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Open AccessEditorial

Botulinum Neurotoxins: From Toxin to Medicine

by Andrea Santamato

Toxins 2023, 15(10), 621; https://doi.org/10.3390/toxins15100621 - 20 Oct 2023

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Abstract

Ancient scientific manuscripts indicate that Dr [...] Full article

(This article belongs to the Special Issue Botulinum Neurotoxins: From Toxin to Medicine)

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14 pages, 1278 KiB

Open AccessArticle

Increasing the Passive Range of Joint Motion in Stroke Patients Using Botulinum Toxin: The Role of Pain Relief

by Carlo Trompetto, Lucio Marinelli, Laura Mori, Nicola Bragazzi, Giulia Maggi, Filippo Cotellessa, Luca Puce, Lucilla Vestito, Franco Molteni, Giulio Gasperini, Nico Farina, Luciano Bissolotti, Francesco Sciarrini, Marzia Millevolte, Fabrizio Balestrieri, Domenico Antonio Restivo, Carmelo Chisari, Andrea Santamato, Alessandra Del Felice, Paolo Manganotti, Carlo Serrati and Antonio Currà Show full author list Hide full author list

Toxins 2023, 15(5), 335; https://doi.org/10.3390/toxins15050335 - 13 May 2023

Cited by 3 | Viewed by 1978

Abstract

By blocking the release of neurotransmitters, botulinum toxin A (BoNT-A) is an effective treatment for muscle over-activity and pain in stroke patients. BoNT-A has also been reported to increase passive range of motion (p-ROM), the decrease of which is mainly due to muscle [...] Read more.

By blocking the release of neurotransmitters, botulinum toxin A (BoNT-A) is an effective treatment for muscle over-activity and pain in stroke patients. BoNT-A has also been reported to increase passive range of motion (p-ROM), the decrease of which is mainly due to muscle shortening (i.e., muscle contracture). Although the mechanism of action of BoNT-A on p-ROM is far from understood, pain relief may be hypothesized to play a role. To test this hypothesis, a retrospective investigation of p-ROM and pain was conducted in post-stroke patients treated with BoNT-A for upper limb hypertonia. Among 70 stroke patients enrolled in the study, muscle tone (Modified Ashworth Scale), pathological postures, p-ROM, and pain during p-ROM assessment (Numeric Rating Scale, NRS) were investigated in elbow flexors (48 patients) and in finger flexors (64 patients), just before and 3–6 weeks after BoNT-A treatment. Before BoNT-A treatment, pathological postures of elbow flexion were found in all patients but one. A decreased elbow p-ROM was found in 18 patients (38%). Patients with decreased p-ROM had higher pain-NRS scores (5.08 ± 1.96, with a pain score ≥8 in 11% of cases) than patients with normal p-ROM (0.57 ± 1.36) (p < 0.001). Similarly, pathological postures of finger flexion were found in all patients but two. A decreased finger p-ROM was found in 14 patients (22%). Pain was more intense in the 14 patients with decreased p-ROM (8.43 ± 1.74, with a pain score ≥ 8 in 86% of cases) than in the 50 patients with normal p-ROM (0.98 ± 1.89) (p < 0.001). After BoNT-A treatment, muscle tone, pathological postures, and pain decreased in both elbow and finger flexors. In contrast, p-ROM increased only in finger flexors. The study discusses that pain plays a pivotal role in the increase in p-ROM observed after BoNT-A treatment. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins: From Toxin to Medicine)

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16 pages, 1807 KiB

Open AccessArticle

Pain Reduction in Cervical Dystonia Following Treatment with IncobotulinumtoxinA: A Pooled Analysis

by Alberto Albanese, Jörg Wissel, Wolfgang H. Jost, Anna Castagna, Michael Althaus, Georg Comes, Astrid Scheschonka, Matteo Vacchelli and Hyder A. Jinnah

Toxins 2023, 15(5), 333; https://doi.org/10.3390/toxins15050333 - 12 May 2023

Cited by 3 | Viewed by 2079

Abstract

This analysis pooled pain severity data from four phase 3 and 4 studies of incobotulinumtoxinA (incoBoNT-A) for the treatment of cervical dystonia (CD) in adults. CD-related pain severity was assessed at baseline, each injection visit, and 4 weeks after each injection of incoBoNT-A [...] Read more.

This analysis pooled pain severity data from four phase 3 and 4 studies of incobotulinumtoxinA (incoBoNT-A) for the treatment of cervical dystonia (CD) in adults. CD-related pain severity was assessed at baseline, each injection visit, and 4 weeks after each injection of incoBoNT-A using the Toronto Western Spasmodic Torticollis Rating Scale pain severity subscale or a pain visual analog scale. Both were analyzed using a score range of 0–10 and pain was categorized as mild, moderate, or severe. Data for 678 patients with pain at baseline were assessed and sensitivity analyses evaluated pain responses in the subgroup not taking concomitant pain medication (n = 384 at baseline). At Week 4 after the first injection, there was a mean change of −1.25 (standard deviation 2.04) points from baseline pain severity (p < 0.0001), with 48.1% showing ≥ 30% pain reduction from baseline, 34.4% showing ≥50% pain reduction from baseline, and 10.3% becoming pain free. Pain responses were sustained over five injection cycles with a trend to incremental improvements with each successive cycle. Pain responses in the subgroup not taking concomitant pain medication demonstrated the lack of confounding effects of pain medications. These results confirmed the pain relief benefits of long-term treatment with incoBoNT-A. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins: From Toxin to Medicine)

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15 pages, 2011 KiB

Open AccessArticle

Replacement of the Mouse LD₅₀ Assay for Determination of the Potency of AbobotulinumtoxinA with a Cell-Based Method in Both Powder and Liquid Formulations

by Elena Fonfria, Elizabeth Marks, Lisa-Marie Foulkes, Rebecca Schofield, Daniel Higazi, Sam Coward and Alistair Kippen

Toxins 2023, 15(5), 314; https://doi.org/10.3390/toxins15050314 - 29 Apr 2023

Cited by 1 | Viewed by 2342

Abstract

Botulinum neurotoxins (BoNTs) are important therapeutic agents. The in vivo median lethal dose (LD₅₀) assay has been commonly used to measure the potency of BoNT commercial preparations. As an alternative, we developed cell-based assays for abobotulinumtoxinA in both powder (Dysport^® [...] Read more.

Botulinum neurotoxins (BoNTs) are important therapeutic agents. The in vivo median lethal dose (LD₅₀) assay has been commonly used to measure the potency of BoNT commercial preparations. As an alternative, we developed cell-based assays for abobotulinumtoxinA in both powder (Dysport^®, Azzalure^®) and liquid (Alluzience^®) formulations using the in vitro BoCell^® system. The assays demonstrated linearity over 50–130% of the expected relative potency, with a correlation coefficient of 0.98. Mean recoveries of 90–108% of the stated potency were observed over this range. The coefficients of variation for powder and liquid formulations, respectively, were 3.6% and 4.0% for repeatability and 8.3% and 5.0% for intermediate precision. A statistically powered comparability assessment of the BoCell^® and LD₅₀ assays was performed. Equivalence was demonstrated between the assays for the liquid formulation at release and end of shelf life using a paired equivalence test with predefined equivalence margins. For the powder formulation, the assays were also shown to be equivalent for release samples and when determining loss of potency following thermal degradation. The BoCell^® assay was approved for establishing the potency of abobotulinumtoxinA for both powder and liquid formulations in Europe and for the powder formulation only in the USA. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins: From Toxin to Medicine)

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10 pages, 1963 KiB

Open AccessArticle

Trends in Botulinum Toxin Use among Patients with Multiple Sclerosis: A Population-Based Study

by Djamel Bensmail, Pierre Karam, Anne Forestier, Jean-Yves Loze and Jonathan Lévy

Toxins 2023, 15(4), 280; https://doi.org/10.3390/toxins15040280 - 12 Apr 2023

Cited by 4 | Viewed by 1767

Abstract

There are limited real-world data on the use of botulinum toxin type A (BoNT-A) in patients with multiple sclerosis (MS). Accordingly, this nationwide, population-based, retrospective cohort study aimed to describe BoNT-A treatment trends in patients with MS between 2014 and 2020 in France. [...] Read more.

There are limited real-world data on the use of botulinum toxin type A (BoNT-A) in patients with multiple sclerosis (MS). Accordingly, this nationwide, population-based, retrospective cohort study aimed to describe BoNT-A treatment trends in patients with MS between 2014 and 2020 in France. This study extracted data from the French National Hospital Discharge Database (Programme de Médicalisation des Systèmes d’Information, PMSI) covering the entire French population. Among 105,206 patients coded with MS, we identified those who received ≥1 BoNT-A injection, administered within striated muscle for MS-related spasticity and/or within the detrusor smooth muscle for neurogenic detrusor overactivity (NDO). A total of 8427 patients (8.0%) received BoNT-A injections for spasticity, 52.9% of whom received ≥3 BoNT-A injections with 61.9% of the repeated injections administered every 3 to 6 months. A total of 2912 patients (2.8%) received BoNT-A injections for NDO, with a mean of 4.7 injections per patient. Most repeated BoNT-A injections within the detrusor smooth muscle (60.0%) were administered every 5 to 8 months. There were 585 patients (0.6%) who received both BoNT-A injections within striated muscle and the detrusor smooth muscle. Overall, our study highlights a broad range of BoNT-A treatment practices between 2014 and 2020 in patients with MS. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins: From Toxin to Medicine)

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14 pages, 2454 KiB

Open AccessArticle

Characterization of Serotype CD Mosaic Botulinum Neurotoxin in Comparison with Serotype C and A

by Shin-Ichiro Miyashita, Shura Karatsu, Mako Fujiishi, I Hsun Huang, Yuki Nagashima, Tamaki Morobishi, Keita Hosoya, Tsuyoshi Hata, Min Dong and Yoshimasa Sagane

Toxins 2023, 15(2), 123; https://doi.org/10.3390/toxins15020123 - 3 Feb 2023

Cited by 3 | Viewed by 1748

Abstract

Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, cleaves proteins involved in neurotransmitter release, thereby triggering flaccid paralyses, which are responsible for botulism. BoNT is classified into seven serotypes (BoNT/A-G); BoNT/A and BoNT/B are used as medical therapeutics and anti-wrinkle reagents. In this [...] Read more.

Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, cleaves proteins involved in neurotransmitter release, thereby triggering flaccid paralyses, which are responsible for botulism. BoNT is classified into seven serotypes (BoNT/A-G); BoNT/A and BoNT/B are used as medical therapeutics and anti-wrinkle reagents. In this study, we investigated the efficacy of BoNT/CD, a mosaic toxin of BoNT/C and BoNT/D, to assess its potential as a therapeutic alternative for BoNT/A. In a cultured neuron assay, BoNT/CD cleaved syntaxin and SNAP-25 with higher efficacy than BoNT/C and BoNT/A. Intramuscularly administrated BoNT/CD induced dose-dependent muscle paralysis, and the paralysis lasted ~21 days in a mouse digit abduction score assay (BoNT/A-induced paralysis lasted ~30 days). BoNT/C failed to induce local paralysis without systemic toxicity. Multiple alignment analyses of the amino acid sequences of the receptor binding domain (H_C) of eight BoNT/CDs and two BoNT/Ds showed sequence clustering in five groups. Comparing BoNT/CD strain 003-9 (BoNT/CD_003-9) and strain 6813 (BoNT/CD₆₈₁₃) showed that both BoNT/CDs displayed similar efficacies in cultured neurons, but BoNT/CD_003-9 displayed higher efficacy in a mouse model than BoNT/CD₆₈₁₃. These findings suggest that BoNT/CD may be a potential alternative for patients who do not respond to existing BoNT-based therapeutics. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins: From Toxin to Medicine)

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12 pages, 946 KiB

Open AccessArticle

Reasons and Determinants of BoNT-A Treatment Discontinuation in Patients Living with Spasticity: A 10-Year Retrospective Analysis

by Nicoletta Cinone, Luigi Santoro, Stefania Spina, Salvatore Facciorusso, Marco Battaglia, Alessio Baricich, Pasqua Marcogiuseppe and Andrea Santamato

Toxins 2022, 14(10), 675; https://doi.org/10.3390/toxins14100675 - 29 Sep 2022

Cited by 4 | Viewed by 2226

Abstract

Background: The present study aimed to evaluate the reasons and determinants of BoNT-A discontinuation in patients with stroke, multiple sclerosis, spinal cord injury, and traumatic brain injury. Methods: It is a retrospective study of 56 discontinuer patients treated with botulinum toxin between January [...] Read more.

Background: The present study aimed to evaluate the reasons and determinants of BoNT-A discontinuation in patients with stroke, multiple sclerosis, spinal cord injury, and traumatic brain injury. Methods: It is a retrospective study of 56 discontinuer patients treated with botulinum toxin between January 2011 and December 2021. Discontinuation rates and their predictors were estimated using Kaplan–Meier, Log rank test, and Cox’s regression method of analyses. Results: The mean age was 56.54 years, 53.57% were affected by post-stroke spasticity, 17.86% by spinal cord injury, 12.5% and 16.07% by traumatic brain injury and multiple sclerosis, respectively. The median discontinuation time was 5 months. The main reason for discontinuation were logistic problems (37%) and orthopedic surgeries or intrathecal baclofen (27%). Discontinuers were more likely to have severe spasticity (R = 1.785), have no pain (HR = 1.320), no access to rehabilitation services (HR = 1.402), and have cognitive impairment (HR = 1.403). Conclusions: The main reasons for discontinuation are related to logistic issues (due to distance or the absence of an adequate caregiver) and surgical interventions for spasticity, including intrathecal baclofen. It is crucial to identify possible predictors of discontinuation to improve the effectiveness of a multidisciplinary management. The study confirms the crucial role of rehabilitation and caregivers in achieving better long-term outcomes. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins: From Toxin to Medicine)

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10 pages, 1381 KiB

Open AccessArticle

Does Ultrasound Guidance Improve the Effectiveness of Neurotoxin Injections in Patients with Cervical Dystonia? (A Prospective, Partially-Blinded, Clinical Study)

by Małgorzata Tyślerowicz, Jarosław Dulski, Justyna Gawryluk and Jarosław Sławek

Toxins 2022, 14(10), 674; https://doi.org/10.3390/toxins14100674 - 28 Sep 2022

Cited by 5 | Viewed by 1742

Abstract

Aim: The aim of this study was to evaluate the efficacy of ultrasound guidance (US) in the treatment of cervical dystonia (CD) with botulinum neurotoxin type A (BoNT-A) injections in comparison to anatomical landmarks (AL). To date, US is routinely used in many [...] Read more.

Aim: The aim of this study was to evaluate the efficacy of ultrasound guidance (US) in the treatment of cervical dystonia (CD) with botulinum neurotoxin type A (BoNT-A) injections in comparison to anatomical landmarks (AL). To date, US is routinely used in many centers, but others deny its usefulness. Materials and Methods: Thirty-five patients (12 males, 23 females) with a clinical diagnosis of CD were included in the study. Intramuscular administration of BoNT-A was performed using either US guidance, or with AL, in two separate therapeutic sessions. The efficacy of BoNT-A administration was assessed with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), Tsui modified scale, Craniocervical Dystonia Questionnaire (CDQ-24) and Clinical Global Impression—Improvement scale (CGI-I). Additionally, patients at therapeutic sessions were digitally recorded and evaluated by two blinded and independent raters. Results: A significant decrease in total TWSTRS, severity subscale TWSTRS, Tsui score, and CDQ-24 was found in both the AL and US group; however, in the TWSTRS disability and pain subscales, a significant decrease was found only in the US group. Moreover, US guided treatment also resulted in a greater decrease in TWSTRS, Tsui score and CDQ-24 compared to anatomical landmarks use only. Conclusions: US guidance might be helpful in improving the results of BoNT-A injections in cervical dystonia, reducing associated pain and disability; however, more studies are needed to evaluate its clinical efficacy. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins: From Toxin to Medicine)

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