RU2349322C2 - Method of obstructive jaundice treatment - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly gastoenterology, and obstructive jaundice treatment. It involves enteric administration of pharmaceutical composition including the following components, wt %: xymedon - 0.25-0.3, magnesium sulfate - 1.15-1.25, the rest is bile.

EFFECT: improved somatic and psychological state of patient due to complex effect of composition, by applying the composition independently or as auxiliary therapeutic medium in complex with other therapeutic measures, in patient preparation for radical surgical recovery of impaired bile passage.

2 cl, 2 ex

Description

The invention relates to medicine, in particular to surgery, oncology, and in particular to methods of treating obstructive jaundice in the pathology of the biliary tract and blockade of the biliary tract.

Normal digestion and motor function of the intestine largely depend on the supply of bile, which creates favorable conditions for the action of pancreatic enzymes (trypsin, lipase) and neutralizes the acidic gastric contents in the duodenum.

In violation of the passage of bile, even in cases of partial (less than 500 ml per day) or complete cessation of its passage into the intestine, pronounced digestion, absorption of the products of the digestion of fats and fat-soluble vitamins - A, D, E, K.

At the same time, due to the lack of bile in the intestine, which is necessary for the absorption of fats by the intestinal wall, the absorption of fat-soluble vitamin K, which is delivered mainly to food, stops. Vitamin K takes part in the formation of prothrombin and promotes normal blood coagulation [Filatov AN, Kotovschikova MA Blood coagulation in clinical practice. Medgiz, 1963, - 160; Pathological physiology / Ed. A.D. Ado and I.R. Petrova. M .: "Medgiz", 1957]. An early sign of hypovitaminosis K is a low content of prothrombin in the blood. If its content is reduced to 35%, there is a risk of hemorrhage due to injuries, and if it is reduced to 15-20%, severe bleeding can develop.

The early return of bile in patients with external bile fistulas, with developed acholy in the body is known, as our reports and many authors testify, and are widely used in biliary tract surgery [Izmailov SG, Parshikov VV, Popov A.N ., Izmailov G.A. Treatment and prevention of acholia syndrome. Nizhny Novgorod, 2004, 109]. However, there are absolutely no reports on the use of the method for the prevention and treatment of cholemic bleeding with mechanical unresolved jaundice - cholemia. Our early studies showed that endogenous intoxication develops in the body of patients with obstructive jaundice, which is greatly enhanced in the postoperative period with a sharp aggravation of the operated homeostasis [Izmailov SG et al. Treatment and prevention of acholia syndrome: Nizhny Novgorod, 2004; Popov A.N., Izmailov S.G. et al. Acholia syndrome in biliary tract surgery. Kazan, 2003; Troitsky K.I., Izmailov S.G. et al. Obstructive jaundice. Nizhny Novgorod, 2002]. The obtained experimental and clinical data during the treatment of patients with obstructive jaundice allow us to assert with confidence that substitution preventive and therapeutic therapy of this group of patients should be comprehensive, intensive, with the mandatory inclusion of enteral administration of bile, as a pathogenetically substantiated method.

A known method of treating hepatic insufficiency in patients with obstructive jaundice by removing bile by external drainage of the biliary tract. Then auto-gall is sorbed, lyophilized, packaged in hard gelatin capsules and administered orally in 6-10 capsules per day in 3-4 doses 10 minutes before meals for 3-13 days [Patent 2132194 RU A61K 35/413] (prototype). A similar method provides [RF patent application 94001617, A61B 17/00, A61N 5/06] return of bile after preliminary purification on sorption coals with ultraviolet radiation and the addition of sodium hypochlorite solution.

However, these methods have the following disadvantages:

- the patient is preliminarily subjected to surgical intervention, a T-shaped drainage of the common bile duct is inserted inside it through the large duodenal nipple into the duodenum, which relates to traumatic and technically difficult operations, giving a high percentage (up to 30%) of complications, especially in elderly and senile age [Milonov OB, Toskin KD, Zhebrovsky VV Postoperative complications and dangers in abdominal surgery. M .: Medicine, 1990, 560; Kolker I.I., Zhumadilov J.Sh. Prevention of postoperative purulent-inflammatory complications. Alma-Ata: “Science”, 1988, 144];

- in the vast majority of cases, these methods do not lead to normalization of prothrombin in the peripheral blood and do not eliminate the high risk factor for the genesis of hemorrhagic syndrome.

Known pharmacological compositions and methods for the prevention and treatment of obstructive jaundice in connection with cholelithiasis by the administration of 50-100 ml of an aqueous solution of acidic glycoprotein isolated by isoelectric focusing from mammalian bile at a concentration of 10 ^-14 -10 ^-22 mol / l [Patent No. 2207149 RU A61K 38/17, A61K 35/413, A61P 1/16]; chenodeoxycholic acid preparations [RF Patent Application No. 98106092, A61K 31/575, A61P 1/16]; orotic acid products with amino acids [Patent No. 2257208 RU А61К 31/505, А61К 31/34, А61К 9/20, А61Р 1/16], which are used mainly in cases of inflammation of the extrahepatic bile ducts, liver and pancreas.

Treatment of diseases of the hepatopancreatoduodenal zone involves the production of operative decompression of the biliary tract with subsequent enteral replenishment of bile loss. All analogues are aimed at reducing mortality and postoperative complications, preventing the development of irreversible changes in the hepatopancreatoduodenal organs.

A specific therapeutic agent for bleeding associated with a low blood content of prothrombin is Vikasol, a synthetic water-soluble analogue of vitamin K [Mashkovsky MD Medicines M .: "Medicine", 2005]. However, its use also has significant disadvantages:

- etiotropic therapy is aimed only at the effect of replacing vitamin K deficiency;

- there is no restoration of absorption of vitamin K by the intestines;

- there is a danger of the genesis of hypercoagulation, which we ascertained in 3 cases;

- intolerance to the drug is possible with the development of side effects and an allergic reaction;

- the drug is absolutely contraindicated in case of increased blood coagulation in the patient’s history [Filatov AN, Kotovschikova MA Blood coagulation in clinical practice. Medgiz, 1963];

- in cases of parenteral administration, the formation of post-injection infiltrates and abscesses is not excluded.

The objective of the invention is a method for the treatment of obstructive jaundice, expanding the range of known methods.

The method gains independence in exploratory surgical interventions for unresectable tumors, as well as in individuals with extremely pronounced concomitant diseases, in cases of operational risk of the fourth degree.

The technical result of the proposed method consists in correcting the disturbed process of digestion and absorption of fats, normalizing blood coagulation, improving the regenerative ability of tissues and intestinal motility, which reduces the number of complications.

The technical result is achieved by the proposed method, including in complex therapy, the enteral administration of a specially developed, original pharmacological composition (Ximagel) containing xymedon, magnesium sulfate and bile, taken in the following proportions in wt.%:

Ximedon 0.25-0.3 Magnesium sulfate 1.15-1.25 Bile rest

in a dose of 100-150 ml orally 3-4 times a day after or with food.

The optimal doses of the ingredients of the proposed composition were selected experimentally based on accepted when using the individual components in clinical practice [Mashkovsky M.D. Medicines M .: "Medicine", 2005].

When searching for the most effective constituent components, the authors proceeded from the working hypothesis that the enteric administration of a complex drug can normalize the altered functional activity of the intestine, thereby correcting the disturbed blood coagulation system, strengthening compensatory and adaptive mechanisms, and increasing the body's resistance to pathogenic effects of endogenous and exogenous origin.

According to generally accepted methods and methods of pharmaceutical pharmacology for the preparation of drugs, the proposed composition was prepared as follows. Samples of powdered xymedon and magnesium sulfate were placed in a glass measuring bowl and then xenogenic bile was added in its native form or in powder, followed by simple mixing of the components. The resulting mixture was sterilized at a temperature of 120 ° C for 30 minutes.

The pharmaceutical individual ingredients included in the composition are authorized for practical use by the Ministry of Health of the USSR and the RSFSR with preliminary approval by the Pharmacological Committee and are described in the literature [Mashkovsky M. D. Medicines M .: "Medicine", 2005]. However, the proposed composition is created taking into account the detected potentiation of the action of a single pharmacological agent. In this case, the effect of their combined effect is greater than the sum of the effects of each agent taken separately. An unobvious positive result is achieved, which makes it possible to consider the invention as useful and meets the criterion of inventive step.

Xymedon is one of the simplest domestic non-glycoside analogues of pyrimidine nucleosides. Xymedon (1,2-dihydro-4,6-dimethyl-N- (β-hydroxyethyl) -pyrimidone-2) is a non-glycosidic analogue of pyrimidine nucleosides, which distinguishes it from previously studied simple pyrimidine bases (methyluracil, pentoxyl). Since 1993, the drug is approved for industrial production and clinical use in the complex treatment of burn patients as a stimulant of reparative and regenerative processes (Order of the Ministry of Health of the Russian Federation No. 287 of 12/07/93; registration certificate No. 93/287/7). It has a multivalent effect: immunomodulating, hepatoprotective, reparative, contributes to the normalization of protein metabolism, functional activity of the liver, intestinal motility [Izmailov SG et al. Xymedon in clinical practice. NMGA, N. Novgorod, 2001]. However, in an isolated form with traditional oral administration, in the form of a tablet form, the prothrombin-educational effect of the drug is not clinically expressed. In addition, Xymedon is deprived of a sedative, hypnotic effect, which must be achieved in the treatment of patients with diseases of the biliary system.

Magnesium sulfate (MgSO ₄ · 7H ₂ O) is a bitter salt, readily soluble in water. It has a choleretic, antispasmodic, detoxifying, laxative and calming effect on the central system, and also enhances diuresis [Mashkovsky M.D. Medicines M .: "Medicine", (2005)]. The introduction of magnesium sulfate in the proposed mixture, along with its main effect - liquefaction and increase in the volume of intestinal contents, leads to a relief of the bowel movement, potentiates the therapeutic effect of Ximedon.

Bile, which contains bile acids, bile pigments (red-brown-bilirubin and green (biliverdin), formed by the breakdown of red blood cells, as well as cholesterol (a fat-like substance) and inorganic salts. Bile enhances the action of digestive enzymes secreted by the pancreas, preserves they are destroyed by neutralizing acidic gastric juice, converts the breakdown products of fats into substances that are soluble in water, which contributes to their absorption.

Since with obstructive jaundice with complete or even partial blockage of the common bile duct, bile does not enter the duodenum at all, this disrupts the process of digestion and absorption of fats, the intestines are not disinfected, its peristalsis, especially the distal sections, slows down, causing constipation and flatulence due to the resulting large amount of gas.

From the intestines, typical symptoms are observed. The chair becomes acholic, acquires a clay, gray color. The response to stercobilin is negative. Feces are high in fatty acids. Hemoconia in the blood is not detected, i.e. alimentary lipemia (the presence of fat in the blood with fatty foods) with obstructive jaundice is absent [Konchalovsky MP Textbook of Internal Medicine. M.-L. 1939; 467-468]. The test is very simple and consists in the fact that if you give a healthy subject a piece of bread, 50 g of fat and after 2 hours look at his drop of blood in an ultramicroscope, then you can see plasma formations with shiny grains having a Brownian motion on a dark background - these are hemoconia, small particles of fat that are absorbed in the intestines and entered the general circulation.

Therefore, it is not paradoxical, in view of the excessive content of bile in the body’s media, in the presence of cholemia, there are clearly reasoned indications for reasonable intermittent intestinal administration of natural bile. However, the generally accepted enteral route of administration through the mouth contains an element of non-aesthetics, and the ingestion of bile into the stomach has an ulcerogenic effect on its mucous membrane [Popov A.N. et al. Acholia syndrome in biliary tract surgery. Kazan: LLC Pechatny Dvor, 2003]. Oral administration of bile is accompanied by inflammation of the gastric mucosa with the development of atrophic gastritis, adversely affects the production of hydrochloric acid [Kadyrov UZ, Karotina TA Absorption of water, sodium chloride and glucose from the small intestine with prolonged loss of bile. In: Problems of the physiology of humans and animals in hot climates. Tashkent, 1965; 222-225]. Based on this, it is advisable to inject bile gradually, directly into the duodenum, without distorting the normal passage of bile.

For treatment, native cattle bile was used. Sterilization of bile was carried out at a temperature of 120 ° C for 30 minutes At this temperature and the duration of the provision of bile, bacterial growth was not detected in it during microbiological studies. Ultimately, they received products that meet the requirements for solutions. Such a technology for producing sterile bovine bile was used by E.G. Minushkin, 1971 [S.G. Izmaylov et al. Treatment and prevention of acholia syndrome. Nizhny Novgorod, 2004, 107].

In addition, a method was used to obtain sterile lyophilized native bile in glutoid capsules. Xenogenic bile was first perfused through cellulose acetate membranes for microbiological analysis, located in the column for filtration in a certain order as pores were reduced. In the 1st layer there are two membranes with a pore size of 0.91-1.05 microns; in the 2nd layer, 0.551-0.65 μm, in the 3rd layer two membranes with a pore size of 0.251-0.35 μm in order to remove possible decomposition products from bile. Filtered bile was collected in sterile glassware, poured into 0.5 ml glass ampoules and freeze-dried in an EDVARS type apparatus. Then bile was packaged in glutoid capsules immediately before use [A. Popov et al. Acholia syndrome in biliary tract surgery. Kazan: LLC Pechatny Dvor 2003, 193].

It is possible to harvest xenogel by drying in the form of tablets, powder [Popov AN Acholia syndrome in biliary tract surgery. Diss. Dr. med. sciences. Kazan, 1998]. So, Dudenas V.G. et al. (1987) offer a spray method, and Seybutis A.G., Kononov I.N. (1978) - freeze-drying of bovine bile, rabbits or poultry [Dudenas V.T., Savitskas A.B., Bernatnis D.A. Tabletting of bird bile obtained by spray drying. Abstracts 4th Congress of Pharmacists of the Lithuanian SSR. Vilnius 1987; 70-71].

All authors with the early oral return of auto-bile, in cases of prolonged functioning of the external bile fistula, received positive results. The evidence of the effectiveness of the replenishment of bile deficiency arising from its loss is beyond doubt.

The proposed method for the treatment of obstructive jaundice is as follows.

The patient, preferably transnasally, is injected with a nipple probe into the duodenum, using a thin elastic tube or a standard duodenal probe. Technically, this procedure is carried out by simply swallowing a nipple tube with a bead at the end or using a guide (ureter catheter, etc.) or an endoscope. Then, a standard sterile system for infusion therapy is attached to the free protruding end of the probe to administer the Ximagel drug composition (heated to 36-37 ° C). The latter is administered fractionally during or after meals 3-4 times a day, preferably at the rate of 400-500 ml per day.

For clinical testing of the proposed pharmaceutical therapeutic composition "Ximagel" was taken the main experimental group of 10 patients with obstructive jaundice caused by inoperable tumors of the intra- and extrahepatic biliary tract.

The drug composition in solution was administered through an established probe, which in many cases served as an independent therapeutic measure, causing intestinal decompression, due to often developing flatulence. The probe made it possible to significantly simplify the process of administering drugs and to conduct rational nutrition. The probe is necessary especially in cases where the patient has problems with appetite, food intake (difficulty swallowing, etc.). Less often, capsules with bile were given to patients along with xymedon and magnesium sulfate in the same dosages as in solution.

In patients of the main (experimental) group, hemorrhagic syndrome was not detected in any case. In the course of treatment in all patients on the 3-5th day of treatment, an improvement in the general condition of the patient, a weakening of the pain syndrome, and a decrease in itching were noted. Intestinal peristalsis was revived, as evidenced by the appearance of intestinal noises and suppression of flatulence, the stool became colored - the reaction to sterkobilin was positive. The amount of fatty acids in feces has been significantly reduced. Hemoconia was detected in the blood. A reliable positive dynamics of blood biochemical parameters during therapy was revealed: an increase in prothrombin content (%) from 35.4 ± 1.6 to 88.2 ± 2.3; total protein (g / l) from 60.2 ± 1.7 to 67.4 ± 1.2 and albumin (%) from 48.1 ± 1.4 to 59.7 ± 2.2; a decrease in bilirubin (μmol / L) from 20.8 ± 0.7 to 15.6 ± 1.5, ALT, ACT, and alkaline phosphatase (U / L). Patients well tolerated the claimed medicinal composition. Only two after 1-2 minutes had a slight weakness, a feeling of heat, which passed through 4-5 minutes. Coagulation according to Mas-Magro before treatment was within 7.4 ± 1.2 minutes, after treatment - 3.7 ± 1.1 minutes.

To illustrate, we give one example of the successful application of the proposed method in patient S., 59 years old, with a diagnosis of obstructive jaundice caused by cancer of the large duodenal nipple. Received April 3, 2000 in the surgical department 2.5 months after the disease. The gradual development of jaundice was noted; numerous combs and hemorrhages are visible on the skin. A positive symptom of curvoise, the liver is dense, enlarged, ultrasound and laparoscopy were performed. Blood tests: HB - 9.1%; Er. - 3 × 10 ¹² / l; l - 11.4 × 10 ⁹ ; p. - 8%; S. - 5.6%; E. - 2%, lymph. - 30%, mon. - 2%; ESR - 29 mm / h; bilirubin - 295 μmol / l, prothrombin - 40%; Mas-Magro coagulability; alkaline phosphatase activity - 198 μmol / L. Assigned to complex therapy with the inclusion of Ximagzhel. The condition has improved. Dyspeptic symptoms disappeared. Prothrombin levels increased to 70%. Simple cholecystostomy was performed under local anesthesia. The patient refused a radical operation. Discharged home.

A control group of 18 patients with a similar nature of obstructive jaundice receiving conventional treatment is divided into 3 subgroups: 1st (7) receiving antispasmodics, hepatoprotectors, enzyme preparations, etc., 2nd (5) - bile with xymedon and 3 -th (6) - bile. In addition, data from early studies of the effects of xymedon on the functional activity of the liver and gastrointestinal tract were taken into account.

In the control group, by the end of treatment, indices of the functional state of the digestive organs improved, but they were less pronounced than in patients of the experimental group. So, in patients of the 3rd subgroup receiving only bile, intestinal motor function was moderately improved with positive dynamics of peripheral blood biochemical parameters. The content of prothrombin (%) increased from 39.6 ± 0.8 to 74.1 ± 1.2; total protein (g / l) from 58.7 ± 0.9 to 62.4 ± 1.3. However, signs such as skin itching, general weakness, activity in behavior, remained the same. We give one of the examples.

Patient D., 63 years old, was admitted on November 14, 2000 with a diagnosis of obstructive jaundice, cancer of the head of the pancreas. Sick for more than 3 months, when he began to note weakness. Jaundice appeared, discoloration of feces. Only severe skin itching forced the patient to see a doctor. The general condition is serious. The pulse is 66 beats per minute, rhythmic. HELL 100/60 mm HB Ascites is determined. Marked yellowness of the skin and sclera. On the skin combs, hemorrhages. Prothrombin blood 40%. Paraclinical studies have confirmed the malignancy of the genesis of jaundice. Bile was introduced through a transnasally established probe. Against the background of improved biochemical parameters, skin itching did not have a clear tendency to weaken, and only after the connection of xymedon was it possible to eliminate it.

More noticeable subjective and objective positive changes were observed in the 2nd subgroup, which testified to the potentiating effect of xymedon administered by bile. Biochemical parameters of this subgroup approached the data of the experimental group. The smallest effect was achieved in persons of the 1st subgroup, in whom an increase in prothrombin level, although it took place in the early stages, was notable for instability and necessitated frequent and long-term injections of Vikasol. In one patient, after administration of the drug, pronounced Quincke edema was noted, which with great difficulty was eliminated by hormone therapy. In two cases, hemorrhagic syndrome developed. Particular inefficiency was expressed in the absence of positive changes in the motor-evacuation activity of the intestine: anorexia, constipation, and flatulence remained. We give one of the examples.

Patient K., 62 years old, was admitted on September 20, 1998 with complaints of severe general weakness, itching, dull pain in the right hypochondrium, weight loss. It was treated for about 4 months on an outpatient basis by a therapist. An overview radiography of the abdominal cavity revealed an increase in the size of the liver, which is determined by panoplasty. Laparoscopy - a tightly filled gall bladder, metastases in the liver are visible. Conclusion - obstructive jaundice of malignant origin. Symptomatic therapy was prescribed with the inclusion of vikasol, since areas of hemorrhage appeared on the body. Blood tests remained unchanged: leukocytes 9.01 × 10 ⁹ / l, bilirubin - 306 μmol / l, except for prothrombin, the content of which from 46% increased to 56%. The patient's condition did not improve. She was discharged home under the supervision of a regional oncologist.

As shown above, the results of treatment of patients with obstructive jaundice, it is optimal to use the proposed composition with the introduction of its intraduodenal sounding.

Clinical trials of the proposed method for the treatment of obstructive jaundice showed its significant advantages compared to those used in practice.

The method is safe, simple in technical design and easily tolerated by patients. Intraduodenal or oral administration of the proposed medicinal composition - "Ximagel" - allows you to:

- to correct the disturbed process of digestion and absorption of fats, as evidenced by the appearance of colored feces;

- revitalization of intestinal motility, constipation and flatulence are eliminated, appetite improves;

- the content of prothrombin in the blood rises with the normalization of blood coagulation, hemorrhages are not detected;

- there is no development of allergic reactions;

- the psychological status improves, mood improves, headaches decrease;

- suppressed tissue regenerative abilities are stimulated.

The method can be applied both as an independent therapeutic technique, and as an adjunct in combination with other therapeutic measures, in preparing patients for radical surgical restoration of the impaired bile passage.

The proposed method for the treatment of obstructive jaundice using a special, original composition is not described in the literature and is new.

The claimed technical result is achieved only by the proposed method of treatment, therefore, the present invention meets the criterion of inventive step.

The claimed invention may find application in clinical practice.

Claims (2)

1. A method for the treatment of obstructive jaundice, including enteral administration of a drug in complex therapy, characterized in that a pharmacological composition consisting of the following ingredients is used as a medicine, wt.%:
xymedon 0.25-0.3 magnesium sulfate 1.15-1.25 bile rest 2. The method according to claim 1, characterized in that the composition is administered fractionally 3-4 times, 100-150 ml after or with food.