Botox approved for overactive bladder treatment

Botulinum therapy and urology

The use of Botox in urology has become a new effective method for treating diseases of the genitourinary system. The method is based on the use of botulinum toxin, which by its nature is an organic neurotoxin with a complex protein structure. It is actively used to treat bladder dysfunction and urinary problems. The mechanism of action of the substance is conventionally divided into 3 stages.

1. Binding of a molecule in a special way to the presynaptic membrane.
2. Neurons of the bound toxin enter the cytoplasm by endocytosis. They cause protease activity with selective destructive effects on certain molecular structures.
3. Blocks the release of acetylcholine in the presynaptic endings of cholinergic neurons.

In other words, there is a prolonged blockade of neuromuscular transmission (muscle chemodenervation). Pathological muscle stimulation, which is caused by spasm, is interrupted, or excessive tone is weakened. Precision injection of BT into the affected area makes it possible to correct their behavior. These areas are the walls of the bladder, prostate, sphincter, and pelvic floor muscles. Botulinum therapy in urology shows a decent positive result in the treatment of such diseases:

• detrusor hyperreflexia;
• dysfunctional urination;
• impaired urination due to prostatic hyperplasia with benign indicators;
• detrusor-sphincter dyssenergy (DSD);
• prostatitis.

Botulinum therapy in Moscow is carried out with the Chinese-made drug Lantok.

For what diseases is botulinum toxin used?

Treatment with botulinum therapy allows wheelchair patients to get rid of cystostomy, which is complicated by detrusor overactivity, continuous attacks of pyelonephritis, reflux, which impede the ability to naturally empty the bladder. The procedure increases the volume of the bladder, prevents pyelonephritis, and cures cystostosomes. In some cases, patients regain the ability to urinate independently. Botulinum toxin in urology is effective against the following diseases.

1. Overactive bladder. The most common causes of neurogenic detrusor overactivity are back injuries, multiple sclerosis and other neurological diseases that impair nerve conduction. Frequent urination or urge incontinence may be accompanied by incontinence. During urethrocystoscopy, the drug is injected into the detrusor with an endoscopy needle, which triggers its partial chemodenervation. It, in turn, reduces the frequency of urination during the day and incontinence. The method is used in critical cases when other methods of therapy do not have the desired effect. Positive dynamics after the procedure are observed in most patients.
2. Impaired bladder emptying function. Partial blockade of neuromuscular transmission by the neurotoxin leads to the resumption of coordinated urine output, including flow rate. To improve urination, Botox is injected into the area of ​​the striated urethral sphincter. In many cases, it is possible to achieve results when the patient can completely refuse autocatheterization, and there is no need for bladder drainage. Due to the action of injections during urination, intraurethral resistance is reduced. Due to this reaction, reflux is prevented, which is caused by progressive renal failure and reduced renal function.
3. For chronic pelvic pain syndrome, injections are made into one of four zones - musculus levator ani, prostate gland, urethral sphincter, pelvic floor muscles. As a result, pain subsides and bladder capacity is restored.
4. Pancreatic adenoma today is supplemented with injections of neurotoxin. After the course, adenomatous nodes are significantly reduced, due to which normal urination is resumed. It is used in cases of ineffectiveness of conservative treatment methods with high rates of surgical intervention.

Other areas of botulinum therapy include chronic urinary retention caused by functional obstruction in meningomyelocele. The method is also widely used for interstitial cystitis.

Use of botulinum toxin in urology

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“Everything is poison and everything is medicine, and only measure makes one thing different.” This saying of the ancients fully applies to botulinum toxin, one of the most potent biological toxins, discovered by van Ermengem in 1895 [8]. The toxin is produced by the gram-positive anaerobic spore-forming microorganism Clostridium botulinum. The first cases of botulinum toxin poisoning were described in the 1700s in Germany after eating spoiled sausage. Hence the name “botulism” or “sausage poisoning” - from the Latin botulus, which means “black (blood) sausage.”

Currently, the botulinum toxin molecule is synthesized in the form of a simple polypeptide chain [2]. There are 8 serological subtypes of botulinum toxin: A, B, C1, C2, D, E, F, G, each of which has antigenic and serological characteristics, but has a similar structure. Botulism in humans can be caused by serotypes A, B, E, F, G, but type A is the most potent.

The mechanism of action of the toxin is to block the release of acetylcholine from the presynaptic membrane at the neuromuscular synapse

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At the onset of action, the original botulinum toxin molecule is cleaved to form active forms consisting of two polypeptide chains linked by a disulfide bridge, a heavy one (approximately 100 kDa) and a light one (approximately 50 kDa), containing a zinc atom [7] (Fig. 1). The heavy chain ensures selective binding of the toxin to the cell membrane of the neuromuscular synapse. After binding, the toxin is absorbed by active endocytosis into the presynaptic terminal, forming toxin-containing vesicles. In the vesicles, the disulfide bridge of the toxin is broken, the light chain enters the cytoplasm and cleaves the transport protein of the presynaptic membrane SNAP-25, blocking the release of acetylcholine into the synaptic cleft without disrupting the synthesis and deposition of acetylcholine in presynaptic nerve endings [6] (Fig. 2). The pharmacological effect of the process is persistent chemodenervation, and the clinical manifestation is relaxation of muscle structures. In the interval from 1 to 2 months. after injection of botulinum toxin in the injection area, histological studies revealed the formation of new nerve endings, with the formation of new neuromuscular synapses. This process is called sprouting (from the English sprout
- “to sprout”). In most cases, previous muscle activity is restored within 3–6 months. after administration of the toxin, but often this can occur after a year or more [1].

Rice. 1. Structure of the botulinum toxin molecule

Rice. 2. The mechanism of action of botulinum toxin (according to D. Kedlaya). The left half of the diagram shows the mechanism for the release of acetylcholine from the nerve ending into the synaptic cleft using a complex of proteins (SNAP-25, syntaxin, synaptobrevin). The right half of the diagram shows the penetration of botulinum toxin into the nerve ending through active endocytosis with the formation of toxin-containing vesicles. In the vesicles, the disulfide bridge of the toxin is broken, the light chain enters the cytoplasm and cleaves the transport protein of the presynaptic membrane SNAP-25, blocking the release of acetylcholine into the synaptic cleft

In recent years, experiments on rats have shown that botulinum toxin not only suppresses the release of acetylcholine, but also reduces the release of norepinephrine [5]. This circumstance significantly expands the possibilities of using botulinum toxin in various fields of medicine.

To date, botulinum toxin is produced by several pharmaceutical companies - hence its different commercial names. In the USA, the drug is produced by the pharmaceutical company Allergan under the name botulinum toxin (Botox) and by the company Elan under the name Myobloc, in England it is the drug Dysport produced by Spevwood-Vaccine and Research Laboratory.

The clinical use of botulinum toxin in medicine began in the 80s. last century, when the Californian ophthalmologist A. Scott used the toxin in the treatment of strabismus. In 1989, the US Food and Drug Administration approved the use of botulinum toxin type A ( botulinum toxin

) for the treatment of strabismus, benign blepharospasm and disorders associated with dysfunction of the VII cranial nerve, and botulinum toxin type B (Myoblock) for the treatment of patients with cervical dystonia (spasmodic torticollis).

The use of botulinum toxin in urology is associated with the successful treatment of detrusor-sphincter dyssynergia (DSD) in patients with spinal injuries [3]. These observations were the basis for the use of the toxin in neurological patients with urinary dysfunction due to non-relaxing striated urethral sphincter, and then in patients with decreased or absent detrusor contraction who want to urinate by increasing intra-abdominal pressure.

There are reports of good results from the use of botulinum toxin in patients with idiopathic and neurogenic detrusor overactivity, in patients with benign prostatic hyperplasia, with obstructive urination due to sling operations, as well as in patients with interstitial cystitis and chronic pelvic pain syndrome [4]. It is emphasized and should be agreed that further large-scale studies are needed to clarify the therapeutic effectiveness and expand the use of botulinum toxin in urology.

Our observations of the use of botulinum toxin since May 2003 include 6 patients (4 men and 2 women) with neurogenic dysfunction of the lower urinary tract aged 18 to 64 years (average age 28.5 years). In 2 patients, there was a decrease in the contractility of the detrusor, in 3, DSD was diagnosed, and in 1, the sub-urethral sphincter did not relax. The decrease in detrusor contractility in one patient was caused by myelodysplasia, and in the other by Schmorl's hernia. The volume of residual urine in a patient with myelodysplasia was 300 ml, so the patient used intermittent autocatheterization to empty the bladder. In a patient with Schmorl's hernia, the volume of residual urine was 150 ml. The average and maximum urinary flow rates in these patients ranged from 3.2–3.8 and 6.4–6.8 ml/s, respectively. The value of detrusor pressure at maximum urination rate in a patient with myelodysplasia was 32 cmH2O. Art., and the patient with Schmorl’s hernia has 37 cm of water. Art. The cause of development of DSD in three patients was multiple sclerosis, Schmorl's hernia and ischemic stroke of the spinal cord during surgery. The amount of residual urine in these patients ranged from 145 to 189 ml. All patients noted extremely difficulty urinating; the average values ​​of the average and maximum urination flow rate were 2.9 and 7.4 ml/s. In one patient with hemorrhagic stroke due to rupture of a cerebral aneurysm, a complex urodynamic study revealed signs of non-relaxing urethral sphincter, increased sensitivity and decreased adaptive capacity of the bladder. The patient underwent intermittent catheterization because the volume of residual urine was 500 ml.

We used botulinum toxin type A (botulinum toxin)

Allergan (USA). Botulinum toxin is produced as a lyophilized white powder in 10 ml vacuum glass vials, closed with a rubber stopper and an airtight aluminum closure. One bottle contains 100 units of botulinum toxin. According to the company's recommendations, the lyophilized powder is diluted with a sterile 0.9% sodium chloride solution without preservatives in a volume of 8 ml so that 1 ml of the resulting solution contains 12.5 U of botulinum toxin. Dilution was carried out without shaking the contents. In 1 patient with a non-relaxing subcutaneous urethral sphincter, the intraurethral method was used, and in the rest, the transperineal method of administering botulinum toxin was used. All patients were administered 100 U of botulinum toxin.

Introduction technique. With the intraurethral method

epidural anesthesia was used to administer botulinum toxin. During urethrocystoscopy, the area of ​​the sub-urethral sphincter was determined. An endoscopic needle from Cook was used to administer the drug. The prepared drug is injected 2.0 ml deep into the subcutaneous sphincter of the urethra at 3, 6, 9 and 12 hours of the conventional dial, i.e. 25 units at each point.

Transperineal technique:

The position of the patient on the gynecological chair with legs apart and bent at the knees. The skin of the perineum was treated with an antiseptic solution. In men, under the control of the index finger inserted into the rectum and resting on the apex of the prostate, under which the sub-urethral sphincter is located, a special needle-electrode with an insulating Teflon coating is inserted into a point located 2 cm laterally and above the anus on both sides. The tip of the needle should be in close proximity to the apex of the prostate gland (Fig. 3). In women, the needle is inserted under the control of the index finger inserted into the vagina, to a point located 1 cm lateral and above the external opening of the urethra to a depth of 1.5–2.0 cm (Fig. 4). In all cases, the position of the needle is controlled by the characteristic sound of the speaker of the electromyograph connected to the needle-electrode (Fig. 5, 6). 50 U of botulinum toxin in 4 ml of saline was injected into each of the two points.

Rice. 3. Scheme of administration of botulinum toxin into the striated urethral sphincter in men

Rice. 4. Scheme of administration of botulinum toxin into the striated urethral sphincter in women

Rice. 5. Needle-electrode for searching the muscle and injecting botulinum toxin

Rice. 6. Electromyograph for searching muscles during botulinum toxin injection

When administering the drug on an outpatient basis, patients were observed for 1 hour after injection and then released.

Treatment results were assessed 10 and 30 days after botulinum toxin administration. In 2 patients with decreased detrusor contractility, residual urine disappeared 10 days after the administration of botulinum toxin. At the same time, patients noted that emptying the bladder occurs with moderate tension of the muscles of the anterior abdominal wall (Valsalva maneuver). This observation was confirmed by the results of a urodynamic study, which noted a decrease in the average values ​​of abdominal pressure at which urine was released from the external urethral opening from 74.5 to 42 cm of water. Art.

In 3 patients with DSD, residual urine was not detected 10 days after the administration of botulinum toxin. The average maximum urine flow rate increased from 7.4 to 14.2 ml/sec. One of the patients who used the Creda technique (compression of the lower abdomen with hands) to completely empty the bladder abandoned this technique due to adequate urination.

In a patient with no relaxation of the suburethral sphincter after a hemorrhagic stroke, 10 days after the injection of botulinum toxin, urination became possible using the Valsalva maneuver with a residual urine volume of no more than 100 ml.

A patient with decreased detrusor contractility who underwent autocatheterization of the bladder noted spontaneous urination 7 days after the injection of botulinum toxin. After urination using abdominal pressure and subsequent use of Cred, the absence of residual urine was noted. As a result, the patient refused intermittent bladder catheterization.

When re-examined 1 month after the administration of botulinum toxin, the therapeutic effect was observed to persist in all patients.

We did not observe any complications during the injection of botulinum toxin and in the early period after its administration. 1 woman reported little urine leakage during exercise for 12 days after drug administration.

In conclusion, I would like to note that to date, pathogenetically based therapy aimed at restoring lost control by the central nervous system over the function of the lower urinary tract has been of limited importance. The use of botulinum toxin for adequate bladder emptying in neurological patients is a promising area of ​​neurourology

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This is primarily due to the simple administration technique, the good therapeutic effect of the drug and the absence of side effects. Further research will answer a number of questions related to the frequency of drug administration and the development of addiction, as well as identify new indications for the use of botulinum toxin in urology. Literature:
1. Orlova O.R., Yakhno N.N. Use of Botox (botulism toxin type A) in clinical practice. Guide for doctors. Moscow, 2001

2. Dolly JO: General properties and cellular mechanisms of neurotoxins, in Jankovic, J. and Hallet, M. (eds): Therapy with Botulinum Toxin. New York, Marcel Dekker. 1994

3. Dykstra DD, Sidi AA, Scott AB, Pagel JM, Goldish GD: Effects of botulinum A toxin on detrusor–sphincter dyssynergia in spinal cord injury patients. J Urol 1988; 139:919

4. Leippold T, Reitz A, Schurch B. Botulinum toxin as a new therapeutic option for voiding disorders: Current State of the art. Euro Urol 2003; 44(2): 165–74

5. McNeil BK, Smith CP, Franks ME, et al. Effect of botulinum toxin A on urethral neurotransmitter release: Implications on somatic/autonomic nerve transmission. J Urol 165:277

6. Sett'm L. S. The action of botulinum toxin at the neuromuscular junction. Med. Biol. 1981; 59, p 11–20

7. Simpson LL: Peripheral actions of the botulinum toxins, in Simpson, LL (ed): Botulinum Neurotoxin and Tetanus Toxin. New York, Academic Press. 1989; p 153–178

8. van Ermengem E: Ueber einen neuen anaeroben Bacillus and seine Beziehungen zum Botulisms. Ztsch Hyg Infect. 1897; 26:1

Technique for performing botulinum toxin injections

A botulinum therapy specialist inserts a cystoscope into the patient and passes a rigid metal needle with an insertion depth scale through a special channel. Butolotoxin is diluted in prescribed proportions, according to the technological instructions. The medicine is administered into the bladder with pinpoint injections of 1 ml of solution at a concentration of 100-300 units. 4 injections are made into the sphincter at 3, 6, 9, 12 o'clock on the conventional dial. Doctors in China practice 8-point injection of the drug at an intermediate distance from the cervix, which is effective for severe cramps. For complex patients with no independent urine drainage reflex, a catheter is inserted for 4 days from the first days of the procedures. During this time, botulinum toxin comes into effect. When contacting the Botulinum Therapy Center, specialists will calculate the correct dosage after examination and determining the degree of complexity of the disease.

Complications

• deterioration of the patient's general condition;
• pain after the anesthesia wears off;
• complete paralysis of the bladder, which occurs due to improper Botox injections;
• dysfunction of smooth muscles in the urinary organ.

As we can see from the presented complications, with the correct tactics of drug administration, they are minimal and go away quickly. Therefore, the procedure is considered practically safe, and its effect is much faster than with drug treatment of urinary incontinence.

Benefits of botulinum therapy

A responsible botulinum therapy clinic will always announce the advantages of the method:

• the drug is not addictive;
• long validity – about 8 months;
• the drug can be used multiple times;
• an effective and safe method of treating urinary dysfunction.

When treating diseases of the genitourinary system with botulinum toxin, not only does urination improve and is completely restored, but also the quality of life of patients improves, and kidney function is preserved.

For some time now, vaginismus has been treated with butulinotherapy. With this diagnosis, injections are injected into the muscle tissue of the pelvic floor to relieve spasm, which makes it possible to perform normal sexual intercourse.

A specialist will be able to tell you how much botulinum therapy costs in an outpatient clinic after examining you and determining the number and complexity of procedures.

Pharmacotherapy for overactive bladder

Anticholinergic drugs are the first line of pharmacotherapy. This group of drugs includes oxybutin, tolterodine, solifenocin, trospium chloride and propiverine. Unfortunately, the use of anticholinergic drugs is limited by the development of side effects, such as dry mouth, visual impairment, constipation and urinary retention, which in turn necessitates the search for new, more effective and safe drugs.

Muscarine antagonists were developed to affect the main link in the bladder contraction mechanism - acetylcholine. It is known that acetylcholine, released by parasympathetic nerve fibers of the bladder, causes detrusor contractions by activating muscarinic receptors.

Potassium channel modulators Potassium channels play a leading role in cellular excitability. Potassium ion currents through these channels lead to hyperpolarization of the membrane, which in turn inhibits the opening of calcium channels, blocking the entry of calcium into the cell and leading to relaxation of the myocyte. The use of such drugs in clinical practice, unfortunately, has not been successful.

Vanilloids Intravesical administration of capsacin leads to the development of a clinical effect. However, the use of capsacin is limited by side effects such as severe pain and irritation of the bladder mucosa.

The low effectiveness and large number of side effects of drug therapy have prompted the search for new methods of treating bladder overactivity.

Is patient preparation necessary before Botox therapy?

Preliminary local anesthesia with localization in the bladder is allowed. The installations are carried out in 15 minutes. Male patients will receive short-term intravenous anesthesia. When botulinum toxin injections are performed transperianally into the external sphincter zone, the patient is not given an anesthetic. In this case, men and women are given an ultra-thin electromyography needle, which makes a painless puncture and has an injection port.

Our center uses botulinum therapy at a price that allows many patients to achieve a comfortable standard of living and get rid of bladder emptying dysfunction.

Prospects for treating urological diseases using botulinum therapy

The introduction of BT today has confirmed its effectiveness in curing many urological problems. They are able to quickly restore the functions of independent urination, eliminate both enuresis and difficult urine drainage. In addition to the diagnoses described above, foreign and domestic doctors see the prospect of treating CPPS (chronic pelvic pain syndrome) and interstitial cystitis with botulinum toxin.

To determine what other clinical indications BT can be used and its capabilities, it is necessary to conduct additional research into the mechanisms of action of botulinum toxin.

Our specialists will explain to all patients the effectiveness and principle of the botulinum therapy procedure, the cost of which will be set based on the diagnosis and severity of the disease. In any case, the procedure will be affordable and accessible to all social groups of the population.

Reviews:

• After long-term treatment with various methods of DSD, I finally decided to undergo botulinum therapy. It was carried out under anesthesia. The procedure went quickly, after the anesthesia wore off, I felt a little discomfort when urinating, but it became much easier to urinate already on the 4th day.

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