Preparation Of Botulinum Toxin Type Research Articles

Dose selection of Incobotulinumtoxin A for the treatment of spasticity and sialorrhea in cerebral palsy: results of a retrospective multicenter study

Introduction. In patients with infantile cerebral palsy (CP), botulinum therapy is used to treat both muscle tone disorders and sialorrhea. Therefore, it is logical to use one preparation of botulinum toxin type A to treat spasticity and sialorrhea in one injection procedure. The aim of the work is to conduct a retrospective analysis of data from 15 centres that treat patients with cerebral palsy and use the botulinum therapy method to determine the optimal doses of IncobotulinumtoxinA (IBTA) for the treatment of spasticity and chronic sialorrhea in real clinical practice. Materials and methods. The treatment results of 389 children with cerebral palsy (including 211 (54.2%) boys) with IBTA were analyzed. The majority were children with bilateral forms of cerebral palsy - 312 (80.2%). The average age of the patients was 5.27 ± 3.71 years, the average weight of the patients was 18.8 ± 10.9 kg. Results. The total dose of IBTA in the group of 389 patients with cerebral palsy for the treatment of spasticity was 163.74 ± 80.65 U (25-550; 95% CI 155.7-171.7) and 10.4 ± 5.4 U/kg body weight (1,25-29.7; 95% CI 9.8-10.9). The total dose of IBTA in the group of patients with cerebral palsy with simultaneous treatment of spasticity and chronic sialorrhea (n = 16) was significantly higher: 267.18 ± 124.57 U (115-570; 95% CI 200.8-333.6) and 13, 0 ± 7.1 U/kg (5.8-24.6; 95% CI 9.2-16.8). In the lower extremities, the most frequent target muscles were the gastrocnemius (55.0% of cases; 95% CI 49.9-60.0) and semitendinosus / semimembranous muscle (46.3% of cases; 95% CI 41.2-51.4 ), and in the upper limbs - pronator teres (48.6% of cases; 95% CI 43.5-53.7) and biceps brachii (28.8% of cases; 95% CI 24.3-33.6). Limitations of the study. The limitations of our work are the use of an open retrospective study format, a relatively small sample of patients with chronic sialorrhea, the absence of long-term follow-up of patients and the results of repeated IBTA injections. Conclusion. If it is necessary to use botulinum therapy for the treatment of spasticity and sialorrhea in a child with CP, it is optimal to use the product IncobotulinumtoxinA, which will allow correction of two pathological manifestations in one procedure and can shorten the intervals between repeated injection cycles.

Комбинированное лечение тяжелой амблиопии, сочетанной с несодружественной эзотропией (клинический случай)

Purpose - to evaluate the effectiveness of a joint method for the treatment of severe amblyopia, combined with uncomfortable esotropia, including chemodenervation of the extraocular muscle and subsequent pleoptic treatment using the «Ambliokor» medical complex. Material and methods. The patient is 3 years old. Diagnosis: unfriendly non-paralytic esohypertropia with a prevalence of OD; amblyopia, severe OD, moderate OS, mixed astigmatism OU. The treatment was carried out in 2 stages. At the first stage in order to eliminate the dysbinocular factor of amblyopia, chemodenervation of the internal rectus muscle of the right eye with the preparation of botulinum toxin type A «Botox» was performed by the intraoperative technique. After 1 month, at the second stage, a complex pleoptic treatment was carried out. Results. After chemodenervation, 1 month later, orthotropy in the primary gaze position without glasses and with glasses was achieved. The vertical deviation significantly decreased to 5 degrees in the position of adduction of the eyeballs. The right lead was restored fully. The forced turn of the head was eliminated. After the third course of complex pleoptic treatment, visual acuity with correction was 0.7 on the right and 0.8 on the left. Restoration of central visual fixation in the right eye was noted. The simultaneous nature of vision was revealed. The deviation angle of the eyes in the primary gaze position without glasses and with glasses to the nose did not exceed +7 degrees according to Hirshberg. Hypertropia persisted in adduction up to 10 degrees according to Hirschberg (hyperfunction of the inferior oblique muscle) in both eyes. «V»-syndrome persisted. The patient is planned to surgically weaken the hyperfunction of the inferior oblique muscle of both eyes, followed by the continuation of a complex of pleopto-orthoptic treatment. Conclusion. The existing extensive base of various methods of influencing the functions of the amblyopic eye allows for successful treatment of even severe amblyopia. Key words: amblyopia, unfriendly esotropia, chemodenervation, pleoptic treatment.

Efficiency of Different Preparations of Botulinum Toxin Type A, Xeomin and Dysport, in the Management of Spastic Upper Limb After Stroke

The present study quantifies the effect of the two botulinum toxin type A products, Xeomin and Dysport, with approval from the National Agency for Medicines and Medical Devices of Romania (ANMDMR), for the treatment of the spastic upper limb following a stroke. The results obtained in the present study show a good efficiency of using both products in the spasticity of the upper limb, and a maintenance of the results obtained for both products for a minimum period of 3 months. Also, at higher doses, the results of the study show better improvement of spasticity and upper limb function on the evaluation scales, but the local effect is not maintained for a longer period.

Efficiency of Different Preparations of Botulinum Toxin Type A, Xeomin and Dysport, in the Management of Spastic Upper Limb After Stroke

The present study quantifies the effect of the two botulinum toxin type A products, Xeomin and Dysport, with approval from the National Agency for Medicines and Medical Devices of Romania (ANMDMR), for the treatment of the spastic upper limb following a stroke. The results obtained in the present study show a good efficiency of using both products in the spasticity of the upper limb, and a maintenance of the results obtained for both products for a minimum period of 3 months. Also, at higher doses, the results of the study show better improvement of spasticity and upper limb function on the evaluation scales, but the local effect is not maintained for a longer period. Keywords: toxinum botulinum type A, Xeomin, Dysport, spasticity

Clinical uses of botulinum toxin A in smile aesthetic modification.

In this article we review the pharmacodynamics of commercially available preparations of botulinum toxin type A, and discuss the potential uses of the drug in smile modification. A major emphasis is placed on applications relevant to modern dental practice, and to the complications arising from its use. Botulinum toxin A, when applied correctly, is a safe and effective means of achieving aesthetic smile modification, with limited data on any demonstrable long-term adverse effects.

Optimal dosage of botulinum toxin type A for treatment of glabellar frown lines: efficacy and safety in a clinical trial.

Various preparations of botulinum toxin type A (BTX-A) are used to reduces glabellar (frown) lines. However, dose-related safety and efficacy of intramuscular injections of a widely used, locally produced BTX-A in China has not been established. Assessment of dose-dependent safety and efficacy of Chinese botulinum toxin type A (Hengli BTX-A [HBTX-A]) intramuscular injections on glabellar lines. Four hundred eighty-eight BTX-A-naive participants were included in the double-blind trial and randomly divided into placebo (n = 122), low-dose (n = 183), and high-dose (n = 183) treatment groups for injection with saline solution, 10 units and 20 units of HBTX-A, respectively, at 4 sites in the corrugator muscle and 1 site in the procerus muscle. Outcomes were recorded before treatment and after 7, 30, 60, and 120 days, including glabellar line severity at maximum contraction and relaxation. Significantly greater improvement was observed in both HBTX-A groups in comparison with the placebo group (p < .05). Better efficacy was obtained in the high-dose treatment group. More participants developed adverse events after treatment with HBTX-A doses, than with the placebo (p < .05). Twenty-unit HBTX-A provided optimal improvement in glabellar lines, and its use might minimize injection frequency while maintaining acceptable safety.

Fields of Effects of 2 Commercial Preparations of Botulinum Toxin Type A at Equal Labeled Unit Doses

This article provides new data on a controversial issue, the influence of doses on the diffusion characteristics of 2 botulinum toxins type A. OBJECTIVE To assess the fields of effect of abobotulinumtoxinA and onabotulinumtoxinA at the same labeled unit dose (1:1 U) comparing sweat gland and muscle activity. A prospective, single-center, randomized, double-blind study was conducted at the Brazilian Center for Studies in Dermatology in Porto Alegre, Brazil. The participants included 19 women. Each patient received 2 U of abobotulinumtoxinA on one side of the forehead and 2 U of onabotulinumtoxinA on the other side. Horizontal and vertical diameter and area of the fields of anhidrotic effect, the amplitude of evoked compound muscle action potentials, and the 4-point validated Wrinkle Severity Scale were assessed at 28 days. The horizontal and vertical diameters of the fields of effect and the areas were significantly larger for onabotulinumtoxinA than those obtained for abobotulinumtoxinA. There were no significant differences between the products in the Wrinkle Severity Scale scores and Evoked Compound Muscle Action Potentials. OnabotulinumtoxinA had significantly more diffusion than abobotulinumtoxinA when isovolumetric injections of the same labeled unit dose of the products were injected. CONCLUSIONS AND RELEVANCE Although many studies state that diffusion is product dependent and abobotulinumtoxinA diffuses more than onabotulinumtoxinA, findings from the present study confirm that diffusion is dose dependent and the more potent dose tested diffuses more. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01732809.

Blefarospazm ve Hemifasiyal Spazmda Botilinum Toksin Tip A (Botox®)'nın Etkinlik ve Güvenirliği

Objective: Botox®, a preparation of botulinum toxin type A, is most widely used for blepharospasm (BPS) and hemifacial spasm (HFS). In this study, we present 82 patients who have been treated with Botox®. Material and Methods: This retrospective study included 15 BPS and 67 HFS patients who admitted to our clinic between May 2007 and December 2011. Botox® was diluted by sterile saline to adjust the dose to 5U/0.1 ml before injection. Pretarsal administration was applied. The average dose of Botox® required for an optimal response was 30-35 MU for BPS, 25-30 MU for HFS. Results: The therapeutic effect started after 3 to 5 days, and initial repetitive efficacy intervals (REI) [2nd REI, BPS (13,9 months) and HFS (5,8 months)] were longer than the last mean REI [7th REI, BPS (5.9 months) and HFS (3.7 months)], and there were statistically significant differences between BPS and HFS groups (p<0.05). The treatment was effective in both BPS and HFS. Adverse effects occurred in 7.29% of the injection series. Conclusion: BTX-A is established as an effective and safe agent in the treatment of BPS and HFS. The side effects of BTA-X administration may be reduced with the help of injection material used and the application technique.

Effectiveness of Switching Therapy from Complexing Protein-containing Botulinum Toxin Type A to a Formulation with Low Immunogenicity in Spasticity after Stroke: A case report

Some patients receiving botulinum toxin type A therapy develop immunological resistance due to the production of neutralizing antibodies against the neurotoxin, thus partially or completely reducing the therapeutic effect. We report here neurophysiological and clinical findings for a 58-year-old man treated with botulinum toxin type A for spasticity after ischaemic stroke, who became a secondary non-responder patient. Subsequent treatment with a different preparation of botulinum toxin type A had a great therapeutic effect on his spasticity. The muscles injected and the dosages were the same for each treatment, but evaluation with the Modified Ashworth Scale after treatment with the second preparation showed a reduction of approximately 2 points compared with the first examination. The clinical results were also supported by extensor digitorum brevis testing of the right muscle, which showed a reduction in compound muscle action potential, whereas it was unchanged in the non-injected muscle. No side-effects were reported, and after 1 year of treatment with this formulation clinical benefits were still evident. The neurophysiological and clinical results obtained in this patient suggest that switching therapy from a complexing protein-containing product to a product potentially free of complexing proteins, which has low immunogenicity, may be a viable therapeutic option in secondary non-responder patients.

Treatment of Upper Limb Spasticity after Stroke: One-Year Safety and Efficacy of Botulinum Toxin Type A NT201

A new preparation of botulinum toxin type A called NT 201, free from complexing proteins, potentially with low antigenicity has been used in the therapy of spasticity in stroke patients. This was an open-label study reported the safety and the efficacy of one-year treatment with NT 201 evaluating the therapeutic effect on functional disability and on quality of life in upper limb spasticity after stroke. Patients received a botulinum toxin therapy in the upper injected intramuscularly. After inoculation, patients were submitted to a motor rehabilitation program for upper limb injected three times/week. Re-treatment was permitted at 12 weeks after the prior treatment. Safety assessment included evaluation of adverse events and efficacy was measured by Modified Ashworth Scale for spasticity (MAS), Spasm Frequency Score (SFS) for the daily spasms, and Disability Assessment Scale (DAS) for disability. Of 35 consecutive patients (13 women and 12 men) screened for study eligibility, 20 (6 women and 14 men) patients (mean age 63,4±7,03) were included in this study and were submitted to NT 201 therapy for one year. At the baseline, botulinum toxin dose in the upper limb ranged from 160 to 450U, whereas total dose in the last treatment administrated was reduced respect the first injections ranging from 120 to 350U. All the enrolled patients completed the year-long study and reported an improvement of clinical picture. MAS, was statistically (px003C;0,001) reduced in all muscles at T1 (mean score ±SD: 2.65±0.67) and T2 (mean score±SD: 2.55±0.60) in comparison to the baseline T0 (mean score±SD: 3.9 ±0.78). Significant reduction (px003C;0,001) from baseline T0 (mean score ±SD: 3.25±0.78) was also noted in SFS at T1 (mean score ±SD: 1.55±0.51) and T2 (mean score±SD :1.30±0.47). The DAS score showed a reduction of the T1score (mean score ±SD: 1.70±0.47) and T2 score (mean score ±SD: 1,40 ±0,50) respect to baseline T0 score (mean score ±SD: 2,65 ±0,48) statistically significant (p≤003C;0,001). No adverse effects were observed in these patients. NT 201 appeared to be an efficacious and well-tolerated long-term treatment option for patients with upper limb spasticity after stroke, obtaining a substantial improvement in functional disability, muscle hypertone, and daily spasms.

Field effect of two commercial preparations of botulinum toxin type A: A prospective, double-blind, randomized clinical trial

The dose equivalence of commonly used commercial preparations of botulinum toxin type A, Dysport (abotulinumtoxinA [ABO] 500 U, Ipsen Biopharm Limited, Wrexham, United Kingdom) and Botox (onabotulinumtoxinA [ONA] 100 U, Allergan, Irvine, CA), remains unclear. We sought to evaluate the field effect for ABO and ONA at dose equivalences of 2.5:1.0 U and 2.0:1.0 U, in both muscular and sweat gland activity. In all, 59 female patients with forehead wrinkles were enrolled. Patients were randomized for dose equivalence between ABO and ONA, group A (2.0:1.0 U, ABO:ONA) or group B (2.5:1.0 U, ABO:ONA) administered in the frontalis muscles. Clinical assessment, Minor test, and electromyography evaluations were performed at baseline, 28 days, and 112 days. In group B, the field of anhidrotic effect of ABO showed a greater area and larger horizontal diameter than ONA at 28 and 112 days. At maximum frontalis muscle activity (day 112) patients receiving ABO demonstrated greater improvement based on the Wrinkle Severity Scale. No differences were found in frontalis muscle activity at rest between groups A and B based on results of Wrinkle Severity Scale, electromyography, and interindividual variability data at 28 and 112 days. Currently, there are no objective measurements other than electromyography to evaluate the field effect of botulinum toxin type A in muscles. At a dose equivalence of 2.0:1.0 U (ABO:ONA), similar field effects were found for both muscle and sweat gland activity. At a higher dose equivalence of 2.5:1.0 U (ABO:ONA), injections of ABO showed greater area and larger horizontal diameter in field of anhidrotic effect at 28 and 112 days than ONA.

Blind Multicenter Study of the Efficacy and Safety of Injections of a Commercial Preparation of Botulinum Toxin Type A Reconstituted up to 15 Days Before Injection

It is recommended that attention be given to the shelf life of botulinum toxin type A (BT-A) after its reconstitution. To assess the efficacy and safety of 500 U of BT-A after reconstitution up to 15 days after injection. BT-A vials were diluted 15 days, 8 days, and 8 hours before injection. One hundred five volunteers were randomized to one of three treatment groups, according to dilution dates. They were evaluated at baseline and 28, 56, 84, and 112 days after treatment. At each visit, the investigator and the volunteer evaluated the motility of the treated area using a 4-point qualitative scale. Five independent specialists, who scored the motility of the treated area on the same scale, blind analyzed photographs taken at each visit. The reconstituted vials of BT-A were stored and analyzed before and after the study. No significant difference was shown between the groups. No evidence of contamination was found in the BT-A vials. The results confirm the possibility of injecting 500 U of BT-A up to 15 days after its reconstitution safely and without loss of efficacy.

Clinical use of botulinum toxin

Summary Botulinum neurotoxin type A inhibits the release of acetylcholine from cholinergic motor and autonomic nerves. Intramuscular injection leads to muscle relaxation, and intradermal injection reduces sweat gland secretion. The recommended dose depends on which preparation of botulinum toxin type A is used and its dilution, the size of the muscle or gland being injected, and the method used to localise the injection site. Repeat doses are usually required as the effect of the toxin wears off after 3–4 months. Therapy including stretching, splinting and strengthening may prolong the effect of muscle relaxation. Realistic goal setting before treatment is vital.

Multicenter double-blind study of the efficacy of injections with a commercial preparation of botulinum toxin type A reconstituted in different weeks

Multicenter double-blind study of the efficacy of injections with a commercial preparation of botulinum toxin type A reconstituted in different weeks

A Randomized Pilot Study Comparing the Action Halos of Two Commercial Preparations of Botulinum Toxin Type A

A Randomized Pilot Study Comparing the Action Halos of Two Commercial Preparations of Botulinum Toxin Type A

A Randomized Pilot Study Comparing the Action Halos of Two Commercial Preparations of Botulinum Toxin Type A

The determination of the action halos of botulinum toxin type A aids in targeting specific muscles and/or sweat glands, thereby preventing the occurrence of side effects. The objective of this study was to compare the action halos of two commercial preparations of botulinum toxin type A, Dysport (Ipsen, Slough, UK) and BOTOX (Allergan, Irvine, CA). Eighteen volunteers received applications of both products into randomized sides of the frontalis muscle. Equivalent doses of 5 U of Dysport and 2 U of BOTOX were injected using the same technique, in the same volume (0.02 mL), and at a controlled depth. Twenty-eight days later, clinical and photographic assessments were performed. All the areas around the injected points were regular, round, or slightly oval and showed similar effects in the muscles and sweat glands. No statistically significant differences were observed between the mean sizes of the diameters of the halos produced by the two products. Injections of Dysport and BOTOX at an equivalence ratio of 2.5:1 U, respectively, applied at the same volume and depth, using the same technique resulted in similar action halos with regard to muscular and sweat gland activity. Both products seem to be safe and very predictable.

Mouse diaphragm assay for detection of antibodies against botulinum toxin type B

With the advent of a commercial preparation of botulinum toxin type B (BT-B) for treatment of cervical dystonia detection of antibodies against BT-B (BT-B-AB) becomes necessary. For this purpose, we carried out a mouse diaphragm assay (MDA) by continuous measurement of the twitch force of a mouse hemidiaphragm preparation elicited by electric stimulation of its phrenic nerve. After exposing the preparation to BT-B 3 ng/ml the time to half-maximal twitch force reduction (paralysis time [PT]) was 69 +/- 4 min (n = 25). Addition of sera from patients with antibodies against BT-A produced a PT of 68 +/- 5 min (n = 24), whereas addition of sera from controls with antibodies against tetanus toxoid produced a PT of 67 +/- 6 min (n = 30). When defined amounts of BT-B-AB were added to the MDA, PT was prolonged. This prolongation was correlated closely to the amount of BT-B-AB added, thus producing a calibration curve. The threshold for BT-B-AB detection was 0.4 mU/ml. When sera from 7 patients (4 women, 3 men; age 50.6 +/- 14.2 years) with cervical dystonia (Toronto Western Spasmodic Torticollis Rating Scale score, 18.9 +/- 2.9) and complete secondary failure of BT-B therapy (NeuroBloc; Elan Pharmaceuticals, Shannon, Ireland; 12,229 +/- 2,601 MU/injection series, 1.86 +/- 0.69 injection series before complete secondary therapy failure; 100.4 +/- 15.8 days between injection series with normal therapeutic effect) were tested, BT-B-AB titers of more than 10 mU/ml were found in all of them. The MDA can be used to measure neutralizing BT-B-AB titers quantitatively and with adequate sensitivity and specificity. Further studies are necessary to understand the role of intermediate BT-B-AB titers in partial BT-B therapy failure.

Crystalline Preparation of Botulinum Toxin Type a (Botox): Degradation in Potency with Storage

Laryngeal injection of botulinum toxin type A is currently the most effective method of treating spasmodic dysphonia. Botox, a crystalline preparation of botulinum toxin type A, is the only toxin approved for clinical use in the United States and is packaged in vials of 100 mouse units (MU). One MU corresponds to the calculated median lethal intraperitoneal dose (LD50) injected in mice. The logistic problems arising from the need for repeated injections of small amounts of Botox have been addressed by several investigators by refreezing unused Botox for use at a later time. Although FDA labeling recommends that Botox not used within 4 hours of reconstitution be discarded, data regarding degradation in potency after reconstitution and refreezing are not currently available. Using the LD50 Swiss-Webster mouse bioassay and statistical analysis by the Probit procedure, a 69.8% loss in potency was found when Botox was reconstituted, immediately frozen, and then assayed 2 weeks later (p < 0.0001). Statistically significant degradation in potency was seen after refrigerator storage for 12 hours (p = 0.007), but not for 6 hours (p = 0.16). Clinical implications regarding the dilution, use, and storage of Botox are discussed.