Botulinum toxin - a new word in clinical neuropharmacology

Botulinum toxin injections have become the method of choice for a number of severe conditions that are resistant to conventional therapy. Compliance with the rules for the use of botulinum toxin developed on the basis of clinical experience allows maintaining the sensitivity of patients to preparations containing it for a long time.

Botulinum toxin type A (BT-A), a protein consisting of heavy (100 kD) and light (50 kD) chains connected by a disulfide bridge, is the most potent toxin of the 7 antigenically distinct neurotoxins synthesized by the anaerobic bacterium Cl . botulinum. The high affinity of BT-A to cholinergic nerve endings and its ability to block the exocytosis of acetylcholine (ACCh) into the synaptic cleft of the neuromuscular synapse due to the destruction of the SNAP-25 protein complex make it possible to achieve a state of long-term chemical denervation with local intramuscular injection of the toxin. The clinical effect of BT-A is manifested in the form of muscle relaxation and the possibility of correcting muscle tone and movement disorders. However, the therapeutic effect of BT-A is reversible. ACh transmission is restored by sprouting of nerve terminals and the formation of new synaptic contacts, which usually occurs within 3-4 months and again provides innervation to the paralyzed muscle. Therefore, BT-A injections should be repeated.
The possibility of using the therapeutic potential of botulinum toxin was first expressed by Kerner J. at the beginning of the 19th century. Kerner's prophetic prediction came true in 1981, when ophthalmologist Scott A. published the first report on the treatment of strabismus with BT-A. Scott A. paved the way for clinical studies of BT-A in many medical specialties - ophthalmology, neurology, otolaryngology, pediatrics, gastroenterology, urology, cosmetology, etc. Over the past quarter century, there has been a steady trend towards expansion of both official,

Rationale for treatment with botulinum neurotoxin

BT-A acts both on extrafusal muscle fibers and intrafusal fibers of muscle spindles, thereby reducing the activity of alpha and gamma motor neurons. This allowed the use of the toxin in conditions with increased muscle activity, such as dystonia and spasticity. BT-A also blocks transmitter release at the endings of the pre- and postganglionic cholinergic nerves of the autonomic nervous system, which has aroused interest in its use for increased smooth muscle activity (eg, achalasia) or pathological glandular activity (eg, hyperhidrosis). Recent studies indicate the ability of BT-A to inhibit the release of glutamate associated with the calcitonin gene, as well as the inflammatory mediator substance P, which allows more reasonable use of BT-A in the treatment of pain syndromes.

Safety of BT-A treatment

Because BT-A is increasingly being used for a wide range of approved and unapproved indications, it is important to have as much knowledge as possible about its safety and tolerability. It is recognized that BT-A treatment has a very good safety and tolerability profile. This statement is supported by many years of clinical experience with the use of the toxin in a number of therapeutic indications, including dystonia, spasticity, smooth muscle disorders, glandular diseases and pain syndromes. The safety of BT-A has been carefully evaluated in numerous randomized, placebo-controlled and open-label studies across a wide range of therapeutic indications. local diffusion of the toxin into adjacent areas: for example, dysphagia after injection of BT-A into the muscles of the neck in the treatment of torticollis or ptosis of the upper eyelid and diplopia in cases of treatment with BSP or HS. The limitation of neurotoxin diffusion from the injection site is related to the dose of the drug, the volume of the injected solution, and the injection technique. As the degree of target tissue chemodenervation produced by the toxin is dose-dependent, so the side effects of BT-A are considered to be dose-dependent. However, there are also opposite opinions. So, Lees AJ et al. did not find a correlation between the dose of the toxin and the incidence of dysphagia in the treatment of cervical dystonia (CD).

In addition to local side effects, there is a possibility of systemic distribution of the toxin that can cause damage to more distal cholinergic nerve endings, which is confirmed by the results of an electromyographic study (EMG). The local mechanism of action of BT-A minimizes the risk of developing systemic effects that may be of an immune nature - for example, rare cases of flu-like symptoms, brachial plexus neuropathy. Isolated cases of generalized weakness (botulism-like syndrome) are also described, the pathogenesis of which remains unclear. It is assumed that the degree of binding of the toxin to the receptors of the newly grown nerve endings is weakened, and the effect of BT-A after repeated injections can manifest itself at a distance from the injection site due to a certain systemic distribution.

rare cases of flu-like symptoms, brachial plexus neuropathy. Isolated cases of generalized weakness (botulism-like syndrome) are also described, the pathogenesis of which remains unclear. It is assumed that the degree of binding of the toxin to the receptors of the newly grown nerve endings is weakened, and the effect of BT-A after repeated injections can manifest itself at a distance from the injection site due to a certain systemic distribution.
rare cases of flu-like symptoms, brachial plexus neuropathy. Isolated cases of generalized weakness (botulism-like syndrome) are also described, the pathogenesis of which remains unclear. It is assumed that the degree of binding of the toxin to the receptors of the newly grown nerve endings is weakened, and the effect of BT-A after repeated injections can manifest itself at a distance from the injection site due to a certain systemic distribution.

Due to the correlation of the clinical effect of this type of therapy with the degree of local blockade of the neuromuscular transmission, the use of BT-A in diseases with previous damage to the neuromuscular transmission is contraindicated. The literature describes a case of a systemic effect with local administration of a toxin in the form of a subclinical myasthenic syndrome. However, in recent publications, one can find descriptions of the successful use of botulinum toxin preparations in the treatment of spastic torticollis in patients suffering from myasthenia. Published studies of the long-term use of BT-A confirm the maintenance of a favorable safety profile. Adverse events observed in this case were usually localized at the injection site, were mild or moderate in severity, were reversible and non-systemic. A meta-analysis of the safety and tolerability of BT-A showed that the only side effects that were observed significantly more often in the treatment of CD and BSP compared with controls were local weakness and ptosis. In general, the results of randomized controlled trials and experience of long-term use of BT-A in the clinic characterize this method of treatment as safe with a potentially lower risk of complications compared with alternative therapies.

Officially approved contraindications to the use of BT-A are few. These include pregnancy, and in the acute stages of various diseases, the introduction of the next dose is recommended to be postponed until recovery. In the literature, however, there is not a single report on the negative impact of BT-A on pregnancy, labor or the newborn. Moreover, a number of publications indicate the safe repeated use of BT-A during pregnancy.
Finally, the widespread use of BT-A for the correction of hyperkinetic wrinkles in healthy individuals is another strong evidence of the safety of this therapy.

Practical aspects of treatment of BT-A

BT-A is injected into the affected target tissues (striated and smooth muscles, glands, skin). The choice of an effective dose depends mainly on muscle mass - larger muscles require larger doses. Smaller doses may be required in patients with pre-existing weakness, women and patients with low body weight.

Pathologically active muscles are characterized by the presence of muscle hypertrophy, density, soreness, and visible abnormal muscle activity. EMG may be useful in monitoring Bt-A injection into small or deep muscles.

Bt-A induced blockade of cholinergic transmission usually persists for 3-4 months. Patients need repeated injections at regular intervals of 12 weeks or more. The onset of improvement is usually noted 1-2 weeks after the introduction of BT-A.
Effectiveness of BT-A treatment

BT-A has proven to be a highly effective treatment method. The degree of clinical effectiveness of BT-A is influenced by many factors, such as dose, number and place of injections, muscle activity and temperature. Elevated temperature inhibits the effect of BT-A, and conversely, hypothermia increases the average duration of neuromuscular block by 7 days.

The undisputed leaders in the number of observations and accumulated experience in the use of BT-A are diseases of the nervous system, the basis of the clinical picture of which is muscle spasms. Local injections of BT-A into target muscles that form pathological dystonic movements and postures are the method of choice in the treatment of severe and resistant to other types of therapy focal dystonia, such as CD and BSP. In these diseases, BT-A provides an effect sufficient to eliminate pathological muscle contractions while maintaining normal function.

From 70 to 90% of patients suffering from CD, note a significant improvement in postural deformity and a clear analgesic effect of BT-A. More precise administration of the toxin under EMG control allows the use of lower dosages. Relapses of the disease, as a rule, do not reach the initial severity, in connection with which the doses of BT-A with repeated injections can be reduced. The main goal of CD treatment is to achieve a stable curative remission.

Local injections of BT-A have now become a recognized method of choice in the treatment of patients with a fairly common form of focal dystonia - BSP. Treatment with the toxin provides a long-term absence of symptoms of the disease until the development of remission. Twelve-year observation of Haussermann P. et al. for patients, BSP confirmed that treatment with BT-A provides a long-term absence of symptoms of the disease.
The introduction of BT-A into the practice of treating HPS led to a significant improvement in almost 100% of cases. The goals of HPS therapy include the provision of functional improvement, as well as the prevention of possible aesthetic complications. Elston JS believes that BT-A is the simplest and safest treatment for HPS, leading to a weakening of pathological muscle contractions for an average of 15 weeks.<

Another important indication for the use of BT-A is spasticity, a state of hypertonicity with increased tendon reflexes, caused by the loss of inhibitory control by central neurons. BT-A injections offer a new targeted approach to the management of spasticity. Indications for the appointment of BT-A include spasticity, which hinders the function and daily activities of the patient; spasticity resistant to traditional methods of treatment; spasticity involving antagonist muscles interacting with agonist function. The use of BT-A for the treatment of spasticity has several advantages. This method is easy to perform and can be performed on an outpatient basis, and the toxin does not cause side effects characteristic of systemic drugs and other treatments for spasticity.

The goals of therapy for BT-A spasticity include improving function (mobility and dexterity) and, as a result, facilitating rehabilitation, reducing pain, preventing the development of contractures, facilitating hygiene procedures and improving the patient's quality of life. The functional effect is undoubtedly the main goal of treatment, the achievement of which, however, cannot be expected in cases with limited or absent active movements in the joint.

Among the factors influencing the effectiveness of therapy for spasticity with BT-A, the combination of injections with physiotherapy and other rehabilitation methods is additionally distinguished. The combined use of different types of treatment at an early stage of recovery (less than 12 months after a stroke) can improve the long-term mobility of patients. A number of studies have demonstrated the possibility of improving the effectiveness of the treatment of spasticity using electrical stimulation.

Many studies indicate the positive effects of BT-A injections in terms of increasing range of motion, reducing muscle tone or improving gait in patients with cerebral palsy. The peculiarities of the use of BT-A in pediatric practice include the introduction of a toxin into a growing muscle and the calculation of the required dose, taking into account the patient's weight. Eames NWA study results allow us to talk about the possibility of using BT-A to increase the length of the gastrocnemius muscle in children with cerebral palsy, able to walk independently.
effect with an average duration of 19 weeks in 82% of cases of BT-A administration. MacLean JG et al. consider BT-A therapy as an integral component in the long-term treatment of cerebral palsy and recommend the use of nerve stimulation during injection.

Ways to increase the effectiveness of BT-A in cerebral palsy include the correct selection of patients, the correct choice of target muscles, the mandatory combination with physiotherapy and other methods rehabilitation program.

Resistance to BT-A treatment

Most patients with dystonia and spasticity need BT-A injections for many years. In some cases, sensitivity to treatment may be absent already at the first administration of the drug. This situation is called primary resistance. In a retrospective multicenter study with a large number of observations (758 patients), there was no clinical effect in 3% of cases of cerebral palsy. The reasons for the primary resistance to BT-A, according to Poewe W., are probably heterogeneous and include incorrect identification of muscles for injection, failure to identify deep muscles, insufficient dosages, and the possibility of low titers of neutralizing antibodies.

In some cases with a good initial effect develops tolerance to treatment, called secondary resistance.

Secondary resistance can be caused by the formation of antibodies to the toxin. Patients receiving higher individual doses or frequent booster injections are thought to be at a higher risk of developing antibodies. Therefore, the smallest effective doses of BT-A should be administered and as rarely as possible. The recommended interval between injections is at least 12 weeks. It is believed that younger patients are at higher risk of developing antibodies.

What is the management of patients with positive tests for neutralizing antibodies? The presence of antibodies is not a sentence for the patient, depriving him of hope for the possibility of effective treatment. Such patients have a chance of successful therapy with serotype B toxin injections. In addition, the antibody titer also undergoes evolution. After discontinuation of treatment with BT-A, in most patients, titers of anti-botulinum toxin type A antibodies decrease, giving them the opportunity to re-use BT-A drugs.

In cases with negative tests for antibodies, other causes of secondary resistance are possible, among which, according to Gelb DJ et al., the main one is the possible change in the dystonic pattern of the neck muscles in CD. This change can be overcome with EMG-guided injections.
the main one is the possible change in the dystonic pattern of the neck muscles in CD. This change can be overcome with EMG-guided injections.

the main one is the possible change in the dystonic pattern of the neck muscles in CD. This change can be overcome with EMG-guided injections.

Numerous studies have shown that BT-A injections are a treatment option with high therapeutic potential. Local application of BT-A clearly weakens dystonic and non-dystonic hyperkinesis, reduces the severity of spasticity, thereby improving the quality of life of patients and their functionality. BT-A therapy is well tolerated by patients and has a favorable safety profile.

According to .pharmateca.ru