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Botulinum Toxin Type B and Dystonia Bibliography1: Semin Neurol 2001;21(1):85-90 Brashear A. The use of botulinum toxin to treat cervical dystonia (CD) has dramatically improved the quality of life of patients with this disabling, often painful disease. Two forms of toxins, botulinum toxin type A (BTX-A) and botulinum toxin type B (BTX-B), have each been studied in large multicenter trials in subjects with CD. A study of BTX-A demonstrated improvement of 5.15 to 10.65 degrees in head position using the Cervical Dystonia Severity Scale (CDSS) in those treated with BTX-A (trade name BOTOX) compared with placebo. A study in patients who continued to respond to BTX-A and a similarly designed study in patients who were resistant to BTX-A demonstrated statistical improvement in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) in those treated with BTX-B (evaluated as NeuroBloc) compared with placebo. The potential availability of both forms of toxin will allow physicians to offer further treatment options to patients with CD. PMID: 11346029 [PubMed - in process]
2: Am J Health Syst Pharm 2001 Feb 1;58(3):200, 202 Neurotoxins licensed as treatment for neck neuromuscular disorder. Publication Types: PMID: 11217174 [PubMed - indexed for MEDLINE]
3: Neurology 2000;55(12 Suppl 5):S29-35 Lew MF, Brashear A, Factor S. Cervical dystonia (CD) is characterized by abnormal, involuntary contractions of the cervical and/or shoulder muscles. Direct injection of Botulinum toxin type A (BTX-A) into the affected muscles has been used successfully to treat this condition. However, clinical resistance to BTX-A therapy develops in a limited number of patients. Moreover, an unknown proportion of treated patients have a suboptimal response to their present therapy. BTX-B is antigenically distinct from BTX-A and possesses a different mechanism of action. Three randomized, double-blind, placebo-controlled clinical trials evaluated the safety and efficacy of BTX-B (Elan's BTX-B evaluated as NeuroBloc) as a treatment for patients with CD. Patients received a single dose of BTX-B ranging from 2,500 to 10,000 U. The primary efficacy evaluation for each of these studies used the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score. Additional efficacy measures included the TWSTRS severity, disability, and pain subscale scores, as well as the Patient Analog Pain Assessment and Patient's and Physician's Global Assessments of Change. In all three studies, groups receiving BTX-B displayed statistically significant improvements in TWSTRS total score and other efficacy end points compared with those who received placebo treatment. The clinical benefits after BTX-B treatment lasted 12 to 16 weeks and were observed in both BTX-A-responsive and BTX-A-resistant patients. In general, treatment with BTX-B was well tolerated and most of the reported adverse events were of short duration, mild to moderate in severity, and anticipated. The results from the three controlled clinical trials demonstrate the safety and efficacy of BTX-B in the treatment of patients with CD, including those who are resistant to BTX-A treatment. Publication Types: PMID: 11188982 [PubMed - indexed for MEDLINE]
4: Neurology 2000;55(12 Suppl 5):S22-8 The biochemistry of botulinum toxin type B. Setler P. Elan Pharmaceuticals Corporation, South San Francisco, CA 94080, USA. Botulinum toxin type B (BTX-B) is a member of a family of neurotoxins produced by the anaerobic bacteria Clostridium botulinum. BTXs specifically inhibit acetylcholine release at the neuromuscular junction and cause muscle paralysis in humans. The mechanism of action of BTXs involves inactivation of the neural exocytotic pathway by proteolytic cleavage of components of the exocytotic apparatus. Purified BTXs have been used clinically to treat disorders of muscle contraction, such as spasticity and dystonia. BTXs are purified as high molecular weight complexes that contain additional bacterial proteins which function to protect the toxin molecule. BTX complexes are stable in solution only at acidic pH. A new method was developed to purify intact BTX-B complexes. The resulting liquid formulation of high specific activity BTX-B (Elan's BTX-B evaluated as NeuroBloc) is buffered at pH 5.6 and demonstrates long-term stability at 2 to 25 degrees C. PMID: 11188981 [PubMed - indexed for MEDLINE]
5: Eur J Neurol 2000 Nov;7(6):713-8 Dressler D. The success of botulinum toxin (BT) injections for treatment of cervical dystonia depends on precise identification of dystonic muscles and on quantification of their dystonic involvement. Conventionally, this is attempted by clinical examination analysing the dystonic head position. In this presentation, a more systematic approach is sought by using an electromyography (EMG)-based evaluation procedure. In 10 consecutive patients with cervical dystonia not previously exposed to BT clinical examination, analysing the dystonic head position was performed to classify patients into four groups with similar dystonic head positions. Additionally, a 2-channel concentric needle EMG was used to measure the amplitudes of dystonic and maximal voluntary activities in sternocleidomastoid (SCM), splenius capitis (SC) and trapezius/semispinalis capitis (T/SS) muscles bilaterally. The ratio between both amplitudes, the dystonia ratio, was used to quantify dystonic muscle involvement. In all patients dystonia ratios could be calculated. In patients with similar head positions, EMG evaluation revealed different qualitative and quantitative dystonic involvement patterns. In six patients, there were discrepancies in identification of dystonic muscles between clinical examination and EMG evaluation. EMG evaluation excluded dystonic involvement in five patients. All excluded muscles were SCM. In one of these patients, additional T/SS involvement was detected by EMG evaluation. In one patient, SC involvement was revealed by EMG evaluation. All dystonic muscle involvement detected by EMG evaluation represented genuine dystonic muscle coactivation rather than compensatory muscle activity. The EMG evaluation presented allows quantitative and qualitative identification of dystonic muscle involvement which cannot be achieved by clinical examination. Both pieces of information may be helpful for optimization of BT therapy. PMID: 11136361 [PubMed - indexed for MEDLINE]
6: Neurology 1999 Oct 22;53(7):1439-46 Brashear A, Lew MF, Dykstra DD, Comella CL, Factor SA, Rodnitzky RL, Trosch R, Singer C, Brin MF, Murray JJ, Wallace JD, Willmer-Hulme A, Koller M. OBJECTIVE: To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with cervical dystonia (CD). BACKGROUND: BoNT/B is a form of chemodenervation therapy for the treatment of patients with CD. METHODS: The authors performed a 16-week, randomized, multicenter, double-blind, placebo-controlled trial of BoNT/B in patients with CD who continue to respond to botulinum toxin type A. Placebo, or 5,000 U or 10,000 U of BoNT/B was administered in two to four muscles involved clinically in CD. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 was the primary efficacy measure. Clinical assessments and adverse events were recorded for treatment day 1 and at weeks 2, 4, 8, 12, and 16. RESULTS: A total of 109 patients were enrolled randomly across all three treatment groups. The mean improvement in the TWSTRS-Total scores in each group at week 4 was 4.3 (placebo), 9.3 (5,000 U), and 11.7 (10,000 U). For the prospectively defined primary contrast (10,000 U versus placebo), highly significant differences were noted for the primary (TWSTRS-Total, baseline to week 4, p = 0.0004) and supportive secondary (Patient Global Assessment, baseline to week 4, p = 0.0001) outcome measures. Improvement in pain, disability, and severity of CD occurred for patients who were treated with BoNT/B when compared with placebo-treated patients. Overall, improvements associated with BoNT/B treatment were greatest for patients who received the 10,000-U dose. The duration of treatment effect for BoNT/B was 12 to 16 weeks for both doses. CONCLUSION: Botulinum toxin type B (NeuroBloc) is safe and efficacious at 5,000 U and 10,000 U for the management of patients with cervical dystonia. Publication Types: PMID: 10534248 [PubMed - indexed for MEDLINE]
7: Neurology 1999 Oct 22;53(7):1431-8 Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia Brin MF, Lew MF, Adler CH, Comella CL, Factor SA, Jankovic J, O'Brien C, Murray JJ, Wallace JD, Willmer-Hulme A, Koller M. OBJECTIVE: To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with type A-resistant cervical dystonia (CD). Background: Local intramuscular injections of BoNT are an effective therapy for CD. After repeated use, some patients become resistant to therapy. BoNT/B, effective in type A toxin-responsive patients, is proposed as an alternative therapy for type A-resistant patients. METHODS: The authors performed a 16-week, double-blind, placebo-controlled trial of BoNT/B in type A-resistant patients with CD. After resistance to therapy was confirmed with the frontalis-type A test, placebo or 10,000 U BoNT/B was administered in a single session into two to four clinically involved muscles. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was the primary efficacy measurement. TWSTRS-Total, three visual analog scales (Patient Global Assessment of Change, Principal Investigator Global Assessment of Change, Patient Analog Pain Assessment), and adverse events were assessed at baseline and weeks 2, 4, 8, 12, and 16. RESULTS: A total of 77 patients participated (38 placebo, 39 active). Improvements in severity, disability, and pain were documented in the BoNT/B-treated group. TWSTRS-Total scores were improved in the BoNT/B-treated group at weeks 4 (p = 0.0001), 8 (p = 0.0002), and 12 (p = 0.0129). All three visual analog scales demonstrated improvements at week 4 (p < 0.0001, 0.0001, and 0.001). A Kaplan-Meier analysis supported a duration of effect of 12 to 16 weeks in the active group. Dry mouth and dysphagia were self-limited adverse effects, reported more commonly in the BoNT/B group. CONCLUSIONS: Botulinum toxin type B (BoNT/B) (NeuroBloc) is safe and efficacious for the management of patients with type A-resistant cervical dystonia with an estimated duration of treatment effect of 12 to 16 weeks. Publication Types: PMID: 10534247 [PubMed - indexed for MEDLINE]
8: Adv Neurol 1998;78:227-30 Cullis PA, O'Brien CF, Truong DD, Koller M, Villegas TP, Wallace JD. Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48093, USA. Publication Types: PMID: 9750919 [PubMed - indexed for MEDLINE]
9: Mov Disord 1997 Sep;12(5):772-5 Truong DD, Cullis PA, O'Brien CF, Koller M, Villegas TP, Wallace JD. Botulinum toxin (BTX) injection is considered the treatment of choice for patients with cervical dystonia (torticollis). We conducted a pilot, open-label, dose-escalation study with BTX type B in 12 patients who no longer responded clinically to injections with BTX type A. At the doses tested, BTX type B was safe and well tolerated without evidence of dose-limiting toxicity in this patient population. Mild-to-moderate adverse events generally resolved quickly and included asthenia, pain, nausea, dysphagia, hypertonia, and tremor. No serious adverse events or antibodies to type-B treatment were reported. Low-dosing-session (100-899 units) and high-dosing-session (900-1,500 units) groups were defined based on units administered per dosing session. Toronto Western Spasmodic Torticollis Rating Scale-Severity Scale (TWSTRS-Severity), Patient Analogue Pain Scale, and Physician and Patient Global Assessment Scales were measured during this study. The TWSTRS-Severity mean maximum percent improvement from baseline demonstrated a 9.9% versus 28.8% difference between the low-dose and high-dose groups, respectively. EFfectiveness was noted for the high-dose group on the Patient Analogue Pain Scale but not on the Global Assessment Scales. PMID: 9380065 [PubMed - indexed for MEDLINE]
10: Neurology 1997 Sep;49(3):701-7 Lew MF, Adornato BT, Duane DD, Dykstra DD, Factor SA, Massey JM, Brin MF, Jankovic J, Rodnitzky RL, Singer C, Swenson MR, Tarsy D, Murray JJ, Koller M, Wallace JD. We enrolled and treated 122 patients with idiopathic cervical dystonia in a double-blind, placebo-controlled safety and efficacy study of botulinum toxin type B (BotB). Both A-responsive and A-resistant patients were enrolled. Patients received intramuscular injections of either BotB (2,500 U, 5,000 U, or 10,000 U) or placebo. The primary outcome measure of efficacy was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at 4 weeks following study drug administration. Secondary measures of efficacy were TWSTRS-Severity, -Disability, and -Pain subscale scores, and Analog Pain Assessment, Investigator Global Assessment, Patient Global Assessment, and Sickness Impact Profile scores. Duration of effect was estimated with an intent-to-treat analysis of responders. Safety measures included clinical parameters, laboratory tests, and adverse events. The primary and most of the secondary analyses indicated a statistically significant treatment effect and a dose response. BotB is safe, well tolerated, and efficacious in the treatment of cervical dystonia at the doses tested. Publication Types: PMID: 9305326 [PubMed - indexed for MEDLINE]
11: Neurology 1997 Jul;49(1):189-94 Human response to botulinum toxin injection: type B compared with type A. Sloop RR, Cole BA, Escutin RO. Department of Neurology, Loma Linda University School of Medicine, CA 92354, USA. Despite the clinical potential of botulinum toxin type B (BTXB) for treating focal dystonia, hemifacial spasm, and other movement disorders, particularly in those resistant to botulinum toxin type A (BTXA), no objective human data exist to compare the muscle paralysis resulting from these two botulinum toxin subtypes. To objectively compare the human muscle paralysis resulting from intramuscular injections of BTXB with that from BTXA, we measured the extensor digitorum brevis (EDB) M wave amplitude four times before and six times after injection with 17 different doses of BTXB (from 1.25 to 480 units) in 17 healthy volunteers. This established a dose-response curve that we compared with the previously published BTXA dose-response curve. After the establishment of the dose-response curve, we injected 10 new volunteers with five different doses of BTXB and BTXA measuring EDB M wave amplitude 4 times before and 13 times over 57 weeks after injection. The volunteers were randomized by dose and received BTXA and BTXB in opposite EDB muscles. The effect of the toxin in all volunteers was expressed as percent decline in M wave amplitude postinjection (% paralysis). The maximal paralysis 2 weeks postinjection with 320 to 480 mouse units (MU) of BTXB was 50 to 75%, whereas maximal paralysis was 70 to 80% with 7.5 to 10 MU of BTXA. Postexercise M wave facilitation on day 9 postinjection averaged 63% for BTXB and 20% for BTXA. Seven weeks postinjection, BTXB-induced paralysis had improved by 66% with complete improvement by 11 weeks postinjection, whereas BTXA-induced paralysis had improved by only 6% at 7 weeks, and at 57 weeks postinjection 22% of the original muscle paralysis was still present. Thus, human muscle paralysis resulting from BTXB injection is not as complete or long-lasting as that resulting from BTXA. Publication Types: PMID: 9222189 [PubMed - indexed for MEDLINE]
12: Neurology 1995 Nov;45(11):2109-10 Tsui JK, Hayward M, Mak EK, Schulzer M. Publication Types: PMID: 7501169 [PubMed - indexed for MEDLINE]
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