- Email: [email protected]
Real-world treatment utilization and safety of onabotulinumtoxinA for chronic migraine from an observational study in the European union
Abstracts / Toxicon 123 (2016) S2eS90
before treatment to 11.8 (3.0) mm at Week 2 (P<0.05) and 9.4 (4.7) mm at Week 6 (P<0.01). Four patients experienced mild ptosis that resolved after 5 weeks, and 1 patient also experienced nondisabling diplopia that resolved at Week 6. Conclusions: Few studies report the use of BoNT in the treatment of epiphora. This pilot study showed that incobotulinumtoxinA injections were well tolerated and reduced symptoms and improved QoL in patients with obstructive or functional epiphora. Controlled studies in larger populations are required. Keywords: Epiphora; IncobotulinumtoxinA; Quality of life 160. STRUCTURAL AND FUNCTIONAL STUDIES OF CLOSTRIDIUM BOTULINUM RIBONUCLEOTIDE REDUCTASE Markel Martínez Carranza, Pål Stenmark*. Department of Biochemistry and Biophysics, Stockholm, Sweden
Stockholm
University,
* Corresponding author: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. E-mail address:[email protected].
Introduction and objectives: Ribonucleotide reductase (RNR) is an essential enzyme that catalyzes the conversion between ribonucleotides and deoxyribonucleotides. Class Ia RNRs are the most thoroughly studied, and they consist of an a subunit and b subunit oligomer. The a subunit contains the active site and 2 allosteric sites, one for regulation and one for activation; the b subunit is a metalloprotein that generates a free radical required for the catalysis. Given its phylogenetic classification, Clostridium botulinum RNR belongs to a previously uncharacterized class, which makes it interesting to study. Furthermore, this RNR requires oxygen for its catalytic function, which is an unusual feature for an anaerobic bacterium. Methods: We performed structural studies on C botulinum RNR via x-ray crystallography. Results and conclusions: We report a 2 Å crystal structure of the RNR b subunit. Two dimers are present in the asymmetric unit, and the metal sites are populated with 2 Fe atoms. Keywords: Ribonucleotide reductase enzyme; X-ray crystallography
S61
* Corresponding author: Department of Biophysics and Biochemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden. E-mail address: [email protected].
Introduction and objectives: The clostridial neurotoxin family is composed of the tetanus (TeNT) and botulinum neurotoxins (BoNT), which cause the diseases tetanus and botulism, respectively. These extremely potent toxins recognize motor and periphery neurons with high affinity and specificity, resulting in inhibition of neurotransmission, thereby causing paralysis. Our aim is to determine the mechanism of binding of the clostridial neurotoxins to their receptors using biophysical methods, in particular, x-ray crystallography. Understanding these complex interactions should help in the development of vaccines and antitoxin therapies as well as in the engineering of novel biopharmaceuticals. Methods: X-ray crystallography; Isothermal titration calorimetry (ITC). Results: The crystal structures of the binding domain of BoNT/A and TeNT were solved in complex with ganglioside polysaccharides, providing the molecular details of receptor recognition. Binding affinities measured by ITC were shown to be much weaker than expected for these soluble carbohydrates. Conclusions: We propose that the glycan part of the ganglioside receptors mainly provides abundance and specificity, whereas the interaction with the membrane itself and protein receptor brings about the strong total binding of the toxin to the neuronal membrane. Keywords: BoNT; Gangliosides; Receptor binding; TeNT 162. REAL-WORLD TREATMENT UTILIZATION AND ONABOTULINUMTOXINA FOR CHRONIC MIGRAINE OBSERVATIONAL STUDY IN THE EUROPEAN UNION
SAFETY OF FROM AN
Manjit Matharu a,*, Julio Pascual b, Ingela Nilsson Remahl c, Andreas Straube d, Arlene Lum e, Gudarz Davar e, Dawn Odom f, Lee Christina Proctor f, Lia Gutierrez g, Elizabeth Bennett f, h i Andrews , Catherine Johannes . a Headache Group, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; b Department of Neurology, University Hospital Marqu es de Valdecilla, Santander, Spain; c Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden; d Department of Neurology, Klinikum Grosshadern, Munich, Germany; e Clinical Development, Allergan plc, Irvine, CA, USA; f Biostatistics, RTI Health Solutions, Research Triangle Park, NC, USA; g Pharmacoepidemiology and Risk Management, RTI Health Solutions, Barcelona, Spain; h Epidemiology, RTI Health Solutions, Research Triangle Park, NC, USA; i Pharmacoepidemiology and Risk Management, RTI Health Solutions, Waltham, MA, USA * Corresponding author: Queen Square, London WC1N 3BG, UK. E-mail address: [email protected].
Fig. 1. Cartoon representation of the 2 Å resolution crystal structure of C botulinum RNR b subunit dimer.
161. STRUCTURAL STUDIES OF CLOSTRIDIAL NEUROTOXINS BINDING TO GANGLIOSIDE RECEPTORS €ran Widmalm b, Pål Geoffrey Masuyer a, Ronnie P.-A. Berntsson a, Go a, * Stenmark . a Department of Biophysics and Biochemistry, Arrhenius Laboratory, Stockholm University, Sweden; b Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Sweden
Introduction and objectives: We examine real-world treatment utilization patterns and safety of onabotulinumtoxinA for the prophylactic treatment of chronic migraine (CM) in routine clinical practice. Methods: This was a prospective, observational, postauthorization study in adult patients with CM treated with onabotulinumtoxinA (NCT01432379). Data were collected at the first study injection and approximately every 3 months for 52 weeks for utilization or 64 weeks for safety data. Data are summarized using descriptive statistics. Results: Eighty-five physicians (81% neurologists) were recruited at 58 practices in the United Kingdom, Germany, Spain, and Sweden. A total of 1160 patients were enrolled (average age, 46.6 years [range¼19-79]; 84.2% female; 97.8% Caucasian); 85.8% had a diagnostic history of CM/transformed migraine. At baseline, patients reported an average 7.7 (standard deviation [SD]¼6.9) headache-free days per usual month, and 50.6% had used onabotulinumtoxinA for CM in the past. A total of 4017 study treatments were observed. The median number of injection sites (n¼31) and total dose (155 U) were consistent across all treatment sessions, with a median 13.7 weeks reported between sessions. Most patients (74.4%) indicated they were satisfied/extremely satisfied with onabotulinumtoxinA treatment for CM. At least one treatment-related adverse event (AE) was reported by 291 patients (25.1%); most frequently reported was neck
before treatment to 11.8 (3.0) mm at Week 2 (P<0.05) and 9.4 (4.7) mm at Week 6 (P<0.01). Four patients experienced mild ptosis that resolved after 5 weeks, and 1 patient also experienced nondisabling diplopia that resolved at Week 6. Conclusions: Few studies report the use of BoNT in the treatment of epiphora. This pilot study showed that incobotulinumtoxinA injections were well tolerated and reduced symptoms and improved QoL in patients with obstructive or functional epiphora. Controlled studies in larger populations are required. Keywords: Epiphora; IncobotulinumtoxinA; Quality of life 160. STRUCTURAL AND FUNCTIONAL STUDIES OF CLOSTRIDIUM BOTULINUM RIBONUCLEOTIDE REDUCTASE Markel Martínez Carranza, Pål Stenmark*. Department of Biochemistry and Biophysics, Stockholm, Sweden
Stockholm
University,
* Corresponding author: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. E-mail address:[email protected].
Introduction and objectives: Ribonucleotide reductase (RNR) is an essential enzyme that catalyzes the conversion between ribonucleotides and deoxyribonucleotides. Class Ia RNRs are the most thoroughly studied, and they consist of an a subunit and b subunit oligomer. The a subunit contains the active site and 2 allosteric sites, one for regulation and one for activation; the b subunit is a metalloprotein that generates a free radical required for the catalysis. Given its phylogenetic classification, Clostridium botulinum RNR belongs to a previously uncharacterized class, which makes it interesting to study. Furthermore, this RNR requires oxygen for its catalytic function, which is an unusual feature for an anaerobic bacterium. Methods: We performed structural studies on C botulinum RNR via x-ray crystallography. Results and conclusions: We report a 2 Å crystal structure of the RNR b subunit. Two dimers are present in the asymmetric unit, and the metal sites are populated with 2 Fe atoms. Keywords: Ribonucleotide reductase enzyme; X-ray crystallography
S61
* Corresponding author: Department of Biophysics and Biochemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden. E-mail address: [email protected].
Introduction and objectives: The clostridial neurotoxin family is composed of the tetanus (TeNT) and botulinum neurotoxins (BoNT), which cause the diseases tetanus and botulism, respectively. These extremely potent toxins recognize motor and periphery neurons with high affinity and specificity, resulting in inhibition of neurotransmission, thereby causing paralysis. Our aim is to determine the mechanism of binding of the clostridial neurotoxins to their receptors using biophysical methods, in particular, x-ray crystallography. Understanding these complex interactions should help in the development of vaccines and antitoxin therapies as well as in the engineering of novel biopharmaceuticals. Methods: X-ray crystallography; Isothermal titration calorimetry (ITC). Results: The crystal structures of the binding domain of BoNT/A and TeNT were solved in complex with ganglioside polysaccharides, providing the molecular details of receptor recognition. Binding affinities measured by ITC were shown to be much weaker than expected for these soluble carbohydrates. Conclusions: We propose that the glycan part of the ganglioside receptors mainly provides abundance and specificity, whereas the interaction with the membrane itself and protein receptor brings about the strong total binding of the toxin to the neuronal membrane. Keywords: BoNT; Gangliosides; Receptor binding; TeNT 162. REAL-WORLD TREATMENT UTILIZATION AND ONABOTULINUMTOXINA FOR CHRONIC MIGRAINE OBSERVATIONAL STUDY IN THE EUROPEAN UNION
SAFETY OF FROM AN
Manjit Matharu a,*, Julio Pascual b, Ingela Nilsson Remahl c, Andreas Straube d, Arlene Lum e, Gudarz Davar e, Dawn Odom f, Lee Christina Proctor f, Lia Gutierrez g, Elizabeth Bennett f, h i Andrews , Catherine Johannes . a Headache Group, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; b Department of Neurology, University Hospital Marqu es de Valdecilla, Santander, Spain; c Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden; d Department of Neurology, Klinikum Grosshadern, Munich, Germany; e Clinical Development, Allergan plc, Irvine, CA, USA; f Biostatistics, RTI Health Solutions, Research Triangle Park, NC, USA; g Pharmacoepidemiology and Risk Management, RTI Health Solutions, Barcelona, Spain; h Epidemiology, RTI Health Solutions, Research Triangle Park, NC, USA; i Pharmacoepidemiology and Risk Management, RTI Health Solutions, Waltham, MA, USA * Corresponding author: Queen Square, London WC1N 3BG, UK. E-mail address: [email protected].
Fig. 1. Cartoon representation of the 2 Å resolution crystal structure of C botulinum RNR b subunit dimer.
161. STRUCTURAL STUDIES OF CLOSTRIDIAL NEUROTOXINS BINDING TO GANGLIOSIDE RECEPTORS €ran Widmalm b, Pål Geoffrey Masuyer a, Ronnie P.-A. Berntsson a, Go a, * Stenmark . a Department of Biophysics and Biochemistry, Arrhenius Laboratory, Stockholm University, Sweden; b Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Sweden
Introduction and objectives: We examine real-world treatment utilization patterns and safety of onabotulinumtoxinA for the prophylactic treatment of chronic migraine (CM) in routine clinical practice. Methods: This was a prospective, observational, postauthorization study in adult patients with CM treated with onabotulinumtoxinA (NCT01432379). Data were collected at the first study injection and approximately every 3 months for 52 weeks for utilization or 64 weeks for safety data. Data are summarized using descriptive statistics. Results: Eighty-five physicians (81% neurologists) were recruited at 58 practices in the United Kingdom, Germany, Spain, and Sweden. A total of 1160 patients were enrolled (average age, 46.6 years [range¼19-79]; 84.2% female; 97.8% Caucasian); 85.8% had a diagnostic history of CM/transformed migraine. At baseline, patients reported an average 7.7 (standard deviation [SD]¼6.9) headache-free days per usual month, and 50.6% had used onabotulinumtoxinA for CM in the past. A total of 4017 study treatments were observed. The median number of injection sites (n¼31) and total dose (155 U) were consistent across all treatment sessions, with a median 13.7 weeks reported between sessions. Most patients (74.4%) indicated they were satisfied/extremely satisfied with onabotulinumtoxinA treatment for CM. At least one treatment-related adverse event (AE) was reported by 291 patients (25.1%); most frequently reported was neck