- Email: [email protected]
210. Depression: botulinum toxin enters the field of psychiatry
Abstracts / Toxicon 93 (2015) S2eS67
(29/54) for onabotulinumtoxinA + SC versus 29% (17/59) for saline + SC (P<0.05). Change in pain score was weakly associated with change in muscle tone at week 12 among patients with moderate to severe spasticity at baseline (r¼0.146). Conclusions: This is the first large, targeted, randomized controlled trial showing statistically significant and clinically meaningful improvement in pain with onabotulinumtoxinA treatment for poststroke spasticity. Keywords: Botulinum neurotoxin type A; Muscle spasticity; Pain 208. ABOUT THE DISAPPEARANCE AND PECULIAR REAPPEARANCE OF BONT/A Kai Wohlfarth a, *, Andreas Rummel b, Hans Bigalke b Department of Neurology, BG Kliniken Bergmannstrost Halle/S., Department of Pharmacology, Asclepios Campus Hamburg, Semmelweis University, Budapest; b Department of Toxicology, Medical University Hannover, Germany a
*Corresponding author: Merseburger Strasse 165, Halle/S., D-06112, Germany. E-mail address: [email protected]
Commercial BoNT/A products contain the excipient albumin. This additive plays an important role because albumin protects the toxin from inactivation if diluted at concentrations in the nanogram range. The degree of protection depends on the concentration of albumin. The underlying mechanism is attributed to the prevention of an unspecific binding of toxin at low concentration to glass and plastic surfaces. It is hypothesized that albumin or any other protein occupies unspecific binding sites allowing the toxin to stay in solution. Thus, once the surfaces are saturated either by albumin or an excess of toxin, low concentrations of toxin should remain available even in the absence of additional albumin in the toxin solution. To verify this hypothesis, commercially available purified 150-kD neurotoxin (List Biological Laboratories, Campbell, CA, USA) was reconstituted at a concentration of 100 mg/mL in the absence of albumin. Measurement of activity was conducted at a concentration of 150 pg/mL either in the absence or presence of albumin using a mouse phrenic-nerve hemidiaphragm assay. In the first series of experiments, the surfaces of glass vials and organ baths were saturated with neurotoxin (8 ng/mL). Subsequently, an experiment was started in which the toxin was applied without extra albumin. However, in the face of presaturation of surfaces, the toxin was inactivated. Moreover, the assumed surface-bound toxin was unable to paralyze the organ when an experiment was started in the absence of neurotoxin. Thus, surface-bound toxin was not capable of protecting toxin at low concentrations and did not diffuse from its putative binding sites. In a second series of experiments, toxin was diluted in a glass vial at low concentration without extra albumin. As expected, inactivation was observed when the solution was tested for activity. Accordingly, it was assumed that toxin sticks to the glass surfaces. The so-called toxindepleted solution was transferred to a second vial, allowing binding of the remaining toxin to the toxin-free surface. This approach was repeated three times; hence, the final solution should be free of any toxin. Surprisingly, activity reappeared when albumin was added to the final solution. Thus, the extra albumin did not prevent nonspecific binding but protected the toxin from a transient inactivation that was reversible by albumin. The reversibility was a time-dependent process. Activity had decreased continuously when the time interval between preparation of the solution and addition of albumin was increased. We conclude that albumin inhibits a reversible inactivation that underlies a process of aging. The inactivation might be due to reversible formation of inactive dimers or polymers. Keywords: Albumin; Botulinum toxin; Inactivation 209. FOODBORNE BOTULISM ANTISERUM
IN
2
ADULTS
NOT TREATED
BY
Kai Wohlfarth a, *, Katja Kollewe b, Olaf Niederstraßer a, Annemarie Boldt a, Katrin Dreibrodt a, Tobias Schmidt a, Andreas Rummel c, Hans Bigalke c a Department of Neurology, BG Kliniken Bergmannstrost Halle/S., Department of Pharmacology, Asclepios Campus Hamburg, Semmelweis University Budapest, Hungary; b Department of Neurology, Medical University
Hannover, Germany; Hannover, Germany
S65 c
Department of Toxicology, Medical University
*Corresponding author: Merseburger Strasse 165, Halle/S., D-06112, Germany. E-mail address: [email protected]
Ingestion of botulinum toxin (BoNT) can cause the rare disease of botulism, which is primarily characterized by flaccid paralysis. Seven major BoNT serotypes (A to G) have been identified. Serotypes A, B (which seems to predominate in Europe), and E are primarily related to foodborne botulism. The case fatality rate for botulinum poisoning is about 15%. We report 2 cases of foodborne botulism following a meal consisting of homemade canned beans, which had been inadequately preserved. Consumption of this meal caused acute symmetric, descending flaccid paralysis with prominent bulbar palsies, such as diplopia, dysarthria, dysphonia, and dysphagia presenting more than 48 hours after exposure. The patients were admitted to a hospital and required immediate intensive care, including assisted ventilation, for several weeks. The diagnosis was confirmed by mouse bioassay neutralization test using trivalent antitoxin to BoNT serotypes A, B, and E. However, timely treatment with equine antitoxin was not performed because too much time elapsed between the start of symptoms and the making of the correct diagnosis. In the clinical course, both patients also showed obstipation and hypoacusis, and one patient experienced a generalized analgesia to painful mechanical stimuli. During the hospital stay, those symptoms gradually decreased. Hypoacusis and generalized analgesia indicate cerebral and spinal poisoning; thus toxin must have reached the central compartment, probably by axonal transport. Following a protracted hospital course, prolonged mechanical ventilation, and physical rehabilitation, both patients survived. Four months later, 1 patient developed a moderatedand the other a borderlinedtiter of serum antibodies to BoNT serotype B, detected using an ex vivo assay (mouse phrenic-nerve hemidiaphragm assay). This result clearly indicates poisoning with BoNT serotype B capable of activating the immune system by oral intake. Keywords: Analgesia; Foodborne botulism; Hypoacusis; Immune response 210. DEPRESSION: PSYCHIATRY
BOTULINUM
TOXIN
ENTERS
THE
FIELD
OF
M. Axel Wollmer a, *, Michelle Magid b, Eric Finzi c, Tillmann H.C. Kruger d, Henry T. Robertson e, Brett Keeling b, Stefanie Jung a, Jason S. Reichenberg b, Norman E. Rosenthal f a Asklepios Clinic NorthdOchsenzoll, Asklepios Campus Hamburg, Medical Faculty, Semmelweis University, Germany; b Departmentof Psychiatry, University of Texas Southwestern at Seton Family of Hospitals, Austin, TX, USA; c Chevy Chase Cosmetic Center, Chevy Chase, MD, USA; d Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover, Germany; e Department of Analytics, Seton Family of Hospitals, Austin, TX, USA; f Capital Clinical Research Associates, Rockville, MD, USA *Corresponding author: Asklepios Clinic North, Ochsenzoll, Asklepios Campus Hamburg, Medical Faculty, Semmelweis University; Asklepios Clinic North, Ochsenzoll, Langenhorner Chaussee 560, Hamburg 22419, Germany. E-mail address: [email protected]
In 3 consistent randomized controlled trials, we have recently shown that a single treatment of botulinum toxin type A (BTA) injections into the glabellar region can produce a strong and sustained reduction in the symptoms of major depression. This effect may be explained by facial feedback mechanisms: the contraction of the corrugator muscles not only expresses negative emotions, it also elicits a feedback to the brain that maintains and reinforces these emotions, which is interrupted by the treatment. We now corroborate the role of BTA in the treatment of depression using a meta-analysis of pooled individual patient data from our studies. Data for all baseline variables and clinical end points that are shared by all 3 of the primary studies was reanalyzed as one study (N¼134), using a multiple regression model. In the pooled sample, there were no differences in any of the shared baseline variables between the BTA (n¼59) and the placebo group (n¼75). BTA was superior to placebo
S66
Abstracts / Toxicon 93 (2015) S2eS67
(P0.0001e0.03) in all efficacy outcomes. The improvement in the Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale was 45.7% in the BTA group vs 14.6% in the placebo group at the primary end point 6 weeks after baseline, corresponding to response rates of 54.2% vs 10.7% (odds ratio [OR], 11.1; 95% confidence interval [CI], 4.3e28.8; number needed to treat [NNT], 2.3) and remission rates of 30.5% vs 6.7% (OR, 7.3; 95% CI, 2.4e22.5; NNT, 4.2). Similar results were obtained for the self-rating on the Beck Depression Inventory. BTA was equally effective as a sole and as an adjunctive treatment. With this meta-analysis, evidence for a role for BTA in the treatment of depression is now near Ia level. These findings may also have implications for the treatment of other psychiatric disorders that abound in negative emotions. Keywords: Botulinum neurotoxin; Major depressive disorder; Metaanalysis; Randomized controlled trial 211. DO CLINICALLY EQUIVALENT DOSING RATIOS EXIST BETWEEN DIFFERENT FORMULATIONS OF BOTULINUM NEUROTOXIN A IN THE TREATMENT OF ADULT SPASTICITY, DYSTONIA, BLEPHAROSPASM, AND HEMIFACIAL SPASM: A SYSTEMATIC REVIEW Younan Zhang a, Karen Coulton a, *, Raymond Rosales b, Austen P. Moore c, Melanie Plested a a PAREXEL Consulting, London, UK; b University of Santo Tomas and Hospital, Manila, Philippines; c The Walton Centre NHS Foundation Trust, Liverpool, UK *Corresponding author: HERON Commercialization, PAREXEL Consulting, 160 Euston Road, London NW1 2DX, UK. E-mail address: [email protected]
Introduction and Objectives: The existence of a clinically equivalent dosing ratio that allows clinicians to substitute one formulation for another has been a subject of debate. The objective of this systematic review was to determine whether clinically equivalent dosing ratios exist between abobotulinumtoxinA (Dysport) and other licensed formulations of botulinum neurotoxin type A (BoNT/A) in the treatment of cervical dystonia, blepharospasm, hemifacial spasm, and adult upper and lower limb spasticity. Methods: Electronic databases and references were searched from database start to 23 August 2013; 129 citations describing 94 unique studies investigating abobotulinumtoxinA, onabotulinumtoxinA (Botox), or incobotulinumtoxinA (Xeomin) vs placebo or another BoNT/A formulation were included. Efficacy and safety data were extracted. Four approaches were used: review of studies specifically reporting a ratio, meta-regression of dose-efficacy data reported across studies, comparison of mean doses reported in included studies, comparison of doses recommended in product labeling. Results: Calculated dosing ratios varied greatly among indications and within indications when calculated via the different analytical approaches. Calculated abobotulinumtoxinA:onabotulinumtoxinA dosing ratios ranged from 1.67:1 to 6.41:1. AbobotulinumtoxinA:incobotulinumtoxinA ratios ranged from 1.20:1 to 5.75:1. Dose ratios in the clinical context appear to be driven by induction of adverse events and /or loss of efficacy. Conclusions: Following a full review of published literature, we concluded that no identified clinically equivalent dosing ratio exists among different BoNT/A products across all indications and within specific indications. If the decision to switch among different BoNT/As is taken, clinicians should refer to the Summary of Product Characteristics (SmPC) for advice on dose. Not using dose conversion ratios allows the dose to be tailored according to patient needs and also allows the physician to distribute the dose of a vial among the muscles of a limb as appropriate. Keywords: Botulinum neurotoxin A; Cervical dystonia; Dose ratio; Dysport; Spasm; Spasticity 212. BOTULINUM NEUROTOXIN TYPE A AFFECTS MUSCLE CELLS BUT NOT MUSCLE-DERIVED FIBROBLASTS Simona Zanotti a, Dimos Kapetis b, Sara Gibertini a, Marina Mora a, Franco Molteni c, * a Muscle Cell Biology Laboratory, Neuromuscular Disease and Immunology Unit, Fondazione IRCCS Istituto Neurologico “C. Besta,” Milan, Italy; b Bioinformatics Unit, Fondazione IRCCS Istituto Neurologico “C. Besta,”
Milan, Italy; c Department of Rehabilitation Medicine, Villa Beretta Rehabilitation Center, Ospedale Valduce, Costa Masnaga, Italy *Corresponding author: Ospedale Valduce, Via Nazario Sauro 17, 23845, Costa Masnaga, Italy. E-mail address: [email protected]
Botulinum neurotoxin (BoNT) is widely used for treating skeletal muscle spasticity. Experimental results of in vivo BONT treatment are limited because spasticity has been difficult to reproduce in animal models. Reports are mainly focused on the effects of BONT at the neuromuscular junction, while relatively little is known about the effect of the toxin on the muscle cell itself. Research aimed at establishing the mechanisms of BONT action in vitro mainly involves study of neuronal cell models. We investigated cellular mechanisms and key mediators targeted by BONT using an in vitro approach in muscle cell cultures from normal controls. We separated positive myoblast-enriched populations and negative fibroblast populations by immunomagnetic selection, and differentiated myoblasts from myotubes in these cell lines. Myoblast, myotube, and fibroblast cultures in basal condition or treated with incobotulinumtoxinA (Xeomin), a purified BONT type A (BONT/A) product, were collected for microarray investigation. Bioinformatics analysis revealed a major effect of BONT/A on the transcriptome of muscle cells while that of muscle-derived fibroblasts appeared to be very little affected. In myoblasts, mainly those genes that are involved in cell cycling were down- regulated; in myotubes, genes involved in inflammation were up-regulated, and genes involved in muscle contraction were down-regulated. Validation at transcript level, by reverse transcriptase polymerase chain reaction (RT-PCR), and at protein level, by immunocytochemistry and western blot, confirmed the microarray results. We demonstrate that BONT/A treatment in vitro affects intrinsic properties of the muscle cell. The BONT effect on skeletal muscle in vivo could involve different aspects: by modulating the cell cycle, BONT/A could reduce fiber regeneration; by increasing inflammation, it could act on myonecrosis; and by down-regulating contractile proteins, it could reduce muscle stiffness. A future in vivo evaluation of spastic muscle may help in ameliorating the management of spasticity with BONT. Keywords: Botulinum toxin A; IncobotulinumtoxinA; Myoblasts; Myotubes; Transcriptome 213. MULTICENTER PROSPECTIVE COHORT STUDY ON PATIENT SATISFACTION AFTER INCOBOTULINUMTOXINA INJECTION IN CERVICAL DYSTONIA Manuela Zardoni a,*, Cristina Bana b, Caterina Nascimbene b, Claudio Mariani c, Camillo Foresti d, Mario Coletti Moja e, Franco Valzania f, Maura Danni g, Silvia Lori h, Siglinde Lanzinger i, Maurizio Osio b a degli Studi di Milano, Italy; b A.O. Luigi Clinica Neurologica, Universita degli Studi di Sacco, Milano, Italy; c Clinica Neurologica Universita Milano, A. O. Luigi Sacco, Milano, Italy; d A.O. Ospedali Riuniti di Bergamo, Bergamo, Italy; e Ospedale Mauriziano Umberto I, Torino, Italy; f Nocsae - Nuovo Ospedale Civico S Agostino Estense, Modena, Italy; g A.O. Umberto I, Ancona, Italy; h Policlinico Careggi, Firenze, Italy; i Ospedale Zonale di Brunico, Brunico, Italy *Corresponding author: Via G.B. Grassi 74, Milano, Milano, Lombardia 20157, Italy. E-mail address: [email protected]
Introduction and Objectives: Cervical dystonia (CD) is a disabling focal dystonia. There are many scales for patient evaluation, to quantify patient disability and satisfaction after treatment, but they are infrequently used in clinical practice. Primary objective: to evaluate patient satisfaction after incobotulinumtoxinA treatment for CD. Secondary objective: to assess correlation between variation of disease severity at clinical evaluations and patient satisfaction. Methods: In this multicenter, prospective, observational cohort study, each patient underwent a complete clinical evaluation (including Tsui Rating Scale) at entry and 3 months after treatment (second examination). A self-assessment questionnaire (Disability Scale of the Toronto Scale for Spasmodic Torticollis) was administered at entry (baseline), after 1 week and every 2 weeks for 3 months. Statistical analysis of data collected from clinical evaluations and self-assessment questionnaires was performed. A comprehensive measure of the scores was obtained by using a template matching approach.
(29/54) for onabotulinumtoxinA + SC versus 29% (17/59) for saline + SC (P<0.05). Change in pain score was weakly associated with change in muscle tone at week 12 among patients with moderate to severe spasticity at baseline (r¼0.146). Conclusions: This is the first large, targeted, randomized controlled trial showing statistically significant and clinically meaningful improvement in pain with onabotulinumtoxinA treatment for poststroke spasticity. Keywords: Botulinum neurotoxin type A; Muscle spasticity; Pain 208. ABOUT THE DISAPPEARANCE AND PECULIAR REAPPEARANCE OF BONT/A Kai Wohlfarth a, *, Andreas Rummel b, Hans Bigalke b Department of Neurology, BG Kliniken Bergmannstrost Halle/S., Department of Pharmacology, Asclepios Campus Hamburg, Semmelweis University, Budapest; b Department of Toxicology, Medical University Hannover, Germany a
*Corresponding author: Merseburger Strasse 165, Halle/S., D-06112, Germany. E-mail address: [email protected]
Commercial BoNT/A products contain the excipient albumin. This additive plays an important role because albumin protects the toxin from inactivation if diluted at concentrations in the nanogram range. The degree of protection depends on the concentration of albumin. The underlying mechanism is attributed to the prevention of an unspecific binding of toxin at low concentration to glass and plastic surfaces. It is hypothesized that albumin or any other protein occupies unspecific binding sites allowing the toxin to stay in solution. Thus, once the surfaces are saturated either by albumin or an excess of toxin, low concentrations of toxin should remain available even in the absence of additional albumin in the toxin solution. To verify this hypothesis, commercially available purified 150-kD neurotoxin (List Biological Laboratories, Campbell, CA, USA) was reconstituted at a concentration of 100 mg/mL in the absence of albumin. Measurement of activity was conducted at a concentration of 150 pg/mL either in the absence or presence of albumin using a mouse phrenic-nerve hemidiaphragm assay. In the first series of experiments, the surfaces of glass vials and organ baths were saturated with neurotoxin (8 ng/mL). Subsequently, an experiment was started in which the toxin was applied without extra albumin. However, in the face of presaturation of surfaces, the toxin was inactivated. Moreover, the assumed surface-bound toxin was unable to paralyze the organ when an experiment was started in the absence of neurotoxin. Thus, surface-bound toxin was not capable of protecting toxin at low concentrations and did not diffuse from its putative binding sites. In a second series of experiments, toxin was diluted in a glass vial at low concentration without extra albumin. As expected, inactivation was observed when the solution was tested for activity. Accordingly, it was assumed that toxin sticks to the glass surfaces. The so-called toxindepleted solution was transferred to a second vial, allowing binding of the remaining toxin to the toxin-free surface. This approach was repeated three times; hence, the final solution should be free of any toxin. Surprisingly, activity reappeared when albumin was added to the final solution. Thus, the extra albumin did not prevent nonspecific binding but protected the toxin from a transient inactivation that was reversible by albumin. The reversibility was a time-dependent process. Activity had decreased continuously when the time interval between preparation of the solution and addition of albumin was increased. We conclude that albumin inhibits a reversible inactivation that underlies a process of aging. The inactivation might be due to reversible formation of inactive dimers or polymers. Keywords: Albumin; Botulinum toxin; Inactivation 209. FOODBORNE BOTULISM ANTISERUM
IN
2
ADULTS
NOT TREATED
BY
Kai Wohlfarth a, *, Katja Kollewe b, Olaf Niederstraßer a, Annemarie Boldt a, Katrin Dreibrodt a, Tobias Schmidt a, Andreas Rummel c, Hans Bigalke c a Department of Neurology, BG Kliniken Bergmannstrost Halle/S., Department of Pharmacology, Asclepios Campus Hamburg, Semmelweis University Budapest, Hungary; b Department of Neurology, Medical University
Hannover, Germany; Hannover, Germany
S65 c
Department of Toxicology, Medical University
*Corresponding author: Merseburger Strasse 165, Halle/S., D-06112, Germany. E-mail address: [email protected]
Ingestion of botulinum toxin (BoNT) can cause the rare disease of botulism, which is primarily characterized by flaccid paralysis. Seven major BoNT serotypes (A to G) have been identified. Serotypes A, B (which seems to predominate in Europe), and E are primarily related to foodborne botulism. The case fatality rate for botulinum poisoning is about 15%. We report 2 cases of foodborne botulism following a meal consisting of homemade canned beans, which had been inadequately preserved. Consumption of this meal caused acute symmetric, descending flaccid paralysis with prominent bulbar palsies, such as diplopia, dysarthria, dysphonia, and dysphagia presenting more than 48 hours after exposure. The patients were admitted to a hospital and required immediate intensive care, including assisted ventilation, for several weeks. The diagnosis was confirmed by mouse bioassay neutralization test using trivalent antitoxin to BoNT serotypes A, B, and E. However, timely treatment with equine antitoxin was not performed because too much time elapsed between the start of symptoms and the making of the correct diagnosis. In the clinical course, both patients also showed obstipation and hypoacusis, and one patient experienced a generalized analgesia to painful mechanical stimuli. During the hospital stay, those symptoms gradually decreased. Hypoacusis and generalized analgesia indicate cerebral and spinal poisoning; thus toxin must have reached the central compartment, probably by axonal transport. Following a protracted hospital course, prolonged mechanical ventilation, and physical rehabilitation, both patients survived. Four months later, 1 patient developed a moderatedand the other a borderlinedtiter of serum antibodies to BoNT serotype B, detected using an ex vivo assay (mouse phrenic-nerve hemidiaphragm assay). This result clearly indicates poisoning with BoNT serotype B capable of activating the immune system by oral intake. Keywords: Analgesia; Foodborne botulism; Hypoacusis; Immune response 210. DEPRESSION: PSYCHIATRY
BOTULINUM
TOXIN
ENTERS
THE
FIELD
OF
M. Axel Wollmer a, *, Michelle Magid b, Eric Finzi c, Tillmann H.C. Kruger d, Henry T. Robertson e, Brett Keeling b, Stefanie Jung a, Jason S. Reichenberg b, Norman E. Rosenthal f a Asklepios Clinic NorthdOchsenzoll, Asklepios Campus Hamburg, Medical Faculty, Semmelweis University, Germany; b Departmentof Psychiatry, University of Texas Southwestern at Seton Family of Hospitals, Austin, TX, USA; c Chevy Chase Cosmetic Center, Chevy Chase, MD, USA; d Department of Psychiatry, Social Psychiatry and Psychotherapy, Medical School Hannover, Germany; e Department of Analytics, Seton Family of Hospitals, Austin, TX, USA; f Capital Clinical Research Associates, Rockville, MD, USA *Corresponding author: Asklepios Clinic North, Ochsenzoll, Asklepios Campus Hamburg, Medical Faculty, Semmelweis University; Asklepios Clinic North, Ochsenzoll, Langenhorner Chaussee 560, Hamburg 22419, Germany. E-mail address: [email protected]
In 3 consistent randomized controlled trials, we have recently shown that a single treatment of botulinum toxin type A (BTA) injections into the glabellar region can produce a strong and sustained reduction in the symptoms of major depression. This effect may be explained by facial feedback mechanisms: the contraction of the corrugator muscles not only expresses negative emotions, it also elicits a feedback to the brain that maintains and reinforces these emotions, which is interrupted by the treatment. We now corroborate the role of BTA in the treatment of depression using a meta-analysis of pooled individual patient data from our studies. Data for all baseline variables and clinical end points that are shared by all 3 of the primary studies was reanalyzed as one study (N¼134), using a multiple regression model. In the pooled sample, there were no differences in any of the shared baseline variables between the BTA (n¼59) and the placebo group (n¼75). BTA was superior to placebo
S66
Abstracts / Toxicon 93 (2015) S2eS67
(P0.0001e0.03) in all efficacy outcomes. The improvement in the Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale was 45.7% in the BTA group vs 14.6% in the placebo group at the primary end point 6 weeks after baseline, corresponding to response rates of 54.2% vs 10.7% (odds ratio [OR], 11.1; 95% confidence interval [CI], 4.3e28.8; number needed to treat [NNT], 2.3) and remission rates of 30.5% vs 6.7% (OR, 7.3; 95% CI, 2.4e22.5; NNT, 4.2). Similar results were obtained for the self-rating on the Beck Depression Inventory. BTA was equally effective as a sole and as an adjunctive treatment. With this meta-analysis, evidence for a role for BTA in the treatment of depression is now near Ia level. These findings may also have implications for the treatment of other psychiatric disorders that abound in negative emotions. Keywords: Botulinum neurotoxin; Major depressive disorder; Metaanalysis; Randomized controlled trial 211. DO CLINICALLY EQUIVALENT DOSING RATIOS EXIST BETWEEN DIFFERENT FORMULATIONS OF BOTULINUM NEUROTOXIN A IN THE TREATMENT OF ADULT SPASTICITY, DYSTONIA, BLEPHAROSPASM, AND HEMIFACIAL SPASM: A SYSTEMATIC REVIEW Younan Zhang a, Karen Coulton a, *, Raymond Rosales b, Austen P. Moore c, Melanie Plested a a PAREXEL Consulting, London, UK; b University of Santo Tomas and Hospital, Manila, Philippines; c The Walton Centre NHS Foundation Trust, Liverpool, UK *Corresponding author: HERON Commercialization, PAREXEL Consulting, 160 Euston Road, London NW1 2DX, UK. E-mail address: [email protected]
Introduction and Objectives: The existence of a clinically equivalent dosing ratio that allows clinicians to substitute one formulation for another has been a subject of debate. The objective of this systematic review was to determine whether clinically equivalent dosing ratios exist between abobotulinumtoxinA (Dysport) and other licensed formulations of botulinum neurotoxin type A (BoNT/A) in the treatment of cervical dystonia, blepharospasm, hemifacial spasm, and adult upper and lower limb spasticity. Methods: Electronic databases and references were searched from database start to 23 August 2013; 129 citations describing 94 unique studies investigating abobotulinumtoxinA, onabotulinumtoxinA (Botox), or incobotulinumtoxinA (Xeomin) vs placebo or another BoNT/A formulation were included. Efficacy and safety data were extracted. Four approaches were used: review of studies specifically reporting a ratio, meta-regression of dose-efficacy data reported across studies, comparison of mean doses reported in included studies, comparison of doses recommended in product labeling. Results: Calculated dosing ratios varied greatly among indications and within indications when calculated via the different analytical approaches. Calculated abobotulinumtoxinA:onabotulinumtoxinA dosing ratios ranged from 1.67:1 to 6.41:1. AbobotulinumtoxinA:incobotulinumtoxinA ratios ranged from 1.20:1 to 5.75:1. Dose ratios in the clinical context appear to be driven by induction of adverse events and /or loss of efficacy. Conclusions: Following a full review of published literature, we concluded that no identified clinically equivalent dosing ratio exists among different BoNT/A products across all indications and within specific indications. If the decision to switch among different BoNT/As is taken, clinicians should refer to the Summary of Product Characteristics (SmPC) for advice on dose. Not using dose conversion ratios allows the dose to be tailored according to patient needs and also allows the physician to distribute the dose of a vial among the muscles of a limb as appropriate. Keywords: Botulinum neurotoxin A; Cervical dystonia; Dose ratio; Dysport; Spasm; Spasticity 212. BOTULINUM NEUROTOXIN TYPE A AFFECTS MUSCLE CELLS BUT NOT MUSCLE-DERIVED FIBROBLASTS Simona Zanotti a, Dimos Kapetis b, Sara Gibertini a, Marina Mora a, Franco Molteni c, * a Muscle Cell Biology Laboratory, Neuromuscular Disease and Immunology Unit, Fondazione IRCCS Istituto Neurologico “C. Besta,” Milan, Italy; b Bioinformatics Unit, Fondazione IRCCS Istituto Neurologico “C. Besta,”
Milan, Italy; c Department of Rehabilitation Medicine, Villa Beretta Rehabilitation Center, Ospedale Valduce, Costa Masnaga, Italy *Corresponding author: Ospedale Valduce, Via Nazario Sauro 17, 23845, Costa Masnaga, Italy. E-mail address: [email protected]
Botulinum neurotoxin (BoNT) is widely used for treating skeletal muscle spasticity. Experimental results of in vivo BONT treatment are limited because spasticity has been difficult to reproduce in animal models. Reports are mainly focused on the effects of BONT at the neuromuscular junction, while relatively little is known about the effect of the toxin on the muscle cell itself. Research aimed at establishing the mechanisms of BONT action in vitro mainly involves study of neuronal cell models. We investigated cellular mechanisms and key mediators targeted by BONT using an in vitro approach in muscle cell cultures from normal controls. We separated positive myoblast-enriched populations and negative fibroblast populations by immunomagnetic selection, and differentiated myoblasts from myotubes in these cell lines. Myoblast, myotube, and fibroblast cultures in basal condition or treated with incobotulinumtoxinA (Xeomin), a purified BONT type A (BONT/A) product, were collected for microarray investigation. Bioinformatics analysis revealed a major effect of BONT/A on the transcriptome of muscle cells while that of muscle-derived fibroblasts appeared to be very little affected. In myoblasts, mainly those genes that are involved in cell cycling were down- regulated; in myotubes, genes involved in inflammation were up-regulated, and genes involved in muscle contraction were down-regulated. Validation at transcript level, by reverse transcriptase polymerase chain reaction (RT-PCR), and at protein level, by immunocytochemistry and western blot, confirmed the microarray results. We demonstrate that BONT/A treatment in vitro affects intrinsic properties of the muscle cell. The BONT effect on skeletal muscle in vivo could involve different aspects: by modulating the cell cycle, BONT/A could reduce fiber regeneration; by increasing inflammation, it could act on myonecrosis; and by down-regulating contractile proteins, it could reduce muscle stiffness. A future in vivo evaluation of spastic muscle may help in ameliorating the management of spasticity with BONT. Keywords: Botulinum toxin A; IncobotulinumtoxinA; Myoblasts; Myotubes; Transcriptome 213. MULTICENTER PROSPECTIVE COHORT STUDY ON PATIENT SATISFACTION AFTER INCOBOTULINUMTOXINA INJECTION IN CERVICAL DYSTONIA Manuela Zardoni a,*, Cristina Bana b, Caterina Nascimbene b, Claudio Mariani c, Camillo Foresti d, Mario Coletti Moja e, Franco Valzania f, Maura Danni g, Silvia Lori h, Siglinde Lanzinger i, Maurizio Osio b a degli Studi di Milano, Italy; b A.O. Luigi Clinica Neurologica, Universita degli Studi di Sacco, Milano, Italy; c Clinica Neurologica Universita Milano, A. O. Luigi Sacco, Milano, Italy; d A.O. Ospedali Riuniti di Bergamo, Bergamo, Italy; e Ospedale Mauriziano Umberto I, Torino, Italy; f Nocsae - Nuovo Ospedale Civico S Agostino Estense, Modena, Italy; g A.O. Umberto I, Ancona, Italy; h Policlinico Careggi, Firenze, Italy; i Ospedale Zonale di Brunico, Brunico, Italy *Corresponding author: Via G.B. Grassi 74, Milano, Milano, Lombardia 20157, Italy. E-mail address: [email protected]
Introduction and Objectives: Cervical dystonia (CD) is a disabling focal dystonia. There are many scales for patient evaluation, to quantify patient disability and satisfaction after treatment, but they are infrequently used in clinical practice. Primary objective: to evaluate patient satisfaction after incobotulinumtoxinA treatment for CD. Secondary objective: to assess correlation between variation of disease severity at clinical evaluations and patient satisfaction. Methods: In this multicenter, prospective, observational cohort study, each patient underwent a complete clinical evaluation (including Tsui Rating Scale) at entry and 3 months after treatment (second examination). A self-assessment questionnaire (Disability Scale of the Toronto Scale for Spasmodic Torticollis) was administered at entry (baseline), after 1 week and every 2 weeks for 3 months. Statistical analysis of data collected from clinical evaluations and self-assessment questionnaires was performed. A comprehensive measure of the scores was obtained by using a template matching approach.