RU2466755C2 - Method for conducting intraorganic medicine electrophoresis of bladder - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: bladder is released, washed with distilled water, and a drug solution is introduced therein. An intrabladder electrode representing a catheter provided with a cylinder on its proximal end and three tips on its distal end, as well as with an electrical conductor with its distal end coupled with a current source. One of the tips is used to fill the cylinder with air or physiological saline, and another one - to introduce drug substances, and the electrical conductor is wired through the third tip. On a proximal end of the catheter, there are window openings for liquid injection and ejection from a bladder cavity. At a level of these openings, inside of the catheter, there is a steel guide presented in the form of a symmetrical single spiral wound with turns touching of the diametre matched with an internal diametre of the catheter, and of the length 1/3 exceeding the length of said openings. An external electrode is presented in one layer of pull-ups made of a combined cloth consisting of elastane, wool and metal in the relation of 1:16:16. The electrode is processed by a conducting gel used to coat pelvic and perineal regions.

EFFECT: improved drug penetration into bladder tissues, including in patients with decreased physiological volume of bladder ensured by more tight adherence of the external electrode to the pelvic and perineal regions and increased skin current conductivity, eliminated direct contact of the intrabladder electrode with a bladder mucosa, avoiding injuries of the bladder walls.

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Description

The invention relates to medicine, in particular to urology and can be used for intraorgan drug electrophoresis to treat bladder diseases such as superficial and muscle-invasive bladder cancer, bacterial and interstitial cystitis, overactive bladder, and also for the prevention of relapse and progression of superficial and muscle-invasive bladder cancer after transurethral resection of a bladder tumor.

External electrodes are usually used to conduct drug electrophoresis on the bladder with direct current. One rectangular-shaped electrode is placed over the projection area of the bladder (anode). Another electrode is placed in the projection of the first or third lumbar vertebrae (cathode). The drug substance is introduced using catheterization of the bladder (RU 2250784 C1, 2005).

With drug electrophoresis, the substances administered penetrate to a shallow depth and can only reach the subcutaneous fat layer. The deep penetration of substances introduced by direct current is impeded by the complex membrane structure of the skin and its electrochemical activity, the presence of free highly mobile ions in the surface tissues, pronounced polarization in the skin, and binding of the drugs administered by the polyelectrolyte structures of the skin. Drugs received during the procedure from the skin and subcutaneous tissue gradually diffuse into the lymphatic and blood vessels and are delivered to all organs and tissues (Balneology and physiotherapy (manual), edited by V.M. Bogolyubov: in 2 volumes. T. 1 .-- M .: Medicine, 1985, 561 p. S.322).

As a prototype for the closest technical essence, we have chosen the method of intravesical drug electrophoresis (VPEF) of doxorubicin in superficial bladder cancer (Rolevich A.I., Sukonko O.G., Krasny S.A., Zhukovets A.G. Intravesical electrophoresis of doxorubicin with superficial bladder cancer. Results of a prospective randomized trial. / Oncourology, 2005, No. 2, p. 34-39).

The method consists in the fact that during the procedure under aseptic conditions, the bladder is released from the urine by a catheter and washed twice with distilled water in order to maximize the removal of urine electrolytes. 2 flat electrodes (cathodes) of 60 cm ² each are attached to the suprapubic region and the sacral region. A solution of 50 mg of doxorubicin in 150 ml of distilled water is injected into the bladder through a catheter. Then, an intravesical electrode (anode) is introduced into the catheter's lumen so that its working part is opposite the hole in the catheter. The cathodes and anode are connected to the DTGE-70-01 electrotherapy apparatus. They turn on the electric current and its strength slowly (within 1 min) increases from 5 to 15 mA. The procedure lasts 20 minutes, after which the bladder is empty and the catheter is removed.

The authors of this study state that in one case (4.5%) an electrochemical burn of the bladder was observed. The reason for this complication is the contact of the intravesical electrode with the wall of the bladder during the session of VEPF. The clinical picture of an electrochemical bladder burn is the symptoms of severe cystitis (dysuria, macrohematuria), refractory to conservative treatment. Cystoscopy reveals a peptic ulcer of the mucous membrane at the bottom of the bladder, covered with fibrin, with severe perifocal edema and hyperemia. The authors of the study note that it seems extremely advisable to prevent the development of this complication. It consists, in the opinion of A.I. Rolevich et al., In preventing contact of the intravesical electrode with the wall of the bladder. For this, a sufficient volume of filling the bladder with a solution of doxorubicin (at least 150 ml) is used. The inability to fill the bladder with such a volume due to the small functional capacity of the latter is a contraindication to conducting VPEF. (Rolevich A.I., Sukonko O.G., Krasny S.A., Zhukovets A.G. A method for the treatment of superficial bladder cancer using intravesical electrophoresis of doxirubicin. - Instructions for use. Designing institution: State Research Center for Medical Oncology and Radiology named after NN Aleksandrov, Authors: Doctor of Medical Sciences OG Sukonko, Candidate of Medical Sciences SA Red, Candidate of Medical Sciences SL Polyakov, Candidate of Medical Sciences A.G. Zhukovets, Candidate of Medical Sciences A.I.Rolevich, Minsk, 2009 - Website of urologists of Belarus - www. UROBEL. UROWEB. RU).

The disadvantages of the method selected as a prototype are:

- the risk of trauma to the walls of the bladder in connection with the introduction of an intravesical electrode, which is a metal conductor, into the lumen of the catheter; trauma to the walls of the bladder can be caused by an electric burn when the electrode comes into contact with the mucosa, as well as perforation of the wall of the bladder and urethra in the event of a metal conductor leaving the catheter;

- wetting the indifferent electrode with water, which leads to its rapid evaporation and, as a result, a decrease in the conductivity of the patient’s skin and an increase in the density of force fields on the skin surface, which leads to unpleasant sensations and can cause electric burns;

- the introduction of the intravesical electrode and the drug substance is carried out on the same channel of the catheter, which leads to the loss of part of the drug solution;

- the transverse electrophoresis technique, according to which the electrodes are placed parallel to each other, in particular on the pubic and sacral areas, leads to an uneven distribution of force fields and, as a result, to incomplete coverage of the bladder wall with an electric field, which reduces the efficiency of intraorgan drug electrophoresis;

- insufficient transport efficiency of lightly charged and large molecules of drugs;

- limiting the use of the method in patients with insufficient physiological capacity of the bladder, since there is a danger of contact of the electrode with the mucous membrane of the organ.

The objective of the invention is to increase the efficiency of intraorgan drug electrophoresis of the bladder, which consists in:

- increasing the reliability of the procedure by preventing trauma to the walls of the bladder;

- improving the penetration of drugs into the tissue of the bladder and reducing the loss of drug substance when it is introduced;

- expansion of the patient population due to patients with insufficient physiological capacity of the bladder.

The technical result of the invention is:

- the exclusion of direct contact of the intravesical electrode with the mucous membrane of the bladder;

- providing a more snug fit of the outer electrode to the areas of the pelvis and perineum;

- providing a more complete coverage of the bladder wall with an electric field;

- increase the conductivity of the skin of the patient;

- the exception of conducting the intravesical electrode and the drug substance on the same channel of the catheter;

- improving the efficiency of transport of lightly charged and large molecules of drugs.

The technical result of the invention is achieved by the fact that under aseptic conditions, the bladder is released from urine by catheterization, washed with distilled water, a drug solution is introduced into it and intravesical and external electrodes are used. The intravesical electrode is a catheter equipped with a balloon at its proximal end, three tips at its distal end, and an electric wire connected to the distal end with a current source and the proximal end with a metal conductor. One of the tips is for filling the balloon with air or saline. The second is for the administration of drugs. An electric wire is drawn through the third tip. At the proximal end of the catheter, there are made hole openings for fluid inlet and outlet from the bladder cavity, at the level of which there is a metal conductor inside the catheter made in the form of a symmetrical single-row spiral, which is wound round to round. The diameter of the turns corresponds to the inner diameter of the catheter. The length of the symmetrical single-row spiral is 1/3 longer than the length of the fenestrated openings for the entry and exit of fluid from the cavity of the bladder. The outer electrode, made in one layer in the form of pants made of a combination fabric consisting of elastane, wool and metal in the following ratio of components: 1:16:16, is treated with a conductive gel and covers the pelvic and crotch areas. During electrophoresis of drugs with lightly charged and large molecules, penetrant substances are additionally introduced into the drug solution. For patients with a reduced physiological capacity of the bladder, the drug solution is administered before the urge to urinate occurs.

The invention is illustrated by drawings, where Fig. 1 schematically shows an external electrode (Application for utility model No. 20130370/14, filed July 20, 2010. Decision to grant a patent dated October 18, 2010), where:

1 - outer electrode made in one layer in the form of underpants; 2 - an opening for genitals; 3 - apparatus for supplying current.

The outer electrode is made of metallized yarn containing 50% metal and 50% wool, as well as elastane. To obtain the fabric necessary for one sample of the outer electrode, 220 grams of metallized yarn containing 50% metal and 50% wool and 7 grams of elastane are taken, which are knitted into a combined fabric consisting of 48.5% metal, 48.5 % wool and 3% elastane. From the resulting fabric make patterns of the front and rear panels of the outer electrode in the form of pants and sew. An opening for the genitals is cut out on the front panel in the crotch part of it.

The outer electrode can be supplied in individually sealed packaging of various sizes, male and female.

Figure 2 schematically depicts an intravesical electrode (Application for utility model No. 2012929654/20, application. July 15, 2010), where:

4 - tip for filling the balloon with air or saline; 5 - tip for the administration of drugs; 6 - a tip for conducting an electric wire; 7 - a metal conductor made in the form of a symmetrical single-row spiral; 8 - fenestrated holes for input and output of fluid from the cavity of the bladder; 9 - cylinder; 10 - electric wire; 3 - apparatus for supplying current.

The method is as follows.

When the patient is lying on a couch, an intravesical electrode is inserted into the bladder. Through tip 4 to fill the balloon 9 with air or saline, 20-30 ml of saline is injected to fix the electrode in the cavity of the bubble. Through the tip 5 for drug administration, the bladder is freed from the urine and washed twice with distilled water in order to maximize the removal of urine electrolytes. A Janet syringe is connected through the tip 5 for the administration of medicinal substances and through the openings for the introduction and withdrawal of fluid from the cavity of the bladder 8, a drug substance is introduced into the bladder in contact with a symmetrical single-row spiral 7 connected to the electric wire 10. If the physiological capacity of the bladder is preserved drive at least 200 ml of the drug substance, and if it is reduced, until the urge to urinate occurs. During electrophoresis of drugs with lightly charged and large molecules, penetrant substances are additionally introduced into the drug solution.

We introduced penetrant substances with Mitomycin C (a neutral compound that, under the influence of an electric field, combines with Na ions and acquires a weak positive charge-cation). As penetrant substances, we used a solution of DMSO (Dimethyl sulfoxide) 10% and nystatin 1 million units.

After the introduction of the drug solution, the Janet syringe is disconnected and the tip 5 for drug administration is closed with a stopper.

An electric wire 10 exiting through the tip 6 is connected to the apparatus for supplying current 3.

After the introduction of the intravesical electrode, an external electrode is applied to the pelvic area, made in one layer in the form of underpants 1 made of a combination fabric consisting of elastane, wool and metal in the following ratio of components: 1:16:16, after having previously treated the electrode with a conductive gel. We used Uniagel gel (universal electrode gel for medicine and hardware cosmetology). Manufacturer - Geltek - Medica, Russia. Viscosity - 8-9 Pa × s; pH 6.5-7.0. The specific conductivity is 0.6-0.8 S / m.

Through the hole for the genitals 2, the external genitalia in men are removed and the intravesical electrode in women is removed. The outer electrode, made in one layer in the form of panties 1, made of a combination fabric consisting of elastane, wool and metal in the following ratio of components: 1:16:16, is connected to the apparatus for supplying current 3 using crocodile forceps to the holders for crocodile tongs. We used the ELFOR-PROF current supply apparatus.

After the introduction of the intravesical electrode and application of the external electrode to the pelvic region, the apparatus for supplying current 3 ELFOR-PROF is turned on and the strength of the electric current is slowly (over 1 min) increased from 5 to 15 mA. The procedure lasts 20 minutes, after which the bladder is empty and the intravesical electrode is removed.

Distinctive essential features of the invention and a causal relationship between them and the achieved result:

- The intravesical electrode is a catheter equipped with a balloon at its proximal end, three tips at its distal end, one of the tips to fill the balloon with air or saline, the second to administer drugs, and an electric wire is passed through the third tip.

The presence of a separate tip for the administration of drugs excludes the conduct of an intravesical electrode and drug substance along the same channel of the catheter, which prevents the loss of drug substance when it is introduced.

- The intravesical electrode, which is a catheter, is also equipped with an electric wire connected to the distal end with a source for supplying current, and the proximal one with a metal conductor. At the proximal end of the catheter, there are made hole openings for fluid inlet and outlet from the bladder cavity, at the level of which there is a metal conductor inside the catheter, made in the form of a symmetrical single-row spiral, which is wound round to round, with a diameter corresponding to the inner diameter of the catheter and length 1/3 exceeding the length of the fenestrated openings for the entry and exit of fluid from the cavity of the bladder.

The presence of a metal conductor inside the catheter at the level of the openings for the introduction and withdrawal of fluid from the cavity of the bladder eliminates the direct interaction of the metal conductor with surrounding tissues and, accordingly, prevents damage to the mucous membrane of the lower urinary tract.

The location of the metal conductor inside the catheter can also achieve a more reliable fixation of the metal conductor.

The intravesical electrode and the catheter are one, therefore, unlike the prototype method, there is no need to insert the electrode into the lumen of the catheter.

The implementation of the metal conductor in the form of a symmetrical single-row spiral, which is wound round to round, allows you to maintain contact of the drug substance with the entire surface of the proximal part of the metal conductor, while placing it inside the catheter.

The diameter of the symmetrical single-row spiral corresponds to the inner diameter of the catheter for its tight fixation.

The length of the symmetrical single-row spiral is 1/3 longer than the length of the opening for fluid inlet and outlet from the bladder cavity for tight fixation of the metal conductor inside the catheter, as well as to ensure free access of the drug substance to the conductive element.

- An outer electrode made in a single layer in the form of pants made of a combination fabric consisting of elastane, wool and metal in the following ratio of components: 1:16:16, cover the pelvic and crotch areas.

The execution of the outer electrode in a single layer in the form of pants, in contrast to the prototype, provides a more snug fit of the outer electrode to the pelvic and crotch areas, and also provides a more complete coverage of the bladder wall with an electric field, which reduces the current density on the skin surface, while providing uniform distribution of force fields in the wall of the bladder, thereby improving the penetration of drugs into the tissue of the bladder.

The implementation of the outer electrode of elastane, wool and metal with the following ratio of components: 1:16:16, gives the outer electrode the necessary elasticity, hygroscopicity and conductive properties and provides a tight fit of the electrode to the entire surface of the small pelvis.

- The outer electrode is treated with a conductive gel.

Processing the electrode with a conductive gel ensures constant and tight contact of the electrode with the skin of the perineum and small pelvis of the patient, which increases the conductivity of the skin of the patient.

- When electrophoresis of drugs with lightly charged and large molecules, penetrant substances are additionally introduced into the drug solution, which is necessary to increase the efficiency of transport of lightly charged and large molecules of drugs, which, in turn, improves the penetration of drugs.

- For patients with a reduced physiological capacity of the bladder, the drug solution is administered before the urge to urinate occurs.

When using the prototype method in order to prevent contact of the intravesical electrode with the wall of the bladder, a sufficient volume of filling the last with doxorubicin solution, i.e. with a volume of at least 150 ml, is used, which is impossible in patients with reduced functional capacity of the bladder, which is a contraindication to carrying out VPEP. In the claimed method, filling the bladder with a sufficient volume of a drug solution (at least 150 ml) is not a prerequisite, since there is no direct contact of the intravesical electrode with the wall of the bladder, which allows the method to be used in patients with reduced physiological capacity of the bladder. The necessary volume of the drug solution in patients with a reduced physiological capacity of the bladder is determined by the urge to urinate.

The set of distinctive essential features is new and allows you to:

- to exclude direct contact of the intravesical electrode with the mucous membrane of the bladder, which prevents trauma to the walls of the bladder, which, in turn, increases the reliability of the procedure, and also expands the patient population due to patients with reduced physiological capacity of the bladder;

- reduce the loss of drug substance during its administration by eliminating the conduct of an intravesical electrode and drug substance through the same channel of the catheter;

- to improve the penetration of drugs into the tissue of the bladder due to a more tight fit of the outer electrode to the pelvic and perineal regions and more complete coverage of the bladder wall with an electric field, as well as increasing the conductivity of the patient’s skin and increasing the efficiency of transport of lightly charged and large molecules of drugs.

Examples of clinical performance of the method

Example 1. Outpatient card No. 3018. Patient B., 62 years old.

Patient B., 62 years old, was an outpatient examination and treatment at the urology clinic from 08/28 to 10/01/09. With a diagnosis of Recurrent neoplasm of the bladder T1N0M0Gx, transurethral resection of the bladder with a tumor on July 23, 2007. Benign stage I prostate hyperplasia, chronic cystitis, remission. On admission, he complained of a periodic admixture of blood in the urine, pains in the suprapubic and lumbar region on the left, aggravated by urination, frequent urination during the day and night up to 3 times. The patient was shown repeated endoscopic surgical treatment. The patient received a course of intraorgan neoadjuvant chemotherapy of mitomycin electrophoresis (Kiova, Japan) in a single dose of 20 mg with 10% DMSO in 200 ml of physiological saline according to the claimed method.

Current 10-15 mA, duration 20 minutes The procedures were performed 2 times a week for 3 weeks until a total dose of mitomycin of 120 mg was reached. 09/25/2010, transurethral resection of a bladder tumor was performed. A comparative morphological study of tumor tissue samples before and after intravesical electrophoresis with mitomycin with DMSO showed a distinct therapeutic pathomorphosis, expressed in a decrease in the mitotic index and tumor cell viability index, and an increase in the proportion of pathological and “lethal” mitoses. No adverse events and side effects in the early and late postoperative period were noted. Control cystoscopy during 1 year of observation with 3-month intervals and cytology data did not reveal tumor recurrence.

Example 2. Outpatient card No. 3134. Patient I., 37 years old.

I was on an outpatient examination and treatment in the clinic from March 29 to April 30, 10, before visiting for more than 3 years I regularly visited doctors of various specialties (general practitioners, urologists, gynecologists, neuropathologists and general practitioners), complaining of pain in the lower sections of the abdomen of varying intensity and duration, rapid urination day and night up to 25 times a day, periodic imperative urination and episodes of urinary incontinence. Conducted early treatment gave an insufficient and short-term effect, accompanied by side effects from other organs and systems. As a result of a comprehensive examination in the clinic, the patient was diagnosed with an overactive bladder with idiopathic hyperactivity detrusor, refractory form. Due to the ineffectiveness of the repeatedly conducted traditional conservative oral therapy, a course of intraorgan drug electrophoresis of oxybutynin hydrochloride (M-anticholinergic) in a dosage of 10 mg in 120 ml of physiological saline was prescribed by the present method. The patient had a reduced function of the bladder, therefore, the drug solution was administered in a volume of 120 ml, as the patient had the urge to urinate. The total number of procedures was 10 (every other day, 3 times a week), current strength 10-15 mA, duration 20 minutes. After completion of treatment, a lasting positive effect was achieved. Pain in the lower abdomen was stopped and disturbed no more than once every 2 months, the number of urinations per day decreased to 10, imperative urges and episodes of urinary incontinence disappeared. The quality of life has improved and sexual activity has normalized. During the course of therapy, as well as after it, any complications from the bladder, skin, as well as other organs and systems were not observed.

The inventive method of conducting intraorgan drug electrophoresis of the bladder has been tested in the clinic of urology of the Military Medical Academy. S.M. Kirov in 22 patients, 18 women and 4 men. The age of patients is from 20 to 65 years. 16 patients with a diagnosis of overactive bladder, 6 - neoplasm of the bladder. In none of the cases were complications observed. The duration of the achieved therapeutic effect was observed from 6 to 18 months.

The inventive method of intraorgan drug electrophoresis of the bladder, in contrast to the prototype method, allows:

- to exclude direct contact of the intravesical electrode with the mucous membrane of the bladder, which prevents trauma to the walls of the bladder, which, in turn, increases the reliability of the procedure, and also expands the patient population due to patients with reduced physiological capacity of the bladder;

- reduce the loss of drug substance during its administration by eliminating the conduct of an intravesical electrode and drug substance through the same channel of the catheter;

- to improve the penetration of drugs into the tissue of the bladder due to a more tight fit of the outer electrode to the pelvic and perineal regions and more complete coverage of the bladder wall with an electric field, as well as increasing the conductivity of the patient’s skin and increasing the efficiency of transport of lightly charged and large molecules of drugs.

Claims (2)

1. The method of intraorgan drug electrophoresis of the bladder, including the aseptic release of the bladder from the urine by catheterization, rinsing it with distilled water, introducing a drug solution into it and using the intravesical and external electrodes, characterized in that the intravesical electrode is introduced into the urinary bladder A bubble is a catheter equipped with a balloon at its proximal end, three tips at its distal end, and an electrical water connected to the distal end with a source for supplying current, and the proximal one with a metal conductor, one of the tips to fill the balloon with air or physiological saline, the second to inject drugs, and an electric wire is drawn through the third tip, at the proximal end of the catheter fenestrated openings for fluid inlet and outlet from the bladder cavity, at the level of which inside the catheter there is a metal conductor made in the form of a symmetrical single-row spiral and which is wound turn to turn, with a diameter corresponding to the inner diameter of the catheter, and a length exceeding the length of 1/3 fenestrated holes for input and output of fluid from the cavity of the bladder; the outer electrode, made in one layer in the form of pants made of a combination fabric consisting of elastane, wool and metal in the following ratio of components: 1:16:16, is treated with a conductive gel and covers the pelvic and crotch areas; during electrophoresis of medicinal substances having lightly charged and large molecules, penetrant substances are additionally introduced into the medicinal solution. 2. The method according to claim 1, characterized in that for patients with a reduced physiological capacity of the bladder, the drug solution is administered before the urge to urinate occurs.