Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.69 (botulinum neurotoxin)
 1,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We assessed the severity and temporal profile of distant neuromuscular effects from a single dose (280 units) of botulinum neurotoxin injected into neck muscles for torticollis. We performed single-fiber EMG studies on the biceps brachii of six patients to measure jitter (20 pairs) and fiber density on the initial treatment day and then again, at least once more, after 2 to 12 weeks. No patient developed weakness beyond the neck muscles or decrement of the biceps response to repetitive 3-Hz nerve stimulation. Between the baseline and the last follow-up study, the average of mean MCD increased from 29 microseconds to 38 microseconds (31%). Mean fiber density increased concurrently or earlier from 1.35 to 1.79 (33%). There were no electrophysiologic signs of presynaptic blockade, even at 2 and 4 weeks. The effects we observed are compatible with stimulation of terminal sprouting by the neurotoxin, without significant presynaptic inhibition of acetylcholine release. We therefore believe that higher dosages of the neurotoxin may be used if clinically indicated.
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PMID:Neuromuscular effects distant from the site of botulinum neurotoxin injection. 284 80

Esotropia from chronic sixth nerve palsy or paresis usually requires surgery. Chemodenervation of the antagonist medial rectus muscle, while popular for the treatment of acute sixth nerve palsies and pareses, has not been used extensively for chronic cases. In this study, 22 patients with sixth nerve palsies or partially recovered palsies of greater than 5 months duration were treated with chemodenervation. The etiologies of the sixth nerve palsies were trauma (n = 7), tumor (n = 4), infection/inflammation (n = 3), nerve compression from aneurysm or increased intracranial pressure (n = 4), congenital (n = 1), ischemia (n = 2), and idiopathic (n = 1). The mean preinjection deviation was 41 prism diopters. A total of 38 injections were administered (mean, 1.7 per patient). Each patient received an injection of 2.5 to 7.5 units (mean, 4.1) of botulinum neurotoxin A to the ipsilateral medial rectus muscle. Treatment success was assessed 6 months after the last injection. A course of chemodenervation significantly improved the alignment of 9 of the 22 patients (41%). The mean postinjection deviation was 8 delta. Seven patients (32%) had single binocular vision in primary position restored. These patients had a mean horizontal binocular field of 70 degrees (range, 40 degrees to 100 degrees). Thirteen patients (59%) had only modest improvement and required surgery. The data suggest that injection of botulinum neurotoxin A is a useful treatment for some patients with chronic sixth nerve weakness. A course of chemodenervation therapy compares less favorably with transposition surgery with concomitant neurotoxin injection for the treatment of these difficult problems.
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PMID:The efficacy of botulinum neurotoxin A for the treatment of complete and partially recovered chronic sixth nerve palsy. 771 9

Botulism is a paralyzing disease caused by the toxin of Clostridium botulinum. The toxin produces skeletal muscle paralysis by producing a presynaptic blockade to the release of acetylcholine. Recent studies have pinpointed the site of action of the several types of botulinum neurotoxin at the nerve terminal. Since the discovery of the toxin about 100 years ago, five clinical forms of botulism have been described: 1) classic or foodborne botulism; 2) wound botulism; 3) infant botulism; 4) hidden botulism; 5) inadvertent botulism. A clinical pattern of descending weakness is characteristic of all five forms. Almost all human cases of botulism are caused by one of three serotypes (A, B, or E). Classic and wound botulism were the only two forms known until the last quarter of this century. Wound botulism was rare until the past decade. Now there are increasing numbers of cases of wound botulism in injecting drug users. Infant botulism, first described in 1976, is now the most frequently reported form. In infant botulism spores of Clostridium botulinum are ingested and germinate in the intestinal tract. Hidden botulism, the adult variant of infant botulism, occurs in adult patients who usually have an abnormality of the intestinal tract that allows colonization by Clostridium botulinum. Inadvertent botulism is the most recent form to be described. It occurs in patients who have been treated with injections of botulinum toxin for dystonic and other movement disorders. Laboratory proof of botulism is established with the detection of toxin in the patient's serum, stool, or wound. The detection of Clostridium botulinum bacteria in the stool or wound should also be considered evidence of clinical botulism. Electrophysiologic studies can provide presumptive of botulism in patients with the clinical signs of botulism. Electrophysiologic testing can be especially helpful when bioassay studies are negative. The most consistent electrophysiologic abnormality is a small evoked muscle action potential in response to a single supramaximal nerve stimulus in a clinically affected muscle. Posttetanic facilitation can be found in some affected muscles. Single-fiber EMG studies typically reveal increased jitter and blocking, which become less marked following activation. The major treatment for severe botulism is advance medical and nursing supportive care with special attention to respiratory status.
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PMID:Clinical spectrum of botulism. 958 23

Synaptosomal associated protein of 25 kDa (SNAP-25) is a cytoplasmic protein that participates in the docking and fusion of synaptic vesicles with the nerve terminal in preparation for neurotransmitter release. SNAP-25 is also a substrate for three of the seven serotypes of botulinum neurotoxin (BoNT). Intoxication by BoNT/A, /C1 or /E results in weakness and paralysis of skeletal muscle due to cleavage of SNAP-25 (and syntaxin la in the case /C1) at discrete serotype-specific sites. To elucidate the role of SNAP-25 in muscle function in more detail, contractility and neuromuscular transmission were studied in a mutant mouse model termed coloboma. The coloboma mutation results from a contiguous deletion of 1-2 centiMorgans on chromosome 2, which includes the entire SNAP-25 locus and three other identified genes. Homozygotes do not survive beyond gestation day 6; heterozygotes (Cm/+) have a normal life-span but express reduced levels of SNAP-25 mRNA and protein in the brain. The consequences of the Cm/+ mutation on twitch and tetanic tension, quantal release of neurotransmitter and spinal motoneuron expression of SNAP-25 were examined in the present study. Contrary to expectations, Cm/+ mice exhibited no alteration in twitch tension and generated normal tetanic tension even at the highest frequency examined (800 Hz). Microelectrode recordings revealed that MEPP amplitude and frequency were both within control limits. The ventral spinal cord of Cm/+ mice showed no deficiency in SNAP-25 content and immunohistochemical examination of nerve terminals in Cm/+ mice disclosed that SNAP-25 levels and distribution were similar to those of control mice. It is concluded that spinal motor neurons up-regulate SNAP-25 to preserve vital neuromuscular function.
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PMID:Neuromuscular transmission and muscle contractility in SNAP-25-deficient coloboma mice. 1182 11

Botulinum toxin type A (BoNT-A) produced by the bacterium Clostridium botulinum is a potent inhibitor of acetylcholine release in the neuromuscular junction and has been used to treat many disorders related to excessive muscle contraction. However, BoNT-A has recently been used in pain therapy to treat myofascial pain, low back pain and various types of headaches, including migraine. The purpose of this study is to investigate the antinociceptive effect of BoNT-A and its underlying mechanism in the rat formalin inflammatory pain model. BoNT-A (3.5, 7, 15 and 30 U/kg) or vehicle was administered to the plantar surface of the right hindpaw of male Sprague-Dawley rats. BoNT-A dose-dependently (P<0.05) inhibited formalin-induced nociceptive behavior during phase 2 but not during phase 1 when administered 5 h to 12 days before formalin challenge. The onset of the antinociceptive effect started at 5 h after pre-treatment and this effect lasted for at least 12 days. BoNT-A (7 U/kg) also reduced edema. Consistent with the lack of effect in the formalin phase 1, BoNT-A, at 15 U/kg, had no effect on acute thermal nociception; no local muscle weakness was observed at this dose. Pre-treatment of rats with BoNT-A (3.5, 7 or 15 U/kg) all significantly reduced formalin-evoked glutamate (Glu) release. These results demonstrate that local peripheral injection of BoNT-A significantly reduces formalin-induced nociceptive behaviors with the absence of obvious muscle weakness. Such an antinociceptive effect of BoNT-A is associated with the inhibition of formalin-induced release of Glu (and/or neuropeptides) from primary afferent terminals.
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PMID:Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. 1471 98

We report a case of botulism in a 54-hour-old infant with rapidly progressive fulminant paralysis and rapid spontaneous recovery atypical for infant botulism. Clostridium baratii and type F botulinum neurotoxin were isolated from the patient's stool. This unique presentation with rapid recovery is consistent with pharmacokinetics of type F botulinum neurotoxin. Interestingly, a muscle biopsy also revealed pathologic changes early in the disease course. This article reports the youngest known case of infant botulism and only the third reported case of this disease caused by type F neurotoxin. Botulism should be considered in patients of any age with subacute or acute neuromuscular weakness.
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PMID:Infant botulism, type F, presenting at 54 hours of life. 1573 Sep 1

Efficacy of botulinum toxin type B (BoNT B) for the treatment of type A-resistant (AR) and non-A-resistant (NAR) cervical dystonia (CD) has been demonstrated in several single injection studies. There is little data available on long-term therapy with repeated injection sessions and it is unknown if AR and NAR patients respond in a similar manner over time. To evaluate the long-term efficacy and safety of BoNT B in AR and NAR CD patients, we carried out a prospective, open-label study examining 10 repeated dosing sessions of BoNT B in 34 patients with CD (15 AR and 19 NAR). Dosing was started at 10,000 units and could be increased to 25,000. Assessments included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and a patient global assessment at each baseline (injection) and Week 4 (peak effect) visit. Change in TWSTRS total was the primary efficacy end point. Data was analyzed using repeated-measures analysis of variance. BoNT B therapy resulted in an overall significant improvement of CD (P<0.001) and improvement was seen in all 10 individual sessions (2.5 years). The magnitude of response decayed over time (P<0.001). There was no difference between AR and NAR patients with regard to dose, treatment effect, or decay in response. The AR group perceived (patient global) treatment as being less effective (P=0.047). Dry mouth frequency decreased with each session despite increasing doses whereas flu-like syndrome and weakness increased. BoNT B therapy provides long-term benefit for CD patients but the magnitude of response diminishes over time. The cause of this decay is probably multifactorial. AR and NAR CD patients respond in a similar fashion.
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PMID:Efficacy and safety of repeated doses of botulinum toxin type B in type A resistant and responsive cervical dystonia. 1595 34

In Switzerland, the incidence of equine botulism and acute pasture myodystrophy have remarkably increased in the last five years. Equine fodder-borne botulism in Europe is most likely caused by Clostridium botulinum types C and D that produce the toxins BoNT/C and BoNT/D. Horses showing signs suggestive of botulism (muscle weakness and tremors, reduced tongue tone, slow chewing, salivation and difficulties swallowing, drooping eyelids, mydriasis), especially patients that have fed on suspect fodder (mostly haylage), must be treated with anti-serum as soon as possible. They also need intensive care, which is often difficult to provide and always expensive in the face of a guarded to poor prognosis. Therefore, prevention (high standards of forage quality and vaccination) is all the more important. Pasture myodystrophy is an acute disease with signs of rhabdomyolysis and lethality rate over 90%. It affects grazing horses under frosty, windy and rainy conditions. Preliminary results indicate that Clostridium sordellii and Clostridium bifermentans producing lethal toxin may play a role in pasture myodystrophy. Our efforts concentrate on developing a new subunit vaccine for equine botulism and understanding the ethiology and pathogenesis of pasture myodystrophy with the goal of improving prevention against these highly fatal diseases that present a significant risk to our horse population.
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PMID:Equine botulism and acute pasture myodystrophy: new soil-borne emerging diseases in Switzerland? 1707 63

The seven serotypes (A-G) of botulinum neurotoxin (BoNT) are proteins produced by Clostridium botulinum and have multifunctional abilities: (i) they target cholinergic nerve endings via binding to ecto-acceptors (ii) they undergo endocytosis/translocation and (iii) their light chains act intraneuronally to block acetylcholine release. The fundamental process of quantal transmitter release occurs by Ca2+-regulated exocytosis involving sensitive factor attachment protein-25 (SNAP-25), syntaxin and synaptobrevin. Proteolytic cleavage by BoNT-A of nine amino acids from the C-terminal of SNAP-25 disables its function, causing prolonged muscle weakness. This unique combination of activities underlies the effectiveness of BoNT-A haemagglutinin complex in treating human conditions resulting from hyperactivity at peripheral cholinergic nerve endings. In vivo imaging and immunomicroscopy of murine muscles injected with type A toxin revealed that the extended duration of action results from the longevity of its protease, persistence of the cleaved SNAP-25 and a protracted time course for the remodelling of treated nerve-muscle synapses. In addition, an application in pain management has been indicated by the ability of BoNT to inhibit neuropeptide release from nociceptors, thereby blocking central and peripheral pain sensitization processes. The widespread cellular distribution of SNAP-25 and the diversity of the toxin's neuronal acceptors are being exploited for other therapeutic applications.
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PMID:The structure and mode of action of different botulinum toxins. 1711 44

Botulinum toxin type-A (BoNT-A) prevents the release of acetylcholine at cholinergic junctions, thereby causing temporary muscle weakness lasting 3-4 months. It is now widely used to treat a broad range of clinical disorders characterized by muscle hyperactivity. BoNT-A has proved effective in the management of several neurological conditions and, in particular, in the management of movement disorders (e.g. blepharospasm, cervical dystonia, laryngeal dystonia, limb dystonia, hemifacial spasm, focal tics, tremor and other hyperkinetic disorders). As a treatment of spasticity, BoNT-A can improve mobility and dexterity as well as preventing the development of distressing and costly secondary complications. In cerebral palsy, BoNT-A is of value, being able to delay or even avoid surgery until motion patterns have become established.
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PMID:Clinical value of botulinum toxin in neurological indications. 1711 46


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