Onset dynamics of type A botulinum neurotoxin-induced paralysis

Experimental studies have demonstrated that botulinum neurotoxin serotype A (BoNT/A) causes flaccid paralysis by a multi-step mechanism. Following its binding to specific receptors at peripheral cholinergic nerve endings, BoNT/A is internalized by receptor-mediated endocytosis. Subsequently its zinc-dependent catalytic domain translocates into the neuroplasm where it cleaves a vesicle-docking protein, SNAP-25, to block neurally evoked cholinergic neurotransmission. We tested the hypothesis that mathematical models having a minimal number of reactions and reactants can simulate published data concerning the onset of paralysis of skeletal muscles induced by BoNT/A at the isolated rat neuromuscular junction (NMJ) and in other systems. Experimental data from several laboratories were simulated with two different models that were represented by sets of coupled, first-order differential equations. In this study, the 3-step sequential model developed by Simpson (J Pharmacol Exp Ther 212:16–21,1980) was used to estimate upper limits of the times during which anti-toxins and other impermeable inhibitors of BoNT/A can exert an effect. The experimentally determined binding reaction rate was verified to be consistent with published estimates for the rate constants for BoNT/A binding to and dissociating from its receptors. Because this 3-step model was not designed to reproduce temporal changes in paralysis with different toxin concentrations, a new BoNT/A species and rate (kS) were added at the beginning of the reaction sequence to create a 4-step scheme. This unbound initial species is transformed at a rate determined by kS to a free species that is capable of binding. By systematically adjusting the values of kS, the 4-step model simulated the rapid decline in NMJ function (kS ≥0.01), the less rapid onset of paralysis in mice following i.m. injections (kS = 0.001), and the slow onset of the therapeutic effects of BoNT/A (kS < 0.001) in man. This minimal modeling approach was not only verified by simulating experimental results, it helped to quantitatively define the time available for an inhibitor to have some effect (tinhib) and the relation between this time and the rate of paralysis onset. The 4-step model predicted that as the rate of paralysis becomes slower, the estimated upper limits of (tinhib) for impermeable inhibitors become longer. More generally, this modeling approach may be useful in studying the kinetics of other toxins or viruses that invade host cells by similar mechanisms, e.g., receptor-mediated endocytosis

Long-term quality of life in cervical dystonia after treatment with abobotulinum toxin A: a 2-year prospective study

Subsai Kongsaengdao,1,2 Narong Maneeton,3 Benchalak Maneeton3 1Division of Neurology, Department of Medicine, Rajavithi Hospital, Department of Medical Services, Public Health Ministry, Bangkok, Thailand; 2Department of Medicine, College of Medicine, Rangsit University, Bangkok, Thailand; 3Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand Background: The short-term quality of life (QoL) in cervical dystonia (CD) after treating with abobotulinum toxin A (Abo-BTX A) and neubotulinum toxin A (Neu-BTX A) have been studied in Thai CD patients.However; the long-term study has not been published. Objective: The aim of the present study was to determine long-term improvement of the health-related quality of life (HRQoL) after eight injections of Abo-BTX A over 2 years in CD patients. Patients and methods: A 2-year prospective study on the QoL of CD patients, as measured by HRQoL, before and after receiving eight injections of Abo-BTX A at 3-month intervals over a 2-year treatment period was performed. The disease-specific HRQoL was assessed before and after the treatment by using the Cervical Dystonia Impact Profile-58 (CDIP-58) questionnaire. The general HRQoL was assessed by using the Medical Outcomes 36-Item Short Form Health Survey (SF-36), while depressive disorder screening was assessed by using the Center of Epidemiologic Studies-Depression (CES-D) questionnaire. The SF-36 and CES-D questionnaire were administered before treatment and every 3 months before the next injection for a 2-year period. Results: A total of 20 CD patients were enrolled from January 2013 to December 2015. CDIP-58 showed a significant improvement after long-term injections of Abo-BTX A in all domains (P &lt; 0.001). However, only vitality domain of SF-36, which assessed general HRQoL, showed a significant improvement after long-term injections (P&nbsp;= 0.037). There was no prevalence of depressive disorder in all patients (CES-D score &lt;20) in this study. Conclusion: The Abo-BTX A injections at 3-month intervals over a 2-year period improved the CDIP-58 scores, which assess disease-specific HRQoL, as well as an increased vitality domain of general HRQoL. No patient suffered from depression in this study. Keywords: cervical dystonia, abobotulinum toxin A, health-related quality of life, depressive disorder, 36-Item Short Form Health Survey, Cervical Dystonia Impact Profile-58 questionnair

Quality of life in cervical dystonia after treatment with botulinum toxin A: a 24-week prospective study

Subsai Kongsaengdao,1,2 Benchalak Maneeton,3 Narong Maneeton3 1Division of Neurology, Department of Medicine, Rajvithi Hospital, Department of Medical Services, Public Health Ministry, Bangkok, Thailand; 2Department of Medicine, College of Medicine, Rangsit University, Bangkok, Thailand; 3Department of Psychiatry, Faculty of Medicine, Chiang Mai University, Thailand Objective: This study aimed to identify possible improvements in disease-specific health-related quality of life (HRQoL) after multiple injections of botulinum toxin A over 24 weeks in Thai cervical dystonia (CD) patients.Materials and methods: A 24-week prospective study comparing HRQoL of Thai CD patients before and after multiple injections of botulinum toxin A at 3-month intervals was performed. Disease-specific HRQoL was assessed by using the Cervical Dystonia Impact Profile-58 questionnaire (CDIP-58) and the Craniocervical Dystonia Questionnaire-24 (CDQ-24). General HRQoL was assessed by using the Medical Outcomes&rsquo; 36-Item Short Form Health Survey (SF-36) and the EuroQoL 5-dimension questionnaire (EQ-5D). All the assessments were performed before and after the 24-week treatment period.Results: A total of 20 CD patients were enrolled in this study from April to December 2011. CDIP-58 and CDQ-24 scores, which assess disease-specific HRQoL, showed a significant improvement after 24 weeks of treatment by botulinum toxin A (P&lt;0.001). However, EQ-5D and SF-36 scores, which assess general HRQoL, showed no significant improvement after the treatment (P&gt;0.05).Conclusion: CD patients&rsquo; disease-specific HRQoL improved after being treated with multiple botulinum toxin A injections. However, general HRQoL was not improved. Keywords: cervical dystonia, botulinum toxin A, the health-related quality of life, 36-Item Short Form Health Survey, EuroQoL 5-dimension questionnaire, Cervical Dystonia Impact Profile-58 questionnaire, Craniocervical Dystonia Questionnaire-2