Concept: Botulinum toxin
Botulinum neurotoxins (BoNTs), etiological agents of the life threatening neuroparalytic disease botulism, are the most toxic substances currently known. The potential for the use as bioweapon makes the development of small-molecule inhibitor against these deadly toxins is a top priority. Currently, there are no approved pharmacological treatments for BoNT intoxication. Although an effective vaccine/immunotherapy is available for immuno-prophylaxis but this cannot reverse the effects of toxin inside neurons. A small-molecule pharmacological intervention, especially one that would be effective against the light chain protease, would be highly desirable. Similarity search was carried out from ChemBridge and NSC libraries to the hit (7-(phenyl(8-quinolinylamino)methyl)-8-quinolinol; NSC 84096) to mine its analogs. Several hits obtained were screened for in silico inhibition using AutoDock 4.1 and 19 new molecules selected based on binding energy and Ki. Among these, eleven quinolinol derivatives potently inhibited in vitro endopeptidase activity of botulinum neurotoxin type A light chain (rBoNT/A-LC) on synaptosomes isolated from rat brain which simulate the in vivo system. Five of these inhibitor molecules exhibited IC(50) values ranging from 3.0 nM to 10.0 µM. NSC 84087 is the most potent inhibitor reported so far, found to be a promising lead for therapeutic development, as it exhibits no toxicity, and is able to protect animals from pre and post challenge of botulinum neurotoxin type A (BoNT/A).
Recent reports suggest that botulinum neurotoxin (BoNT) A, which is widely used clinically to inhibit neurotransmission, can spread within networks of neurons to have distal effects, but this remains controversial. Moreover, it is not known whether other members of this toxin family are transferred between neurons. Here, we investigate the potential distal effects of BoNT/A, BoNT/D, and tetanus toxin (TeNT), using central neurons grown in microfluidic devices. Toxins acted upon the neurons that mediated initial entry, but all three toxins were also taken up, via an alternative pathway, into non-acidified organelles that mediated retrograde transport to the somato-dendritic compartment. Toxins were then released into the media, where they entered and exerted their effects upon upstream neurons. These findings directly demonstrate that these agents undergo transcytosis and interneuronal transfer in an active form, resulting in long-distance effects.
OBJECTIVES:: Cumulative evidence support a beneficial effect of botulinum toxin A (BTX-A) in postherpetic neuralgia (PHN). We aimed to assess efficacy, safety, and tolerability of BTX-A in the management of PHN, performing a randomized, double-blind, single-dose, placebo-controlled trial. METHODS:: Thirty adults with PHN were randomized either to BTX-A or placebo. Severity of pain was evaluated by patients using a visual analogue scale (VAS) and quality of sleep was assessed using a 5-item questionnaire. Primary outcome was reduction in VAS score, with a greater than 50% reduction being considered clinically significant. Secondary outcomes were reduction in sleep score and maintenance of VAS score after treatment, with over 50% maintenance considered clinically meaningful. RESULTS:: Thirteen patients from the experimental arm achieved an at least 50% reduction in VAS score, compared with none of the placebo patients (NNT=1.2, 95% CI, 2-1; ARR=0.87, 95% CI, 055-096; P<0.001). BTX-A patients showed significant reduction in VAS pain scores between baseline and week 2, which persisted for a median period of 16 weeks. BTX-A patients showed significant reduction in sleep scores between baseline and week 2, which remained unchanged until 16th week (P<0.001). Treatment was well tolerated. DISCUSSION:: Data confirm that BTX-A is effective and well tolerated in the treatment of PHN.
Clostridium botulinum neurotoxin (BoNT) is a multidomain protein in which the individual modules work in synchronized cooperative action in order to enter into neurons and inhibit synaptic transmission. The di-chain protein is made up of the ~50 kD light chain and the ~100 kD heavy chain. The HC can be further subdivided into the N-terminal translocation domain (H(N)) and the C-terminal Receptor Binding Domain (H©). BoNT entry into neurons requires the toxin to utilize the host cell’s endocytosis pathway where it exploits the acidic environment of the endosome. Within the endosome the H© triggers the H(N) to change conformation from a soluble protein to a membrane inserted protein-conducting channel in precise timing with LC refolding. The LC must partially unfold to a translocation competent conformation in order to be translocated by the H(N) channel in an N to C terminal direction. Upon completion of translocation, the LC is released from the HC and allowed to interact with its substrate SNARE protein. This article discusses the individual functions of each module as well as the mechanisms by which each domain serves as a chaperone for the others, working in concert to achieve productive intoxication.
Efficacy of carbamazepine combined with botulinum toxin a in the treatment of blepharospasm and hemifacial spasm
- Yan ke xue bao = Eye science / "Yan ke xue bao" bian ji bu
- Published about 5 years ago
To observe the efficacy of the combined treatment of carbamazepine and botulinum toxin A for blepharospasm and hemifacial spasm.
National Outbreak of Type A Foodborne Botulism Associated with a Widely Distributed Commercially Canned Hot Dog Chili Sauce.
- Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
- Published about 5 years ago
Background. On July 7 and 11, 2007, respectively, health officials in Texas and Indiana reported 4 possible cases of type A foodborne botulism to the US Centers for Disease Control and Prevention. Foodborne botulism is a rare and sometimes fatal illness caused by consuming foods containing botulinum neurotoxin.Methods. Investigators reviewed patients' medical charts and food histories. Clinical specimens and food samples were tested for botulinum toxin and neurotoxin-producing Clostridium spp. Investigators conducted inspections of the cannery that produced the implicated product.Results. Eight confirmed outbreak associated cases were identified from Indiana (2), Texas (3), and Ohio (3). Botulinum toxin type A was identified in leftover chili sauce consumed by the Indiana patients and one of the Ohio patients. Cannery inspectors found violations of federal canned-food regulations that could have led to survival of C. botulinum spores during sterilization. The company recalled 39 million cans of chili. Following the outbreak, the US Food and Drug Administration inspected other canneries with similar canning systems and issued warnings to the industry about the danger of C. botulinum and the importance of compliance with canned food manufacturing regulations.Conclusion. Commercially produced hot dog chili sauce caused these cases of type A botulism. This is the first US foodborne botulism outbreak involving a commercial cannery in more than 30 years. Sharing of epidemiologic and laboratory findings allowed for the rapid identification of implicated food items and swift removal of potentially deadly products from the market by US food regulatory authorities.
Abstract Purpose: To compare the effects of botulinum toxin injection with and without needle electromyographic guidance for the treatment of spasticity. Method: A randomized controlled study was conducted in a tertiary university hospital. Twenty-seven adult hemiplegic patients with spasticity due to brain or spinal cord damage were included. Spastic muscles were injected with botulinum toxin with or without EMG guidance. The modified Ashworth scale and modified Barthel index in each patient pre- and post-injection were documented. Results: In group A, which consisted of 15 patients (55.55%), the injection was administered with needle electromyographic guidance, while in 12 patients (44.44%) of group B without electromyographic guidance with the use of anatomic landmarks only. The follow-up period was 3 months. At 3 weeks post-injection, spasticity was decreased (p < 0.05) in all patients and the mean (SD) reduction of spasticity was higher (p < 0.05) in group A (1.67 (0.5)) than group B (1.25 (0.46)). Similarly, the mean (SD) functional modified Barthel index improved statistically significantly (p < 0.001) post-injection (45.37 (8.43)) than pre-injection (54.07 (9.610), especially in group A (p < 0.05). Conclusion: The effectiveness of intramuscular botulinum toxin injection for the treatment of spasticity in hemiplegic patients is superior when performed with needle electromyographic guidance than without electromyography. Implications for Rehabilitation It is recommended that botulinum toxin muscle injections of hemiplegic limbs be performed with EMG guidance More spasticity reduction and functional improvement at 3 months post-injection was observed in patients injected with botulinum toxin by the use of combined EMG guidance and anatomic landmarks EMG guidance might also save amount of botulinum toxin due to less spasticity observed during injection than when injection is performed with anatomic landmarks only.
- Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
- Published over 4 years ago
Painful legs moving toes (PLMT) is a rare disorder characterized by an often-severe painful sensation in the legs associated with involuntary movement of the toes. The treatment can be challenging given the poor response to pharmacotherapy. We present a patient with PLMT who obtained substantial benefit in both pain and severity of involuntary movement with botulinum toxin type A injections for more than 3years.
BACKGROUND: Use of Botulinum toxin type A (BTX-A) for facial wrinkles is well-documented, but current methods of subjective evaluation by clinicians and patients fail to objectively quantify the magnitude and duration of facial muscle paralysis. OBJECTIVE: (a) Determine the locus of facial muscular tension; (b) Quantify and monitor muscular paralysis and subsequent return; © Continuously correlate the appearance of wrinkles and muscular tension using non-invasive digital image speckle correlation (DISC) to measure treatment efficacy; (d) Corroborate objective data with existing rating scales (subject global assessment and facial lines outcome-11). METHODS: Two sequential images of slight facial motion (frowning, raising eyebrows) are taken with a camera for n = 6 patients pre- and post-treatment at different time points up to 24 weeks. DISC processes the images to produce a vector map of muscular displacement to obtain spatially resolved information regarding facial tension. RESULTS: We observed maximum paralysis (≥70%) at 2 weeks, and the rate of recovery varied widely ranging from 2 to 5 months, with two patients continuing to exhibit reduced contraction at 24 weeks. Vector analysis of pre-treatment contraction correctly predicted injection site and illustrated lines of maximum tension. CONCLUSIONS: Digital image speckle correlation can precisely track the degree of contraction of different muscle groups following BTX-A injection. It can help predict injection site, quantify muscle paralysis, and monitor the recovery following BTX-A injection. Results were found to be reproducible across six patients.
INTRODUCTION: Anal fissures can be resistant to treatment and some patients may undergo several trials of medical therapy before definitive surgery.. It would be useful to identify predictors of poor response to medical therapy.. This study assesses the role of anorectal physiological criteria to identify patients with anal fissure predicted to fail Botulinum toxin (BT) treatment METHOD: A retrospective analysis of anorectal physiological data collected for patients with resistant chronic anal fissures referred to one consultant surgeon between 2007-2011 was undertaken. These were correlated with treatment plans and healing rates. RESULTS: Twenty-five patients with idiopathic chronic anal fissures underwent anorectal physiology studies and were subsequently treated with BT injection. Eleven had a characteristic high-frequency low-amplitude ‘saw tooth’ waveform or Anal Sphincter Fibrillation (ASF) and higher anal sphincter pressures. Nine of these patients (82%) had resolution of their anal fissure symptoms following treatment with BT. Of 14 patients with no evidence of ASF and a greater range of anal sphincter pressures, only 1 (7%) had resolution following BT.. CONCLUSION: ASF appears to be an anorectal physiological criterion that helps predict response of anal fissures to BT injection. This could help streamline fissure management. © 2013 The Authors. Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.