RU2708524C1 - Method of treating and preventing urination disorders - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to medicine, specifically to urology. 40 ml of blood is withdrawn from the ulnar vein in test tubes containing 0.5 ml of sodium citrate. Then the test tubes are inverted 6 times, centrifuged in 2 stages with cooling. First centrifugation step is performed for 5 minutes at RCF 300 and t=12 °C, resulting plasma completely collected without destruction of leukocyte and thrombocyte layer. Further, the second stage of centrifugation is performed during 17 minutes at RCF 700 and t=12 °C. Lower plasma layer from each test tube is collected in sterile 10 ml syringe. Immediately prior to introduction, temperature activation is performed by incubation at t=37 °C for 15 minutes. Anesthesia is performed. Through a cystoscope, the bladder is filled with 150 ml of 0.9 % sodium chloride solution. Cystoscopy is performed, during which an injection needle is inserted into a cystoscope, and 20–25 injections are performed into the bladder wall at 1–2 mm at angle of 30–45 degrees under direct imaging conditions, each time introducing 0.5 ml of autoplasma each time. Injection points of the preparation are uniformly distributed throughout the surface of the bladder mucosa, including in the region of the Lieto triangle. If latter is 0.5 ml, a syringe with normal saline is used to introduce the remaining autoplasma. After the PRP introduction, the bladder is emptied, the cystoscope and the needle are removed from the urethra.EFFECT: method enables successful treatment and prevention of urination disorders, increases urine volume when urinating, increases urine flow rate in patients.1 cl, 1 dwg, 1 ex

Description

The invention relates to medicine, namely to urology, and can be used in the complex treatment and prevention of urination disorders, accompanied by chronic recurrent infections of the lower urinary tract and / or urgent urination, enriched with platelets autoplasma prepared by a new method.

Chronic recurrent lower urinary tract infections are one of the most pressing problems of modern medicine, and urology in particular. The number of published scientific works in the field of treatment of this pathology in the world literature is growing every year, this indicates the importance of the issue and its unresolved.

Almost half of women have experienced an episode of acute cystitis at least once in their lifetime, with every third female member having an exacerbation of cystitis before the age of 24 years. With age, the number of factors complicating the development of chronic cystitis increases: sexual intercourse, use of spermicides, change of sexual partner, urinary incontinence, atrophic vaginitis due to estrogen deficiency, increased volume of residual urine, catheterization of the bladder. (Bonkat G., Pickard R., Bartoletti R. et al. EAU guidelines on urological infection / European Association of Urology, 2017 // https://uroweb.org/wp-content/uploads/19-Urological-infections_2017_web.pdf )

By definition, chronic cystitis (HC) is a long-standing inflammatory reaction of the bladder wall.

Current recommendations for the treatment and prevention of HC include treatment of relapses with antibacterial drugs, behavioral therapy (for example, urination after intercourse, hygiene, reduced fluid intake, etc.), hormone replacement therapy in postmenopausal women, prevention of immunoactive drugs and probiotics, cranberry drugs, intravesical installations of hyaluronic acid and chondroitin sulfate. (Gadzhieva Z.K., Kazilov Yu.B. Features of the approach to the prevention of recurrent lower urinary tract infections // Urology. Russian clinical recommendations with modern data from leading Russian specialists. - 2013. - No. 3. - P. 65-76).

These measures are aimed not only at stopping the acute inflammatory process, but also at restoring the natural protective mechanisms of the genitourinary system.

A known method of treating radiation damage to the bladder (http://www1.fips.ru/wps/portal/IPS_Ru#docNumber=57&docId=aefc0d20dfee052625fb6b5dff1ed114) using autoplasma. Various therapeutic drugs in therapeutic doses, incubated for 30 minutes at 37 ° C with autoplasma, are administered 2 times a week, repeating the manipulations 4 times per treatment course. The method is as follows. From the peripheral (ulnar) vein, the patient draws 150 ml of blood into a standard sterile vial with glugicir, which is centrifuged for 15 minutes at 1500 rpm. Blood plasma is taken, the cell suspension is reinfused to the patient intravenously, drip. The necessary drugs are added to the blood plasma, depending on the established disease and clinical situation, and incubated at 37 ° C for 30 minutes. Then autoplasma with the drug is administered to patients with diseases of the bladder for deposition of drugs in prevesical tissue, as an option for administration, directly departing 0.5 cm to the right and left of the external opening of the urethra parallel to the catheter inserted into the urethra. In this puncturing option, the volume of injected liquid should not exceed 10 cm ³ . Undoubtedly, this method helps to stop the inflammatory process in paravesical fiber, increase the local concentration of chemotherapeutic drugs or antibiotics, against the background of reduced indicators of their general toxic effect, as well as lengthening the residence time of drugs in the body of patients, specifically in the area of the pathological process, which allows drugs to be administered less frequently than with systemic use. In this case, autoplasma in this method is not injected directly into the wall of the bladder, which, accordingly, does not have a direct pathogenetic or symptomatic effect on the processes occurring in the wall of the bladder during urination disorders, accompanied by chronic recurrent infections of the lower urinary tract and / or urgent urges to urinate.

The technical problem of the present invention is that it is necessary to develop a method for the treatment and prevention of recurrence of HC.

The problem is solved by the action of growth factors of platelet-rich plasma injected into the thickness of the bladder wall. In particular, the following factors contribute to the relief of the chronic inflammatory process in the bladder wall, as well as the restoration of its protective mechanisms: epidermal growth factor (EGF) - stimulates the growth and differentiation of epithelial cells; fibroblast growth factors (FGFs), is a stimulator of angiogenesis and growth of endothelial cells, fibroblasts; platelet growth factor (PDGF), activates smooth muscle fibroblasts and myocytes, cell growth, stimulates the synthesis of collagen and glycosaminoglycans, enhances the formation of granulation tissue, and also stimulates angiogenesis. (The use of autoplasma enriched with platelets in clinical practice / EE Achkasov [et al.] // Biomedicine. - 2013. - No. 4. - S. 46-59).

Platelet-rich plasma, on average, contains 5,000 times higher concentration of platelets than in peripheral blood, and, consequently, of the above growth factors, which, when introduced into the wall of the bladder, trigger its repair mechanisms.

The invention is illustrated in the drawing: FIG. - a schematic representation of the location of intra-wall injection in the bladder.

The method is implemented as follows.

It was traditionally believed that recurrent UTIs result from the repeated colonization of uropathogens, however, new data indicate the ability of them to form microbial associations in urothelium protected by biofilms. Such colonies may contain several dozen types of microorganisms. Being protected, they do not cause an immune response and persist after treatment of an acute infection. The regenerative processes of the epithelium contribute to the release of these bacteria, potentially leading to recurrent infections (Davis C., Rantell A. Lower urinary tract infections in women // Br J Nurs. 2017. V. 26. No. 9. - P. 12-19) .

Estrogen deficiency is accompanied by a decrease in blood circulation in the pelvic organs, which leads to ischemia of the genitourinary system. The diameter of the arteries decreases, the number of small vessels decreases, and their walls become thinner. Similar changes are observed in the veins and venous plexuses located subepithelially.

Estrogen deficiency leads to a decrease in blood circulation in the pelvic organs, which, in turn, contributes to ischemia of the genitourinary system. There is a decrease in the diameter of arteries and veins, thinning of their walls, a decrease in the number of small vessels. (Serov V.N. Therapy of urogenital disorders due to estrogen deficiency // Obstetrics, gynecology and reproduction. 2010. - T4, No. 1. - P. 21-36.

Intravesical therapy aimed at restoring the glycosaminoglycan layer of urothelium is effective, but does not completely solve the problem.

Despite the large number of works devoted to the treatment of urination disorders in women suffering from recurrent lower urinary tract infections, a solution to the problem has not yet been found.

For the treatment and prevention of urination disorders, an autoplasma enriched in platelets (PRP) and prepared as follows is used.

Blood is taken from the ulnar vein under aseptic conditions of the treatment room into tubes containing 0.5 ml of sodium citrate. The total volume of blood taken is 40 ml. Then the tubes are slowly inverted 6 times.

The centrifugation is carried out in 2 stages in a Hettich Zentrifugen cooled centrifuge.

The first centrifugation is performed for 5 min at RCF 300 and t = 12 C. The resulting plasma is completely collected in a sterile tube, without destroying the layer of leukocytes and platelets, and then it is subjected to the second stage of centrifugation for 17 min at RCF 700 and t = 12 C. (Amable et al. Stem Cell Research & Therapy 2013, 4:67. Perez AG at al. Relevant Aspects of Centrifugation Step in the Preparation of Platelet-Rich Plasma. ISRN Hematol. 2014 Mar 25; 2014: 176060.)

Next, the lower plasma layer from each tube is collected in a sterile 10 ml syringe. The result is 10-12 ml of platelet-rich plasma. Then immediately place it in storage for at least 1 hour in the refrigerator at t = 4 C.

Immediately prior to administration, its temperature activation is carried out by incubation at t = 37 ° C for 15 minutes.

To activate platelets, followed by the release of growth factors, thrombin, calcium chloride, collagen, or a combination thereof are used, as a rule. The concentration of growth factors in activated PRP directly depends on the dose of the activator. (Lacoste E, Martineau I, Gagnon G. Platelet concentrates: effects of calcium and thrombin on endothelial cell proliferation and growth factor release. J Periodontol. 2003; 74: 1498-507). The ideal concentration of platelet activators leading to optimal release of growth factors upon activation of PRP does not currently exist. (Dawood AS, Salem N.A. Current clinical applications of platelet-rich plasma in various gynecological disorders: An appraisal of theory and practice. Clin Exp Reprod Med. 2018 Jun; 45 (2): 67-74. Jo CH et al Optimizing platelet-rich plasma gel formation by varying time and gravitational forces during centrifugation. J Oral Implantol 2013; 39: 525-32).

In the process of activation, a sufficiently thick gel is formed, the introduction of which is extremely difficult through the needle, which requires clot extraction, centrifugation, dilution. In our opinion, the best option for introducing PRP through a 23 G needle into the bladder wall is platelet activation in vivo under the action of activators contained in their own tissues.

While PRP is incubated at body temperature (37 ° C), the patient should be in the operating room or cystoscopy room, depending on the type of anesthesia.

Then, local anesthetic is injected into the urethra by intraurethral injection of the lidocaine gel to facilitate the administration of the cystoscope. 10 minutes before the procedure, 3 ml of a gel containing lidocaine hydrochloride, chlorhexidine dihydrochloride are injected. Local anesthesia of the walls of the bladder is performed by instillation of a 1-2% solution of lidocaine to reduce sensations when injecting into the wall of the bladder; the installation is carried out immediately before the procedure, and the anesthetic should be in the bladder for about 15-30 minutes to ensure a sufficient level of pain relief; Before the procedure, the lidocaine solution must be removed from the bladder, then injected into the bladder saline solution (rinse) and remove it again.

After local anesthesia, sedation may be indicated by intravenous sedation.

During the treatment procedure, the type of anesthesia is determined by the attending physician and / or anesthetist in order to ensure the proper level of patient safety and comfort.

Through a cystoscope, the bladder is filled with 150 ml of 0.9% sodium chloride solution, cystoscopy is performed, during which plasma is directly injected into the bladder wall to a depth of 1-2 mm at an angle of 30-45 degrees. In this case, it is necessary to avoid excessive stretching of the bladder in order to minimize thinning of its wall. After they inspect the entire surface of the bladder and its lumen before administering the drug, then the injection needle is inserted into the cystoscope. We used injeTAK® Laborie cystoscopic needles with an adjustable needle length of 2-5 mm insertion depth and 23G needle diameter.

In conditions of direct visualization, 20-25 injections are systematically performed into the wall of the bladder, each time introducing 0.5 ml of autoplasma depending on the amount of received PRP. The depth of injection is approximately 1-2 mm. The injection points of the drug should be evenly distributed, including in the region of the Lieto triangle (Fig. 1). The tip of the bladder is often thin, so injections in this area are not performed at all. PRP syringes change as they empty. With the introduction of the last 0.5 ml, use a syringe with saline to inject the remaining autoplasma.

After the introduction of PRP, the bladder is emptied, the cystoscope and the needle are removed from the urethra. After the procedure, a permanent catheter can be inserted in connection with hematuria, which should be removed after 24 hours. In our clinical cases, hematuria was not observed, therefore, the installation of a catheter was not required.

The procedure is performed both in inpatient and outpatient settings.

Important! The administration of drugs acting as anticoagulants (warfarin and other coumadin derivatives; acetylsalicylic acid (including low-dose aspirin); clopidogrel / ticlopidine) should be stopped no later than 3 days before the introduction of autoplasma, and can be resumed only the day after procedures.

A prerequisite for the procedure is the absence of exacerbation of cystitis.

Examples of practical implementation.

The above method treated 6 patients who signed the informed consent. All patients were diagnosed with chronic recurrent cystitis. Three menopause are more than 4 years old, one of them also has genital prolapse II tbsp. according to POP-Q, in another patient with cystoscopy revealed leukoplakia of the bladder.

Three patients of reproductive age: one revealed detrusor hypotension during cystometry (residual urine of 60, 80 ml with a volume of urine output of 150, 180 ml, respectively), the other had a clinically dry overactive bladder, for this reason for 6 months. receives treatment with solifenacin 5 mg once a day, with varying degrees of success).

A positive effect of treatment was noted in all six. It should be noted that in the presence of an overactive bladder as a result of treatment, a decrease in the frequency of urination and peremptory urges increased the functional capacity of the bladder; in the presence of detrusor hypotension, an improvement in the flow rate of urine and a decrease in the volume of residual urine.

The relapse-free period is from 5 to 11 months. No complications recorded.

Therefore, the proposed method of treatment by introducing platelet-rich autoplasma into the wall of the bladder is quite effective in treating chronic cystitis, including in combination with overactive bladder, detrusor hypotension, menopause, or without bladder leukoplakia.

The advantages of the method are its high efficiency, low cost, no side effects, good tolerance.

Patient B., 54 years old, was in the treatment of the urology department with a diagnosis of chronic recurrent cystitis. Menopause since 2010. Complained of frequent exacerbations of chronic cystitis, periodically discomfort, burning sensation when the bladder is full, after it is empty.

The diagnosis was established on the basis of complaints, medical history, examination, laboratory and instrumental data (ultrasound of the bladder, cystoscopy, uroflowmetry). Urinalysis (general and bacteriological analyzes, Nechiporenko urine analysis), blood (total detailed and biochemical (urea, creatinine, bilirubin, total protein, glucose) analyzes), prothrombin index, APTT, fibrinogen are normal. On examination, genital prolapse was not detected; the external opening of the urethra is usually located. Urination diary: daily urination with a volume of 70-230 ml 8 times, diuresis daily 1280 ml, night 300 ml. No nighttime urination was noted. Quality of life was assessed using questionnaires EQ-5D-5L, Russian version, OAB-q, Brief Pain Inventory (BPI).

Relapses were observed every 1.5-2-3 months. over the last 5 years.

In this regard, antibacterial, anti-inflammatory, hormone replacement teparia (estriol 0.5 mg in the form of vaginal suppositories), prophylactic treatment with immunoactive drugs and probiotics, and also the installation of sodium hyaluronate solution according to the standard scheme (4-6 weeks, one installation every 7 days) were prescribed. , then once every four weeks 2-4 times). Treatment led to remission of chronic cystitis lasting from 1 to 6 months. as much as possible.

The first stage in aseptic conditions of the treatment room from the patient’s ulnar vein into tubes containing 0.5 ml of sodium citrate was taken with a total volume of 40 ml of venous blood. The tubes were slowly inverted 6 times, then centrifuged in a two-stage centrifuge with Hettich Zentrifugen cooling.

The first centrifugation was carried out for 5 min at RCF 300 and t = 12 C. The resulting plasma was completely collected in a sterile tube, without destroying the layer of leukocytes and platelets, and then was subjected to the second stage of centrifugation for 17 min at RCF 700 and t = 12 C.

Next, the lower plasma layer from each tube was collected in a sterile 10 ml syringe. The result was 10.5 ml of plasma.

Immediately prior to administration, its temperature activation was carried out by incubation at t = 37 ° C for 15 min.

The second stage, under sterile conditions, the patient was administered 10.5 ml of pre-prepared autoplasma under local anesthesia (intraurethral 3.0 ml gel containing lidocaine hydrochloride, intravesical 50 ml 1% lidocaine hydrochloride solution - exposure 15 min).

Through a cystoscope, the bladder was filled with 150 ml of 0.9% sodium chloride solution, cystoscopy is performed, during which plasma is injected directly into the bladder wall to a depth of 1-2 mm from an incubator.

Under the conditions of direct visualization, 21 injections were performed sequentially, 0.5 ml of autoplasm into the region of the urinary bladder triangle and the body of the bladder.

At the end of the procedure, a Foley catheter No. 18 (Ch, Fr) was installed for 24 hours. Hematuria is not marked.

The procedure was performed with an interval of 3 months. (for this patient, a total of three times). The observation period at the moment was 11 months, no exacerbations of chronic cystitis were noted. The patient did not receive any other treatment for chronic cystitis. When examined after 3 months. the cystoscopic picture normalized. Urination diary: daily urination with a volume of 150-300 ml 5 times, diuresis daytime 1200 ml, nightly 380 ml. An improvement in the performance of all questionnaires and scales was noted. In addition, subjectively, the patient noted an increase in urine volume during urination, an increase in urine flow rate. There is persistent positive dynamics.

Claims (1)

A method for the treatment and prevention of urination disorders, including the use of platelet-rich autoplasma (PRP), for this 40 ml of blood is taken from the ulnar vein into tubes containing 0.5 ml of sodium citrate, then the tubes are slowly inverted 6 times, centrifugation is carried out in 2 stages with cooling: the first stage of centrifugation is performed for 5 minutes at RCF 300 and t = 12 ° C, the resulting plasma is completely collected without destroying the layer of leukocytes and platelets, and then subjected to the second stage of centrifugation in those 17 min at RCF 700 and t = 12 ° С, then the lower plasma layer from each tube is collected in a sterile 10 ml syringe, immediately before administration, it is temperature activated by incubation at t = 37 ° С for 15 min; then anesthetized; then through a cystoscope, the bladder is filled with 150 ml of 0.9% sodium chloride solution, cystoscopy is performed, during which an injection needle is inserted into the cystoscope, and 1-2 mm deep into the bladder wall at an angle of 30-45 degrees under direct visualization 20-25 injections, each time introducing 0.5 ml of autoplasma, while the injection points of the drug are evenly distributed over the entire surface of the bladder mucosa, including in the region of the Lietot triangle; with the introduction of the last 0.5 ml, use a syringe with saline to inject the remaining autoplasma; after the introduction of PRP, the bladder is empty, the cystoscope and the needle are removed from the urethra.

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