Botulinum Toxin: An Update on Pharmacology and Newer Products in Development.

Since its introduction as a treatment for strabismus, botulinum toxin (BoNT) has had a phenomenal journey and is now recommended as first-line treatment for focal dystonia, despite short-term clinical benefits and the risks of adverse effects. To cater for the high demand across various medical specialties, at least six US Food and Drug Administration (FDA)-approved formulations of BoNT are currently available for diverse labelled indications. The toxo-pharmacological properties of these formulations are not uniform and thus should not be used interchangeably. Synthetic BoNTs and BoNTs from non-clostridial sources are not far from clinical use. Moreover, the study of mutations in naturally occurring toxins has led to modulation in the toxo-pharmacokinetic properties of BoNTs, including the duration and potency. We present an overview of the toxo-pharmacology of conventional and novel BoNT preparations, including those awaiting imminent translation from the laboratory to the clinic.

Assessment of the effects of sugammadex on coagulation profiles using thromboelastographic parameters.

This study evaluated the effects of sugammadex at conventional doses of 2 and 4 mg/kg on the coagulation profile by analyzing thromboelastographic parameters and performing a traditional laboratory coagulation analysis. A total of 100 patients undergoing arthroscopic shoulder surgery were enrolled. The patients were randomly divided into the 2 mg and 4 mg groups. The laboratory coagulation test and thromboelastographic analysis were performed before and 15 min after administering sugammadex. Prothrombin time (PT) was significantly prolonged after sugammadex administration than before it in intragroup comparisons of the 2 mg group (12.8 ± 0.6 s vs. 13.6 ± 0.7 s, p < 0.001) and the 4 mg group (13.0 ± 0.5 s vs. 13.7 ± 0.5 s, p < 0.001). R time, derived from thromboelastography, was also significantly prolonged after sugammadex administration (4.7 ± 1.8 min vs. 5.8 ± 2.1 min, p = 0.005). In conclusion, the conventional doses of 2 or 4 mg/kg sugammadex prolonged PT. Sugammadex 4 mg/kg also prolonged R time, although the value was within the normal range. Therefore, physicians should be cautious with the higher sugammadex dose, particularly in patients with a high risk of bleeding because the higher dose was associated with less coagulation.Trial registration: KCT0002133 (https://cris.nih.go.kr).

The role of botulinum toxin in multimodal treatment of spasticity in ambulatory children with spastic Cerebral Palsy: extensive evaluation of a cost-effectiveness trial.

BACKGROUND: A cost-effectiveness trial (the Space Bop study) on the added value of botulinum toxin injections (BoNT-A) in the leg muscles, as part of a multimodal intervention for ambulatory children with spastic cerebral palsy in the context of a single distinct cycle of care was performed recently by our group. For a broad set of effect outcomes, we found that BoNT-A had no added value if children received comprehensive rehabilitation. However, this counterintuitive finding was met with scepticism. OBJECTIVE: Since several noteworthy facts and experiences were recorded during the course of the trial and the dissemination phase, the aim of this paper was to describe and discuss some crucial aspects of, and barriers to, the Space Bop study, related to context and perspective, design and results, as well as publication and implementation. METHODS: This paper discusses 5 issues: (i) the design, interpretation and presentation of previous research; (ii) the role of one's own clinical experience and interpretation; (iii) the aims of (BoNT-A) treatment; (iv) conflict of interest, role of industry, and the role of history; (v) optimal treatment modalities and dose-response relationships. CONCLUSION: Despite the unambiguous findings from the Space Bop study, several factors hindered acceptance of the results. Awareness of these factors is important when performing rehabilitation research and disseminating and implementing research findings.

Long-term treatment of blepharospasm with botulinum toxin A: a service-based study over a 16-year follow-up in southern China.

OBJECTIVE: To elucidate the effect of long-term treatment with botulinum toxin A (BTX-A) for blepharospasm. Prevalence data and clinical features in southern China and influencing factors for selecting BTX-A treatment were explored. METHODS: We collected data retrospectively from 338 consecutive patients diagnosed with blepharospasm over 16 years to assess prevalence data and clinical features. Thereafter, all patients were classified into BTX-A (n = 135) or non-BTX-A (n = 203) treatment groups according to the patients' requests in order to explore the factors influencing whether BTX-A treatment was chosen. Furthermore, dynamic follow-up data were analyzed to evaluate the long-term efficacy in the BTX-A group. RESULTS: The prevalence was 23.3 per million, with an onset age of 50.3 ± 12.3 years and a female:male ratio of 2.4:1; the most common symptom was excessive blinking (91.2%). The symptom severity and psychological assessment scores were significantly decreased by treatment with BTX-A (p < 0.01), and there was no significant difference in response duration with the prolongation of BTX-A injections. Adverse events occurred 52 times (5.0%) among 1038 injections. The symptom severity and psychological assessment scores and the occurrence of eye-opening difficulty were higher, and medical expenses and the symptom tolerability rate were lower in the BTX-A group than in the non-BTX-A group (p < 0.05). CONCLUSION: The onset age was earlier than that in Western countries. However, starting BTX-A treatment early is justified, even though a higher dosage was needed to maintain reliable long-term efficacy. Additionally, symptom severity and medical expenses are the primary factors affecting whether patients select BTX-A treatment.

Longitudinal neurophysiological assessment of intramuscular type-A botulin toxin in healthy humans.

The aim of this study is to assess the neurophysiological abnormalities of type A botulin toxin-infiltrated human muscle, and their evolution over time. Seried cMAP measurements, 3 and 20 Hz repetitive nerve stimulation, EMG, SFEMG over 3 months from toxin injection. Our findings consist in lack of decrement with 3 Hz repetitive nerve stimulation and facilitation with 20 Hz repetitive nerve stimulation; progressive increasing of jitter; early appearance of fibrillations; small and short motor unit action potential in the first 3 weeks, followed by increasing of MUAP amplitude and duration, with polyphasic morphology. Although claimed as highly specific and sensible, neuromuscular junction facilitation is an inconstant finding in human botulism. Therefore, lack of neuromuscular junction facilitation cannot exclude a diagnosis of botulism. Our findings are compatible with a process of acute denervation followed by distal reinnervation, favored by terminal nerve sprouting.

Epidemiology, Prevention, and Assessment of Tardive Dyskinesia and Advances in Treatment.

​​ Tardive dyskinesia (TD) is a disorder characterized by involuntary movements, typically of the orofacial muscles and also of the extremities and other muscle groups. The condition is associated with exposure to dopamine receptor blocking agents, including antipsychotics. Because the indications and off-label uses for these agents have expanded over the last 2 decades, a larger number of patients are receiving antipsychotic medications than in the past. While evidence suggests that patients being treated with second-generation antipsychotics have less risk for developing TD than those treated with first-generation antipsychotics, the decreased risk is not as great as was originally expected. In addition, patients with chronic psychiatric conditions often require long-term use of antipsychotics, putting them at risk for TD. This article addresses the prevalence, risk factors, and prevention of TD; assessment strategies including diagnostic criteria and rating scales; and evidence for TD treatments, including 2 newly approved medications: deutetrabenazine and valbenazine. ​​​.

Drug Development and Challenges for Neuromuscular Clinical Trials.

Drug development process faces many challenges, including those encountered in clinical trials for neuromuscular diseases. Drug development is a lengthy and highly costly process. Out of 10 compounds entering first study in man (phase 1), only one compound reaches the market after an average of 14 years with a cost of $2.7 billion. Nevertheless, according to the Centers for Medicare and Medicaid services, prescription drugs constituted only 9 % of each health care dollar spent in USA in 2013. Examples of challenges encountered in neuromuscular clinical trials include lack of validated patient-reported outcome tools, blinding issues, and the use of placebo in addition to lack of health authority guidance for orphan diseases. Patient enrollment challenge is the leading cause of missed clinical trial deadlines observed in about 80 % of clinical trials, resulting in delayed availability of potentially life-saving therapies. Another specific challenge introduced by recent technology is the use of social media and risk of bias. Sharing personal experiences while in the study could easily introduce bias among patients that would interfere with accurate interpretation of collected data. To minimize this risk, recent neuromuscular studies incorporate as an inclusion criterion the patient's agreement not to share any of study experiences through social media with other patients during the study conduct. Consideration of these challenges will allow timely response to the high unmet medical needs for many neuromuscular diseases.

Skin Biomechanical Changes after Injection of Onabotulinum Toxin A: Prospective Assessment of Elasticity and Pliability.

OBJECTIVE: This study aimed to test the hypothesis that the administration of onabotulinum toxin A will result in an increase in skin pliability and elasticity. STUDY DESIGN: A prospective case series with planned data collection in which patients were treated with onabotulinum toxin and assessed at baseline, 2 weeks post-injection, and 2 months post-injection. SETTING: A private cosmetic surgery clinic associated with a tertiary academic hospital. SUBJECTS AND METHODS: Forty women were prospectively enrolled to receive onabotulinum toxin A into their glabella, forehead, and lateral orbit. Outcomes were assessed at baseline, 2 weeks posttreatment, and 2 months posttreatment using the Cutometer MPA 580. Skin pliability (Uf) and the elastic recoil (Ua/Uf) were recorded as the 2 primary outcome measures. RESULTS: There was a significant effect of onabotulinum toxin on skin elasticity (f = 47.8, P = .001) with a mean (+/- SE) increase in elastic recoil of 20% (4.4%) for the glabellar region (P < .001) and 18% (4.0%) for the lateral orbit (P < .0001). There was a significant effect of the treatment on skin pliability (f = 46.9, P < .001) with a mean (+/- SE) increase of 26% (5.4%) for the lateral orbit (P = .001) and 52% (8.3%) for the glabellar region (P < .001). CONCLUSION: Injection of onabotulinum toxin into the lateral orbital, forehead, and glabellar regions results in skin that has increased pliability as well as increased elastic recoil. Although this study demonstrates the positive effect of onabotulinum toxin on biomechanical parameters, it is unclear what specific histological changes are occurring within the skin.

Botulinum toxin type A for the treatment of urinary tract dysfunction in neurological disorders.

Botulinum toxin type A injections represent an important therapeutic option for patients with neurogenic urinary dysfunction in whom conservative treatment has not been effective. The nurse's role in ensuring that these patients receive appropriate assessment and treatment is discussed.

An objective assessment of botulinum toxin A effect on superficial skin texture.

The botulinum toxin A (BTX-A) role on elimination of hyperkinetic wrinkles is consolidated, although relying on subjective methods of assessment. A prospective open-label study was performed on 10 patients to objectively analyze superficial skin texture changes caused by BTX-A in the glabellar area. Skin areas were reproduced by silicon replica technique at baseline, 1 month, and 6 months after treatment. Takahashi's parameters (roughness, anisotropy, microsulcus number, and width) were obtained from scanning electron microscopy (SEM) analysis and compared using the Wilcoxon signed rank test. SEM images showed skin texture changes, and software analysis gave parameters for statistical analysis, allowing an objective evaluation. Statistically significant parameter modifications were evidenced. BTX-A effectiveness in wrinkle treatment was confirmed, and no differences in skin texture parameters from baseline to toxin action end were noted.

Anesthesia for intraoperative neurophysiologic monitoring of the spinal cord.

Intraoperative neurophysiologic monitoring (INM) using somatosensory and motor evoked potentials (MEPs) has become popular to reduce neural risk and to improve intraoperative surgical decision making. Intraoperative neurophysiologic monitoring is affected by the choice and management of the anesthetic agents chosen. Because inhalational and intravenous anesthetic agents have effects on neural synaptic and axonal functional activities, the anesthetic effect on any given response will depend on the pathway affected and the mechanism of action of the anesthetic agent (i.e., direct inhibition or indirect effects based on changes in the balance of inhibitory or excitatory inputs). In general, responses that are more highly dependent on synaptic function will have more marked reductions in amplitude and increases in latency as a result of the synaptic effects of inhalational anesthetic agents and similar effects at higher doses of intravenous agents. Hence, recording cortical somatosensory evoked potentials and myogenic MEPs requires critical anesthetic choices for INM. The management of the physiologic milieu is also important as central nervous system blood flow, intracranial pressure, blood rheology, temperature, and arterial carbon dioxide partial pressure produce alterations in the responses consistent with the support of neural functioning. Finally, the management of pharmacologic neuromuscular blockade is critical to myogenic MEP recording in which some blockade may be desirable for surgery but excessive blockade may eliminate responses. A close working relationship of the monitoring team, the anesthesiologist, and the surgeon is key to the successful conduct and interpretation of INM.

Domestic swine model for the assessment of chemical warfare agent-anesthetic interactions: some effects of sulfur mustard.

A domestic swine model was developed to examine the interaction of chemical warfare agents with anesthetics and other drugs used during general anesthesia. Animals were fully instrumented, and clinically relevant physiological parameters were monitored throughout the experimental procedures. Exposure of animals under halothane anesthesia to the chemical warfare agent sulfur mustard (HD; 1 mg/kg intravenous) produced mild signs of systemic intoxication during the subsequent 5 hours. Induction doses of ketamine 1 hour after HD exposure resulted in periods of profound apnea, with continued respiratory distress for the next 2 hours. When animals were treated with HD 1 hour after the initiation of ketamine anesthesia, severe and persistent convulsion-like muscular activity was observed within 45 minutes of HD administration. This nonpurposeful activity was not ameliorated by diazepam but was dramatically reduced or eliminated by resumption of halothane anesthesia. Treatment of HD-intoxicated pigs with succinylcholine produced a prolonged apnea resulting in death. In these apparently mildly HD-intoxicated animals, the introduction of ketamine or succinylcholine can rapidly induce potentially life-threatening situations.