Pharmacokinetics and pharmacodynamics of incobotulinumtoxinA influencing the clinical efficacy in post-stroke spasticity

Introduction: Post-stroke spasticity is a disabling neurological condition and may have a significant impact on quality of life. Ability to carry out activities of daily living is often compromised and painful contractures in the affected limbs may also develop. The prevalence of spasticity may be as high as 40% within the first year after the initial stroke event. Management of this condition focuses on improving muscle tone, function and pain. IncobotulinumtoxinA is effective in treating focal spasticity.

Areas covered: This review will summarize outcomes from incobotulinumtoxin A phase III trials in upper limb spasticity. Pharmacodynamics and pharmacokinetics will also be discussed along with future studies and possible indications. Literature searches used for this review include; PubMed and www.clinicaltrials.gov searches. Congress abstracts and case reports are not included.

Expert opinion: IncobotulinumtoxinA, is a 150 kiloDalton neurotoxin without complexing proteins and is well tolerated in patients with spasticity. There is an 80% improvement reported on spasticity and disability in several phase III studies. In the future, higher doses for upper and lower limb spasticity may be considered. Antibody formation does not seem to limit the administration of higher doses. Prospective studies are evaluating the efficacy of incobotulinumtoxin in children and adolescents with cerebral palsy. Furthermore, the clinical efficacy and immunogenic status of other botulinum neurotoxin A subtypes are currently under investigation.     

Botulinum toxin A treatment of adult upper and lower limb spasticity

This article discusses the treatment of spasticity with botulinum toxin A as a new approach in the neurological rehabilitation of patients after stroke. Clinical studies have been reviewed to provide information about target groups, technical aspects and the advantages and disadvantages of treating spasticity with botulinum toxin A. Open and controlled studies showed that the intramuscular injection of Dysport 500 to 1,500U or Botox 100 to 300U could reversibly relieve upper limb flexor and lower limb extensor spasticity. A reduced muscle tone, pain relief, better hand hygiene and improved walking function were the main benefits. Patients tolerated the treatment well. Activity or, if not possible, electrical stimulation of the injected muscles may enhance the effectiveness of the costly toxin. Serial casting is another option. With respect to the action of botulinum toxin A, it is suggested that the effect of the toxin could be mediated by paresis of both the extrafusal and intrafusal muscle fibres, thereby altering the afferent discharge in the muscle.     

Botulinum toxin treatment of adult spasticity : a benefit-risk assessment.

Injections of botulinum toxin have revolutionised the treatment of focal spasticity. Before their advent, the medical treatment for focal spasticity involved oral anti-spasticity drugs, which had decidedly non-focal adverse effects, and phenol injections. Phenol injections could be difficult to perform, could cause sensory complications and had effects that were of uncertain duration and magnitude. Furthermore, few neurologists knew how to perform them as they were mostly the province of rehabilitation specialists. Botulinum toxin can produce focal, controllable muscle weakness of predictable duration, without sensory adverse effects.Randomised clinical trials (RCTs) involving patients with spasticity resulting from a variety of diseases (mainly stroke and multiple sclerosis) have clearly shown that botulinum toxin type A (Dysport and Botox) can temporarily (for approximately 3 months) reduce spastic hypertonia in the elbow, wrist and finger flexors of the upper limbs, and the hip adductors and ankle plantar flexors in the lower limbs. The clinical benefits from this reduction of neurological impairment are best shown in the upper limb, with less disability of passive function and reduced caregiver burden. In the lower limbs, there is improved perineal hygiene from hip adductor injections. The benefits of reducing ankle plantar flexor tone are less well established. Pain is also reduced, possibly by mechanisms other than muscle weakness. Improved active function has not yet been clearly demonstrated in RCTs, only in open-label trials. The safety of botulinum toxin-A is impressive, with minimal (mainly local) adverse effects.There are little data on the use of botulinum toxin type B (Myobloc or Neurobloc) in spasticity and the only RCT that has examined this did not show tone reduction; dry mouth appeared to be a very common adverse effect. There are also very little data to allow a benefit-risk comparison of phenol and botulinum toxin injections; each have their clinical and technical advantages and disadvantages, and phenol is much less costly than botulinum toxin.     

High Doses of Botulinum Toxin Type A for the Treatment of Post-Stroke Spasticity: Rationale for a Real Benefit for the Patients

In the past few years, there was a great interest in the use of higher doses of botulinum toxin type A, especially in case of upper and lower limb severe spasticity. To date, only one prospective, non-randomized, single-arm, multicenter, open-label, dose-titration study with the employment of incobotulinum toxin up to 800 U has been published, and the authors investigated safety and tolerability. Other researches showed efficacy in spasticity reduction, but there is a lack of evidence about the reasons to use high doses of botulinum toxin. This short communication highlights the benefits of higher doses for subjects with upper and lower limb spasticity.     

Botulinum toxin type A in post-stroke upper limb spasticity

Abstract

Objective:

To evaluate the efficacy and safety of one-time injections of botulinum toxin type A (BoNTA) in Japanese patients with post-stroke upper limb spasticity.     

Electrical Stimulation of Injected Muscles to Boost Botulinum Toxin Effect on Spasticity: Rationale,Systematic Review and State of the Art

Botulinum toxin type A (BoNT-A) represents a first-line treatment for spasticity, a common disabling consequence of many neurological diseases. Electrical stimulation of motor nerve endings has been reported to boost the effect of BoNT-A. To date, a wide range of stimulation protocols has been proposed in the literature. We conducted a systematic review of current literature on the protocols of electrical stimulation to boost the effect of BoNT-A injection in patients with spasticity. A systematic search using the MeSH terms “electric stimulation”, “muscle spasticity” and “botulinum toxins” and strings “electric stimulation [mh] OR electrical stimulation AND muscle spasticity [mh] OR spasticity AND botulinum toxins [mh] OR botulinum toxin type A” was conducted on PubMed, Scopus, PEDro and Cochrane library electronic databases. Full-text articles written in English and published from database inception to March 2021 were included. Data on patient characteristics, electrical stimulation protocols and outcome measures were collected. This systematic review provides a complete overview of current literature on the role of electrical stimulation to boost the effect of BoNT-A injection for spasticity, together with a critical discussion on its rationale based on the neurobiology of BoNT-A uptake.     

Treatment options for deep vein thrombosis

Importance of the field: Anticoagulation is the main therapy for acute deep vein thrombosis (DVT) of the limbs. Over the last five decades, there has been little progress in the development of oral anticoagulant therapies. More recently, we have been experiencing a rapidly changing situation thanks to the development of new orally active anticoagulants.

Areas covered in this review: The aim of this review is to highlight main published data on direct thrombin and FXa inhibitors. The electronic database PubMed website and abstract proceedings were used to identify studies.

What the reader will gain: The main characteristics of these new classes of anticoagulant drugs, the development program of the most advanced molecules and the most recent published data on Phase III trials on DVT treatment for both the acute phase and the secondary prevention of the disease are reviewed.

Take home message: Oral administration, predictable anticoagulant responses, low potential for drug–drug interactions and first published clinical data render direct thrombin and factor Xa inhibitors good candidates to replace oral vitamin K antagonist and low molecular weight heparins for DVT treatment.     

Spasticity associated with cerebral palsy in children: guidelines for the use of botulinum A toxin

Botulinum A toxin produces selective and reversible chemodenervation that can be employed to balance muscle forces across joints in children with cerebral palsy (CP). Currently, there are two commercially available botulinum A toxin formulations (BOTOX) and Dysport). The amount of botulinum A toxin required depends upon the number of muscles that are targeted, and the size of the patient. In order to achieve adequate chemodenervation with botulinum A toxin, the following conditions must be met: (i) a sufficient number of units of toxin must be injected in order to neutralize neuromuscular junction (NMJ) activity; (ii) an appropriate drug volume is required in order to optimize the delivery of the toxin to the NMJs; and (iii) localization of the injecting needle through the fascia of the target muscle is necessary. Localization of the injection may be facilitated by active electromyography, ultrasonography, palpation of the muscle belly, and/or use of anatomic landmarks. Botulinum A toxin injections are indicated for use in pediatric patients with CP to: (i) improve motor function by balancing muscle forces across joints; (ii) improve health-related quality of life by decreasing spasticity and/or decreasing caregiver burden; (iii) decrease pain from spasticity; (iv) enhance self-esteem by diminishing inappropriate motor responses; and (v) provide a presurgical diagnostic tool. Following intramuscular injections of botulinum A toxin, short-term benefits of reduced spasticity are observed in approximately 70-82% of children. The intermediate term (1-2 years) efficacy rate is approximately 50%. The most common deformity treated with toxin injections in pediatric patients with CP is equinus foot deformity. However, efficacy of toxin injections for the management of crouched gait, pelvic flexion contracture, cervical spasticity, seating difficulties, and upper extremity deformity also has been documented. In addition, toxin injections have been shown to manage painful muscle spasticity associated with surgery or application of casts and painful cervical spasticity with or without dystonia. Toxin injections can also be used as a diagnostic tool to determine the appropriateness of other interventions by observing the muscle response to the injection in order to gain additional information for the development of a treatment plan. Botulinum A toxin, when used in appropriate doses, is well tolerated.     

Effects of educational interventions on the smoking cessation service provided by community pharmacists: A systematic review

ObjectiveThis systematic review aimed to evaluate the effectiveness of educational interventions on the smoking cessation service provided by community pharmacists.MethodsA systematic literature search was performed in May–July 2021, in electronic databases, which included PubMed (MEDLINE), Embase, and Web of Science. Studies were included in this systematic review if they were original articles published in English language from 2010 to 2021 and evaluated the effect of any types of educational interventions intended to improve the ability of community pharmacists to provide smoking cessation services.ResultsIn total, 12 studies were included for this systematic review. The effectiveness of the educational interventions across the included studies was measured using a range of outcomes, which can be broadly categorized into 3 categories, namely changes in pharmacists' self-efficacy, knowledge, and attitude toward providing smoking cessation service, changes in pharmacists' smoking cessation practices, and changes in the effectiveness of community pharmacy based smoking cessation services. Included studies reported that educational interventions can improve pharmacists' self-efficacy, knowledge, and attitude toward smoking cessation, as well as pharmacists’ smoking cessation practices. Though the evidence is limited, improvement in the effectiveness of community pharmacy based smoking cessation services has also been observed.ConclusionAny form educational interventions can positively impact improve community pharmacists' self-efficacy, knowledge, and attitude toward smoking cessation, as well as pharmacists’ smoking cessation practices, but it is currently uncertain whether these outcomes are able to translate into higher effectiveness of the community pharmacy based smoking cessation services.     

A practical overview of tizanidine use for spasticity secondary to multiple sclerosis,stroke, and spinal cord injury

ABSTRACT

Objective: Tizanidine is an imidazoline central α₂-adreno­ceptor agonist widely used to manage spasticity secondary to conditions such as multiple sclerosis (MS), stroke, and spinal cord injury (SCI). While there is wide­spread use of tizanidine in clinical practice, little practical information is available to assist prescribers with the effective use of tizanidine for spasticity management. The aim of this review is to provide an up-to-date overview of tizanidine and its use in the management of spasticity associated with acquired (SCI), static (stroke), and progressive neurological (MS) diseases.

Scope: An unfiltered literature search of the term ‘tizanidine’ was undertaken on the Medline database resulting in 311 papers. As the review focused on tizanidine clinical pharmacokinetics, efficacy, and tolerability, with comparisons limited to the oral antispastic agents baclofen, diazepam, and dantrolene, 53 articles were selected for detailed assessment.

Findings: Tizanidine, an α₂-adrenoceptor agonist, is a short-acting drug with larger interpatient variability, and linear pharmacokinetics that is dosage form-dependent. Clinical trials have demonstrated that the efficacy of tizanidine is comparable to that of baclofen or diazepam with global tolerability data favoring tizanidine. A clinical case presentation demonstrated the effective use of tizanidine in combination with baclofen as a logical avenue for improved spasticity control.

Conclusions: There is a large body of evidence for the effective use of tizanidine monotherapy in the manage­ment of spasticity. A case study demonstrates that combination therapy can effectively control spasticity while better managing dose-dependant adverse events, although additional studies need to be performed to confirm these results.     

Therapeutic potential of the chemokine–receptor duo fractalkine/CX3CR1: an update

Introduction: The chemokine fractalkine/CX3CL1 and its highly selective receptor CX3CR1 mediate critical physiological events during inflammatory responses. The fractalkine/CX3CR1 axis has been shown to play a key role in the pathogenesis and the progression of a large number of diseases in which imbalance of the immune response is frequently seen. Since our last review published in early 2010, the fractalkine/CX3CR1 axis has gained vast attention as a potential therapeutic target in the scientific community, which can be clearly seen in the large number of studies that have been published on this issue since then.

Areas covered: A Medline/PubMed search was performed to detect all recently published studies on the role of the fractalkine/CX3CR1 axis as a therapeutic target in a wide range of clinical diseases.

Expert opinion: Recently published studies further underline the high potential of the fractalkine/CX3CR1 axis as a major target for future treatment of pain, inflammation and cancer. However, no clinical trials on novel therapeutics targeting fractalkine or CX3CR1 have been initiated so far, so that the fractalkine/CX3CR1 axis does still not find application in daily clinical practice.     

Steroids in regional analgesia

Importance of the field: Local injections of steroids have been widely practiced to provide regional analgesia for the treatment of a wide variety of musculoskeletal pain syndromes. However, evidence regarding the effectiveness of steroid injections is not substantial. Also, there have been reports of catastrophic complications associated with their use.

Areas covered in this review: The evidence currently available in the literature (Database: Ovid MEDLINE 1950 to 2010) is reviewed. The areas covered include the analgesic mechanisms of steroids, indications for steroid injections and their effectiveness, as well as the risks and precautions for steroid injections.

What the reader will gain: This is an up-to-date review on the clinical application of steroid injections for regional analgesia, which will give the reader an insight on how to maximize the benefits of steroids while minimizing their side effects and complications.

Take home message: Although steroid injections are generally considered effective and safe in the treatment of painful condition of limbs, their use in the treatment of chronic back pain is still controversial and serious complications have been reported. More studies on outcome and safety are warranted.     

Post Hoc Subgroup Analysis of the BCause Study Assessing the Effect of AbobotulinumtoxinA on Post-Stroke Shoulder Pain in Adults

AbstractBotulinum toxin type A is approved for the focal treatment of spasticity; however, the effectiveness of abobotulinumtoxinA (aboBoNT-A) in patients with shoulder pain who have set reduced pain as a treatment goal is understudied. In addition, some patients encounter delays in accessing treatment programs; therefore, the suitability of aboBoNT-A for pain reduction in this population requires investigation. These factors were assessed in aboBoNT-A-naive Brazilian patients in a post hoc analysis of data from BCause, an observational, multicenter, prospective study ({"type":"clinical-trial","attrs":{"text":"NCT02390206","term_id":"NCT02390206"}}NCT02390206). Patients (N = 49, n = 25 female; mean (standard deviation) age of 60.3 (9.1) years; median (range) time since onset of spasticity of 16.1 (0–193) months) received aboBoNT-A injections to shoulder muscles in one or two treatment cycles (n = 47). Using goal attainment scaling (GAS), most patients achieved their goal of shoulder pain reduction after one treatment cycle (72.1%; 95% confidence interval: 57.2–83.4%). Improvements in GAS T-score from baseline, clinically meaningful reductions in pain score at movement, and clinically meaningful increases in passive shoulder abduction angle further improved with repeated treatment more than 4 months later, despite treatment starting at a median of 16.1 months after the onset of spasticity. These findings support the further investigation of aboBoNT-A injections in chronic post-stroke shoulder pain.Plain Language SummaryAfter a stroke, patients often experience shoulder pain, which can lead to difficulty with arm movement and interfere with their rehabilitation. Some patients also experience difficulty or delays in receiving treatment. Botulinum toxin injections can be used to improve muscle pain and function. The BCause trial looked at how one or two doses of a specific type of botulinum toxin injection, called abobotulinumtoxinA (aboBoNT-A), into shoulder muscles could help patients with shoulder pain following a stroke. This analysis of the BCause trial included 49 Brazilian patients aged 18–80 years who had suffered a stroke in the previous year and who set reduced shoulder pain as a goal of their treatment. They had not previously received any botulinum toxin injections. The researchers looked at how helpful the injections were by using a scale that measured how well each patient achieved their treatment goal. Additionally, researchers measured pain levels, muscle tone, range of shoulder movement, and quality of life before and after treatment. The results showed that aboBoNT-A injections helped most patients to reach their goal of reduced shoulder pain. Patients receiving repeated aboBoNT-A injections experienced further improvements in how much they could move their shoulder after more than 4 months compared with at the start of the study. Patients’ and caregivers’ quality of life was also improved after treatment compared with before. The researchers considered these results to be clinically meaningful—that is, the improvements with aboBoNT-A were likely to provide a real benefit for patients, caregivers, and clinicians.     

Rattlesnake Neurotoxins: Biochemical and Biological Aspects

Abstract

A number of rattlesnake venoms contain potent neurotoxic protein complexes that have phospholipase A₂ activity. Data derived from studies of some of these neurotoxins indicate that neuromuscular transmission is blocked. The primary action appears to be at presynaptic sites, but at high doses interactions with cholinergic receptors reduce postsynaptic responses. The toxin complexes are mixtures of closely related isoforms, each composed of two distinct and separable subunits. The basic protein subunit is a phospholipase which is somewhat toxic whereas the acidic constituent is devoid of toxicity and lacks enzymatic activity. Even though the two subunits have quite different structures, they have considerable sequence similarity, suggesting a common ancestral origin. The acidic subunit enhances the lethal potency of the basic phospholipase component when the two are combined to generate a reconstituted toxin. Evidence suggests the acidic subunit reduces nonspecific binding of the basic phospholipase to membranes, thereby restricting binding of the neurotoxic component to specific sites on toxin sensitive membranes.

This class of toxins has not been used extensively to study subcellular membrane vesicles or cultured cells. Results from some of our studies with isolated rat brain synaptosomes demonstrated that Mojave toxin and the basic subunit isolated from Mojave toxin alter the uptake and release of neurotransmitters. Recent unpublished studies with cultured muscle cells showed marked effects on the fusion process in which primary myoblasts form myotubes. The toxin also reduces the formation of colonies from several clonal myoblast cell lines. The biochemical bases for these observations remain to be determined.     

Unlabeled uses of botulinum toxins: a review, part 1.

PURPOSE: Efficacy and safety data regarding the unlabeled uses of botulinum toxins are reviewed, and the pharmacology, adverse effects, and characteristics of commercially available botulinum toxins are discussed. SUMMARY: More than 300 articles have been published on the use of botulinum toxins, particularly botulinum toxin type A, to treat conditions characterized by excessive smooth or skeletal muscle spasticity. Botulinum toxins are synthesized by Clostridium botulinum and cause temporary local paralysis of the injected muscle by inhibiting acetylcholine release at the neuromuscular junction. While botulinum toxins have Food and Drug Administration-approved labeling to treat a limited number of spasticity disorders, including cervical dystonia and blepharospasm, the toxins have more than 50 reported therapeutic uses. Among these uses, the most rigorously studied indications include achalasia, essential tremors, palmar hyperhidrosis, chronic anal fissures, headache prophylaxis, and limb spasticity. The main adverse effects of the toxins are pain and erythema at the injection site, although unintended paralysis of muscles adjacent to the site of toxin injection may also occur. CONCLUSION: Clinical studies support the use of botulinum toxins for certain conditions, although more studies are needed to establish the role of the drug relative to conventional therapies and to determine patient predictors of response. Although botulinum toxins are generally well tolerated, a patient-specific risk-benefit assessment should precede any decision to use them for unlabeled indications.     

Unlabeled uses of botulinum toxins: a review, part 2.

PURPOSE: Efficacy and safety data regarding the unlabeled uses of botulinum toxins are reviewed, and the pharmacology, adverse effects, and characteristics of commercially available botulinum toxins are discussed. SUMMARY: More than 300 articles have been published on the use of botulinum toxins, particularly botulinum toxin type A, to treat conditions characterized by excessive smooth or skeletal muscle spasticity. Botulinum toxins are synthesized by Clostridium botulinum and cause temporary local paralysis of the injected muscle by inhibiting acetylcholine release at the neuromuscular junction. While botulinum toxins have Food and Drug Administration-approved labeling to treat a limited number of spasticity disorders, including cervical dystonia and blepharospasm, the toxins have more than 50 reported therapeutic uses. Among these uses, the most rigorously studied indications include achalasia, essential tremors, palmar hyperhidrosis, chronic anal fissures, headache prophylaxis, and limb spasticity. The main adverse effects of the toxins are pain and erythema at the injection site, although unintended paralysis of muscles adjacent to the site of toxin injection may also occur. CONCLUSION: Clinical studies support the use of botulinum toxins for certain conditions, although more studies are needed to establish the role of the drug relative to conventional therapies and to determine patient predictors of response. Although botulinum toxins are generally well tolerated, a patient-specific risk-benefit assessment should precede any decision to use them for unlabeled indications.     

Drug monitoring and individual dose optimization of antimicrobial drugs: oxazolidinones

Introduction: Oxazolidinones are synthetic antibiotics with bacteriostatic activity against Gram-positive pathogens. Linezolid, the first marketed oxazolidinone, has shown also activity against Mycobaterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Recently, a second agent of this class (tedizolid) has been approved for the treatment of acute bacterial skin and skin structure infections, and other oxazolidinones are under active investigation in clinical trials.

Areas covered: In the present review, we consider factors that affect oxazolidinones pharmacokinetics and their role in reducing the effectiveness of these drugs and increasing the risk of drug-related adverse events. Furthermore, we review the potential role of strategies aimed at individualizing drug doses. A MEDLINE PubMed search for articles published from January 1990 to November 2015 was completed matching the terms oxazolidinones, linezolid, or tedizolid with pharmacokinetics, therapeutic drug monitoring, pharmacology or clinical trials. Moreover, additional studies were identified from the reference list of retrieved papers.

Expert opinion: Consistent evidence is now available showing that therapeutic drug monitoring and guided individual dose optimization of linezolid is justified and feasible in clinical practice to improve tolerability and possibly response to therapy. The role of individualized drug dosing regimens for other oxazolidinones remains to be proven.     

Opioid antagonists for pain

Introduction: Opioid receptor antagonists are well known for their ability to attenuate or reverse the effects of opioid agonists. This property has made them useful in mitigating opioid side effects, overdose and abuse. Paradoxically, opioid antagonists have been reported to produce analgesia or enhance analgesia of opioid agonists. The authors review the current state of the clinical use of opioid antagonists as analgesics.

Areas covered: Published clinical trials, case reports and other sources were reviewed to determine the effectiveness and safety of opioid antagonists for use in relieving pain. The results are summarized. Postulated mechanisms for how opioid antagonists might exert an analgesic effect are also briefly summarized.

Expert opinion: Since the comprehensive review by Leavitt in 2009, few new studies on the use of opioid antagonists for pain have been published. The few clinical trials generally consist of small populations. However, there does appear to be a trend of effectiveness of low doses (higher doses antagonize opioid agonist effects). How opioid antagonists can elicit an analgesic effect is still unclear, but a number of possibilities have been suggested. Although the data do not yet support recommendation of widespread application of this off-label use of opioid antagonists, further study appears worthwhile.     

The effectiveness of direct to healthcare professional communication – A systematic review of communication factor studies

BackgroundDirect to healthcare professional communication (DHPC) is the prevalent regulatory measure to inform about and potentially mitigate newly identified drug risks in EU and USA. According to multiple studies and reviews, however, the effectiveness of DHPC to reduce risk is less than optimal. Prior systematic reviews have indicated that contextual, qualitative knowledge of communication factors related to the clinical setting is needed to further explain and supplement findings in quantitative effectiveness studies.ObjectivesThis article systematically reviews studies of DHPC and, on that basis, describes the communication factors that influence the effectiveness of DHPC in order to discuss future research trajectories.MethodsPubMed, Scopus (including Embase) and Web of Science databases were searched for studies on communication about emergent drug risk to healthcare professionals, excluding studies limited to the quantifiable effect of communication. The search results were deductively categorized using the Communication Sequence Model. Then, prevalent themes within categories were identified and described using thematic analysis.ResultsA total of 16 studies published between 1993 and 2017 were included; 12 based on surveys, 2 on document analysis, and 2 primarily on interviews. The prevalent themes included “Health Care Professionals (HCPs) have less trust in communication from industry than authorities and medical associations”, “HCPs have diverse preferences for how to receive drug risk information” and “Clinical usability of the presented information is less than optimal.”ConclusionCommunication factors in DHPCs are multiple, multi-facetted and are examined primarily by surveys. Future research would benefit from identifying nationally dependent factors and employing methods that better provide knowledge on the qualitative reception and handling of drug risk communication.