BACKGROUND AND OBJECTIVES: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD). METHODS: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses. RESULTS: Of 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, -8.5 [1.93], p < 0.0001; DAXI 250U, -6.6 [1.92], p = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3-29.1) weeks with DAXI 125U and 20.3 (16.7-24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%). DISCUSSION: This study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

• MeSH
• botulotoxiny typ A * škodlivé účinky   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• dystonické poruchy * farmakoterapie   MeSH
• injekce intramuskulární MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nervosvalové látky * škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• tortikolis * farmakoterapie   chemicky indukované   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• botulotoxiny typ A * MeSH
• nervosvalové látky * MeSH

BACKGROUND: Many experimental and clinical studies are conducted to investigate the effects of various applications of botulinum toxin (BTx) in the treatment of radiation related side effects. There are no studies that show clear results about the positive and negative effects of its active clinical use in the long run, and discussions are ongoing. In addition, there is a need for various researches about how BTx can be used and how long it can be used, and the side effects it may cause. BTx-A, which is one of the options in the treatment of side effects that will occur due to radiotherapy, is an effective and safe option. Applying BTx injection to the right place with specific injection methods increases the effectiveness and safety of the treatment. PURPOSE: It has been investigated whether BTx will be a potential tool to perfect the esthetic and functional results in reducing the chronic side effects associated with radiotherapy.

• Klíčová slova
• botulinum toxin, radiotherapy, side effects, treatment, type 2 diabetes,
• MeSH
• botulotoxiny typ A * škodlivé účinky   MeSH
• lidé MeSH
• nervosvalové látky * škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• botulotoxiny typ A * MeSH
• nervosvalové látky * MeSH

PURPOSE: This pooled analysis of data from three Phase 3 studies investigated the effects of incobotulinumtoxinA on spasticity-related pain (SRP) in children/adolescents with uni-/bilateral cerebral palsy (CP). METHODS: Children/adolescents (ambulant and non-ambulant) were evaluated for SRP on increasingly difficult activities/tasks 4 weeks after each of four incobotulinumtoxinA injection cycles (ICs) using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to lower limb [LL] or upper limb [UL] spasticity and respondent type [child/adolescent, interviewer, or parent/caregiver]). IncobotulinumtoxinA doses were personalized, with all doses pooled for analysis. RESULTS: QPS key item responses were available from 331 and 155 children/adolescents with LL- and UL-spasticity, respectively, and 841/444 (LL/UL) of their parents/caregivers. IncobotulinumtoxinA efficacy was evident with the first IC. Efficacy was sustained and became more robust with further subsequent ICs. By Week 4 of the last (i.e. fourth) IC, 33.8-53.3% of children/adolescents reported complete SRP relief from their baseline pain for respective QPS items. Children/adolescents reported reductions in mean LL SRP intensity at levels that surpassed clinically meaningful thresholds. Similarly, parents/caregivers observed complete SRP relief and less frequent SRP with incobotulinumtoxinA. Similar results were found for UL SRP. CONCLUSION: These findings indicate that incobotulinumtoxinA could bring considerable benefit to children/adolescents with spasticity by reducing SRP, even during strenuous activities.

• Klíčová slova
• Botulinum toxin, all movement disorders, all pediatric, cerebral palsy, muscle spasticity, pain,
• MeSH
• bolest farmakoterapie   etiologie   MeSH
• botulotoxiny typ A * terapeutické užití   MeSH
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mozková obrna * komplikace   farmakoterapie   MeSH
• nervosvalové látky * terapeutické užití   MeSH
• svalová spasticita farmakoterapie   etiologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Názvy látek
• botulotoxiny typ A * MeSH
• incobotulinumtoxinA MeSH Prohlížeč
• nervosvalové látky * MeSH

The pooled incidences of treatment-emergent adverse events (TEAEs) were examined by indication using the integrated clinical database of Merz-sponsored, placebo-controlled, or repeat-dose studies of incobotulinumtoxinA in adults with cervical dystonia, blepharospasm, limb spasticity, sialorrhea, or essential tremor of the upper limb. Overall incidences of TEAEs, serious TEAEs, TEAEs leading to discontinuation, fatal TEAEs, TEAEs of special interest (TEAESIs; indicating possible toxin spread), and treatment-related (TR) events were determined for incobotulinumtoxinA and placebo after a single injection and for repeated dose cycles of incobotulinumtoxinA. The most frequent events after a single dose of incobotulinumtoxinA are summarized. After a single cycle, incidences of overall TEAEs were similar between incobotulinumtoxinA and the placebo in most indications, although between-indication differences were observed. Few TEAEs led to incobotulinumtoxinA discontinuation; there were no fatal TEAEs with incobotulinumtoxinA. In general, repeated cycles did not increase the incidence of any event. The most frequent TR-TEAEs were indication-dependent, including dysphagia for indications affecting the head or neck. The TR-TEAESIs across all indications were most commonly muscular weakness, dysphagia and dry mouth. Overall, the results of this pooled analysis support and extend the favorable safety and tolerability profile of incobotulinumtoxinA for the treatment of adult neurological disorders established by individual clinical studies.

• Klíčová slova
• blepharospasm, cervical dystonia, essential tremor, immunogenicity, incobotulinumtoxinA, motor disorders, neurological disorders, safety, sialorrhea, spasticity,
• MeSH
• botulotoxiny typ A * škodlivé účinky   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• lidé MeSH
• nemoci nervového systému * farmakoterapie   MeSH
• nervosvalové látky * škodlivé účinky   MeSH
• poruchy polykání * farmakoterapie   MeSH
• tortikolis * farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• botulotoxiny typ A * MeSH
• incobotulinumtoxinA MeSH Prohlížeč
• nervosvalové látky * MeSH

In post-stroke spasticity (PSS), effective treatment with botulinum neurotoxin (BoNT) is associated with transient decrease in activation of the ipsilesional superior parietal lobule (SPL) and intraparietal sulcus (IPS). We hypothesized that this would be reflected in changes in resting-state functional connectivity (rsFC) of the SPL/IPS. Our aim was therefore to assess rsFC of the ipsilesional SPL/IPS in chronic stroke patients with hemiparesis both with and without PSS and to explore the relationship between SPL/IPS rsFC and PSS severity. To this end, fourteen chronic stroke patients with upper limb weakness and PSS (the PSS group) and 8 patients with comparable weakness but no PSS (the control group) underwent clinical evaluation and 3 fMRI examinations, at baseline (W0) and 4 and 11 weeks after BoNT (W4 and W11, respectively). Seed-based rsFC of the atlas-based SPL and IPS was evaluated using a group×time interaction analysis and a correlation analysis with PSS severity (modified Ashworth scale), integrity of the ipsilesional somatosensory afferent pathway (evoked potential N20 latency), and age. In the PSS group, transient improvement in PSS was associated with increase in rsFC between the ipsilesional IPS and the contralesional SPL at W4. The interhemispheric connectivity was negatively correlated with PSS severity at baseline and with PSS improvement at W4. We propose adaptation of the internal forward model as the putative underlying mechanism and discuss its possible association with increased limb use, diminished spastic dystonia, or improved motor performance, as well as its potential contribution to the clinical effects of BoNT.

• Klíčová slova
• Botulinum toxin, Functional magnetic resonance imaging, Resting-state, Spasticity, Stroke,
• MeSH
• botulotoxiny typ A * terapeutické užití   MeSH
• cévní mozková příhoda * komplikace   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• nervosvalové látky * terapeutické užití   MeSH
• svalová spasticita MeSH
• temenní lalok MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• botulotoxiny typ A * MeSH
• nervosvalové látky * MeSH

BACKGROUND: For many indications, BoNT/A is repetitively injected with the risk of developing neutralizing antibodies (NABs). Therefore, it is important to analyze whether there is a difference in antigenicity between the different licensed BoNT/A preparations. METHODS: In this cross-sectional study, the prevalence of NABs was tested by means of the sensitive mouse hemidiaphragm assay (MHDA) in 645 patients. Patients were split into those having exclusively been treated with the complex protein-free incoBoNT/A preparation (CF-MON group) and those having started BoNT/A therapy with a complex protein-containing BoNT/A preparation (CC-I group). This CC-I group was split into those patients who remained either on abo- or onaBoNT/A (CC-MON group) and those who had been treated with at least two BoNT/A preparations (CC-SWI group). To balance treatment duration, only CC-MON patients who did not start their BoNT/A therapy more than 10 years before recruitment (CC-MON-10 group) were further analyzed. The log-rank test was used to compare the prevalence of NABs in the CF-MON and CC-MON-10 group. RESULTS: In the CF-MON subgroup, no patient developed NABs. In the CC-I group, 84 patients were NAB-positive. NABs were found in 33.3% of those who switched preparations (CC-SWI) and in 5.9% of the CC-MON-10 group. Kaplan-Meier curves for remaining NAB-negative under continuous BoNT/A therapy were significantly different (p < 0.035) between the CF-MON and CC-MON-10 group. CONCLUSION: Frequent injections of a complex protein-containing BoNT/A preparation are associated with significantly higher risks of developing NABs than injections with the same frequency using the complex protein-free incoBoNT/A preparation.

• Klíčová slova
• Botulinum toxin type A preparations, Complex proteins, Difference in antigenicity, IncobotulinumtoxinA, Neutralizing antibodies,
• MeSH
• botulotoxiny typ A * MeSH
• myši MeSH
• nervosvalové látky * MeSH
• neutralizující protilátky MeSH
• průřezové studie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• botulotoxiny typ A * MeSH
• nervosvalové látky * MeSH
• neutralizující protilátky MeSH

PURPOSE: The open-label phase 3 "Treatment with IncobotulinumtoxinA in Movement Open-Label" (TIMO) study investigated longer-term safety and efficacy of incobotulinumtoxin A in children/adolescents with cerebral palsy (CP). METHODS: Patients on standard treatment, with unilateral or bilateral lower limb (LL) or combined upper limb (UL)/LL spasticity received four incobotulinumtoxinA injection cycles (16 or 20 Units/kg bodyweight total [maximum 400 or 500 Units] per cycle depending on ambulatory status/clinical pattern treated), each followed by 12-16 weeks' observation. Treatment for pes equinus was mandatory; flexed knee or adducted thigh were options for unilateral treatment and/or ULs for unilateral/bilateral treatment. The primary endpoint was safety; changes in Ashworth Scale and Gross Motor Function Measure-66 scores, and Global Impression of Change Scale scores at week 4 of each injection cycle were also evaluated. RESULTS: IncobotulinumtoxinA (≤500 Units for ≤98 weeks) was safe, well-tolerated, and effective across all endpoints for multipattern treatment of LL and combined LL/UL spasticity in ambulant/nonambulant children/adolescents with CP. Treatment effects increased with each injection cycle. No new/unexpected safety concerns were identified. CONCLUSION: IncobotulinumtoxinA showed a good safety and tolerability profile, with efficacy over multiple clinical presentations. As an adjunct treatment, it offers an effective, individualized treatment option for pediatric CP-related spasticity.

• Klíčová slova
• Botulinum toxins, Type A, cerebral palsy, movement disorders, muscle spasticity, paediatric,
• MeSH
• botulotoxiny typ A * škodlivé účinky   MeSH
• dítě MeSH
• dolní končetina MeSH
• lidé MeSH
• mladiství MeSH
• mozková obrna * komplikace   farmakoterapie   MeSH
• nervosvalové látky * MeSH
• svalová spasticita farmakoterapie   etiologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• Názvy látek
• botulotoxiny typ A * MeSH
• incobotulinumtoxinA MeSH Prohlížeč
• nervosvalové látky * MeSH

Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate acetylcholine binding and function. Using radioligand binding experiments we investigated their binding mode. We show that neuroactive steroids bind to two binding sites on muscarinic receptors. Their affinity for the high-affinity binding site is about 100 nM. Their affinity for the low-affinity binding site is about 10 µM. The high-affinity binding occurs at the same site as binding of steroid-based WIN-compounds that is different from the common allosteric binding site for alcuronium or gallamine that is located between the second and third extracellular loop of the receptor. This binding site is also different from the allosteric binding site for the structurally related aminosteroid-based myorelaxants pancuronium and rapacuronium. Membrane cholesterol competes with neurosteroids/neuroactive steroids binding to both high- and low-affinity binding site, indicating that both sites are oriented towards the cell membrane..

• Klíčová slova
• Allosteric modulation, Cholesterol, Muscarinic receptors, Neuroactive steroids,
• MeSH
• alosterická regulace účinky léků   fyziologie   MeSH
• androstany metabolismus   farmakologie   MeSH
• androsteny metabolismus   farmakologie   MeSH
• benzimidazoly metabolismus   farmakologie   MeSH
• CHO buňky MeSH
• cholesterol metabolismus   MeSH
• Cricetulus MeSH
• křečci praví MeSH
• lidé MeSH
• nervosvalové látky nedepolarizující metabolismus   farmakologie   MeSH
• neurosteroidy metabolismus   MeSH
• receptory muskarinové metabolismus   MeSH
• triethojodid gallaminia metabolismus   farmakologie   MeSH
• vazebná místa účinky léků   fyziologie   MeSH
• vekuronium analogy a deriváty   metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• androstany MeSH
• androsteny MeSH
• benzimidazoly MeSH
• cholesterol MeSH
• nervosvalové látky nedepolarizující MeSH
• neurosteroidy MeSH
• rapacuronium MeSH Prohlížeč
• receptory muskarinové MeSH
• triethojodid gallaminia MeSH
• vekuronium MeSH
• WIN 51708 MeSH Prohlížeč
• WIN 62577 MeSH Prohlížeč

BACKGROUND: Intrathecal baclofen (ITB) pump delivery systems are safe and effective in the treatment of generalized spasticity in chronic spinal cord injury (SCI). Despite its widespread use, few and discrepant data are available in animal studies on the effects of ITB on cognitive functions, such as memory. The effects of chronic administration of baclofen on humans have not been investigated to date. The aim of this study is to find out, whether a long-term administration of ITB has any effects on cognitive functions in SCI subjects. MATERIALS AND METHODS: In 11 out of 22 subjects with chronic SCI, we performed comprehensive neuropsychological assessment carried out using specialized tests focused on memory and other higher cognitive domains and emotional state. RESULTS: All patients receiving ITB treatment for spasticity relief improved significantly in RAVLT Trials 1-5 (p = 0.049), Logical memory-immediate recall (p = 0.019) and Logical memory-delayed recall (p = 0.008). Visual memory, long-term semantic memory, attention, executive, perceptual and spatial functions, and mood status remained stable. CONCLUSION: No significant decline in memory functions were detected following one year of ITB delivery, creating an opportunity for careful prescription of this treatment in chronic SCI. Moreover, we have detected a significant increase in short-term auditory-verbal memory and logical memory performance.

• Klíčová slova
• Chronic spinal cord injury, intrathecal baclofen, memory, neuropsychological assessment,
• MeSH
• baklofen terapeutické užití   MeSH
• centrálně působící myorelaxancia * terapeutické užití   MeSH
• implantabilní infuzní pumpy MeSH
• lidé MeSH
• poranění míchy * komplikace   farmakoterapie   MeSH
• spinální injekce MeSH
• svalová spasticita farmakoterapie   etiologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• baklofen MeSH
• centrálně působící myorelaxancia * MeSH

BACKGROUND: This randomized phase 3 study with double-blind main period (MP) and open-label extension (OLEX; NCT02002884) assessed incobotulinumtoxinA safety and efficacy for pediatric upper-limb spasticity treatment in ambulant/nonambulant (Gross Motor Function Classification System [GMFCS] I-V) patients, with the option of combined upper- and lower-limb treatment. METHODS: Patients were aged two to 17 years with unilateral or bilateral spastic cerebral palsy (CP) and Ashworth Scale (AS) score ≥2 in treatment-selected clinical patterns. In the MP, patients were randomized (2:1:1) to incobotulinumtoxinA 8, 6, or 2 U/kg body weight (maximum 200, 150, 50 U/upper limb), with optional lower-limb injections in one of five topographical distributions (total body dose ≤16 to 20 U/kg, maximum 400 to 500 U, depending on body weight and GMFCS level). In the OLEX, patients received three further treatment cycles, at the highest MP doses (8 U/kg/upper limb group). Outcomes included AS, Global Impression of Change Scale (GICS), and adverse events (AEs). RESULTS: AS scores improved from baseline to week 4 in all MP dose groups (n = 350); patients in the incobotulinumtoxinA 8 U/kg group had significantly greater spasticity improvements versus the 2 U/kg group (least-squares mean [standard error] for upper-limb main clinical target pattern -1.15 [0.06] versus -0.93 [0.08]; P = 0.017). Investigator's, child/adolescent's, and parent/caregiver's GICS scores showed improvements in all groups. Treatment benefits were sustained over further treatment cycles. AE incidence did not increase with dose or repeated treatment across GMFCS levels. CONCLUSIONS: Data provide evidence for sustained efficacy and safety of multipattern incobotulinumtoxinA treatment in children and adolescents with upper-limb spasticity.

• Klíčová slova
• Botulinum neurotoxin A, Cerebral palsy, IncobotulinumtoxinA, Multipattern treatment, Pediatric, Spasticity,
• MeSH
• botulotoxiny typ A aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• dítě MeSH
• dvojitá slepá metoda MeSH
• hodnocení výsledků zdravotní péče MeSH
• horní končetina patofyziologie   MeSH
• lidé MeSH
• mladiství MeSH
• mozková obrna komplikace   farmakoterapie   MeSH
• nervosvalové látky aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• předškolní dítě MeSH
• svalová spasticita farmakoterapie   etiologie   patofyziologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• botulotoxiny typ A MeSH
• incobotulinumtoxinA MeSH Prohlížeč
• nervosvalové látky MeSH