RU2514093C2 - Device for injection therapy of gastroesophageal reflux disease - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of preparation DAM^+™ for injection treatment of gastroesophageal reflux (gastroesophageal reflux disease).

EFFECT: described is recovery of locking function of gastroesophageal junction with absence of migration, which contributes to extension of arsenal of medications used for treatment of the disease.

5 dwg, 1 tbl

Description

The invention relates to medicine and can be used for injection therapy of gastroesophageal reflux disease (GERD).

Known funds for the treatment of gastroesophageal reflux disease - acid-lowering drugs that are used for conservative treatment. However, its implementation requires quite a long time.

Recently, special attention has been paid to methods of treatment by open and laparoscopic fundoplication, the method of intraluminal fundoplication under the control of gastroscopy is developing intensively. A method of injecting therapy for gastroesophageal reflux disease is under study and is not widespread.

A number of drugs are known that represent inert biopolymers used for injection therapy of GERD. According to the report presented by Dr. Lehman, Enteryx polymer has already been used in more than 1,500 patients [1] Its use has led to a significant improvement in the quality of life and a decrease in acid reflux into the esophagus (in 38%, the esophageal pH-meter met the norm 12 months after the intervention). Twenty-four months after the procedure, 70% of patients did not accept or used a lower dose of proton pump inhibitors than before treatment. As possible mechanisms of action of the procedure, Lehman noted a decrease in the number of transient relaxations of the lower esophageal sphincter and a decrease in the lumen in its area.

At the same time, there are reports of complications and undesirable consequences of the introduction of Enteryx into the wall of the esophagus. Sharon Gillson indicates that the development of complications may be caused by improper transmural administration of the Enteryx polymer. Complications such as pneumonia, atelectasis, mediastinitis, reactive pleurisy, pericarditis, fainting episodes are described [2].

Kamler JP, Lemperle G, S Lemperle, Lehman GA present data on studies of submucosal administration of miniature pig microspheres of polymethyl methacrylate (PPMA) into the region of the lower esophageal sphincter. The introduction of microspheres with PPMA causes a minimal inflammatory reaction, a persistent filling effect, but a migration of microspheres of 40 microns to regional lymph nodes, lungs, and liver is noted. This undesirable effect was eliminated using larger 125 micron microspheres [3].

Currently, there are serial endoscopes, injection needles, and high-pressure syringes that make it possible to perform submucosal administration of the biopolymer into the gastroesophageal junction and lower esophageal sphincter without any technical difficulties. However, the selection of drugs with the necessary therapeutic properties and with minimal undesirable effects is insufficient.

A new technical challenge is to expand the arsenal of drugs for the treatment of gastroesophageal reflux disease, the DAIVT ^{+ ™} preparation for injection treatment of gastroesophageal reflux disease.

DAM ^{+ ™} is a synthetic material for prosthetics of soft tissues [4] (TU 9398-00252820385-2008), is a highly viscous water-containing biopolymer with silver ions. When injected, this material is able to compensate for the deficiency of soft tissues by increasing their volume. DAM ^{+ ™} is used for implantation in the neck area of the bladder for the treatment of stress urinary incontinence under stress, as well as for implantation under the mouth of the ureters in endoscopic treatment of vesicoureteral reflux in children. According to the annotation, the drug does not resolve, is not rejected and is not subject to migrations in the body. This drug is available for purchase in the Russian pharmacy network, has a relatively low cost, and is available in 2 ml per pack. For the treatment of gastroesophageal reflux disease, the DAM ^{+ ™} biopolymer ^has not been used.

A new property of the drug was discovered in experimental studies. Before starting the studies, it was suggested that the introduction of the DAM ^{+ ™} biopolymer into the submucosal layer of the gastroesophageal junction and lower esophageal sphincter can make up for the missing tissue volume in this area, reduce the lumen of the abdominal esophagus and increase the pressure of the opening of the NPS.

The drug was investigated in experiments on experimental animals. 3 acute experiments and 14 chronic experiments were performed on 17 sexually mature laboratory rats weighing from 250 to 350 g.

When performing an acute experiment, an organocomplex — the stomach and abdominal section of the rat esophagus — was distinguished. The esophagus crossed at a distance of 2 cm from the gastroesophageal junction. The stomach intersected at the pyloric level. Carefully washed the contents of the stomach. A PVC tube from the blood transfusion system (outer diameter 4 mm) was passed through the pyloric department to the stomach, and it was hermetically fixed using a ligature. A fluid supply system (physiological saline) and a capillary for measuring pressure in millimeters of water were connected to this tube through a tee. A Nelaton catheter with a diameter of 8 Шр with a trimmed end was tightly connected to the esophagus using a ligature. We began to supply fluid to the stomach at a rate of 120 drops per minute. The moment of opening of the gastroesophageal valve was recorded when fluid appeared in the esophageal catheter. The opening pressure of the gastroesophageal valve was successively measured three times. Then, 0.4 ml of DAM ^{+ ™} gel was injected into the submucous layer of the gastroesophageal junction and the abdominal esophagus, and the bolus size of the preparation was 2 × 2 × 5 mm. Again, the opening pressure of the gastroesophageal valve was measured three times. The measurement results were recorded in the table.

In a series of acute experiments, it was found that the introduction of DAM ^{+ ™} gel into the gastroesophageal junction leads to an increase in the pressure of opening of the cardiac valve by 2.7-3.7 times.

In a chronic experiment, morphological changes in the tissues of the abdominal esophagus were studied at various times after the introduction of a DAM + biopolymer into the submucosal layer, the degree of reaction of surrounding tissues to the preparation, the presence or absence of migration of the introduced gel, the duration of the bolus storage of the drug in the tissues, and the degree of its regression during observation period.

Experimental animals, depending on the timing of observation, were divided into 7 series.

1 series - 2 rats, observation period 1 day;

2 series - 2 rats, observation period 3 days;

3 series - 2 rats, observation period of 7 days;

4 series - 2 rats, observation period of 14 days;

5 series - 2 rats, observation period 21 days;

Series 6 - 2 rats, observation period 1.5 months;

7 series - 2 rats, observation period 3 months.

Experimental animals underwent operations under thiopental anesthesia supplemented with local infiltration anesthesia of 0.5% novocaine.

Technique of operation: Upper laparotomy. The stomach and abdominal esophagus were withdrawn into the wound. DAM ^{+ ™} gel was injected into the submucous layer of the gastroesophageal junction and the distal esophagus under visual control by injection in a volume of 0.3-0.4 ml. At the same time, it was visible that the drug spread upwards along the front surface of the esophagus by 0.5-0.7 cm. Hemostasis was monitored, after which the wound was sutured in layers. The animals received painkillers immediately after the operation, and antibiotic therapy was carried out in the immediate postoperative period.

The animals were withdrawn from the experiment at the indicated times. Under deep thiopental anesthesia, the animals were withdrawn from the experiment by intracardiac injection of ether. Organocomplex was isolated: stomach and abdominal esophagus. The drug was fixed in a 12% neutral formalin solution. Tissue sections were cut out from the gastroesophageal junction and over the 7 mm distal part of the esophagus for morphological examination. Sections were stained with hematoxylin-eosin.

The results of morphological studies.

Macroscopic examination: For all periods of the end of the experiment, similar macroscopic changes were noted: In all cases, the left one for the liver was soldered to the injection site. Visually determined thickening of the distal esophagus. Damage to the esophagus and cardiac section of the stomach in the area of gel injection was not observed.

Microscopic examinations:

1 day The gel is determined in the submucosal layer in the form of a localized bolus with clear boundaries, it is stained blue, has a fine-meshed structure. Tissue reaction is absent (Figure 1).

3 days. The introduced gel is stored in the submucosal layer. No damage to the mucous membrane of the esophagus. In the submucosal layer, the number of lymphocytes and macrophages is slightly increased. Migration of the gel outside the submucosal layer was not observed (Figure 2).

7 days Detachment of the mucous membrane with gel by 1/4 of the diameter of the esophagus is noted. Tissue response is noted only at the border of the gel bolus.

14 days. The gel is retained in the submucosal layer, no migration is noted. The reaction of tissues in the form of the appearance of fibroblasts and fibrocytes along the boundary of the injected gel, there are lymphocytes and macrophages. No mucosal damage. The remaining layers of the wall of the esophagus is not changed (Figure 3).

21 days The presence of a large bolus of the gel in the submucosal layer, a minor tissue reaction of a non-inflammatory nature - there are macrophages, lymphocytes, fibroblasts, fibrocytes in the gel injection zone (Figure 4).

1.5 months. The gel is stored in the submucosal layer, there is no damage to the layers of the wall of the esophagus, the presence of phagocytes in the injection zone is noted.

3 months. - There are signs of fragmentation of the gel bolus, in the injection zone a significant number of phagocytes (Figure 5).

In a series of chronic experiments, no damaging effect of the studied drug DAM ^{+ ™} on rat esophagus tissue was noted. During the observation period, no drug migrations from injection sites were detected. The reaction of surrounding tissues to the drug is insignificant, non-inflammatory in nature. DAM ^{+ ™} gel boluses persist in the administration area for up to 3 months.

Based on experimental studies, it was concluded that the drug DAM ^{+ ™} is promising for clinical use for endoscopic injection therapy of gastroesophageal reflux disease.

Information sources

1. Lehman GA. Injectables for GERD. In: ASGE Clinical Symposium // Endoscopic Therapy for GERD. Program and abstracts of Digestive Disease Week 2004; May 15-20, 2004; New Orleans, Louisiana.

2. Sharon Gillson, Enteryx Recall. About.com Guide October 18, 2005 // http://heartbum.about.com/b/2005/10/18/enteryx-recall.htm

3. Kamler JP, Lemperle G, Lemperle S, Lehman GA. Gastrointest Endosc. 2010 Aug; 72 (2): 337-42. Epub 2010 Jun 11.

4. DAM ^{+ ™} - Instructions for use, approved by order of Roszdravnadzor of 04.29.08.

APPENDIX

Figure 1. Microphotographic histological section of the rat esophagus, observation period - 1 day.

Figure 2. Microphotographic histological section of the rat esophagus, observation period - 3 days.

Figure 3. Microphotographic histological section of the rat esophagus, observation period - 14 days.

Figure 4. Microphotographic histological section of the rat esophagus, observation period - 21 days.

Figure 5. Microphotographic histological section of the rat esophagus, observation period - 3 months.

Table 1. The opening pressure of the cardiac valve of rats before and after the introduction of DAM ^{+ ™} gel into the submucosal layer of the gastroesophageal junction and the abdominal esophagus.

Table 1 NPS opening pressure mm vod 1 experience 2 experience 3 experience Source 10.3 ± 1.5 11.3 ± 1.5 3.16 ± 0.3 After gel injection 28 ± 4,5 30.6 ± 4.7 12 ± 2.6

Claims (1)

The use of DAM ^{+ ™} for injection treatment of gastroesophageal reflux disease.

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