therapeutic indices calculated from the results of these in vivo experiments for the clinically used muscle relaxants are in agreement with their adverse effect profiles in humans. Thus the present test battery seems to be suitable for predicting the possible clinical utility of newly synthesized compounds.

Effects of some centrally acting muscle relaxants on spinal root potentials: a comparative study.

The effects of intravenously administered mephenesin, tolperisone, baclofen, diazepam and midazolam on reflex activity were studied in unanesthetized spinal cats. Monosynaptic, as well as polysynaptic ventral root reflexes, the dorsal root potential and the dorsal root reflex were recorded simultaneously from L6-S1 segments. An analogue integrating method was developed for quantitative monitoring and recording ipsilateral spinal root potentials evoked by stimulation of the tibial nerve. Mephenesin (12.5-50 mg/kg) caused a significant and dose-dependent reduction in the polysynaptic and the dorsal root reflexes, slightly decreased the dorsal root potential but minimally affected the monosynaptic ventral root reflex. Tolperisone (2.5-10 mg/kg) dose-dependently inhibited both ventral root reflexes and the dorsal root reflex. It slightly prolonged the dorsal root potential without affecting the amplitude. Baclofen (0.5 mg/kg) abolished the monosynaptic reflex, partially inhibited the polysynaptic reflex, while dorsal root responses were less attenuated. Both benzodiazepines exerted similar actions, both qualitatively as well as quantitatively: the polysynaptic reflex was partially reduced while the monosynaptic reflex was not modified by diazepam or midazolam. Dorsal root responses were enhanced and the half-time of decay of the dorsal root potential was prolonged. Different patterns of action of muscle relaxants studied here are discussed in terms of their possible mechanisms of action. Profound depressant effects of mephenesin and tolperisone on the dorsal root reflex are in contrast to the small effect of both drugs on the dorsal root potential and might reflect their inhibition of spike-generating mechanisms. For a yet unknown reason, various spinal pathways are affected differentially by baclofen. In spinal cats, the reduction by benzodiazepines of the polysynaptic reflex may be related to the potentiation of some unidentified GABA-ergic inhibitory processes. The use of water-soluble midazolam, as a model compound instead of diazepam, is suggested because the usual organic solvents for diazepam may affect its action.

Suppression of calcium current in a snail neurone by eperisone and its analogues.

The effects of eperisone, tolperisone and isoperisone on the calcium current (ICa) were studied in an identified neurone of Achatina fulica under voltage clamping. At a holding voltage of -50 mV, these drugs inhibited ICa dose dependently without affecting activation time. Eperisone (IC50 = 0.348 mM) and isoperisone (0.226 mM) were significantly more effective than tolperisone (1.089 mM). Eperisone binds competitively with Ca2+ to the Ca2+ channels, based on its effects seen with various extracellular Ca2+ concentrations. The three drugs shifted the steady state inactivation curves in the hyperpolarizing direction. The mean dissociation constants for inactivated Ca2+ channels were calculated to be 0.070 mM (eperisone), 0.162 mM (tolperisone) and 0.014 mM (isoperisone). These values were much lower than their IC50 at Vh of -50 mV, which are reflected as the dissociation constants for resting Ca2+ channels. High frequency stimulation did not potentiate ICa suppression, suggesting that the drugs hardly bind to activated Ca2+ channels. These findings indicate that the selectivities of the Ca2+ channels to the drugs are in the order of their inactivated, resting and open states.

Pharmacological properties of NK433, a new centrally acting muscle relaxant.

The pharmacological properties of NK433 ((-)-(R)-2-methyl-3-(1-pyrrolidinyl)-4'-trifluoromethylpropiophenone+ ++ monohydrochloride), a novel muscle relaxant, were investigated. NK433 inhibited intercollicular decerebrate rigidity (gamma-rigidity) and anemic decerebrate rigidity (alpha-rigidity) dose dependently. NK433 was stronger in inhibiting gamma-rigidity than alpha-rigidity. NK433 inhibited the increase in muscle spindle discharges induced by pinna pinching (gamma-activity) without affecting muscle spindle discharges or neuromuscular transmission. At muscle relaxant doses in decerebrate rigidities, NK433 did not affect the muscle tone induced by morphine-HCl nor that of normal animals. These results suggest that NK433 selectively depresses the excessive muscle tone of decerebrate rigidities through its effects on the central nervous system, and inhibition of gamma-activity causes a preferential depression of gamma-rigidity in comparison to alpha-rigidity. In i.v. experiments, the effects of NK433 on decerebrate rigidities were similar to those of eperisone-HCl and tolperisone-HCl, but in p.o. experiments, NK433 was at least 3 times as potent as eperisone-HCl and tolperisone-HCl.

Effects of a new centrally acting muscle relaxant, NK433 (lanperisone hydrochloride) on spinal reflexes.

(-)-(R)-2-methyl-3-(1-pyrrolidinyl)-4'-trifluoromethylpropiophenone++ + monohydrochloride, lanperisone hydrochloride (NK433) administered intravenously or orally depressed the mono- and polysynaptic reflex potential, dorsal root reflex potential, flexor reflex mediated by group II afferent fibers, patellar and flexor reflexes. These effects were reduced by spinal transection. NK433 inhibited the facilitation of the flexor reflex mediated by group II afferent fibers that was induced by intrathecal administration of noradrenaline-HCl. (+)-(1R,2R)-2-methyl-3-(1-pyrrolidinyl)-1-(4-trifluoromethylphenyl)-1-pr opanol (LPS-9)-HCl, a metabolite of NK433, also inhibited the spinal reflexes. Given orally, NK433 had effects more than three times stronger and tending to be longer-lasting than those of eperisone-HCl. These results suggest that NK433 exerts a non-selective inhibition on spinal reflexes and that inhibition of the descending noradrenergic tonic facilitation within the spinal cord is involved in the mechanism of spinal reflex depression by NK433. LPS-9 could contribute to the potent activity of NK433 after oral administration.

Prophylactic tolperisone for post-exercise muscle soreness causes reduced isometric force--a double-blind randomized crossover control study.

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.

Effect of muscle relaxants on experimental jaw-muscle pain and jaw-stretch reflexes: a double-blind and placebo-controlled trial.

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.

Tolperisone--a novel modulator of ionic currents in myelinated axons.

The actions of tolperisone on single intact Ranvier nodes of the toad Xenopus were investigated by means of the Hodgkin-Huxley formalism. Adding tolperisone to the bathing medium (100 micromol/l) caused the following fully reversible effects: 1. The sodium permeability P'Na was decreased by about 50% in a nearly potential-independent manner while the so-called sodium inactivation curve was shifted in the negative direction by about 3 mV. 2. The remaining parameters of the sodium system, i.e. m, taum and tauh, did not change. 3. The potassium permeability P'K decreased at strong depolarizing potentials (V > 60 mV); hence the permeability constant P(K) decreased by about 8%. However, weak depolarizations (V < 60 mV) caused P'K to increase by about 7%. 4. The potassium activation curve was shifted in the positive direction by about 9 mV and the exponent of n, b, was reduced from about 3.5 to about 1.5. Concentration-response relations for reduction of the sodium permeability constant PNa and of the potassium permeability constant P(K) yielded apparent dissociation constants of about 0.06 mmol/l and 0.32 mmol/l, respectively. The increase of P'K at V = 40 mV, however, was largely concentration-independent. Our findings show that, in contrast to the prevailing view, tolperisone cannot be said to have a so-called lidocaine-like activity, because its effect on potassium permeability in the threshold region is fundamentally different from that of other known local anaesthetics. We infer that this effect, in combination with the decrease in sodium permeability, is responsible for the tendency of tolperisone to reduce excitability and hence for the antispastic action of tolperisone documented by clinical observations.

[Mydeton: a centrally acting muscle relaxant drug from Gedeon Richter LTD]. / Mydeton: a Richter centrális támadáspontú izomrelaxánsa.

Since its introduction in 1959 tolperisone hydrochloride (Mydeton) is still one of the leading products of Gedeon Richter Ltd. It has been successfully applied for treating different painful muscle spasms. The compound is successfully marketed also by several foreign, mostly Japanese, pharmaceutical companies, as a central muscle relaxant agent. The present summary overviews the pharmacology of tolperisone, with special emphasize on its still partly understood way of action. Data from the scientific literature as well as our own experimental results strongly support the hypothesis that inhibition of voltage gated sodium channels is a major component of the mechanism of action of tolperisone. The paper also summarizes the clinical results with tolperisone and the perspectives of the therapeutic use of centrally acting muscle relaxants.

Effect of tolperisone on the resting brain and on evoked responses, an phMRI BOLD study.

Tolperisone is a voltage gated sodium channel blocker, centrally acting muscle relaxant drug, with a very advantageous side effect profile. Like other sodium channel blockers, it has weak affinity to the resting state and high affinity to the open/inactivated state of the channel. In this paper, its effect on BOLD responses in rat brain were elucidated both on the resting brain and paw stimulation evoked BOLD responses. Tolperisone did not exert any visible effect on resting brain, but strongly inhibited the paw stimulation evoked BOLD responses, showing somewhat higher efficacy in brain areas involved in pain sensation. This finding is in a good agreement with its sodium channel blocking profile. In the resting brain, most of the channels are in resting state. Electric train stimuli of the paw results in over activated neurons, where most sodium channels are in open or inactivated state. These data suggest that the very advantageous profile of tolperisone can be explained by its selective action on open or inactivated sodium channels of over-activated neurons in various brain regions rather than by a selective effect in the spinal cord as suggested previously.

Tolperisone: a typical representative of a class of centrally acting muscle relaxants with less sedative side effects.

Tolperisone, a piperidine derivative, is assigned to the group of centrally acting muscle relaxants and has been in clinical use now for decades. The review summarizes the known pharmacokinetics, pharmacodynamics, toxicology and side effects in humans and the clinical use of tolperisone. A future perspective for further exploration of this drug is given.

Tolperisone-type drugs inhibit spinal reflexes via blockade of voltage-gated sodium and calcium channels.

The spinal reflex depressant mechanism of tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50-400 microM), eperisone, lanperisone, inaperisone, and silperisone (25-200 microM) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100-800 microM) 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 [3H]batrachotoxinin A 20-alpha-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 voltage-gated 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.

Observations with high-dose Mydocalm therapy.

The effect of coated Mydocalm tablet, given in 3 x 150-mg daily doses for 3 weeks to 47 patients, simultaneously with physiotherapy, has been examined in comparison to the results of 47 patients treated with physiotherapy solely. In the group of patients receiving Mydocalm as an adjuvant to physiotherapy the alleviation of pain and moderation of muscular hypertonia and spasm were observed within a shorter period. On the basis of the results of these examinations the use of Mydocalm is recommended as an adjuvant to complex therapy, in 300-450-mg daily doses, for the treatment of locomotor diseases accompanied by muscular hypertonia, muscular spasticity, and contracture.

Quantitative evaluation of the tonic vibration reflex (TVR) in the masseter muscle.

PURPOSE: This study evaluated the efficacy of the tonic vibration reflex (TVR) elicited by high-frequency vibration in evaluating masticatory muscle excitability. SUBJECTS AND METHODS: The experiment was performed on 16 male adult volunteers, 20 to 45 years of age, without spontaneous pain or tenderness in the masticatory muscles. The subjects were seated in a chair in a fixed head position with the mouth kept open with a bite block. TVR was elicited by vibratory stimulation applied to the mandible (approximately 15 m/s2, 160 Hz). An electromyogram (EMG) was recorded bilaterally from the masseter muscles and analyzed quantitatively using an arbitrary index (TVR index) calculated from the response. Bite force was measured during clenching using a pressure-sensitive foil. RESULTS: Wide variations in the TVR index (maximum, 22.7%; minimum, 0.9%, average, 7.7%) were observed among individuals. The mean index for five subjects with a clenching habit was significantly higher than that for 11 subjects without a history of clenching. Tolperisone HCl (100 mg taken orally), a gamma-drive depressant, was found to reduce the response for 2 hours. There was a negative correlation (r = -.504, P < .05) between bite force and TVR index when the values on both sides were compared. CONCLUSIONS: The TVR may be of use in evaluating masseter muscle excitability.

Mydocalm treatment of muscular and vascular complaints accompanying climacterics.

Coated Mydocalm tablet, known as striated muscle relaxant and peripheral vasodilator, has been used in climacteric women. The women suffered from muscular and vascular complaints besides the common symptoms of decreased or lacking ovarian function which could not be controlled with oestrogen substitution therapy. Mydocalm significantly moderated these complaints without causing unwanted effects and the majority of the women could be maintained in a complaint-free condition in this respect. According to the opinion of the author the drug is a valuable adjuvant to an adequate hormone therapy.