Medicinal poison
How does botulinum toxin work and what is effective against
Rostec Corporation blog, Naked Science
Most people know botulinum toxin as a "beauty shot", which helps to get rid of wrinkles, but its use has long gone beyond aesthetic medicine. In the material devoted to the use of botulinum toxin for therapeutic purposes, the expert of Rostec State Corporation, medical adviser to the NGO "Microgen" (holding "Natsibio"), candidate of medical Sciences Alexandra Dabizheva talks about how the dangerous poison helps to fight various diseases, including neurological.
"Everything is poison, everything is medicine. Both are determined by the dose," this phrase is attributed to the famous Swiss physician and philosopher, the forerunner of modern pharmacology, Paracelsus. A visual confirmation of his words is almost any modern drug, but one of the most striking examples is botulinum toxin.
The history of the "sausage toxin": from biological weapons to medicine
The symptoms of food botulism were first described in detail in 1817 by the German physician and poet Justinus Kerner. He guessed that a certain toxin leads to muscle paralysis in patients, and suggested that this poison could be used for therapeutic purposes. At that time, an outbreak of poisoning occurred among people who ate black pudding. The word "sausage" sounds like botulus in Latin, so scientists called the new disease botulism.
In 1895, the Belgian bacteriologist Emil van Ermengem studied another outbreak of poisoning in the town of Elselles. 34 musicians played at the funeral, after which they had lunch at the hotel. Soon they had visual disturbances, general weakness, problems with swallowing, speech, shortness of breath. Within a week, three musicians died. The reason was presumably low-quality ham. While investigating this incident, Emil van Ermengem first discovered the botulinum bacillus Clostridium botulinum and studied its toxin. It became clear that this is one of the most dangerous poisons – doses of less than 0.05 micrograms can be fatal to humans.
At the beginning of the XX century in the USA there was another wave of outbreaks of botulism. At that time, it was already known that dangerous bacteria multiply in poorly processed canned foods. This forced manufacturers to improve technology, and people began to be informed about the dangers of homemade canned food. After the First World War, botulinum toxin was mainly considered as a biological weapon.
It was only in the late 1960s, almost two hundred years after Kerner's guesses, that botulinum toxin was first used as a drug. This idea came to the American ophthalmologist Alan B. Scott. He injected a toxin into the eye muscles of a rhesus monkey to correct strabismus. The experiment was successful and was soon repeated in humans. The cosmetic effect of botulinum toxin-based drugs was discovered by chance, during use in ophthalmological practice. In 1989, a new drug was approved in the United States for the treatment of blepharospasm, strabismus and facial nerve dysfunction. The era of botulinum therapy has begun.
How does botulinum toxin work?
Botulinum toxin is a unique drug, and not only because it is the most dangerous poison. Only a few drugs have had the mechanism of action so well studied before clinical use, and few have been able to improve the condition of patients so much.
The excitation from nerves to muscles is transmitted through special structures – synapses. They are narrow gaps between the membranes of neurons and muscle cells. The nerve end contains special bubbles with a carrier molecule (mediator) - acetylcholine. When nerve excitation occurs, acetylcholine enters the synaptic cleft and interacts with receptors on the muscle cell membrane. There is excitement in the muscle, and it contracts.
Botulinum toxin connects to the membrane of the nerve ending and blocks the release of acetylcholine. As a result, the excitement does not go away, and the muscle cannot do its job. The toxin affects motor neurons in the anterior horns of the spinal cord and cranial nerves, which innervate striated (skeletal) muscles, as well as the vagus nerve, innervating smooth muscles in internal organs. With poisoning, the work of the most active muscles suffers the most: oculomotor, pharynx and larynx, as well as respiratory.
Hence the main manifestations of the disease – blurred vision, double vision, impaired pupil response to light, problems with swallowing, speech, breathing. When botulinum toxin acts on muscles that initially worked normally, it causes harm and causes life-threatening conditions. Invaluable benefits begin where there are pathological muscle contractions.
There are seven types of botulinum toxin produced by different serotypes of clostridium. They are designated by the Latin letters A, B, C, D, E, F and G. Toxins A and B are best studied and most widely used in clinical practice. Currently, the pharmacological properties and application possibilities of toxins C, D and F. are being actively studied.
Therapeutic botulinum toxin is obtained in the laboratory directly from Clostridium botulinum bacteria. It is cleaned, bottled and subjected to lyophilization – a special kind of drying, when the drug is frozen, and then the pressure is greatly reduced, as a result of which the water immediately turns into steam.
In this state – in the form of powder – the toxin is packaged and sent to clinics. Before use, the drug should be diluted with saline solution. Botulinum toxin doses are measured in so-called mouse units. One mouse unit includes an amount of the drug that kills half of mice weighing 20 grams within three days after injection into the abdominal cavity.
"Magic Bullet"
About a hundred years ago, the German doctor, immunologist and bacteriologist Paul Ehrlich coined the term "magic bullet". He dreamed of creating a medicine that would find the cause of the disease itself and destroy it without harming the body. Ehrlich managed to realize his idea – he created the first antibacterial drugs in history – sulfonamides. Since then, many more "magic bullets" have appeared in medicine. One of them was botulinum toxin. He helped improve the condition of many people suffering from ophthalmological and neurological disorders.
Botulinum toxin received the first recognition among neurologists because of its effectiveness in dystonia. These diseases are characterized by persistent uncontrolled muscle contractions, as a result of which the patient makes involuntary movements, his body assumes an unnatural position. This group includes such pathologies as blepharospasm – contraction of the circular muscle of the eye; hemifacial spasm or periodic violent contractions of the muscles of half of the face; cervical dystonia – contraction of the neck muscles, which leads to a deviation of the neck from the normal position, focal limb dystonia – spasms in certain muscle groups of the arms or legs.
Botulinum toxin proved to be no less effective in the fight against spastic disorders – pathological muscle tension that occurs with cerebral palsy, multiple sclerosis, elimination of the consequences of stroke, traumatic brain injuries, spinal cord injuries. These drugs were especially useful for children with cerebral palsy.
They helped to restore the functions of the musculoskeletal system, to avoid serious orthopedic problems and the need for surgical intervention, returned the possibility of normal development of the child. Botulinum therapy for spastic disorders is especially effective in combination with other medications, therapeutic gymnastics, massage and physiotherapy.
Botulinum Toxin today
Currently, botulinum toxin injections are used as the main treatment in most patients with focal (in one area of the body) and segmental (in adjacent areas) dystonia. Already the first clinical studies, the results of which were published in 1987, showed the high effectiveness of these drugs. For example, with blepharospasm, the condition significantly improved in 90 percent of patients. Side effects occurred in less than ten percent of cases, they were not dangerous and passed within two weeks.
In Russia, a domestic drug based on botulinum toxin is produced by a full-cycle enterprise NPO Microgen of the holding "Natsibio" of the Rostec State Corporation. Its development began in 2001. The distinctive features of the drug are a high degree of purification, thanks to the use of modern technologies of multiple baromembrane and gel chromatographic separation, and a long duration of exposure.
Today, the drug is successfully used to combat muscle spasms in cerebral palsy and after stroke, blepharospasm and axillary hyperhidrosis. The Russian drug has passed all the necessary clinical trials. Its effectiveness and safety have been proven by long-term application practice. Now the company continues to work on expanding the indications for the use of Russian botulinum toxin in the neurological field.
In addition to all the above directions, there is evidence of the effectiveness of botulinum therapy for various types of headaches. Among them, for example, migraine is a disease in which intense pain in half of the head bothers, they are often accompanied by nausea, vomiting, hypersensitivity to light and sounds. Another type is the so–called tension headaches, which, according to some data, are among the ten most common causes of disability (one of the factors contributing to their development is the tension of the muscles of the skull).
Cervicogenic headaches occur as a result of prolonged stay in an uncomfortable position, with certain movements of the head, and "therapeutic poison" is also effective against them. Botulinum toxin acts not only on the nerves innervating skeletal muscles, but also on the autonomic nervous system, which controls the work of internal organs, various glands. This property also finds therapeutic use.
For example, intradermal injections of botulinum toxin help with essential focal hyperhidrosis – increased sweating in the palms, feet, and armpits. This disorder affects from 3 to 15 percent of people. It cannot be treated with other medications, and operations during which sympathetic nerves are cut are accompanied by high risks. Many pain syndromes in the human body are associated with chronic muscle spasms, and botulinum toxin can also be effective here. First of all, these are conditions such as fibromyalgia, myofascial pain syndrome, chronic pain in the lower back, temporomandibular joint.
Earlier, at one of the interdisciplinary conferences "Veynov Readings", Doctor of Medical Sciences, Professor of the Department of Surgical Diseases of Childhood of the Russian Ministry of Health, Diana Krasavina, who studies the effectiveness of botulinum therapy for relieving spasticity and chronic pain syndrome in children with cerebral palsy, noted: "Spasticity and pain go together. The sooner we create an injection of botulinum therapy into spastic local muscles, the less chance we will give pain."
Botulinum toxin acts not only on the nerves innervating skeletal muscles, but also on the autonomic nervous system, which controls the work of internal organs, various glands. This property also finds therapeutic use. There are cases when sialorrhea (salivation) in Parkinson's disease, amyotrophic lateral sclerosis and other neurodegenerative disorders have been successfully treated with botulinum toxin.
It has been proven effective in pathologies associated with muscle spasms in internal organs – for example, the rectum (anism – persistent constipation due to spasm of the sphincter, cracks of the rectum), bladder (urinary retention due to spasm). Botulinum toxin preparations have been used in neurology for more than thirty years, but their potential has not yet been exhausted. Scientists continue to investigate them and discover new indications.
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