Ботулотоксин: страшный яд или бесценное лекарство

Hundreds of articles have been written about the pharmacological properties, possibilities and side effects of botulinum toxin preparations. Specialists are discussing the methods and techniques of their introduction. It is difficult to add at least one touch to the portrait of this drug. Today, there is a whole family of drugs containing botulinum toxin on the professional market, but they are not "twins" and have different safety and efficacy profiles, as well as differences related to production, composition and application algorithm.

Botox, Dysport, Lantox, Xeomin and other "relatives"

Botox, Dysport, Lantox, Xeomin - all these drugs are really "closest relatives", or rather, these are the commercial names of drugs that represent the same active substance - botulinum toxin type A. This family is not numerous, but that is why it is valuable .

The drugs are representatives of the pharmacological group of cholinergic drugs that reduce the release of acetylcholine. This means that, unlike other cholinergic substances, they are substances of presynaptic action, which distinguishes them into a separate subgroup and makes them dissimilar both in application and in properties.

In modern history, botulinum toxin has come a long way from the most powerful deadly natural poison to a potent nerve agent, and then to a highly effective drug.

The group of anticholinergics with presynaptic action is represented not only by preparations of botulinum toxin type A, but also type B. So these drugs have "brothers" - these are preparations of botulinum toxin type B: neuroblock (Elan Plc., Ireland) and myoblock (Elan Pharmaceutical, USA), which are also successfully used in medicine.

"Sausage Poison", "Saint Vitus Dance" and Napoleon

The history of the emergence of botulinum toxin preparations goes back to the depths of the 18th century, when 13 people fell ill after eating sausage in Germany, six of whom died.

The "godfather" of the study of botulinum toxin can be called the physician, scientist and composer of musical ballads J. Kerner, who in 1817 published in the "Gazette of Natural Sciences and Pharmacology of Tübingen" a description of fatal food poisoning, which, by the way, was known even in times of the Roman Empire. He examined 155 cases of the disease, described the symptoms, personally treated the sick, dissected corpses, fed poisoned sausage to cats, rabbits, birds and fish, and then dissected the carcasses. The researcher came to the conclusion that there is no cure for poisoning, and the main thing in this matter is prevention! Cooking and smoking all meat products is the main means of combating "sausage poison".

Most likely, the German doctor knew the words of Paracelsus - Dosis sola facit venenum (only a dose creates poison). After all, he already then suggested that small doses of "sausage poison" would clearly be useful for treating patients with small chorea, which in those days was called the dance of St. Vitus: one of the symptoms of the disease was hyperkinesis (excessive involuntary movements), and the toxin would help relax the muscles.

The next scientist who became interested in botulism was the Belgian E. van Ermengen. In 1897, he studied samples of infected ham, the consumption of which caused poisoning and death at an Ellezelle Music Society ceremony. E. van Ermengen fed pigeons and rabbits with an extract from this ham and found out that the resulting progressive muscle paralysis leads to death as a result of respiratory arrest.

Based on various experiences, he concluded that this is the most deadly toxin known to mankind (which turned out to be true), and the microorganism that releases this toxin develops into the process of preserving meat products. This is how the bacterial theory appeared, and the isolated microbe was named "in honor" of the Latin name for sausage (botulus) - Bacillus botulinum (currently Clostridium botulinum).

In the same year, Kerner created the first immune serum against botulism. Currently, various serotypes of botulinum toxin are known: type A, discovered by E. van Ermengen in 1896, type B, discovered by Leuchs in 1910, type C - Bengston in 1922, type C3 - Seddon (1922) , type D - Theiler (1920-1927), type E - E. Kushnir (1934), type F - Moller and Scheibel (1960) and finally type G.

Napoleon Bonaparte was also indirectly involved in this whole story: at the time of continuous military campaigns, the emperor promised a prize to those who would invent a reliable way to preserve food. This is how canned food came into being. And since an anoxic environment is ideal for the formation of botulinum toxin, canned foods (without full heat treatment) can retain the toxin for years.

Unexpected side effect

During the Second World War, the toxin was of interest due to the possibility of its use as a bacteriological weapon. Most of the research on the effects of different botulinum toxin serotypes occurred during this period.

C. Lamanna in 1946 was the first to isolate type A toxin in crystalline form (which is the form needed for drug development), and Burgen in 1949 established that the mechanism of action of botulinum toxin is to block neuromuscular transmission. A. Scott in 1973 first tested a neurotoxin on animals, and then, in 1978, on humans, according to a protocol approved by the FDA (USA).

Let's make a reservation that there was nothing inhumane in Scott's research: back in the 1950s. scientists have found that the toxin, purified and highly diluted, can be used in medicine to relax the muscles.

Animal tests were just being conducted at this time.

The results amazed everyone! Repeatedly diluted toxin eliminated strabismus in animals. At the same time, the toxin was not absorbed from the injection site, did not cause side effects, and its effect was almost local.

The search for the optimal technology for purification and production of highly purified crystalline botulinum toxin lasted almost 40 years. In December 1989, primarily thanks to the work of ophthalmologist A. Scott, the FDA (USA) approved botulinum toxin type A for the treatment of strabismus, hemifacial spasm (involuntary unilateral contraction of the facial muscles) and blepharospasm (involuntary closing of the eyes) and gave permission for the use of the drug called Botox - an effective and safe remedy in neurology.

Dozens of enthusiastic physicians and scientists have begun to explore the possibilities of using neurotoxin for other indications. Since that time, the triumphal story of the ascent of botulinum toxin to the medical Olympus began.

In 1990, the first articles on the use of botulinum toxin type A in cosmetic dermatology were published in the journals Dermatology and Surgical Oncology.

The results of 17 thousand courses of treatment (!) for 7 thousand patients were presented.

The cosmetic effects of Neutrotoxin helped to discover a happy accident - as has happened more than once in pharmacology. One of the patients of the ophthalmologist J. Carruthers, who was treated for blepharospasm, noticed that the wrinkles on her face became less pronounced after treatment with botulinum toxin.

It turned out that after the injection of botulinum toxin, patients not only got rid of facial muscle spasms, but also received a friendly, relaxed and youthful face as a ... "side effect"! And although wrinkles were not on the list of indications for the use of this drug, doctors began to use Botox not for its intended purpose. This enticing disappearance of wrinkles after a single injection of botulinum toxin type A quickly led to the spread of this technique. Since 1995, the use of botulinum toxin A for facial rejuvenation has grown exponentially.

Conferences and seminars have been held, although indications for such use have not been approved in either Europe or the USA. In cosmetology in the period from 1997 to 1999. Botox use has increased by 665%! As a result, in 2002, the FDA approved the use of Botox to eliminate mimic wrinkles on the forehead and around the eyes in cosmetology. And a new era began...

There are several types of botulinum toxin (A, B, C, D, E, F, G) that differ in immunological and chemical properties. Botulinum toxin is tasteless, colorless, odorless and is considered the most complex protein that a living organism can synthesize. Its mass corresponds to the upper limit of the possible mass of a protein and is about 150,000 atomic mass units, which is three times the average size of a normal protein chain.

There are no more toxic substances in nature. The most poisonous artificially synthesized substance - dioxide - is 70,000 times weaker than botulinum toxin. The median lethal dose (LD50) for type A is 0.001 µg/kg, but type D is considered the most toxic (LD50 = 0.0004 µg/kg body weight). And although botulinum toxin type A is one of the most poisonous among the 7 existing serotypes and its action lasts longer than the others, it was the first and for a long time the only one on the pharmaceutical market.

Botulinum toxin type B preparations have recently appeared. Other types of toxin are not yet used in medicine, but experimental studies are already underway on the use of types C and F. Currently, the study of botulinum toxin type A is being carried out by dermatologists, otolaryngologists, ophthalmologists, neurologists, proctologists, urologists, gynecologists, gastroenterologists and, of course, cosmetologists and plastic surgeons.

Botulinum toxin type A drug structure

Drugs representing any serotype of botulinum toxin consist of the neurotoxin itself, non-toxic complex proteins and pharmaceutical excipients.

The dosage of drugs is expressed in units of action (ED) or in the so-called. mouse units (MEU): each unit corresponds to the median lethal dose (LD50) for female mice weighing 18-22 g each. When the drug is injected into a human weighing 70 kg (this was established approximately - and on monkeys, not on humans), a lethal dose of 3000 IU (that is, 30 bottles of Botox) is considered.

Existing botulinum toxin type A drugs - Botox, Dysport, Xeomin and Lantox - although they are "closest relatives", they are still not "twins", they have different safety and efficacy profiles, differences related to production, composition and application algorithm.

A drug called Botox  (BotoxR ) is a purified neurotoxin complex - botulinum toxin type A-hemagglutinin (which is produced in the laboratory by microorganisms) combined with human serum albumin. The drug is stored in the freezer and diluted immediately before administration. It occupies a leading position in the pharmaceutical market. Thus, in 2006, 11.5 million Botox injections were performed in the United States. These injections, overtaking liposuction and breast implants, took the honorable first place among aesthetic surgery procedures. Botox is the most studied drug, registered in more than 75 countries.

Dysport is also a purified botulinum toxin type A complex, but has a lower molecular weight, and therefore a higher tissue diffusion of the drug, which may increase the incidence of side effects. According to clinical activity, 3-5 ED of Dysport correspond to 1 ED of Botox. One of the main conditions for the use of drugs is absolute freshness, so it is very important to follow the rules of storage. Refrigeration is sufficient for Dysport, while Botox should be stored in the freezer. In a diluted state, Dysport lasts no more than 1 hour, and Botox - up to 4 hours.

Xeomin (XeominR ) differs from its predecessors Botox and Dysport in that it contains isolated type A neurotoxin, thus it is freed from unnecessary and ineffective complex proteins that burden the immune system patient and increase the risk of addiction. Pure neurotoxin has low immunogenicity with minimal antigenic and protein load on the body. In terms of activity, Botox and Xeomin are identical, but Xeomin is characterized by a faster onset of action. The drug does not require freezing and storage under special conditions, it remains stable when stored at room temperature up to 25°C. Approved for use in 14 countries.

Lantox is also a lyophilisate for solution for injection, like other botulinum toxin type A preparations. It contains inactive ingredients: gelatin, sucrose and dextran. In Lantox, unlike other drugs, the toxin is bound to gelatin, which stabilizes the neurotoxin, preserving its biological activity.

Botox and Dysport use serum albumin as a stabilizer. Both stabilizers have their advantages and disadvantages: the source of gelatin is cattle; serum albumin is obtained from a person (healthy donors). The gelatin that is part of the preparation must be "crystal clear": think of prions and "mad cow disease" (bovine spongiform encephalopathy).

Serum albumin contains the amino acid cysteine, which enhances the aggregation of botulinum toxin and leads to the loss of its toxicity, and therefore, its activity. Therefore, such preparations contain a higher concentration of toxoid compared to lantox. Each ampoule of myoblock (neuroblock) is a ready-made solution for injection and contains type B botulinum toxin in combination with human serum albumin, sodium chloride and sodium succinate. The solution has a low pH, which gives pain when injected. Approximately 1 IU of Botox corresponds to 40 IU of myoblock (neuroblock).

It is known that botulinum toxin B has a stronger and more effective effect on the autonomic nervous system than on the somatic. Therefore, the currently approved use of this type of botulinum toxin is limited to cervical dystonia. Additional studies are needed for the use of these drugs in cosmetology.

The mechanism of action of drugs containing botulinum toxin 

When any botulinum toxin preparation is injected into the tissues, the neurotoxin and the protein complex are separated. It is believed that the mechanism of action of the neurotoxin is due to the blockade of the presynaptic membrane and impaired release of the mediator acetylcholine into the synaptic cleft.

Depending on the type of tissue, cholinergic neuromuscular transmission or cholinergic autonomic transmission of impulses to the sweat, lacrimal, salivary glands or smooth muscles is impaired. And although this process has not yet been fully studied, this mechanism of action is the most likely.

With a conventional intramuscular injection, the onset of action falls on days 2-3, maximum on days 14-15, and after 45 days the effect begins to slowly fade. Blockade of impulse transmission in the synapse is irreversible. It is believed that the resumption of the passage of an impulse through the synaptic cleft occurs due to the formation of new collaterals near the nerve fibers.

Thus, all striated muscles, smooth muscles and sweat glands are potential target organs for treatment with botulinum toxin. Botulinum toxin is concentrated for some time at the site of its intramuscular injection, where it undergoes partial metabolism, then enters the systemic circulation. In the body, it is metabolized very quickly to form simpler molecular structures. It is excreted as metabolites mainly by the kidneys.

Botulinum Toxin Preparation: Poison or Rescue

Botulinum toxin preparations are currently indicated for the treatment of any muscle that is accessible for injection and is in a state of pathological contraction. Here is a far from complete list of diseases in which botulinum toxin preparations are simply necessary.

Strabismus (strabismus), blepharospasm, spastic torticollis, focal dystonia, tics, spasticity, tension headache, cerebral palsy (over 2 years), hemifacial spasm, myofascial pain, tremor, localized hyperhidrosis, spastic dysphonia, pharyngeal dystonia, limb dystonia, esophageal achalasia, spastic bladder, vaginismus, rectal sphincter spasm, anal fissures, entropion, protective ptosis.

There are also rarer diseases in which botulinum toxin preparations are practically the only medicine that eliminates the cause of the disease. For example, the phenomenon of “crocodile tears”, which was described for the first time in 1928 (so far, just over a hundred cases have been registered in the world). This lacrimation that occurs while eating is associated with damage to the facial nerve. The patient involuntarily cries when chewing, especially when eating hard or spicy food.

Or Lucy Frey's syndrome - paroxysmal pain in the temple, ear and lower jaw, accompanied by skin flushing and increased sweating. Attacks are provoked by hot food, physical activity, overheating, emotional stress. It is believed that the basis of the syndrome is a lesion of the ear-temporal nerve. Until recently, the only radical method of treatment was the intersection of the ear-temporal nerve.

Other indications for treatment with botulinum toxin have not yet been sufficiently studied - among them "tennis" elbow (muscle tension), myoclonus of the palate, stuttering, nystagmus, prostatic hyperplasia. All these diseases are awaiting the conclusion of the researchers regarding the effectiveness of the neurotoxin in these cases.

In aesthetic medicine, indications for the use of botulinum toxin type A are mimic wrinkles in the forehead, between the eyebrows and paraorbital areas, back of the nose, chin, horizontal and vertical wrinkles of the neck, corners of the mouth and décolleté.

Contraindications for the use of botulinum toxin preparations

Contraindications to the use of botulinum toxin are few and due to the main mechanism of its action - these are any diseases with a violation of cholinergic transmission. Do not use botulinum toxin simultaneously with drugs that interfere with this transmission, such as aminoglycosides or muscle relaxants. Medicines that prevent blood clotting (such as aspirin) may increase the risk of bleeding.

Special care should be taken with pregnant women as no clinical trials have been conducted in pregnant women and long-term results are unknown. Interestingly, during the entire period of use of botulinum toxin preparations, not a single case of hypersensitivity (allergy) has been described.

Reactions to the auxiliary components of the drug are possible, but not to the botulinum toxin itself.

Is it still poison? Possible side effects

Side effects can occur with all drugs, and botulinum toxin is no exception. Any side effects can be divided into local (occurring at the injection site) and systemic (occurring after the drug enters the systemic circulation).

All side effects (as well as positive curative ones) are completely reversible.

Of the local (local) reactions - these are microhematomas that resolve within a week, short pain at the injection site. In addition, it is possible to spread the effect of the drug to muscle groups located near the injection site, for which the injection was not intended. Such side effects depend on the site of injection of botulinum toxin and manifest as a loss of muscle tone in this muscle group.

For example, in the treatment of blepharospasm, ptosis or lacrimation may occur if the drug spreads to the muscles of the upper eyelid or the smooth muscles of the lacrimal glands. These side effects usually do not require treatment and resolve within 30 days.

The rest of the "surprises" can only arise due to poor-quality performance of the injection procedure itself - damage by the needle to the nerves or vessels passing through the injection site, which is possible with the introduction of any drug, not just botulinum toxin.

Systemic side effects are typical when using large doses of drugs (200 IU and more). Such doses are used in the treatment of neurological diseases, where the drug is injected into large striated muscles. In cosmetic medicine, such dosages are usually not used. Systemic side effects include general weakness, which gradually disappears within a week.

And the last thing - antigenic properties: the entire pharmaceutical industry is fighting them, inventing all kinds of botulinum toxin preparations. According to statistics, antibodies are formed in 1-5% of patients after repeated injections.

The risk of antibody formation when botulinum toxin is administered depends on various factors. One of them is the intervals between injections. They should be as long as possible. The second factor is the number of units of the drug administered for each procedure. It should be as small as possible. The formation of antibodies is facilitated by the introduction of large doses (more than 250 IU), which is again typical for neurological practice. The third factor is the choice of the drug itself, since each of them has a certain biological activity (high specific biological activity indicates a low risk of antibody formation).

Botulinum toxin preparations according to their biological activity are arranged in the following sequence: myoblock (neuroblock) - 5, botox - 60, dysport - 100, xeomin - 167 IU/ng of botulinum neurotoxin. Therefore, for myoblock and neuroblock the risk of developing tolerance is quite high, and for xeomin it is the lowest.

Rules to be observed in aesthetic medicine when using botulinum toxin:

1. To reduce pain and prevent the appearance of microhematomas, it is necessary to apply ice to the injection site before and after injections and use the thinnest needles.

2. Always keep the syringe scale in sight, regardless of the injection site or the direction of the needle tip.

3. Avoid getting the drug into the blood vessels.

4. Respect the anatomical boundaries of the areas.

5. Position the tip of the needle away from the eye.

For information

According to the FDA (USA), for the period 1989-2003. Botox injections resulted in the death of patients in 28 cases. In 2008, the FDA issued a warning that the use of Botox may cause breathing problems and other side effects.

All these cases are not related to aesthetic medicine - they occurred during the medical use of large doses of drugs in the treatment of spastic paralysis in both adults and children. Please note that this disease is not listed in the indications for the use of botulinum toxin in children, and here the doctors acted at their own peril and risk, since dosing, courses and treatment regimens for such diseases have not been developed. Fatalities in adults cannot be definitely attributed to the use of botulinum toxin, as they could be due to the course of diseases present in patients.

To date, the FDA (USA) has not received information on systemic side effects of drugs used for cosmetic purposes. However, there are 1017 reported adverse reactions to botulinum toxin in the WHO database.

Undoubtedly, Botox is a child of the 21st century. If one injection of botulinum toxin can remove the "Greek mask of tragedy", "crow's feet", "frown lines" or "sleep lines" from the face, make the face younger and more friendly, this technique must be used - this logic looked completely unnatural back in the 20th century . But times are changing, and with them views, thoughts and judgments, and now we do not look at botulinum toxin as a poison that causes a terrible disease, botulism: now it is a medicinal drug that helps many.

According to http: allseason.ru

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