Medicine and treatment of dysfunctions of the hepatobiliary system

 

(57) Abstract:

The invention relates to medicine and can be used for the treatment of dysfunctions of the hepatobiliary system of different origin. The essence of the invention is a medicinal product containing the activated form of monoclonal, polyclonal, or natural antibodies to cholecystokinin in small or midget doses, prepared by multiple consecutive breeding and external influences, mainly on homeopathic technology; and a method for the treatment of dysfunctions of the hepatobiliary system by modifying effects of endogenous cholecystokinin, consisting in the use of the activated form of antibodies to cholecystokinin in small and super small doses resulting from multiple serial dilutions and exposure, preferably in a mixture of various, mainly centesimal homeopathic dilutions of these antibodies. The technical result is the creation of safe, effective means for treatment of violations of function of the hepatobiliary system that does not cause tolerance. 2 S. and 1 C.p. f-crystals, 5 PL.

The invention onoprishvili.

In the prior art it is known the use of antibodies for the treatment of pathological syndromes (SU 1131508 And a 61 K 39/00, 1984; SU 1730144 A1, 12 N 7/00, 1992).

There is a method of treating disorders of the function of the hepatobiliary system by medication effects on liver enzyme system and regeneration of liver cells in case of damage (see the Register of medicines of Russia. Encyclopedia of drugs. 2001. M, 2000, S. 1052-1053). While administering the drug on the basis of "essential" phospholipids, which have a hepatoprotective effect.

However, for the expressed therapeutic effect requires prolonged administration of the drug (not less than 3 months).

The invention is directed to the creation of effective means and method for the treatment of dysfunctions of the hepatobiliary system of different origin; safe, non-tolerance building.

The solution of this problem is provided by the fact that the drug contains an activated form of monoclonal, polyclonal, or natural antibodies to cholecystokinin in small or midget doses, prepared by multiple consecutive breeding and external impacts, benefits the Noah system of different origin by modifying effects of endogenous cholecystokinin use of activated forms of ultra-low doses of antibodies to cholecystokinin, the resulting multiple serial dilutions and exposure.

It is preferable to use a mixture of different, mainly centesimal homeopathic dilutions of these antibodies.

Obtained in accordance with the invention, the drug represents a new pharmacological agent, which modifies the biological effects of endogenous cholecystokinin, resulting in pronounced hepatoprotective and hispanoamericano effect is achieved within a few days.

Activation (potentiation) of antibodies to cholecystokinin saves in sverkhrazvetvlennykh solutions or saturated fillers medicines biological (pharmacological) activity, manifested by modification of the molecular, cellular and systemic effects of endogenous cholecystokinin. In contrast to physiological and therapeutic (aktivirovannyh) doses of antibodies to cholecystokinin that suppress the activity of cholecystokinin, an activated form of antibodies to cholecystokinin in small and ultra-low doses impact, qualitatively identical (synergistic, unidirectional) hall of the Method of solid-phase peptide synthesis synthetic polypeptide, corresponding to the oktapeptid cholecystokinin (26-33, amino acid sequence Asp Tight Met Gly Trp Met Asp Phe).

The resulting peptide conjugated with methylated bovine serum albumin as a carrier, is used as the immunogen for immunization of rabbits. Monospecific serum to cholecystokinin obtained by immunization of rabbits specified immunogen well-known scheme (elm O. L. Laboratory methods in infectious immunology. M.: Medicine, 1968-356 c. ). The blood samples are from the marginal ear vein into sterile tubes. After the retraction of the clot serum is separated by centrifugation, heated 10 min at 56oFor decontamination of complement.

Selected antibodies to cholecystokinin sequentially repeatedly bred, simultaneously exposing standardized rules homeopathic technology, to obtain small or ultra-low doses (containing no molecules of the original substance) (see Homeopathic medicines. A guide to description and manufacturing, W. Schwabe, Moscow, 1967, S. 12-38). This produces a uniform decrease in the concentration by serial dilution of 1 volume part of the original substance (anti-Christ. (pages solvent with multiple vertical shaking each received cultivation and use mostly separate containers for each subsequent dilution to obtain the required dose (potency).

External processing in the process of reducing the concentration can be realized by ultrasound, electromagnetic or other physical effects.

Using thus prepared drug, mainly taken in homeopathic practice, pharmaceutical forms and dilutions, in the form of alcoholic or aqueous solutions or tablets (pellets) obtained by soaking before saturation is contained in the dosage form filler potentiated solution or direct introduction of the latter in liquid dosage form.

Example 1.

In the study of hepatoprotective properties of the activated form of antibodies to cholecystokinin (a-h) with therapeutic administration to rats with acute SS-hepatitis acute hepatitis in rats caused by the introduction of a 50% solution S in olive oil at a dose of 1.25 ml/kg intragastrically for 4 days. Immune rabbit affinity purified antibody to cholecystokinin (a mixture of homeopathic dilution C12+C30+C200) (a-h) was administered at 0.5 ml per rat intragastric 1-2 h after injection of hepatotoxin. Control animals received instead of the drug activated distilled water (C12+C30+C200) in the same amount and experimentalnoy and the control group was at least 5 animals. Biochemically in the serum was determined by the content of bilirubin, activity of alkaline phosphatase, aspartate - and alanine-aminotransferase (calculated de Ritis coefficient-AST/Alt) using standard kits Lachema (Czech Republic), Sigmau. Expected weight of the liver (ratio of body mass to the mass of the animal), the indicator determined for the integrated assessment of the availability of hepatotropic influence of xenobiotics. To characterize the antitoxic function of the liver and the activity of microsomal system used geksenalovy test. Geksenal was injected intraperitoneally in the form of 1% solution at a dose of 80 mg/kg of sleep was recorded for the duration of finding the animal in an upright position and lack of reflex turning.

Pieces of liver were fixed in fluid Carnoy, were placed in paraffin. Dewaxed sections were stained with hematoxylin-eosin and in the chronic experiment on van Giesen on connective tissue. On histological preparations were counting the number of hepatocytes in a state of necrosis or apoptosis and shapes mitoses per 1000 hepatocytes. Using an ocular grid gg Avtandilov was determined by the relative area of infiltration of the hepatic parenchyma macrophages liver thickness of 10 μm. Slices were fixed with 4% calcium-formula and stained with Sudan black B. Degree of fatty degeneration was evaluated in points.

The results of the study showed that after 10 days after the beginning of the introduction SS in the serum of rats have a tendency to increase in the activity of AST, Alt and lowering of De Ritis coefficient. Alkaline phosphatase activity statistically significantly increased when compared with the group of intact animals. It is known that hepatic isoforms of alkaline phosphatase excreted in the blood in elevated quantities in cholestasis, because in these conditions increases their diffusion across the sinusoidal membrane of hepatocytes due to zatrudnieniu excretion in the bile. With the introduction of A-X in the background S-hepatitis observed normalization of alkaline phosphatase activity. There is also a decrease in AST activity when compared with group "Hepatitis+water" (PL.2).

On histological preparations of liver of all rats was observed hyperemia, disconnecktie, moderate fatty degeneration and necrosis of individual hepatocytes. In the Central regions of lobules and around periportal vessels, bile ducts was observed focal accumulation of macrophages and lymphocytes. The degree of fatty degeneration and otnositelnosti necrotic hepatocytes was significantly less than in control rats (table.3).

Thus, an activated form of antibodies to cholecystokinin prepared according to homeopathic technology, in terms of intoxication by carbon tetrachloride has a hepatoprotective effect. Drug drug reduces the severity of metabolic and morphological disorders of the liver.

Example 2.

When studying the influence of the activated form of antibodies to cholecystokinin (a-h) in experimental chronic liver disease CCL4rats were injected nutrire-lubochna 50% solution CCL4in olive oil at a dose of 2 ml/kg for 5 weeks 2 times a week, simulating severe chronic toxic hepatitis. With 10 days after the start of intoxication rats were treated with monoclonal antibodies to cholecystokinin (a mixture of homeopathic dilution D6+C30+C1000) intragastrically at a dose of 0.5 ml per rat after 1-2 h after injection of hepatotoxin within 30 days. Control animals received instead of the drug potentiated by homeopathic technology distilled water (a mixture of homeopathic dilution D6+C30+C1000) to the same extent and in the same time frame. Rats were sacrificed through decapitation days after the last drug administration and water.

The result is riodic to a sharp increase in alkaline phosphatase activity when compared with the group of intact animals. Introduction a-h within 30 days leads to a statistically significant decrease in alkaline phosphatase activity of the serum in this group of animals when compared with group "hepatitis + water".

Macroscopically the liver of all rats receiving the drug, and the water was compacted, greyish-brown with uniformly fine-grained surface. On histological preparations of the liver parenchyma presents small slices approximately equal size, separated by layers of connective tissue septa. In saptah lymphohistiocytic infiltration, proliferation of the bile ducts. In the lobules broken beam structure, characterized by fatty degeneration of hepatocytes, especially on the periphery, cholestasis symptoms of varying severity. There is a large number of figures mitoses and hepatocytes with hyperploidy cores. The degree of fatty degeneration, mitotic index and the number of necrotic hepatocytes in rats treated with the drug or water, did not differ. In rats treated with A-X, the relative area of collagen fibers was significantly less than in control animals (table. 5).

Thus, an activated form of antibodies to cholecystokinin, made which reduces the severity of metabolic abnormalities in the liver of rats and delays the development of connective tissue (cirrhosis).

Example 3.

Patient R., 49, a long time abusing alcohol, I went to the doctor with complaints about the yellowness of the skin, heaviness in the right hypochondrium, periodic epigastric pain, radiating to the back, General weakness, weight loss, headaches, daily nosebleeds, alternating constipation with diarrhea. Objectively: the state of moderate severity, skin and visible mucous icterina, skin, spider veins, Palmar erythema. Liver +3 cm from the edge of the costal arch, the edge of a smooth, dense. Ultrasound: liver enlarged, hyperechogenic, portal vein enhanced. The pancreas is enlarged, there are foci with increased echogenicity. In the biochemical analysis of blood: decreased total protein, fibrinogen, elevated levels of total and indirect bilirubin, enzymes ct, Alt, alpha-amylase. HBs antigen - negative. Diagnosis: chronic alcoholic hepatitis, portal cirrhosis, chronic pancreatitis. Appointed: polyclonal affinity purified rabbit antibodies to cholecystokinin (a mixture of homeopathic dilution C12+C30+C200) - 1 tablet 2 times a day. 7 days after the start of treatment: the condition is relatively satisfactory, the patient noted a decrease in pain, improvement in General the levels of total protein, the decrease in the level of bilirubin, transaminases, alpha-amylase. It is recommended to continue taking the drug per 1 tablet 2 times a day. When re-attendance within 1 month: satisfactory condition, no complaints, gained weight 4 kg Objectively: easy subikterichnost mucous membranes, liver +1 cm from the edge of the costal arch; in the biochemical analysis of blood levels of total and indirect bilirubin, enzymes AST, Alt, alpha-amylase is at the upper limit of normal.

Example 4.

Patient T., 56 years of age hospitalized with acute exacerbation of chronic nekal-TB cholecystitis, hypermotor biliary dyskinesia with complaints paroxysmal dull pain and heaviness in the right hypochondrium, nausea and vomiting bile, bloating and constipation. Objective: according to the ultrasound, gallbladder and the common bile duct is dilated, the liver is not changed, the pancreas is enlarged. In the biochemical analysis of blood: increased levels of direct bilirubin, alkaline phosphatase, bile acids, cholesterol. Appointed: monoclonal antibodies to cholecystokinin (a mixture of homeopathic dilution C3+C30+S) - 1 tablet 3 times a day. On the third day of treatment, the patient noted a decrease in pain, no that is and ultrasound of the gall bladder, the common bile duct and the pancreas is normal in size; in the biochemical analysis of blood levels of direct bilirubin, alkaline phosphatase, bile acids, cholesterol within normal limits. After discharge is recommended prophylactic administration of 1 tablet every other day.

Example 5.

Patient L., 62 years of age hospitalized with acute exacerbation of chronic nekal-TB cholecystitis, hypermotor biliary dyskinesia with complaints paroxysmal dull pain and heaviness in the right hypochondrium, nausea and vomiting bile, bloating and constipation. Objective: according to the ultrasound, gallbladder and the common bile duct is dilated, the liver is not changed, the pancreas is enlarged. In the biochemical analysis of blood: increased levels of direct bilirubin, alkaline phosphatase, bile acids, cholesterol. Appointed: natural antibodies to cholecystokinin (a mixture of homeopathic dilution C12+C200) - 1 tablet 3 times a day. Natural antibodies to cholecystokinin were selected from a pool of sera of patients with chronic acalculous cholecystitis. When the allocation method used affinity chromatography (immunosorbent) on columns with sorbed on the solid phase (Sephadex) cholecysto-432).

On the fourth day of treatment, the patient noted a decrease in pain, no nausea and vomiting, improvement of General condition. One week after the start of treatment: the condition is satisfactory, ultrasound of the gall bladder, common bile duct and the pancreas is normal in size; in the biochemical analysis of blood levels of direct bilirubin, alkaline phosphatase, bile acids, cholesterol within normal limits. After discharge is recommended prophylactic administration of 1 tablet every other day.

1. Drug for the treatment of dysfunctions of the hepatobiliary system based on antibodies, characterized in that it contains an activated form of monoclonal, polyclonal, or natural antibodies to cholecystokinin in small or midget doses, prepared by multiple consecutive breeding and external influences, mainly on homeopathic technology.

2. A method for the treatment of dysfunctions of the hepatobiliary system of different origin, characterized in that carry out the modification of the effects of endogenous cholecystokinin by using the activated form of antibodies to cholecystokinin in small and super small doses received way is causesa fact, they use a mixture of various, mainly centesimal homeopathic dilutions of antibodies to cholecystokinin.

 

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SUBSTANCE: invention relates to new antibodies directed against antigenic complex CD3 and can be used in therapeutic aims. Antibody IgG elicits the affinity binding with respect to antigenic complex CD3 wherein heavy chain comprises skeleton of the human variable region in common with at least one CD3 taken among amino acid sequences SEQ ID NO 2, 4 and 6 and their corresponding conservatively modified variants. Light chain comprises skeleton of the rodent variable region in common with at least one CD3 taken among amino acid sequences SEQ ID NO 8, 10 and 12 and their corresponding conservatively modified variants. Antibody is prepared by culturing procaryotic or eucaryotic cell co-transformed with vector comprising recombinant nucleic acid that encodes antibody light chain and vector comprising recombinant nucleic acid that encodes antibody heavy chain. Antibody is administrated in the patient suffering with malignant tumor or needing in immunosuppression in the effective dose. Invention provides preparing chimeric antibodies against CD3 that are produced by expression systems of procaryotic and eucaryotic cells with the enhanced yield.

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33 cl, 5 dwg, 1 ex

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