Injection of botulinum toxin into each splenius capitis muscle at baseline and week 12 was more effective than placebo in reducing the severity of essential head tremor over 18 weeks. Effects waned ...at 24 weeks.
De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and ...screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.
Botulinum toxin type A (BoNTA) products are widely used for therapeutic and aesthetic indications, but there is a need for longer-lasting treatments that maintain symptom relief between injections ...and reduce the frequency of re-treatment. DaxibotulinumtoxinA for Injection (DAXI) is a novel BoNTA product containing highly purified 150-kDa core neurotoxin and is the first to be formulated with a proprietary stabilizing excipient peptide (RTP004) instead of human serum albumin. The positively charged RTP004 has been shown to enhance binding of the neurotoxin to neuronal surfaces, which may enhance the likelihood of neurotoxin internalization. DAXI produces robust, extended efficacy across both aesthetic and therapeutic indications. In an extensive glabellar lines clinical program, DAXI showed a high degree of efficacy, a consistent median time to loss of none or mild glabellar line severity of 24 weeks, and median time until return to baseline of up to 28 weeks. In adults with cervical dystonia, DAXI at 125 U and 250 U significantly improved Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total scores, with a median duration of efficacy of 24 and 20 weeks, respectively, which compares favorably with the 12–14 weeks’ duration reported for approved BoNTA products. Overall, DAXI was well tolerated, and the consistent extended duration of effect suggests that DAXI has the potential to improve the management of both aesthetic and therapeutic conditions.
Plain Language Summary
Botulinum toxin is used to block the nerve signals that cause muscles to contract. Products containing botulinum toxin are commonly given by injection to treat muscle spasms (such as cervical dystonia, a painful condition where the neck muscles contract involuntarily) and for cosmetic treatment of frown lines. However, the effects of the currently approved botulinum toxin products typically wear off about 3–4 months after injection and so the injections must be repeated regularly. A new product called DAXI (DaxibotulinumtoxinA for Injection) has been developed. In this product, the botulinum toxin is formulated with a unique protein (called RTP004) that has been designed to help deliver the botulinum toxin to the nerve cells. Research suggests that the RTP004 protein in DAXI adheres the botulinum toxin to the nerves close to the injection site, potentially making its effect last longer. To date, DAXI has been studied in over 3800 patients. The studies have shown that DAXI is effective for treating neck spasms (cervical dystonia) and for reducing the appearance of frown lines. Importantly, the effects of DAXI lasted up to 6 months, which is longer than seen with other botulinum toxin products. The side effects seen with DAXI are consistent in nature and frequency with those seen with other botulinum toxin products. These findings suggest that DAXI can improve both medical and cosmetic treatments due to its longer-lasting effect.
In some patients treated with botulinum toxin (BT), antibodies are produced in association with certain treatment parameters, patient characteristics and immunological properties of the BT ...preparation used. Therapeutic BT preparations are comprised of botulinum neurotoxin, non-toxic proteins and excipients. Antibodies formed against botulinum neurotoxin can block BT's biological activity. The antigenicity of a BT preparation depends on the amount of botulinum neurotoxin presented to the immune system. This amount is determined by the specific biological activity, the relationship between the biological activity and the amount of botulinum neurotoxin contained in the preparation. For Botox the specific biological activity is 60 MU-EV/ng neurotoxin, for Dysport 100 MU-EV/ng neurotoxin and for Myobloc/NeuroBloc 5 MU-EV/ng neurotoxin. For Myobloc/NeuroBloc this translates into an antibody-induced therapy failure rate of 44% in patients treated for cervical dystonia, whereas for BT type A preparations this figure is approximately 5%. No obvious differences in antigenicity of BT type A preparations have been detected thus far. For the current formulation of Botox, the rate of antibody-induced therapy failure is reportedly less than 1%. To determine the antigenicity of different BT preparations in more detail, prospective studies on large series of unbiased patients with sensitive and specific BT antibody tests are necessary.
Introduction
Thirty years after their approval, botulinum toxin injections still are the first-line therapy for blepharospasm. The aim of our study was to analyze long-term data concerning safety and ...efficacy in a large cohort over decades.
Methods
Treatment data of all patients with blepharospasm and Meige´s syndrome in our outpatient clinic having undergone at least three subsequent treatment sessions with current onabotulinumtoxinA or abobotulinumtoxin A were analyzed with respect to the course of dose, effect duration, side effects, patients´ satisfaction and occurrence/reasons for treatment discontinuation.
Results
The observation period was up to 18 years for onabotulinumtoxinA and 29 years for abobotulinumtoxinA with a total of 1778 and 9319 treatment sessions in 69 patients with onabotulinumtoxinA, 281 with abobotulinumtoxin A and 2 of these having used both products. The dose increased in the first years followed by a stable dose in the following years. The mean dose was 39.1/198.7 mouse units (onabotulinumtoxinA/abobotulinumtoxinA). In over 25% of all sessions, inhibition of the eyelid opening was effectively treated with pretarsal injections. The most common adverse events included ptosis (4%/5%), epiphora/sicca (4%/5%), double vision (1%/1%) and facial asymmetry (1%/1%). Reasons for therapy discontinuation were change to a nearby doctor, age, other diseases, spontaneous improvement, side effects or possible treatment failure. Only one patient was tested positive for neutralizing antibodies against botulinum toxin A.
Conclusion
The treatment of blepharospasm and Meige’s syndrome with onabotulinumtoxinA and abobotulinumtoxinA is safe and effective, also over a long observation period of up to 29 years.
Evidence has shown that botulinum toxin A has advantages in lower urinary tract dysfunctions (LUTDs), especially in interstitial cystitis, urethral sphincter dysfunction, and inflammatory bladder ...disorders which currently cannot be adequately treated with oral pharmacological medications. This Special Issue has collected original or review articles that focus on the novel applications of botulinum toxin A in LUTDs. The research has been updated and contains novel therapeutic applications of botulinum toxin for bladder or urethral dysfunctions. This Special Issue of Toxins provides current knowledge surrounding the status of botulinum toxin in functional urology and LUTDs.
Botulinum neurotoxin (BoNTs; serotypes A, B, E, and F) cause botulism disease in humans, which could be effectively treated using antitoxins. Herein, we established a novel receptor-binding domain ...(RBD)-based antitoxin using recombinant C terminal heavy chain (Hc) domains of BoNTs as immunogens. Immunization of horses with these recombinant Hc domains allowed the purification and digestion of IgGs from hyper-immune sera to produce high-quality and high-efficiency monovalent botulism antitoxin F(ab′)
2
against each BoNT (M-BATs). However, these M-BATs could not bind or neutralize other serotypes of BoNTs, and that there were no cross-protective effects among these M-BATs. This suggested the need to prepare tetravalent antitoxins to neutralize the four BoNTs simultaneously. Thus, these M-BATs were formulated into a novel tetravalent botulism antitoxin (T-BAT), in which a 10-ml volume contained 10000 IU of BoNT/A and 5000 IU of BoNT/B, BoNT/E, and BoNT/F antitoxins. The novel antitoxin preparation could prevent and treat the four mixed botulinum neurotoxins simultaneously in vivo, representing strong efficacy in an animal poisoning model. Moreover, these antibodies in T-BAT could bind the RBD, whereas conventional antitoxins based on inactivated toxins mainly bind the light chain or heavy chain translocation domain (HN) and weakly bind the important RBD in current experimental conditions. The high levels of RBD-specific novel antitoxins can efficiently bind the RBD and neutralize natural or recombinant toxins containing this RBD. The findings of the present study experimentally support the use of RBD-specific antitoxins to treat BoNT serotype A, B, E, and F-mediated botulism. This study demonstrated the concept of developing potent novel multivalent antitoxins against all BoNTs or other toxins, using the RBD of these toxins as an alternative antigen to inactivated toxins.
Key points
• Antitoxins based on the receptor-binding domains of botulinum neurotoxins were made.
• Novel antitoxin binds RBD; traditional antitoxin mainly binds light chain or HN domain.
• A tetravalent antitoxin could prevent and treat the four mixed neurotoxins in vivo.
Botulinum toxins are neurotoxins produced by
. This toxin can be lethal for humans as a cause of botulism; however, in small doses, the same toxin is used to treat different conditions. Even if the ...therapeutic doses are effective and safe, the adverse reactions could be local and could unmask a subclinical impairment of neuromuscular transmissions. There are not many cases of adverse events in the literature; however, it is possible that sometimes they do not occur as they are transient and, if they do occur, there is no possibility of a cure other than to wait for the pharmacological effect to end. Inhibition of botulinum neurotoxin type A (BoNT/A) effects is a strategy for treating botulism as it can provide an effective post-exposure remedy. In this paper, 13,592,287 compounds were screened through a pharmacophore filter, a 3D-QSAR model, and a virtual screening; then, the compounds with the best affinity were selected. Molecular dynamics simulation studies on the first four compounds predicted to be the most active were conducted to verify that the poses foreseen by the docking were stable. This approach allowed us to identify compounds with a calculated inhibitory activity in the range of 316-500 nM.
Objective
Operating room (OR) injection of botulinum toxin (BTX) injection is effective in the management of retrograde cricopharyngeal dysfunction (RCPD). This study aims to analyze the efficacy and ...safety of in‐office (IO) 30 Unit BTX injection into the cricopharyngeus via lateral transcervical approach.
Methods
A retrospective chart review of patients who underwent BTX injection either in the OR or IO for RCPD was performed. Postoperative success, defined by patient‐reported complete or near complete resolution of symptoms, side effects, and complication rates of each group was determined and compared. To determine the learning curve of IO injections, success rates of the injections performed in the early and late 6 months were compared. Chi‐square test was used for determining the statistical significance.
Results
Overall, 78 injections (37 IO and 41 OR) for RCPD were performed by the senior author. The success rate of OR injections (90.2%) is significantly higher than IO injections (64.9%) at the first‐month follow‐up (p = 0.022). No significant difference was found in the side effect rates. Success and side effect rates were also similar in early and late injections (p > 0.05).
Conclusions
IO lateral transcervical BTX injection for RCPD is a safe method that does not require general or topical anesthesia. While the side effects are similar and IO injections have many advantages, the success rates are lower than OR injections.
Level of Evidence
3 Laryngoscope, 134:283–286, 2024
In‐office lateral transcervical botulinum toxin injection for retrograde cricopharyngeal dysfunction is a safe and effective method that does not require general or topical anesthesia.
PDF
