From Molecular Cleavage to Clinical Effect: A Probabilistic Field Model of Botulinum Toxin Action.

Objective To discuss the clinical effect of facial contour remodeling using transplantation of the autologous granular fat grafting combined with botulinum toxin A injection. Methods Negative-pressure liposuction was carried out in the inner thigh or abdomen using liposuction needle connected with an injector, to let stand for layered, discharge lower layer water, rinse, extract the fat particles into a 2 ml syringe, inject into facial depression area with multipoint, multiple-tunnel, and multilayer manner, over injection of about 20%-30% every time. 89 patients received the injection; some accepted two injections; 13 cases were injected in temple (14.6%), and 16 in forehead (17.98%). 30 of them received subcutaneous injection of botulinum toxin A, each side dose was less than 20 U. Results Patients had been followed up for 3-36 months, and obvious improvements were observed in facial contour in the frontal and temporal region as well as the skin texture; the survival rate of fat granule reached to 60%-80%. No hematoma, nodes and infection been observed. Patients combined with botulinum toxin A injection had more ideal facial contour and more satisfaction. Conclusions Autologous fat granules transplantation in the face has stable clinical effect, and combining with botulinum toxin A injection can improve facial contour. It is a safe, ideal treatment in facial rejuvenation and facial contour remodeling and it therefore can be widely recommended in clinical treatment. Key words: Autologous fat grafting; Fat granule; Botulinum toxin A; Contour remodeling

Although left ventricular (LV) pacing has been proposed as an alternative to biventricular (BIV) pacing for heart failure (HF) patients, few comparative data are available on the electromechanical effects of these pacing modalities at mid-term follow-up. To investigate the clinical and echocardiographic effects of LV versus BIV pacing in a mid-term randomized study. After implantation of a device with LV/BIV pacing capabilities, 22 patients with chronic HF and left bundle branch block were randomized to LV or BIV pacing. Patients were assessed both preimplantation and after 3 months by clinical examination, ECG and echocardiography with pulsed tissue Doppler imaging. At 3 months LV pacing improved clinical parameters, LV ejection fraction (+5%, range 5-8%, P = 0.007) and intraventricular dyssynchrony (-40 ms, range -50 to -15 ms, in septal to lateral delay, P = 0.008) to a similar extent to BIV pacing. A decrease in interventricular mechanical delay (-25 ms, range -40 to -5 ms, P = 0.008) and QRS duration (-28 ms, range -40 to -5 ms, P = 0.008) was observed in BIV, but not in LV patients. In this pilot evaluation, LV pacing appeared to be associated with clinical benefits similar to BIV pacing at mid-term follow-up, and this was combined with an improvement in intraventricular dyssynchrony, regardless of variations in interventricular dyssynchrony and QRS duration. Echocardiographic evaluation of intraventricular dyssynchrony seems to be an appropriate method for assessing the chronic response to LV pacing.

There are conflicting reports concerning the variation in duration of symptoms relief for patients with hemifacial spasm who have undergone several injections of botulinum A toxin (BOTX-A). We present our experience of BOTX-A injections in Taiwanese patients to analyze this issues, and to inspect whether the efficacy of treatment depends on the pre-injection severity. From July 1992 to December 1994, 137 patients received injections of BOTX-A. We used objective and subjective score system to evaluate the efficacy and side effects of BOTX-A injection. The overall successful rate of substantial relief of spasm was 88%. The mean duration of response was 20 weeks. Patents with more severe spasm tended to have shorter duration of improvement. The effects of consecutive injections remained fairly constant over the first 4 injections. The BOTX-A injection is an effective and safe treatment for patients with hemifacial spasm and the effect could be sustained over the consecutive injections.

BackgroundAlzheimer’s disease (AD) is a major global health crisis in need of more effective therapies. However, difficult choices to optimize value-based care will need to be made. While identifying preferred therapeutic attributes of new AD therapies is necessary, few studies have explored how preferences may vary between the stakeholders. In this study, the trade-offs among key attributes of amyloid plaque-lowering therapies for AD were assessed using a discrete choice experiment (DCE) and compared between caregivers and neurologists.MethodsAn initial pilot study was conducted to identify the potentially relevant features of a new therapy. The DCE evaluated seven drug attributes: clinical effects in terms of delay in AD progression over the standard of care (SOC), variation in clinical effects, biomarker response (achieving amyloid plaque clearance on PET scan), amyloid-related imaging abnormalities-edema (ARIA-E), duration of therapy, need for treatment titration as well as route, and frequency of drug administration. Respondents were then randomly presented with 12 choice sets of treatment options and asked to select their preferred option in each choice set. Hierarchical Bayesian regression modeling was used to estimate weighted preference attributes, which were presented as mean partial utility scores (pUS), with higher scores suggesting an increased preference.ResultsBoth caregivers (n = 137) and neurologists (n = 161) considered clinical effects (mean pUS = 0.47 and 0.82) and a 5% incremental in ARIA-E (mean pUS = − 0.26 and − 0.52) to be highly impactful determinants of therapeutic choice. In contrast, variation in clinical effects (mean pUS = 0.12 and 0.14) and treatment duration (mean pUS = − 0.02 and − 0.13) were the least important characteristics of any new treatment. Neurologists’ also indicated that subcutaneous drug delivery (mean pUS = 0.42 vs. 0.07) and administration every 4 weeks (mean pUS = 1.0 vs. 0.20) are highly desirable therapeutic features. Respondents were willing to accept up to a 9% increment in ARIA-E for one additional year of delayed progression.ConclusionsCaregivers and neurologists considered incremental clinical benefit over SOC and safety to be highly desirable qualities for a new drug that could clear amyloid plaques and delay clinical progression and indicated a willingness to accept incremental ARIA-E to achieve additional clinical benefits.

Most published literature on the use of botulinum toxin in the treatment of strabismus consists of retrospective studies, cohort studies or case reviews. Although these provide useful descriptive information, clarification is required as to the effective use of botulinum toxin as an independent treatment modality. Six RCTs on the therapeutic use of botulinum toxin in strabismus, graded as low and very low-certainty evidence, have shown varying responses. These include a lack of evidence for effect of botulinum toxin on reducing visual symptoms in acute sixth nerve palsy, poor response in people with horizontal strabismus without binocular vision, similar or slightly reduced achievement of successful ocular alignment in children with esotropia and potential increased achievement of successful ocular alignment where surgery and botulinum toxin are combined. Further high quality trials using robust methodologies are required to compare the clinical and cost effectiveness of various forms of botulinum toxin (e.g. Dysport, Xeomin, etc), to compare botulinum toxin with and without adjuvant solutions and to compare botulinum toxin to alternative surgical interventions in strabismus cases with and without potential for binocular vision.

Objective To develop a method for dynamically observing the biological efficacy of botulinum toxin A (BTX-A) and to investigate the dose-effect relationship between BTX-A dosage and muscle strength.Methods Fifty-four male Sprague Dawley rats were randomly divided into 9 groups.Groups 1-7 were injected intramuscularly with 0.1 ml BTX-A (0.01 U to 4.0 U) into the gastrocnemius on the right side.Rats in group 8 were injected intramuscularly with an equal volume of saline solution as the control group,and group 9 was used to determine the location of injection.Gastrocnemius muscle strength was evaluated using a self-made evaluation system before and after the toxin injection and on the 3rd,7th,14th,21st,30th,45th,60th and 75th day following.Results Muscle strength reached its lowest level on days 3 to 7,with a significant difference in the decline of muscle strength between the test groups and the control group up to day 60.With the lower BTX-A doses (0.01 U,0.1 U,0.5 U,1.0 U),muscle strength had decreased significantly on the 21st day,but recovered to its initial levels in all groups at the same time.There was no significant difference among the 1.0 U,1.5 U,2.0 U and 4.0 U groups. Conclusions Standardized gastrocnemius injection combined with neuromuscular functional evaluation can establish a model of BTX-A dosage and muscle paralysis which can be used to assess the evolution of the biological efficacy of BTX-A. Key words: Botulinum toxin A ; Biological efficacy; Dose-response relationships

Objective To explore the therapeutic effect of different doses of botulinum toxin A injections on bromhidrosis. Methods A total of 200 cases were divided into mild-to-moderate group (N=100) and severe group (N=100) based on the grade of bromhidrosis, and each group was further divided into two groups: low dose group (50 cases) were treated by botulinum toxin A injections (100 U) and high dose group (50 cases) were treated with 200 U for bilateral axillary. The total effective rate and recurrence rate in both groups were compared. Results In the mild to moderate group, after treatment for 3 months, the total effective rate of both groups had no statistical difference (P>0.05), and the same with recurrence rate in 6 months follow-up (P>0.05). In the severe group, after treatment for 3 months, the total effective rate of the high dose group (82%) was significantly higher than that of the low dose group (64%), with statistical significance (χ2=4.110, P<0.05). After 6 months follow-up, recurrence rate in the high dose group (22%) was significantly lower than that of the low dose group(46%), with statistical significance (χ2=6.417, P<0.05). Conclusions A suitable dose of botulinum toxin A can be selected based on the severity of bromhidrosis, which is a individualized therapy for cost savings and might have potential benefits for patients with osmidrosis. Key words: Bromidrosis; Botulinum toxins, type A; Dose-response relationship, drug; Treatment outcome; Disease classification

Journal-related Activities at the 2003 American Society of Anesthesiologists Annual Meeting

Allocation trade-offs of limited resources are thought to ensure the honesty of sexual signals and are often studied using controlled immune challenges. One such trade-off between immunity and ornaments is that involving carotenoids. Phytohemagglutinin (PHA)-induced immune response is a widely used immune challenge, yet more details on the underlying physiological mechanisms and potential costs are needed. We investigated the temporal dynamics of PHA-induced immune response and associated changes in blood carotenoids, body mass and a carotenoid-based coloured signal. We found variation in individual response patterns to PHA after peak swelling was reached, with birds showing either a rapid or a slow subsequent decrease in swelling, suggesting variation in the duration of the immune response and/or inflammation. Body mass did not affect immune response. Plasma carotenoids followed a transient decrease closely matching the dynamics of the swelling. The peak of the immune response was negatively related to initial plasma carotenoid levels and positively correlated to the relative decrease in plasma carotenoids. Individual variation in duration of the swelling could be partly explained by plasma carotenoids; high initial carotenoid levels were associated with a slower decrease of the swelling. These contradictory effects of carotenoids suggest a complex role in the immune response. Bill colour was positively correlated to initial plasma carotenoid concentration but it did not predict or change as a consequence of immune response to PHA. Bill colour thus reflects medium- or long-term quality rather than immediate quality. Taking into account the dynamics of the immune response and that of associated physiological parameters would thus yield new insights into our interpretation of variation in PHA response.

This study was proposed to evaluate the facial contour and electrophysiologic changes of the masseter and temporalis muscles before and after botulinum toxin A injection in the wide lower face (square face). The botulinum toxin A injections were performed on 10 patients for the treatment of square face with masseter hypertrophy. To obtain an objective evaluation of the change in the facial contour, physical measurements, cephalometry, and clinical photographs were taken; and for evaluation of the function of the masseter and temporalis muscles, electromyographic studies were performed before and 1, 3, 5, 7, 9, and 12 months after treatment. By physical measurements and cephalometry, the maximal reduction in lower facial contour (mean reduction, 6.6 mm by physical measurements and 7.5 mm by cephalometry) was observed 3 months after the injection, and increased slowly until 12 months after treatment. The maximal amplitude of the right and left masseter muscles decreased to the lowest value 1 month after treatment, with continuous increase being observed thereafter. There were statistically significant differences at all of the follow-up time points in reduction of lower facial contour by physical measurements and in electromyographic studies of the left masseter muscles. There was no hypertrophy of the temporalis muscle to compensate for the atrophy of the masseter muscles. In this study, there was a 2-month interval between the lowest value of the maximal amplitude of the surface electromyography and the maximal clinical effects following botulinum toxin A injection, and there was similarity between the recovery of the masseter function and the diminution of the clinical effect. The clinical effect of botulinum toxin A persisted for 12 months after treatment on physical measurements, and the authors felt that this long-lasting effect of botulinum toxin A beyond expectation could be explained by incomplete recovery of muscle function.

Background: Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms (EPS). They also, by binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics given in dosages within the clinically effective range do not bring about these adverse clinical effects. To understand how these drugs work, it is important to examine the atypical antipsychotics’ mechanism of action and how it differs from that of the more typical drugs. Method: This review analyzes the affinities, the occupancies, and the dissociation time-course of various antipsychotics at dopamine D2 receptors and at serotonin (5-HT) receptors, both in the test tube and in live patients. Results: Of the 31 antipsychotics examined, the older traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine, fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine. These tight and loose binding data agree with the rates of antipsychotic dissociation from the human-cloned D2 receptor. For instance, radioactive haloperidol, chlorpromazine, and raclopride all dissociate very slowly over a 30-minute time span, while radioactive quetiapine, clozapine, remoxipride, and amisulpride dissociate rapidly, in less than 60 seconds. These data also match clinical brain-imaging findings that show haloperidol remaining constantly bound to D2 in humans undergoing 2 positron emission tomography (PET) scans 24 hours apart. Conversely, the occupation of D2 by clozapine or quetiapine has mostly disappeared after 24 hours. Conclusion: Atypicals clinically help patients by transiently occupying D2 receptors and then rapidly dissociating to allow normal dopamine neurotransmission. This keeps prolactin levels normal, spares cognition, and obviates EPS. One theory of atypicality is that the newer drugs block 5-HT2A receptors at the same time as they block dopamine receptors and that, somehow, this serotonin-dopamine balance confers atypicality. This, however, is not borne out by the results. While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs (with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada) the dosages at which this happens are below those needed to alleviate psychosis. In fact, the antipsychotic threshold occupancy of D2 for antipsychotic action remains at about 65% for both typical and atypical antipsychotic drugs, regardless of whether 5-HT2A receptors are blocked or not. At the same time, the antipsychotic threshold occupancy of D2 for eliciting EPS remains at about 80% for both typical and atypical antipsychotics, regardless of the occupancy of 5-HT2A receptors. Relevance: The “fast-off-D2” theory, on the other hand, predicts which antipsychotic compounds will or will not produce EPS and hyperprolactinemia and which compounds present a relatively low risk for tardive dyskinesia. This theory also explains why l-dopa psychosis responds to low atypical antipsychotic dosages, and it suggests various individualized treatment strategies.

Facial wound healing often results in unsatisfactory scarring with significant aesthetic and psychological impact. Botulinum toxin A (BTX-A) has appeared as a promising intervention to improve cosmetic outcomes by reducing muscle tension during wound healing. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of BTX-A in facial wound management. We conducted a detailed scientific literature database from inception to 15th of May, 2025, following PRISMA 2020 guidelines. All eligible studies comparing BTX-A with control interventions for facial wound healing were included. Primary outcomes were visual analog scale (VAS) scores and scar width measurements. Secondary outcomes included Vancouver Scar Scale scores, patient satisfaction, and adverse events. Meta-regression investigated dose-response relationships. Fifteen studies with total of 607 participants met inclusion criteria. Botulinum toxin A significantly improved VAS scores (standardized mean difference 0.87, 95% CI: 0.45-1.29, P-value<0.001) and reduced scar width by 0.35mm (95% CI: -0.52 to -0.18, P-value<0.001). Meta-regression (R²=24%, P-value=0.032) demonstrated a dose-response relationship with effect size increasing by 0.08 SMD units per U/cm. The 5 to 15U/cm range was identified through safety-efficacy modeling, where doses <5U/cm showed suboptimal efficacy (SMD 0.65), 5 to 15U/cm achieved optimal balance (SMD 0.78-1.18, adverse events 1.1%-6.2%), and >15U/cm showed diminishing returns with increased adverse events. Adverse event rates were comparable between groups (3.9% versus 3.4%, P-value=0.75), with no serious complications reported. Botulinum toxin A demonstrates significant efficacy in improving facial wound cosmetic outcomes with an excellent safety profile. Evidence-based dosing of 5 to 15U/cm provides the best benefit-risk ratio. On the basis of cost-effectiveness evaluation of included studies, the intervention demonstrates favorable benefit-risk ratios for wounds in high-visibility facial areas, with economic modeling suggesting better utility for longer wounds where scar prevention outweighs treatment costs.

Botulinum toxin injected into a muscle may diffuse to nearby muscles thus producing unwanted effects. In patients with hemifacial spasm, we evaluated clinically and neurophysiologically, whether botulinum toxin type A (BoNT-A) diffuses from the injection site (orbicularis oculi) to untreated muscles (orbicularis oris from the affected side and orbicularis oculi and oris from the unaffected side). We studied 38 patients with idiopathic hemifacial spasm. Botulinum toxin was injected into the affected orbicularis oculi muscle alone (at 3 standardized sites) at a clinically effective dose. Patients were studied before (T0) and 3-4 weeks after treatment (T1). We evaluated the clinical effects of botulinum toxin and muscle strength in the affected and unaffected muscles. We also assessed the peak-to-peak amplitude compound muscle action potential (CMAP) recorded from the orbicularis oculi and orbicularis oris muscles on both sides after supramaximal electrical stimulation of the facial nerve at the stylomastoid foramen. In all patients, botulinum toxin treatment reduced muscle spasms in the injected orbicularis oculi muscle and induced no muscle weakness in the other facial muscles. The CMAP amplitude significantly decreased in the injected orbicularis oculi muscle, but remained unchanged in the other facial muscles (orbicularis oris muscle on the affected side and contra-lateral unaffected muscles). In conclusion, in patients with hemifacial spasm, botulinum toxin, at a clinically effective dose, induces no clinical signs of diffusion and does not reduce the CMAP size in the nearby untreated orbicularis oris or contralateral facial muscles.

Overactive bladder (OAB) is a symptom syndrome including urgency, frequency, and nocturia – with or without incontinence. It is a common manifestation of detrusor overactivity (DO). DO is a urodynamic observation of spontaneous or provoked contractions of the detrusor muscle is seen during the filling phase of the micturition cycle. OAB is, therefore, both a motor and sensory disorder. Botulinum toxin is a purified form of the neurotoxin from Clostridium botulinum and has been used in medicine for many years. Over the last 10 years, it has been used for the treatment of DO and OAB when standard treatments, such as bladder training and oral anticholinergic medication, have failed to provide symptom relief. Botulinum toxin acts by irreversibly preventing neurotransmitter release from the neurons in the motor end plate and also at sensory synapses, although the clinical effect is not permanent due to the growth of new connections within treated tissues. It is known that botulinum toxin modulates vanillioid, purinergic, capsaicin, and muscarinic receptor expression within the lamina propria, returning them to levels seen in normal bladders. Clinically, the effect of botulinum toxin on symptoms of OAB and DO is profound, with large effects upon the symptom of urgency, and also large effects on frequency, nocturia, leakage episodes, and continence rates. These effects have been seen consistently within eight randomized trials and numerous case series. Botulinum toxin appears safe, with the only common side effect being that of voiding difficulty, occurring in up to 10% of treated patients. Dosing regimens are variable, depending on which preparation is used, but it is clear that dose recommendations have fallen over the last 5 years. There is limited evidence about the efficacy of repeat treatments. Botulinum toxin is an effective and safe second-line treatment for patients with OAB and DO.

Botulinum toxin (BoNT) is the most potent neurotoxin known, and its clinical effects have been recognized since the end of 19th century. There are seven immunologically distinct serotypes of botulinum toxin; there are two types in routine clinical use - BoNT type A (BoNT-A) and BoNT type B (BoNT-B). Most of the large-scale studies on botulinum toxin have been related to upper and lower limb spasticity. The usefulness of BoNT in the management of spasticity secondary to a variety of clinical conditions is increasing. It is now well accepted for the management of movement disorders, particularly dystonia. There is an increasing evidence base for the use as a management tool in spasticity. The products now have a licence for use in focal spasticity. Dysport is indicated for focal spasticity specifically including arm symptoms associated with focal spasticity in conjunction with physiotherapy.