Poster 108: Dissociation of the 900 kDa Neurotoxin Complex From <i>C. botulinum</i> Under Physiological Conditions

Eisele, Karl-Heinz; Taylor, Harold V.

doi:10.1016/j.pmrj.2010.07.139

Cited by 6 publications

(6 citation statements)

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“…This result is consistent with recent findings that the 150-kDa neurotoxin molecule is released from the 900-kDa complex in less than a minute when exposed to physiological pH values. 11 This time interval is markedly shorter than the time required by BoNT/A to perform the four steps required to block the nerve terminal, 22,24 which can be estimated in terms of hours. To this, one has to add the time required to observe the weakening of muscle contraction, which is estimated in days.…”

Section: Discussionmentioning

confidence: 98%

Assay of diffusion of different botulinum neurotoxin type a formulations injected in the mouse leg

2009

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Botulinum neurotoxin type-A (BoNT/A) is very effective in the therapy of a wide range of human syndromes characterized by hyperactivity of peripheral cholinergic nerve terminals. Little diffusion of this toxin from the site of injection is commonly observed, but even minor changes in this property would greatly affect the validity of the treatment. Different pharmacological formulations of BoNT/A are available, and they may have different diffusion characteristics due to protein complex size, product format, and pharmacological properties. Here we assessed the extent of diffusion of three commercial preparations of BoNT/A: Botox (Allergan), Dysport (Ipsen), and Xeomin (Merz Pharmaceuticals) using a novel and highly sensitive test based on neural cell adhesion molecule (N-CAM) expression in muscle. N-CAM is a membrane glycoprotein that accumulates on muscle fibers after denervation and is not expressed in untreated adult muscle. This allows fine monitoring of the functional diffusion of this toxin, and the sensitivity of this assay is emphasized by the use of the mouse model because of the small muscle dimensions. The results presented here indicate that there is no significant difference between Botox, Dysport, and Xeomin with respect to diffusion into adjacent muscles in the mouse leg.

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Section: Discussionmentioning

confidence: 98%

Assay of diffusion of different botulinum neurotoxin type a formulations injected in the mouse leg

2009

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“…Although CPs are increasing the size of the BT component considerably, clinical as well as pre‐clinical evidence suggests that CP‐containing and CP‐free BT drugs do not diffuse differently within the target tissues [12–14]. Reason for this is the rapid dissociation of the BT component into BNT and CPs immediately after injection, so that diffusion depends for both preparations upon the BNT size, which is identical in all products [15]. A recent study indicates that BNT–CP complexes may dissociate already within the therapeutic BT preparation itself [16].…”

Section: Pharmacologymentioning

confidence: 99%

Five‐year experience with incobotulinumtoxinA (Xeomin^®): the first botulinum toxin drug free of complexing proteins

Dressler

2011

Euro J of Neurology

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In 2005, incobotulinumtoxinA (Xeomin(®) ), a new botulinum toxin (BT) type A drug without complexing proteins (CPs), became available. This paper reviews the specific features of Xeomin(®) and the experience gathered with it during the last 5 years. Compared with conventional BT drugs, Xeomin(®) 's extended shelf live and its simplified temperature restrictions indicate that CPs are not necessary for BT drug stability. Its reduced molecular size does not translate into diffusion differences, and its potency labelling is identical to that of onabotulinumtoxinA (Botox(®) ). With a reduced content of inactivated botulinum neurotoxin, Xeomin(®) should have reduced antigenicity. Lack of CP's may further reduce antigenicity. Xeomin(®) 's therapeutic efficacy against cervical dystonia, blepharospasm and spasticity has been proven in large randomised, double-blind and placebo-controlled studies leading to registrations in many countries. Additional successful clinical use in axillary hyperhidrosis, hemifacial spasm, re-innervation synkinesias and hypersalivation as well as in dystonia and spasticity in extended doses and throughout extended observation periods has been documented meanwhile. Lack of reported cases of antibody-induced therapy failure (ABF), as to date, support the hypothesis of an improved antigenicity.

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“…These complexing proteins protect against the harsh conditions of the gastrointestinal tract, particularly the stomach, and stabilize the neurotoxin. The complex is only stable under acidic pH and readily dissociates under physiologic conditions [3] to liberate the pure neurotoxin, which is solely responsible for the therapeutic effect.…”

Section: Role Of Complexing Proteinsmentioning

confidence: 99%

Xeomin^®: an innovative new botulinum toxin type A

Frevert

2009

Euro J of Neurology

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Botulinum toxin type A (BoNT/A) is a well-established treatment for conditions characterized by muscle and autonomic nerve terminal overactivity, such as cervical dystonia and blepharospasm, and hyperhidrosis, respectively. BoNT/A is not digested in the gastrointestinal tract as it forms a complex with several proteins that protect and stabilize the neurotoxin. However, the pure neurotoxin is solely responsible for the therapeutic effect, and the complexing proteins have been shown to exhibit immunostimulating activity. The complexing proteins are not required for the stabilization of the neurotoxin in a formulation; the complexing proteins immediately dissociate from the neurotoxin at a physiologic pH, so they do not influence the spread of the neurotoxin. Xeomin is the only botulinum toxin that is free from complexing proteins and is stable at room temperature for a period of 4 years. When injected directly into muscles, Xeomin inhibits local neuromuscular cholinergic transmission, causing focal weakness. It binds to motor nerve terminal pre-synaptic receptors, is internalized via receptor-mediated endocytosis and then selectively cleaves a protein called SNAP-25. This is one of several so-called 'SNARE' proteins involved in exocytosis. Cleavage of SNAP-25 inhibits the secretion of acetylcholine causing the paralysis of the muscle. The clinical effects begin 24-72 h after injection, peak at approximately 4-6 weeks and are sustained for several months.

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Poster 108: Dissociation of the 900 kDa Neurotoxin Complex From C. botulinum Under Physiological Conditions

Cited by 6 publications

References 0 publications

Assay of diffusion of different botulinum neurotoxin type a formulations injected in the mouse leg

Assay of diffusion of different botulinum neurotoxin type a formulations injected in the mouse leg

Five‐year experience with incobotulinumtoxinA (Xeomin^®): the first botulinum toxin drug free of complexing proteins

Xeomin^®: an innovative new botulinum toxin type A

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Poster 108: Dissociation of the 900 kDa Neurotoxin Complex From C. botulinum Under Physiological Conditions

Cited by 6 publications

References 0 publications

Assay of diffusion of different botulinum neurotoxin type a formulations injected in the mouse leg

Assay of diffusion of different botulinum neurotoxin type a formulations injected in the mouse leg

Five‐year experience with incobotulinumtoxinA (Xeomin®): the first botulinum toxin drug free of complexing proteins

Xeomin®: an innovative new botulinum toxin type A

Contact Info

Product

Resources

About

Five‐year experience with incobotulinumtoxinA (Xeomin^®): the first botulinum toxin drug free of complexing proteins

Xeomin^®: an innovative new botulinum toxin type A