Tolperisone hydrochloride improves motor functions in Parkinson's disease via MMP-9 inhibition and by downregulating p38 MAPK and ERK1/2 signaling cascade.

The mitogen-activated protein kinase (MAPK) signaling pathway, particularly the p38 MAPK and ERK1/2, has been implicated in the pathogenesis of Parkinson's disease (PD). Recent studies have shown that MAPK signaling pathway can influence the expression of matrix metalloproteinase 9 (MMP-9), known for its involvement in various physiological and pathological processes, including neurodegenerative diseases. This study explores the modulation of MMP-9 expression via the MAPK/ERK signaling cascade and its potential therapeutic implications in the context of PD-associated motor dysfunction. Here, tolperisone hydrochloride (TL), a muscle relaxant that blocks voltage-gated sodium and calcium channels, was used as a treatment to observe its effect on MAPK signaling and MMP-9 expression. Rotenone (RT) exposure in mice resulted in a significant reduction in substantia nigra and primary motor cortex neurons, which were further evidenced by impairments in motor function. When TL was administered, neuron count was restored (89.0 ± 4.78 vs 117.0 ± 4.46/mm2), and most of the motor dysfunction was alleviated. Mechanistically, TL reduced the protein expression of phospho-p38MAPK (1.06 fold vs 1.00 fold) and phospho-ERK1/2 (1.16 fold vs 1.02 fold), leading to the inhibition of MAPK signaling, as well as reduced MMP-9 concentrations (2.76 ± 0.10 vs 1.94 ± 0.10 ng/mL) in the process of rescuing RT-induced neuronal cell death and motor dysfunction. Computational analysis further revealed TL's potential inhibitory properties against MMP-9 along with N and L-type calcium channels. These findings shed light on TL's neuroprotective effects via MMP-9 inhibition and MAPK signaling downregulation, offering potential therapeutic avenues for PD-associated motor dysfunction.

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.

RESUME-1: a Phase III study of tolperisone in the treatment of painful, acute muscle spasms of the back.

Tolperisone is a nonopioid, centrally acting muscle relaxant in clinical development in the USA for the treatment of symptoms associated with acute, painful muscles spasms of the back. CLN-301, RESUME-1, is a 14-day double-blind, randomized, placebo-controlled, parallel-group Phase III study of the efficacy and safety of tolperisone administered orally three-times daily in 1000 male and female subjects at approximately 70 clinical sites in the USA experiencing back pain due to or associated with muscle spasm of acute onset. Tolperisone is a promising therapeutic for managing acute, painful muscle spasms of the back as it appears to lack the off-target CNS effects often seen with conventional skeletal muscle relaxants. Clinical Trials registration number: NCT04671082.

[The assessment of the clinical efficacy and tolerability of complex treatment of patients with acute low-back pain]. / Otsenka klinicheskoi effektivnosti i perenosimosti kompleksnoi terapii patsientov s ostroi bol'yu v nizhnei chasti spiny.

OBJECTIVE: To compare the efficacy and tolerability of different combinations of domestic generics meloxicam (amelotex), tolperisone (calmirex) and B vitamins (compligam B) in the treatment of acute low-back pain. MATERIAL AND METHODS: Ninety patients with acute low-back pain (ICD-10 M54.5) were studied. Indications and prescribing of the drugs was carried out under the international generic name. Pain was assessed using a visual analog pain scale in mm (VAS). To relieve pain, all patients received the non-steroidal anti-inflammatory drug with a favorable safety profile meloxicam (amelotex). With the aim of optimization, 3 therapy regimens were proposed: group 1 (n=30) received amelotex, calmirex, and B vitamins (compligam B). Group 2 (n=30) received amelotex and calmirex. Group 3 (n=30) was treated with amelotex and compligam B. With a decrease in pain by 50% or more from the baseline level and a VAS <40 mm, patients could reduce the dose of amelotex from 15 to 7.5 mg or stop taking it. RESULTS: During treatment, all groups showed a significant regression of pain according to VAS: in group 1 from 77 to 9 mm, in group 2 from 74 to 12 mm, in group 3 from 69 to 14 mm. The maximum statistically significant reduction in pain and the degree of muscle tone was observed in group 1. Adverse reactions occurred in all groups, but they were weak and transient, and did not require correction or discontinuation of therapy. Only one patient from group 3 had a persistent rise in blood pressure. The average duration of temporary disability was 5.8 days in group 1, 7.4 in group 2, and 9.5 days in group 3. High efficacy and good tolerability of all 3 therapy regimens were noted. The combination of amelotex, calmirex and compligam B received the highest rating in the opinion of doctors and patients. CONCLUSION: All 3 treatment regimens optimize therapy in patients with acute low-back pain, reduce the dose and timing of the NSAID administration as well as the risk of adverse reactions. The results indicate that the combination of amelotex, calmirex and compligam B is a synergy of three pain relief systems due to the effect on different pathogenetic mechanisms, thereby providing the maximum analgesic effect, shortening the course of treatment and duration of temporary disability, reducing the risk of relapse and chronicity of pain.

[Results of a randomized double blind parallel study on the efficacy and safety of tolpersione in patients with acute nonspecific low back pain]. / Rezul'taty randomizirovannogo dvoinogo slepogo parallel'nogo issledovaniia éffektivnosti i bezopasnosti primeneniia tolperizona u patsientov s ostroi nespetsificheskoi bol'iu v nizhnei chasti spiny.

AIM: To evaluate the efficacy and safety of tolpersione injection and oral formulations combined with NSAID over NSAID monotherapy in acute non-specific low back pain. MATERIAL AND METHODS: In this randomized double blind study 239 patients were included in the per protocol analysis. The first 5 days of treatment, patients received tolpersione or placebo injection which was followed by per os administration of tolpersione/placebo tablet up to 14 days. NSAID diclofenac tablet was used in both groups through the study. Functionality assessed by the Roland Morris Disability Questionnaire (RMDQ) at day 5 was the primary endpoint. Secondary endpoints were RMDQ at other time points, pain level change at rest and on movement assessed by the Visual Analogue Scale (VAS), the Clinical Global Impression of Improvement/Patient Global Impression of Improvement (CGI-I and PGI-I), change in the range of motion assessed by the distance from the fingertips to the floor, period of disability days, relative (%) changes in the daily dose of diclofenac from the 7th to the 14th day of therapy. RESULTS AND CONCLUSION: The primary and secondary endpoints clearly demonstrated the significant superiority of tolpersione added to NSAID monotherapy over NSAID monotherapy. The safety assessment revealed no statistically significant differences between the two groups. Based on the results, tolpersione injection and per os formulations can be considered an effective and safe drugs in the combined therapy for patients with acute nonspecific back pain.

Comparative study of therapeutic response to baclofen vs tolperisone in spasticity.

BACKGROUND: Spasticity from the upper motor neuron syndrome can result from a variety of conditions affecting the cortex or spinal cord. Some of the more common conditions associated with spasticity include spinal cord injury, cerebral palsy, and post-stroke syndrome. In this study we compared the efficacy and safety of baclofen vs tolperisone in spasticity. One hundred fifty patients with cerebral palsy or post stroke or spinal cord injury associated spasticity were enrolled in present study. Group I comprised of Seventy-five patients receiving baclofen and group II comprised of 75 patients receiving tolperisone. For efficacy measurement 4 evaluation methods were used, 1) Modified Ashworth Scale for muscle tone, 2) Medical research council scale for muscle strength and 3) Barthel Index for functional outcome 4) Coefficient of efficacy. In efficacy evaluation, both groups showed significant improvement in muscle tone, muscle strength and functional outcome at week 6 (Group I, 1.55±0.053, 2.79+0.032, 59.31±1.32; Group II, 1.57±0.053, 3.04±0.032, 73±1.32 respectively). In between the group analysis, there was no significant difference in muscle tone improvement in both the groups after 6 weeks (Group I, 1.055±0.053 vs Group II, 1.57±0.053, p>0.05). Group II showed non-significant but greater improvement in muscle strength (Week 6; Group I, 2.79±0.032 vs Group II, 3.04±0.032, p>0.07). Improvement in functional outcomes was greater in group II as compared to group I (Group I, 59.31±1.32 vs Group II, 73±1.32, p<0.05). Overall efficacy coefficient was greater for group II (3.6) as compared to group I (2.3). Baclofen showed more side effects compared to tolperisone in, asthenia being the most frequent. Tolperisone offers greater improvement in activities of daily living compared to baclofen. Tolperisone is more tolerable drug as compared to baclofen.

Pharmacological interventions other than botulinum toxin for spasticity after stroke.

BACKGROUND: The long-term risk of stroke increases with age, and stroke is a common cause of disability in the community. Spasticity is considered a significantly disabling impairment that develops in people who have had a stroke. The burden of care is higher in stroke survivors who have spasticity when compared with stroke survivors without spasticity with regard to treatment costs, quality of life, and caregiver burden. OBJECTIVES: To assess if pharmacological interventions for spasticity are more effective than no intervention, normal practice, or control at improving function following stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (May 2016), the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 5), MEDLINE (1946 to May 2016), Embase (2008 to May 2016), CINAHL (1982 to May 2016), AMED (1985 to May 2016), and eight further databases and trial registers. In an effort to identify further studies, we undertook handsearches of reference lists and contacted study authors and commercial companies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any systemically acting or locally acting drug versus placebo, control, or comparative drug with the aim of treating spasticity. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion and extracted the data. We assessed the included studies for both quality and risk of bias. We contacted study authors to request further information when necessary. MAIN RESULTS: We included seven RCTs with a total 403 participants. We found a high risk of bias in all but one RCT. Two of the seven RCTs assessed a systemic drug versus placebo. We pooled data on an indirect measure of spasticity (160 participants) from these two studies but found no significant effect (odds ratio (OR) 1.66, 95% confidence interval (CI) 0.21 to 13.07; I2 = 85%). We identified a significant risk of adverse events per participant occurring in the treatment group versus placebo group (risk ratio (RR) 1.65, 95% CI 1.12 to 2.42; 160 participants; I2 = 0%). Only one of these studies used a functional outcome measure, and we found no significant difference between groups.Of the other five studies, two assessed a systemic drug versus another systemic drug, one assessed a systemic drug versus local drug, and the final two assessed a local drug versus another local drug. AUTHORS' CONCLUSIONS: The lack of high-quality RCTs limited our ability to make specific conclusions. Evidence is insufficient to determine if systemic antispasmodics are effective at improving function following stroke.

[The results of the multicenter pharmaco-epidemiological observational project on the use of mydocalm in the treatment of pain syndromes with the muscle spasm].

The prospective multicenter open noncomparative pharmaco-epidemiological observational project on the use of mydocalm in real clinical practice has been completed in 2013. The project has been performed in 2090 clinical/rehabilitation settings in 284 cities of 13 countries using the results of 35,383 patients. The project aimed to assess the safety of treatment (percentage of patients with adverse-effects) and pain relieving efficacy as well as patient's satisfaction with the treatment. In total, 6603 (19%) adverse-effects were recorded. Their severity was evaluated as mild in 84,48%, no serious adverse-effects were noted. The high efficacy of mydocalm in the treatment of pain syndromes with the muscle spasm has been demonstrated. The high level of tolerability and absence of the clinically significant increase of adverse effects in the combination with nonsteroidal anti-inflammatory drugs have been confirmed.

[Evaluation of efficacy and safety of mydocalm in the early rehabilitation of stroke].

An effect of mydocalm on muscle tone and functional rehabilitation in 1700 stroke patients (mean age 63,4 years) has been studied. Patients have been divided into two standardized groups: the basic group (850 persons who received mydocalm) and control one (850 persons who didn't receive mydocalm). The muscle tone was followed up using the Ashworth Scale, pain syndrome was assessed with the Huskisson visual analog scale and a multidimensional verbal-color pain test. The functional rehabilitation was evaluated using Barthel, Lindmark, Scandinavian and Merton & Sutton scales. Psychoemotional condition was assessed with the Beck Depression Questionnaire and the Wakefield Depression Scale, quality of life was measured by the Sickness Impact Profile. The results of the study have revealed that the use of mydocalm result in the improvement of muscle tone, decrease of pain syndrome, increase of functional rehabilitation and improvement of psychoemotional condition and the quality of life of post stroke patients. The findings of the study have demonstrated the good tolerability of mydocalm. Adverse events in the mydocalm group have been identified more rarely than in the control group.

[Spasticity in children cerebral palsy: diagnosis and treatment strategies].

Spasticity in children cerebral palsy has its own peculiarities due to the presence of pathological tonic reflexes, pathological sinkinetic activity during arbitrary movements, disturbance of coordinative interactions of muscle synergists and antagonists, increase of total reflex excitability. Physiotherapeutic methods, massage, therapeutic exercises, kinesitherapy, biological feedback training (BFT), methods of orthopedic correction, neurosurgery are widely used in the treatment of spasticity. The use of botulinum toxin type A is a new effective approach to the treatment of spasticity that improves motor functions and quality of life of children with children cerebral palsy. It is being used in the treatment of children and adolescence in a polyclinic unit of the Moscow psychoneurological hospital since 2001. The experience of treatment with botulinum and wide implementation of this method indicated that botulinum toxin injections in the complex treatment of spasticity allow to optimize approaches to treatment of children and adolescence with children cerebral palsy and to increase significantly the quality of medical-social rehabilitation of patients.

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 randomized, double blind, placebo-controlled study of the efficacy and safety of tolperisone in spasticity following cerebral stroke].

To study the efficacy and safety of tolperisone--a centrally acting muscle relaxant with membrane stabilizing activity--in the treatment of stroke-related spasticity. This was a randomized, double-blind, placebo-controlled, multicenter study with parallel groups. Treatment lasted 12 weeks and was started with a titration period of variable length (dose range 300-900 mg tolperisone daily). The degree of spasticity determined on the Ashworth Scale in the most severely affected joint area was denned as primary target parameter. Hundred and twenty patients (43 females, 77 males) in a mean age of 63,3 +/- 10,6 years were recruited and received treatment. In the majority of patients both limbs of each side were affected by the spasticity which on average had been present for 3,3 +/- 4,4 years. A 62% of the patients were treated with a daily dose >600 mg tolperisone. Tolperisone reduced the mean Ashworth Score by a mean of 1,03 +/- 0,71 compared with a mean reduction of 0,47 +/- 0,54 in the placebo group (p<0,0001). A 78,3% of the patients on tolperisone versus 45% of the placebo patients experienced a reduction by at least 1 point on the Ashworth Scale (p<0,0001). Functional and overall assessments of efficacy confirmed superior efficacy of tolperisone. Adverse events occurred less often on active treatment (n=19) than on placebo (n=26) and were mostly of mild-to-moderate intensity. No withdrawals caused by adverse events were reported in the tolperisone group. The findings of the present study demonstrate the efficacy and excellent tolerance of tolperisone in the treatment of spastic hypertonia following cerebral stroke. Study data further suggest that an individual dose titration which may exceed the recommended maximum dose of 450 mg daily results in optimized therapeutic benefit.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of tolperisone in spasticity following cerebral stroke.

To study the efficacy and safety of tolperisone - a centrally acting muscle relaxant with membrane stabilizing activity - in the treatment of stroke-related spasticity. This was a randomized, double-blind, placebo-controlled, multicenter study with parallel groups. Treatment lasted 12 weeks and was started with a titration period of variable length (dose range 300-900 mg tolperisone daily). The degree of spasticity determined on the Ashworth Scale in the most severely affected joint area was defined as primary target parameter. Hundred and twenty patients (43 females, 77 males) in a mean age of 63.3 +/- 10.6 years were recruited and received treatment. In the majority of patients both limbs of each side (right: n = 59; left: n = 56) were affected by the spasticity which on average had been present for 3.3 +/- 4.4 years. A 62% of the patients were treated with a daily dose >/=600 mg tolperisone. Tolperisone reduced the mean Ashworth Score by a mean of 1.03 +/- 0.71 compared with a mean reduction of 0.47 +/- 0.54 in the placebo group (P < 0.0001). A 78.3% of the patients on tolperisone versus 45% of the placebo patients experienced a reduction by at least 1 point on the Ashworth Scale (P < 0.0001). Functional and overall assessments of efficacy confirmed superior efficacy of tolperisone. Adverse events occurred less often on active treatment (n = 19) than on placebo (n = 26) and were mostly of mild-to-moderate intensity. No withdrawals caused by adverse events were reported in the tolperisone group. The findings of the present study demonstrate the efficacy and excellent tolerance of tolperisone in the treatment of spastic hypertonia following cerebral stroke. Study data further suggest that an individual dose titration which may exceed the recommended maximum dose of 450 mg daily results in optimized therapeutic benefit.

[A study of mydocalm efficiency in the treatment of chronic headache of tension].

Mydocalm was used for the treatment of 31 patients, mean age 45 +/- 4 years, with chronic headache of tension in a dosage of 150 mg 3 times per day during 4 weeks. Twenty-six patients have completed the therapy course. Before- and after treatment, neurological status, dynamics of psychoautonomic disorders, an extent of anxiety and depression, quality of sleep, quality of life, pain syndrome measured by a number of tests, were assessed, along with electromyography and examination of nociceptive reflex. Subjective evaluation of the drug efficacy was taken into account as well. A marked positive effect of mydocalm was observed in 70% of patients, moderate effect--in 30%. A predictor of mydocalm efficacy was severity of muscle tonic syndrome.

[Midocalm in complex therapy of chronic low back pain syndrome].

The aim of the study was to determine whether application of midocalm is appropriate in patients with chronic low back pain (LBP) from the point of view of quality of life (QL), efficacy and tolerance. The subjects were 50 patients with chronic LBP associated with spinal osteochondrosis, who underwent clinical examination and were questioned using four QL questionnaires: Health Assessment Questionnaire (HAQ), Womac osteoarthritis index Womac osteoarthritis index, Oswestry Low Back Pain Disability Questionnaire, and The 36-Item Short-Form Health Survey (SF-36). The subjects were divided into two groups. The 25 patients of Group I were administered nise in a dose of 100 mg twice a day during 10 days, the 25 patients of Group II--nise in a dose of 100 mg twice a day plus midocalm in a dose of 150 mg per day during the first two days and 450 mg per day from the third day through the tenth day. The study showed high efficacy of midocalm in complex therapy of patients with chronic LBP, as well as low rate of adverse reactions and high treatment tolerance. QL of the patients improved. Combining midocalm therapy with nise allows quicker positive effect in patients with chronic LBP and lowers need for long application of non-steroid antiinflammatory drugs.