Botulinum Neurotoxin Type A Research Articles

Novel Topical BoNTA (CosmeTox, Toxin Type A) Cream Used to Treat Hyperfunctional Wrinkles of the Face, Mouth, and Neck

This study aimed to compare the effect of the stabilized novel topical botulinum neurotoxin type A (BoNTA) cream (CosmeTox) and a placebo cream on subjects, to compare clinician-reported outcomes, and to assess the safety and utility of the novel topical BoNTA cream for treating the entire upper face, chin, and neck areas. This study randomized 40 female subjects to receive either topical BoNTA (CosmeTox) cream (2 U/ml) or an identical placebo cream (without BoNTA) on the face, chin, and neck areas. The subjects were followed for 12 weeks. The main outcome measures were the Facial Line Outcomes questionnaire scores and results from the Self-Perception of Age instrument, which assesses age of appearance relative to actual age. The BoNTA topical cream (CosmeTox) treatment produced significant improvements in the Facial Lines Outcome scores, which were maintained throughout the study period and lasted more than 3 months. The BoNTA topical cream treatment also reduced the age of appearance for a majority of subjects. The placebo had no effect on any measure. No serious adverse events occurred during the entire study period. Topical treatment with the stabilized BoNTA cream (CosmeTox) to the entire upper facial lines resulted in significantly improved facial features and age appearance, as measured by the subjects and clinicians. The BoNTA cream (CosmeTox) resulted in a significantly younger, more satisfying, relaxed appearance.

Adeno-Associated Virus Transfer of a Gene Encoding SNAP-25 Resistant to Botulinum Toxin A Attenuates Neuromuscular Paralysis Associated with Botulism

Advances in viral gene therapy have opened new possibilities for treating a range of motor neuron diseases, but these have not yet been translated into clinically applicable therapies because of difficulties in delivery to susceptible/damaged neurons, ambiguities in the identity of gene(s) implicated, and a paucity of means to quantify any physiological improvement. Most of these hurdles can be overcome by using the neuromuscular paralysis induced by botulinum neurotoxin type A (BoNT/A) as a prototype disease. Furthermore, because human botulism, occasionally fatal, causes prolonged muscle disablement as a result of the intraneuronal persistence of the toxin's SNAP-25 (S25)-cleaving protease, development of a genetic approach could lead to a potential treatment for this debilitating disease. Adeno-associated viral delivery of a cleavage-resistant S25 gene (S25-R198T) to chromaffin cells in vitro yielded exocytotically active S25-R198T that diminished subsequent blockade by BoNT/A of evoked catecholamine release. Evaluation in vivo, by administering this virus into rat spinal cord before injecting BoNT/A, showed a decreased inhibition of acetylcholine release as reflected in elevated retention of neuromuscular transmission. A similar, although smaller, protection of synaptic transmission from the toxin was seen after peripherally injecting the therapeutic virus. Such therapy also curtailed nerve sprouting normally induced by BoNT/A. This first demonstration of the utility of a DNA-based therapy for botulism paves the way for further advances in its treatment and for application to genetic disorders of motor neurons.

TAMSULOSIN'S EFFECT ON SYSTEMIC BLOOD PRESSURE AND REFRACTORY NON-NEUROGENIC VOIDING DYSFUNCTION IN A PEDIATRIC POPULATION

You have accessJournal of Urology1 Apr 2008TAMSULOSIN'S EFFECT ON SYSTEMIC BLOOD PRESSURE AND REFRACTORY NON-NEUROGENIC VOIDING DYSFUNCTION IN A PEDIATRIC POPULATION Brian A Vanderbrink, Jordan Gitlin, Sylvia Toro, Emily T Cupelli, and Lane S Palmer Brian A VanderbrinkBrian A Vanderbrink More articles by this author , Jordan GitlinJordan Gitlin More articles by this author , Sylvia ToroSylvia Toro More articles by this author , Emily T CupelliEmily T Cupelli More articles by this author , and Lane S PalmerLane S Palmer More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(08)60868-XAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "TAMSULOSIN'S EFFECT ON SYSTEMIC BLOOD PRESSURE AND REFRACTORY NON-NEUROGENIC VOIDING DYSFUNCTION IN A PEDIATRIC POPULATION." The Journal of Urology, 179(4S), p. 298 © 2008 by American Urological AssociationFiguresReferencesRelatedDetails Volume 179Issue 4SApril 2008Page: 298 Advertisement Copyright & Permissions© 2008 by American Urological AssociationMetricsAuthor Information Brian A Vanderbrink More articles by this author Jordan Gitlin More articles by this author Sylvia Toro More articles by this author Emily T Cupelli More articles by this author Lane S Palmer More articles by this author Expand All Advertisement PDF DownloadLoading ...

The use of botulinum neurotoxin type A (BoNTA) in urology

The use of Botulinum neurotoxin type A (BoNT/A) in the lower urinary tract was pioneered as early as 20 years ago with injections into the urethral sphincter reducing bladder voiding pressures, urethral pressures, and post-void residual urine. Over the past 9 years, the use of BoNT/A has revolutionised the treatment of intractable symptoms associated with the neurogenic or idiopathic overactive bladder, both in adults and children. The duration of clinical improvement is 6-11 months, is accompanied by significant amelioration of patients' quality of life and repeat bladder treatments appear to have sustained effects. Despite evidence for an effect on the afferent pathways, its mode of action in the human bladder remains largely unknown. The use of BoNT/A has also expanded into the painful bladder syndrome and in benign prostatic diseases, with promising preliminary results. This review aims to provide an insight of the use of BoNT/A in the lower urinary tract, addressing issues such as treatment outcomes and safety, mechanisms of action and potential for future research.

Monoclonal Antibody-Based Lateral Flow Assay for Detection of Botulinum Neurotoxin Type A

A rapid lateral flow assay was developed to detect botulinum neurotoxin type A (BoNT/A). The assay was based on the sandwich format using monoclonal antibodies (MAbs) of two distinct specificities. One anti-BoNT/A heavy chain MAb (150-3) was immobilized to a defined detection zone on a porous nitrocellulose membrane, while the other anti-BoNT/A heavy chain MAb (44.1) was conjugated to colloidal gold particles, which served as a detection reagent. The BoNT/A-containing sample was added to the strip and allowed to react with MAb (44.1)-coated particles. The mixture was then passed along the porous membrane by capillary action past the MAb (150-3) in the detection zone, which binds the particles that had BoNT/A bound to their surface, giving a red color within this detection zone with intensity proportional to BoNT/A concentration. In the absence of BoNT/A, no immunogold was bound to the solid-phase antibody. With this method, 50 ng/mL of BoNT/A were detected in less than 10 min. The assay sensitivity can be increased by silver enhancement to 1 ng/mL. The developed BoNT/A assay also showed no cross-reaction to type B neurotoxin (BoNT/B) and type E neurotoxin (BoNT/E).

Botulinum neurotoxin type A injections reduce spasticity in mild to moderate hereditary spastic paraplegia— Report of 19 cases

Hereditary spastic paraplegia (HSP) is characterized by lower extremity spasticity. Symptomatic therapy generally includes physical therapy and oral antispastic agents, in selected cases intrathecal baclofen. Because of the positive results in other treatments of spasticity, the use of botulinum neurotoxin type A (BoNT-A) might also be considered for patients with HSP. We report the effect of BoNT-A injections in 19 unselected patients with HSP treated by the members of the German Spasticity Education Group. In 17 patients, the modified Ashworth scale had improved by one point. In one patient, it improved by three points. Most of the patients reported reduction of spasticity. BoNT-A injections were continued in 11 of 19 patients (57.9%). All of the patients with continued injections had a good or very good global subjective improvement. Patients with less pronounced spasticity and patients with accompanying physical therapy tended to exhibit a better effect. Only four patients reported adverse effects which were increased weakness in three patients and pain in one patient. BoNT-A injections appear to reduce spasticity effectively and safely, especially in patients with mild to moderate spasticity. The preliminary results of our case series should encourage larger studies of BoNT-A injections in HSP.

Development of Capture ELISA Using a Biotinylated Monoclonal Antibody for Detection of Botulinum Neurotoxin Type A

A capture enzyme-linked immunosorbent assay (capture ELISA) was developed to detect Clostridium botulinum neurotoxin type A (BoNT/A) in assay buffer and human serum. The assay is based upon affinity-purified rabbit polyclonal and biotinylated monoclonal antibodies directed against the BoNT/A complex purified from C. botulinum ATCC19397. For the capture ELISA, the optimized amount (2 μg/ml) of rabbit polyclonal antibody was immobilized on ELISA plates to detect BoNT/A (ranging from 0 to 500 ng/ml), which was recognized by 2 μg/ml of the monoclonal antibody. From three independent repeated experiments, standard curves were linear over the range of 0~31.25 ng/ml BoNT/A and the coefficients (r2) ranged from 0.9951~0.9999 for all assays. The inter-variations were typically 0.50~6.93% and the specificity was confirmed by showing no cross-reactivity against BoNT/B and /E. The detection limit of capture ELISA was 0.488 ng/ml, which was close to mouse LD50. In addition, application with BoNT/A-spiking human sera showed a possibility to detect BoNT/A with capture ELISA from the contaminated human sera. Taken together, the newly developed capture ELISA could serve as a rapid and sensitive screening tool for detecting BoNT/A simultaneously from massive specimens.

Bead-based microfluidic toxin sensor integrating evaporative signal amplification

We have devised a microfluidic platform that incorporates substrate-laden silica beads for sensing the proteolytic activity of botulinum neurotoxin type A (BoNT/A)-one of the most poisonous substances known and a significant biological threat. The sensor relies on toxin-mediated cleavage of a fluorophore-tagged peptide substrate specific for only BoNT/A. Peptide immobilized on beads is recognized and cleaved by the toxin, releasing fluorescent fragments into solution that can be concentrated at an isolated port via evaporation and detected using microscopy. Evaporative concentration in combination with a specific channel geometry provides up to a 3-fold signal amplification in 35 min, allowing for detection of low levels of fluorophore-labeled peptide-a task not easily accomplished using traditional channel designs. Our bead-based microfluidic platform can sense BoNT/A down to 10 pg of toxin per mL buffer solution in 3.5 h and can be adapted to sensing other toxins that operate via enzymatic cleavage of a known substrate.

The Analgesic Effect of Botulinum-toxin A on Postwhiplash Neck Pain

The effectiveness of botulinum neurotoxin type A (BTXA) injections in relieving the neck pain and reduced motion that evolve after whiplash injury (WI) has been controversial. To test the long-term efficacy of a tender point injection of BTXA in relieving neck pain in patients with WI. Twenty patients with cervical myofascial pain, 2 to 48 weeks after WI, were randomly assigned to receive either 200 U of BTXA or placebo at 4 tender points and were seen during the follow-ups 3, 6, 9, 12, and 24 weeks after the injections. Outcome measures included the intensity of pain as evaluated by a 10-cm Visual Analog Scale (VAS) and a 5-point Verbal Rating Scale (VRS), quality of life as evaluated by the SF-36 questionnaire, treatment efficacy as per the global assessment of the physician and patient, intensity of pain in response to mechanical pressure, range of cervical motion, and use of other therapies and their adverse effects. A time-dependent improvement in all the parameters was found in both groups, which was consistently larger in the BTXA-treated group, but mostly not at a significant level. Significant differences between the groups were found only in the percentages of patients who achieved 50% or more of reduction in intensity (VAS and average VRS) at 24 weeks (50% vs. 0%, P>0.05 and 70% vs. 11%, P>0.05, respectively). Systemic adverse effects tended to be more common in the BTXA-treated group (40% vs. 0%, P=0.07). Study results suggest that BTXA treatment has some efficacy when administered within 1 year of the WI. However, a large, well-designed clinical trial is needed to draw final conclusions.

Neurologic uses of botulinum neurotoxin type A.

This article reviews the current and most neurologic uses of botulinum neurotoxin type A (BoNT-A), beginning with relevant historical data, neurochemical mechanism at the neuromuscular junction. Current commercial preparations of BoNT-A are reviewed, as are immunologic issues relating to secondary failure of BoNT-A therapy. Clinical uses are summarized with an emphasis on controlled clinical trials (as appropriate), including facial movement disorders, focal neck and limb dystonias, spasticity, hypersecretory syndromes, and pain.

Early Effect on the Overactive Bladder Symptoms following Botulinum Neurotoxin Type A Injections for Detrusor Overactivity

ObjectivesLimited studies to date have reported on the onset of effect of intradetrusor botulinum neurotoxin type A (BoNTA) injections when used to treat the symptoms of the overactive bladder (OAB). Furthermore, few studies have examined the effect of BoNTA on urgency and nocturia, now recognised as the most bothersome symptoms of the OAB syndrome. We studied the immediate effect of BoNTA on the OAB symptoms by recording the daily changes during the week after treatment of patients with neurogenic or idiopathic detrusor overactivity (NDO/IDO). MethodsTwenty-four patients (16 NDO, 8 IDO) treated with 300mu BOTOX® (NDO) or 200mu (IDO) completed a 4-d voiding diary before and 4 wk after treatment and a 7-d diary starting the day immediately after injections. Data were analysed for intragroup daily changes during the first week and for further changes at 4 wk. Parametric t tests were used for statistical analysis (significance at p<0.05). ResultsThe two groups were comparable at baseline for all studied variables. In NDO, significant improvements in urgency, frequency, and nocturia were seen at day 2 post injection and in incontinence at day 3, and were sustained at 4 wk. In IDO, the first significant change in urgency, frequency, and incontinence was seen at day 4, with urgency showing the most consistent changes thereafter. All parameters significantly improved at 4 wk. ConclusionsIntradetrusor BoNTA ameliorates all OAB symptoms within the first week after treatment, but urgency is most rapidly and consistently affected, suggesting an early effect on bladder afferent pathways. Differences in the toxin dose or possibly underlying pathophysiology may account for an earlier trend for symptomatic improvement in the NDO patients.

No difference in efficacy between Xeomin® and Botox® in the treatment of cervical dystonia – a detailed subgroup analysis

Introduction: Treatment of cervical dystonia (CD) with the highly purified Botulinum neurotoxin type A (BTX-A) free of complexing proteins (Xeomin) is mainly based on the largest controlled study of BTX-A ever performed (Benecke et al. 2005) demonstrating that Xeomin is non-inferior to Botox and that in average the efficacy of one Xeomin unit is equivalent to one Botox unit.

Substrate-Modified Hydrogels for Autonomous Sensing of Botulinum Neurotoxin Type A

We report the development of substrate-cross-linked hydrogels for the specific detection of botulinum neurotoxin type A (BoNT/A), the most poisonous toxin known. Peptide-cross-linked BoNT/A-sensitive hydrogels were photopolymerized within microfluidic channels to create autonomous biosensors capable of sensing toxin enzymatic activity with a visual readout.

Bioprotection of Tendon Repair

Tendon-repair techniques have evolved to increase the construct strength of the repair site in order to permit early active range of motion without tendon gap or rupture. The present study evaluated the hypothesis that the injection of botulinum neurotoxin type-A (BoNT-A) into the gastrocnemius muscle will reduce the active force production of that muscle below the force required to rupture the associated, repaired Achilles tendon. Seventy-nine rat Achilles tendons were surgically bisected and were repaired with use of a two-strand core suture with a running epitenon repair. After the repair, the animals were treated with unilateral intramuscular (gastrocnemius) injections of either BoNT-A (6 U/kg body weight) (thirty-seven rats) or saline solution (forty-two rats). Operatively treated ankles were fixed in the neutral position with a percutaneous pin for the first two days after surgery. Unrestricted ankle motion and weight-bearing were allowed after the second postoperative day. An assessment of gap formation or rupture at the repair site, electrophysiologic measurements of force applied to the tendon, and an assessment of the strength of the repaired tendon were performed. Intramuscular BoNT-A injections produced a significant, reversible reduction in active muscle force (p < 0.007). Twitch and tetanus contractions decreased to approximately 25% of the values for the control side within one week, remained at <50% of the values for the control side at one month, and returned to normal levels by six months. The tetanic force capability of the muscles that had been injected with BoNT-A was fivefold to tenfold less than the force required to rupture the associated Achilles tendon for as long as four weeks after tendon repair. The spontaneous Achilles tendon rupture rate of repaired tendons in the BoNT-A group was three times lower than that in the saline solution group at one week, and the tendon rupture force was significantly higher in the BoNT-A group between one and three weeks after repair (p < 0.007). There was no significant difference in tendon rupture force between the two groups after three weeks. Intramuscular gastrocnemius BoNT-A injections were associated with a significant reduction in force-generating potential, such that the muscle was incapable of actively producing enough force to rupture the repaired Achilles tendon in this rat model of tendon repair.

Efficacy and safety of botulinum neurotoxin type A free of complexing proteins (NT 201) in cervical dystonia and blepharospasm

Botulinum neurotoxin type A (BTX-A) weakens voluntary muscle power and is an effective therapy for focal dystonia, including cervical dystonia (CD) and benign essential blepharospasm (BEB). Antibody formation against BTX-A may lead to failure of treatment. NT 201 (XEOMIN®) is a formulation of pure BTX-A that is free of complexing proteins and therefore may have a reduced immunogenic potential in comparison with other BTX-A preparations. In clinical trials, NT 201 was found to be effective, well-tolerated and at least noninferior to a BTX-A preparation containing complexing proteins in the treatment of CD and BEB. There were no differences between the two therapies in terms of onset of action, duration and waning of effect. Future research is aimed at evaluating the benefits of NT 201.

Development and comparison of two immunoassay formats for rapid detection of botulinum neurotoxin type A

We have evaluated two formats of immunoassays for the rapid detection of Clostridium botulinum neurotoxin type A (BoNT/A), in assay buffer and various matrices (human serum and nasal swabs, fresh milk, sugar, flour and talcum). The two formats, a vertical-flow strip immunochromatography (ICT) and a small disposable immunoaffinity column (IAC), were selected because they are both rapid and readily usable in the field without sophisticated equipment. We utilised the same critical reagents to develop and optimise both assays, making it possible to compare the corresponding technologies on the same toxin preparations, without interference due to the properties of the antibodies. Results were interpreted using a standard statistical test (ANOVA) and showed little difference of sensitivity between matrices. Though both assays were completed in 40 min, the sensitivity of the IAC, evaluated at 0.45 pM (5 mouse LD50 units/ml), was 40 to 80 times better than that of the ICT. Furthermore, the sensitivity of the IAC assay was improved to 0.09 pM (1 mouse LD50 unit/ml) when performed on a 5-ml volume of human serum. Thus, the IAC appears to be one of the most sensitive and rapid assays for the detection of BoNT/A reported to date and, because it is also highly transportable, it is amongst the best suited for field diagnosis of BoNT/A poisoning.

Effects of Botox® and Neuronox® on muscle force generation in mice

The current study determined the dose-response relationship for inhibition of muscle force of two commercially available botulinum neurotoxin type-A (BoNTA) preparations (Botox and Neuronox) in a murine model and characterized the time course of recovery from the toxin-induced muscle paralysis. The effect of freezing reconstituted toxin on toxin potency was also determined. The gastrocnemius muscles in male CD-1 mice were injected with either saline or BoNTA (0.3-3.0 U/kg), and muscle force generation was examined following stimulation of the tibial nerve (single twitch and 15-200 Hz tetany). Botox and Neuronox produced nearly equivalent decrements in muscle force (30%-90%) at 4 days after toxin injection. At 28 days after injection (1 U/kg), muscle force had recovered from the effects of both toxin preparations. Maintaining reconstituted toxin at -80 degrees C for up to 5 months did not result in significant loss of toxin activity. The results of this study suggest that Botox and Neuronox produce equivalent responses in a murine model, and, in contrast to other models, muscle recovery is rapid with doses of toxin that produce less than maximal decrements in muscle force.

Botulinum toxin A does not alter capsaicin-induced pain perception in human skin

A genuine peripheral antinociceptive and anti-inflammatory effect of Botulinum neurotoxin type A (BoNT/A) has been proposed but could not be demonstrated in humans so far. Therefore, 100 mouse units of Botulinum toxin A (Dysport®) and placebo were injected in a double blind paradigm in defined skin areas of 50 subjects. At baseline and after 4 and 8 weeks allodynia was induced in the skin areas with capsaicin ointment. Heat and cold pain threshold temperatures were measured with quantitative sensory testing, and threshold intensities upon electrical stimulation with a pain specific surface electrode were determined. No BoNT/A related differences in pain perception were found at any quality. There is neither a direct peripheral antinociceptive effect nor a significant effect against neurogenic inflammation of BoNT/A in humans.

Neuromuscular paralysis and recovery in mice injected with botulinum neurotoxins A and C

Botulinum neurotoxin type A (BoNT/A) is commonly used in human therapy. This treatment may induce immunoresistance and preliminary evaluation of other botulinum neurotoxin serotypes suggested botulinum neurotoxin type C (BoNT/C) to be a good alternative to BoNT/A. Here, we have further characterized the biological activities of BoNT/C using a variety of experimental approaches. Muscle paralysis and time of recovery of mouse hind limb injected with BoNT/A or BoNT/C were assayed with the Digit Abduction Scoring assay. The extent and duration of paralysis were similar with the two toxin serotypes. Extensor digitorum longus or tibialis anterior muscles were dissected at times of complete paralysis and of complete recovery. Muscle weight and force were significantly reduced in mice injected with BoNT/A and BoNT/C, and some atrophy persisted for a long time. In BoNT/C-treated junctions, nerve terminal sprouting was prominent, indicating that the capacity to extend the field of innervation is not hampered by BoNT/C. BoNT/C induced a marked decrease in the frequency of miniature endplate potentials and in the amplitude of endplate potentials. 3,4-diaminopyridine reversed the effect of BoNT/C by increasing the amplitude of synchronized endplate potentials. The present study shows an extensive similarity in the biological activities of BoNT/A and BoNT/C, further supporting the suggestion that BoNT/C is a valid alternative to BoNT/A.

Simulating botulinum neurotoxin with constant pH molecular dynamics in Generalized Born implicit solvent

A new method was proposed by Mongan et al. for constant pH molecular dynamics simulation and was implemented in AMBER 8 package. Protonation states are modeled with different charge sets, and titrating residues are sampled from a Boltzmann distribution of protonation states. The simulation periodically adopts Monte Carlo sampling based on Generalized Born (GB) derived energies. However, when this approach was applied to a bio-toxin, Botulinum Neurotoxin Type A (BoNT/A) at pH 4.4, 4.7, 5.0, 6.8 and 7.2, the p K a predictions yielded by the method were inconsistent with the experimental values. The systems being simulated were divergent. Furthermore, the system behaviors in a very weak acidic solution (pH 6.8) and in a very weak basic solution (pH 7.2) were significantly different from the neutral case (pH 7.0). Hence, we speculate this method may require further study for modeling large biomolecule.