Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amongst all regions of the body, the craniocervical region is the one most frequently affected by dystonia. Whilst blepharospasm--involuntary bilateral eye closure--is produced by spasmodic contractions of the orbicularis oculi muscles, oromandibular dystonia may cause jaw closure with trismus and bruxism, or involuntary jaw opening or deviation, interfering with speaking and chewing. Both forms of dystonia can be effectively treated with botulinum toxin injection. This article summarizes injection techniques in both forms of dystonia and compares doses, potency and efficacy of different commercially available toxins, including Botox, Dysport, Xeomin and Myobloc/NeuroBloc.
 ...
PMID:Botulinum toxin in blepharospasm and oromandibular dystonia: comparing different botulinum toxin preparations. 1641 94

The mouse protection assay (MPA), which is an in vivo assay, is currently the most widely used method for monitoring blocking antibodies (Abs) in botulinum neurotoxin (BoNT)-treated patients. In recent studies we found that a number of the regions on the heavy (H) subunit of BoNT/A that bind blocking mouse Abs coincided, or overlapped, with the regions that bind to mouse synaptosomes (snps). This suggested that blocking anti-BoNT/A Abs would be expected to inhibit BoNT/A binding to snps. In the present work, we analyzed sera from 58 cervical dystonia (CD) patients who had been treated with BOTOX (a preparation of BoNT/A serotype) for blocking Abs by MPA and by their abilities to inhibit in vitro the binding of 125I-labeled active BoNT/A or inactive toxin (toxoid) to mouse brain snps. With active 125I-labeled BoNT/A-snps binding, the MPA-positive sera (n = 30) displayed inhibition levels that were distinctly higher (mean = 21.1 +/- 5.8) than those obtained with MPA-negative sera (n = 28) (mean = -1.3 +/- 3.9; p < 0.0001) or control sera (n = 19) (mean = -3.4 +/- 2.8; p < 0.0001). Similarly, inhibition levels by MPA-positive sera of 125I-labeled toxoid snp-binding (mean = 48.6 +/- 8.7) were distinctly higher than inhibition by MPA-negative sera (mean=10.0+/-7.6; p < 0.0001) or control sera (mean = 1.8 +/- 6.9; p < 0.0001). Thus, using labeled active toxin or toxoid, the inhibition assay correlated very well with the MPA. The inhibitory activity of the non-protective sera generally correlated with the duration of survival after toxin challenge (correlation coefficients of inhibition: active toxin = 0.445; p = 0.0167; inactive toxoid = 0.774; p < 0.0001). It is concluded that the snp-inhibition assay reported here is reliable, reproducible and correlates very well with the MPA. It requires much less serum (0.75% of the amount needed for the MPA) and is considerably less costly than the MPA. With either 125I-labeled active toxin or toxoid, it is possible to distinguish CD sera that have blocking Abs from those that lack such Abs. Since the results with the toxoid were as discriminating as those of the active toxin, it would not even be necessary to use active toxin in these assays.
 ...
PMID:Inhibition by human sera of botulinum neurotoxin-A binding to synaptosomes: a new assay for blocking and non-blocking antibodies. 1646 5

The purpose of this work was to map the entire recognition profile of the H chain of botulinum neurotoxin A (BoNT/A) by Abs in sera that have protective anti-BoNT/A Abs by the mouse protection assay (MPA) from cervical dystonia (CD) patients who had been treated with botulinum neurotoxin, serotype A (BOTOX). In previous studies we found that human anti-tetanus neurotoxin (TeNT) Abs cross-react with BoNT/A and BoNT/B. In the present work we devised an assay procedure for measuring specific anti-BoNT/A Abs in human sera by absorbing out or inhibiting the anti-TeNT Abs with TeNT before analyzing the sera for the anti-BoNT/A Abs. The sera were obtained from 28 CD patients who had become unresponsive to treatment with BoNT/A and the sera were found to protect mice against a lethal dose of BoNT/A. For localization of the Ab-binding regions on the H chain we employed a set of sixty, 19-residue synthetic peptides (except for peptide C31 which was 22 residues) that encompassed the entire H chain sequence 449-1296 and overlapped consecutively by five residues. The pattern of Ab recognition varied from patient to patient, but a very limited set of peptides were recognized by most of the patients. These were, in decreasing amounts of Ab binding, peptide N25 (H chain residues 785-803), C9/C10 (967-985/981-999), C31 (1275-1296), C15 (1051-1069), C20 (1121-1139), N16 (659-677), N22 (743-761), and N4 (491-509). But not every serum recognized all these peptides. The finding that the binding profile was not the same for all the patients is consistent with previous observations that immune responses to protein antigens are under genetic control and that the response to each epitope within a protein is under separate genetic control. Except for the region within C9/C10, the other regions either coincided (N16 and C31), or overlapped (N4, N22, N25, C15 and C20), with the recently mapped synaptosomes (snps)-binding regions on the H chain. The molecular and clinical implications of these findings are discussed.
 ...
PMID:Mapping of the regions on the heavy chain of botulinum neurotoxin A (BoNT/A) recognized by antibodies of cervical dystonia patients with immunoresistance to BoNT/A. 1664 21

Cervical dystonia (CD) is the most common form of focal dystonia treated with botulinum toxin (BoNT) injections. BoNT has been shown in numerous clinical trials to correct the abnormal posture and movement and to markedly reduce pain associated with CD. In addition, BoNT has favorably modified the natural history of the disease by preventing contractures and other complications of CD, such as secondary degenerative changes of the cervical spine and associated radiculopathy. In a long-term follow-up of patients treated for up to 20 years, the duration of response appears to be sustained and the risk of immunoresistance due to blocking antibodies is relatively small. This review provides and update on the treatment of CD with BoNT type A (BOTOX, Dysport, Xeomin and BoNT type B (Myobloc, NeuroBloc.
 ...
PMID:Botulinum toxin therapy for cervical dystonia. 1678 12

Seven children between 2 and 15 years of age with cerebral palsy and upper extremity dystonia were enrolled in an open-label, dose-escalation pilot clinical trial of botulinum toxin type B (Myobloc), injected into the biceps and brachioradialis muscles of I or both arms. The primary outcome measure was the change in maximum speed of hand movement during attempted forward reaching. Escalating doses of 12.5, 25, and 50 U/kg per muscle were injected at each of 3 visits. Reaching speed improved in response to injection, and dystonia scores on the Burke-Fahn-Marsden dystonia scale, the Unified Dystonia Rating Scale, and the Unified Parkinson's Disease Rating Scale improved. There was not a dose-related effect on efficacy. There were no serious adverse events. Two children reported transient weakness. These results support the use of botulinum toxin type B as a safe and effective treatment for upper extremity dystonia in children with cerebral palsy. Larger controlled trials are needed to confirm these results.
 ...
PMID:Botulinum toxin type B improves the speed of reaching in children with cerebral palsy and arm dystonia: an open-label, dose-escalation pilot study. 1760 20

In studies from this laboratory, we localized the regions on the H chain of botulinum neurotoxin A (BoNT/A) that are recognized by anti-BoNT/A antibodies (Abs) and block the activity of the toxin in vivo. These Abs were obtained from cervical dystonia patients who had been treated with BoNT/A and had become unresponsive to the treatment, as well as blocking Abs raised in mouse, horse, and chicken. We also localized the regions involved in BoNT/A binding to mouse brain synaptosomes (snp). Comparison of spatial proximities in the three-dimensional structure of the Ab-binding regions and the snp binding showed that except for one, the Ab-binding regions either coincide or overlap with the snp regions. It should be folly expected that protective Abs when bound to the toxin at sites that coincide or overlap with snp binding would prevent the toxin from binding to nerve synapse and therefore block toxin entry into the neuron. Thus, analysis of the locations of the Ab-binding and the snp-binding regions provides a molecular rationale for the ability of protecting Abs to block BoNT/A action in vivo.
 ...
PMID:Molecular bases of protective immune responses against botulinum neurotoxin A--how antitoxin antibodies block its action. 1819 12

We studied patients with cervical dystonia (CD) to determine clinical features and response to botulinum toxin A (BoNT/A). Patients were submitted to clinical, laboratory and neuroimaging evaluation. BoNT/A was injected locally in 81 patients using electromyographic guidance. Four patients who had had previous treatment were considered to be in remission. The average ages at onset of focal dystonia and segmental dystonia were greater than for generalized dystonia (p<0.0003). The severity of the abnormal head-neck movements were more severe among the patients with generalized dystonia (p<0.001). Pain in the cervical area was noted in 59 patients. It was not possible to determine the etiology of the disease in 62.3% of patients. Tardive dystonia was the most common secondary etiology. A major improvement in the motor symptoms of CD and pain was observed in patients following treatment with BoNT/A. The tardive dystonia subgroup did not respond to the treatment. Dysphagia was observed in 2.35% of the patients.
 ...
PMID:Cervical dystonia: clinical and therapeutic features in 85 patients. 1839 7

We determined the entire profile of the continuous antigenic regions recognized by blocking antibodies (Abs) in sera from 30BoNT/B-treated cervical dystonia (CD) patients who developed unresponsiveness to treatment. The sera protected mice against a lethal dose of BoNT/B. We analyzed Ab binding to a panel of 60 synthetic 19-residue peptides (peptide C31 was 24 residues) that overlapped consecutively by 5 residues and encompassed the entire BoNT/B heavy (H) chain (residues 442-1291). Most Abs recognized a limited set of peptides but the pattern and Ab levels bound varied with the patient, consistent with genetic control of immune responses and with responses to each epitope being separately controlled. Abs were bound by peptides (in decreasing order): C1 (residues 848-866), C10 (974-992), C16 (1058-1076), C14 (1030-1048), N15 (638-656), N21/N22 (722-740/736-754), N24/N25 (764-782/778-796) and N29 (834-852). Peptides N3/N4 (470-488/484-502), N27 (806-824), C2 (862-880), C4 (890-908), C6/C7 (918-936/932-950), C17 (1072-1090), C24 (1170-1188), C29 (1240-1258) and C31 (1268-1291) exhibited low Ab binding. The remaining peptides bound little or no Abs. Of the 30 antisera, 28 (93.3%) had Abs that bound to peptides C1, C10, C14 or C16, and 27 (90.0%) bound to peptide N22. No peptide was recognized by all the antisera, but peptide combinations N24+C1, N22+N24+C1, N24+C1+C10, C10+C14+C16, N22+N24+C1+C10, C1+C10+C14+C16 or N22+N24+C1+C10+C14 bound blocking Abs in 30 (100%) antisera. BoNT/B-treated CD patients had higher Ab levels and bound to more epitopes (at least 11) than did BoNT/A-treated patients (5 regions). The regions recognized by anti-BoNT/B Abs occupied surface areas that displayed no correlation to surface electrostatic potential, hydrophilicity, hydrophobicity, or temperature factor. These regions afford candidates for epitope-specific manipulation of anti-toxin immune responses.
 ...
PMID:Molecular recognition of botulinum neurotoxin B heavy chain by human antibodies from cervical dystonia patients that develop immunoresistance to toxin treatment. 1867 21

We localized the BoNT regions that bind blocking Abs from 28 BoNT/A- and 30 BoNT/B-treated dystonia patients who became unresponsive to, and whose sera protected mice against LD100 of, the correlate BoNT. We analyzed Ab binding to BoNT/A- and BoNT/B-peptide panels, each of which consisted of 60, 19-residue peptides that overlapped consecutively by 5 residues and covered the entire H chain of the correlate toxin. Abs bound to a limited set of peptides but levels varied with patient, consistent with responses to each epitope being under separate MHC control. BoNT/B-treated patients had higher anti-toxin Ab levels and bound more H regions (at least 11) than BoNT/A-treated patients (5 regions). The epitopes were on surface areas that did not correlate with surface electrostatic potential, hydrophilicity, hydrophobicity, or temperature factor. Some epitopes within the two toxins display substantial homology and occupy equivalent 3-D locations, occasionally showing a small shift relative to one another, consistent with recognition adjustments accommodating structural differences between the two BoNTs. Blocking Abs bound to BoNT/A at sites that coincided or overlapped with those involved in synaptosome-binding, thus preventing its binding and blocking its entry into the neuron. On BoNT/B, Ab-binding regions overlapped with the sites that bind to mouse and rat synaptotagmin II or to ganglioside, thereby explaining Ab blocking of BoNT/B action.
 ...
PMID:Immune recognition of BoNTs A and B: how anti-toxin antibodies that bind to the heavy chain obstruct toxin action. 1928

Botulinum toxin has dramatically improved the treatment of cervical dystonia. Prior to the use of botulinum toxin for many neurologic disorders, patients had few effective therapeutic options. Botulinum toxin type B (Myobloc, NeuroBloc) is a new antigenically distinct botulinum toxin with a unique structure and mechanism of action. Preclinical studies have demonstrated that im. injections of botulinum toxin type B effectively induce a dose-dependent paralysis. Controlled clinical trials have shown that it is safe and effective in alleviating symptoms associated with cervical dystonia. Given its efficacy and safety profile, the clinical use of type B toxin is anticipated to expand into other therapeutic areas.
 ...
PMID:Botulinum toxin type B (Myobloc, NeuroBloc): a new choice in cervical dystonia. 1981 Oct 26


<< Previous 1 2 3 4 5 6 7 8 Next >>