Method of treating malignant tumors and complex drug with antitumor action for implementing the method
(57) Abstract:The invention relates to medicine, namely to Oncology. Proposed depending on the nature and severity of the disease the patient on the background infusion-detoxification therapy parenteral introduce a complex preparation containing AFP in the amount of 0.07-0.15 mg, polyene antibiotic, mainly amphotericin b or nystatin, in the amount of from 4.2 to 7.0 mg) and a filler once a day with an interval of three days, the course of 10 infusion-drip infusion. Complex drug with antitumor activity, contains the following components, mg: AFP 0,07-0,15, polyene antibiotic from 4.2 to 7.0, the filler of 3.5 to 5.0. As filler predominantly use the polysaccharide from the group reopoliglyukin poliglyukin or sugar, for example glucose. The method can reduce the dose of drugs and to reduce the cost of treatment. The integrated product has high efficiency of antitumor action, malokomplektnoj, ease of access and long shelf life, 2 S. and 2 C. p. F.-ly. The invention relates to medicine, in particular to cancer and can be used for chemotherapeutic treatment oncologists who help cancer using chemotherapy. The mechanism of action of chemotherapy drugs are divided into alkylating, antimetabolite, alkaloids, antibiotics, hormones, immunomodulators, and some others. In the treatment of different tumor antigens identified their strengths and weaknesses.Due to the relatively low working concentrations are widely used chemotherapy drugs acting on DNA. Alkylation of vital DNA molecules leads to the impossibility of proper cell division and their subsequent elimination. However, the alkylation is exposed simultaneously DNA normal non-cancer cells. To reduce toxicity towards normal cells when using such drugs are additionally used methods of targeted delivery to cancer cells using specific ligands, such as alpha-fetoprotein (AFP). AFP - a transport protein capable of delivering the related substance in cells with appropriate receptors. These receptors are particularly many on actively proliferating cancer cells.There is a method of treatment of primary liver cancer by intraarterial administration of alpha-fetoprotein in an amount of 2-20 mg, mainly 15 mg, at intervals of 7-12 days five (PCSA quantities of AFP, distinguished by long duration and limited use, since the conditions for the selection of patients for treatment by this method are the absence of jaundice and ascites, neoperabelnoy, the absence of severe comorbidities.There is a method of treatment of malignant tumors by intravenous complex preparation containing AFP and estrone conjugate doxorubicin (RF Patent 2026688, class a 61 K 38/00, publ. 20.01.95, bull. 2). For preparation of the comprehensive drug use is not pure AFP and abortive material, which, after the coarse focus to the content of AFP 100 μg/ml and sterilized. Then subjected to conjugation antitumor antibiotic doxorubicin with ligand-estrone in equimolar ratio. Directly for 1-2 hours before intravenous injection concentrate AFP in the amount of 100 ml and 20 mg of the conjugate is mixed and receive one dose of the drug for one injection (single dose of AFP is 10 mg). The General course of treatment is 6 injections (3 times a day with an interval of one week).The disadvantage of this method is the use of high doses of AFP, and the disadvantage of the integrated product is a time-consuming process 2 hours.Closest to the claimed method (prototype) is a method of treatment of primary liver cancer, comprising introducing into the hepatic artery drug doxorubicin dissolved in substance, ULTRAGLIDE, the drug doxorubicin using doxorubicin-estrone dissolved in 96% ethanol at 70-76oWith a dose of 20-60 mg in 10-15 ml of the substance ULTRAGLIDE. Previously (20 minutes) in the hepatic artery enter AFP at a dose of 2-10 mg in 12-15 ml of saline, and re-treatment for 3-4 weeks (RF Patent 2065307, class a 61 K 38/17, publ. 20.08.96, bull. 23).The disadvantages of this method are:
- the complexity of the method associated with separate introduction of the AFP and complex doxorubicin-estrone;
- the use of high concentrations of chemotherapeutic drugs (AFP-2-10 mg, complex doxorubicin-estrone-20-60 mg), which can lead to toxic side reactions;
- high cost of treatment.Closest to the claimed integrated product (prototype) is set for the treatment of primary liver cancer, including doxorubicin-estrone in the amount of 20-60 mg in vials with a capacity of 15 ml, of the substance of ultrablue in two ampoules of 10 ml, AFP in the amount of 2-10 the UNT RF 2065307, class a 61 K 38/17, publ. 20.08.96, bull. 23).The disadvantages of this set are:
the complexity and duration of obtaining sterile complex doxorubicin-estrone and complexity of preparation of the working solution of this medicine: it is dissolved in 0.5-1.5 ml of 96% ethyl alcohol when heated to 70-76oWith the obtained solution was transferred to 10-15 ml of preheated substance, ULTRAGLIDE obtained suspension is cooled to 32-37oAnd injected into the hepatic artery under the control of the x-ray television;
- high concentrations used in the set of products;
- the complexity of the set.The technical objective of the invention is to simplify the known method, to reduce the doses injected drugs and reducing treatment costs.This object is achieved by the proposed method for the treatment of malignant tumors and complex drug with antitumor action to implement this method.Implementation of treatment method.Depending on the nature and severity of the disease the patient on the background infusion-detoxification therapy parenteral impose complex agents who nd the filler once a day with an interval of three days, a course of 10 infusion-drip infusion.Complex drug with antitumor activity, contains the following components, mg:
AFP - 0,07 - 0,15
Polyene antibiotic - 4,2 - 7,0
Filler - 3,5 - 5,0
As a polyene antibiotic used mainly amphotericin b or nystatin.As filler predominantly use sugar, for example glucose or synthetic polymers selected from the group of polysaccharides, for example poliglyukin, reopoliglyukin dextran.The integrated product was obtained as follows: AFP with a purity not less than 98% dissolved in distilled water or saline solution in the amount of 0.07-0.15 mg/ml, add polyene antibiotic in the amount of from 4.2 to 7.0 mg/ml, injected filler in the amount of 3.5-5.0 mg/ml, mix thoroughly and incubated the mixture for 10-12 hours at 18-25oC. Then, the solution is sterilized by filtration Packed in ampoules or vials with a capacity of 1,2 or 3 ml and freeze-dried. The mass ratio of the AFP to the polyene antibiotic and the filler is 1: (60-100): (50-70).Complex preparation (conventional name of Reducin) is a yellow powder, soluble in water vials to complex drug contains: 0.07 to 0.15 mg AFP, from 4.2 to 7.0 mg polyene antibiotic and 3.5-5.0 mg of the appropriate filler. To prepare the working solution of the contents of the ampoule is dissolved in 2-3 ml of sterile water and injected into 200 ml bottle with a carrier suitable for intravenous administration.The inventive method consists in the introduction of new patient comprehensive cancer with anticancer activity, consisting of a vector that is specific to cancer cells and parts (AFP) and non-specific part, containing the cytotoxic agent. As a final use of a fundamentally new kind of channel-forming and surface-active substance (surfactant), namely polyene antibiotics such as amphotericin b or nystatin, previously as an antitumor agent was not used. The target for the action of the new drug are the membranes of intracellular substructures. Such substructures are mitochondria, complementary mechanism, the endoplasmic reticulum (EPR), kernel etc In the disruption of membrane substructures impossible the normal functioning of the cells provided in the normal compartmentalization of different functions. The result is a self-digestion of tumor cells by type induced apoptosis.The main features of the proposed method in comparison with the prototype are:
- patient parenteral and at the same time introducing a complex preparation containing AFP in the amount of 0.07-0.15 mg, polyene antibiotic in the amount of from 4.2 to 7.0 mg and pharmaceutically suitable filler course of 10 injections (drip infusion) once every three days, which allows to simplify the known method, to reduce the dose of the drugs and reduce the cost of treatment.Due to the fact that in the known sources of information similar method of treatment of malignant tumors and complex drug with antitumor action is not detected, it is possible to draw a conclusion on the compliance of the claimed group of inventions criteria of "novelty" and "inventive step".The proposed method was treated 8 patients IV clinical group with cancer is different from the 8 (75%). The remission period of 6 months. up to 1.5 years. In most cases, to obtain a clear clinical effect was only one course of treatment.The invention is illustrated by the following examples of specific performance.Example 1.For preparation of the comprehensive drug Reducin in 1 liter of distilled water and dissolved under stirring 700 mg AFP, 42 g of amphotericin b and 50 g reopoligliukina, then the volume was adjusted to 10 liters. The resulting mixture was incubated for 10-12 hours at room temperature, and then subjected to sterilizing filtration through a membrane filter, Packed in 10,000 ampoules or vials of 1 ml (single dose) and freeze-dried under aseptic conditions. One vial (vial) contains 0.07 mg AFP, 4.2 mg of amphotericin b and 5.0 mg reopoligliukina.Example 2. Comprehensive drug Reducin get analogously to example 1, except that aqueous solution was added 1 g of AFP, 50 g of amphotericin b and 40 g poliglyukina. The result is a product containing per dose: 0.1 mg AFP, 5.0 mg of amphotericin b and 4.0 mg poliglyukina.Example 3. Comprehensive drug is produced analogously to example 1, except that an aqueous solution is added 1.5 g AFP, 70 g am the AFP, 7,0 mg of amphotericin b and 3.0 mg of dextran.Example 4. Comprehensive drug is produced analogously to example 1, except that an aqueous solution is added 750 mg AFP, 60 g of nystatin and 50 g of glucose. The result is a product containing a single dose: 0.075 mg AFP, 6.0 mg nystatin and 5.0 mg of glucose.Example 5.Patient L. , 54 years old, medical history, 587, was admitted to the hospital 02.04.99, with a diagnosis of Central cancer of the right lung Art. IV (relapse, progressive course), cancer of the left breast 2 tbsp. (remission). The patient complains of weakness, shortness of breath, exhausting cough.Survey data. Radiograph of the chest in light from two sides of multiple polymorphic shadow metastases in size from 0.5 to 2.5 cm medium intensity with irregular contours. Shadow mediastinum shifted to the right and extended. The right lung field is reduced in volume, lower 4 ribs intense darkening due to fluid in the pleural cavity.A course of chemotherapy at the CAF scheme. Cyclophosphamide 1 g intravenously at 1 and 8 days, 5-fluorouracil 500 mg intravenously at 1 and 8 days, adriablastin 40 mg intravenously at 2 and 9 days of treatment. Treatment was accompanied by high toxicity without the have introduced a comprehensive drug Reducin, containing 0.07 mg AFP, 4.5 mg of amphotericin B, 5.0 mg of glucose, one every three days, a course of 10 injections. The patient's condition has improved to meet satisfactory one week after completion of treatment. According to x-ray examination of the chest registered a favorable change in the form of reducing the number of metastases in the lungs and the weakening of the intensity of the shadows of dissemination. Fluid in the pleural cavity was not determined. Decreased shortness of breath when climbing up and completely disappeared cough. When treating Reducina was observed fever and chills, which were stopped by the standard drugs.Example 6.Patient M. , 62 year history of 800, was admitted to the hospital with a diagnosis of Central cancer of the right lung Art. IV (adenocarcinoma); widespread metastases head, the right hemisphere of the brain, neck, chest; right-cancerous pleural effusion; chronic deforming bronchitis; emphysema; diabetes type 2 diabetes type; coronary artery disease; angina; secondary immunodeficiency; exhaustion; status after the course of chemotherapy.The treatment program included a course of chemotherapy scheme CAMF. Ill Uchenie was accompanied by endotoxicosis and a sharp deterioration in the condition of the patient. Positive effects were noted.Due to a severe condition of the patient's last scheduled intravenous infusion declare comprehensive drug Reducin containing one dose: 0.075 mg AFP, 5.0 mg nystatin and 5.0 mg reopoligliukina, a course of 10 injections every three days.6 days after the start of treatment by the claimed method marked decrease in the size of subcutaneous metastases. By the end of the treatment achieved a rapid improvement in the underlying disease that manifested itself in a twofold decrease of the sizes of all superficial metastatic nodes, the disappearance of pain in the lower jaw, reducing the rate of exudation in the right pleural cavity. Three times done right-sided pleural puncture confirmed the decrease in the volume of exudate: before treatment, the volume of exudate was 600 ml, one week after treatment - 350 ml, after 3 weeks - 20 ml. improve the function of the Central nervous system manifested in the restoration of full swallowing, in the restoration of the grasping function of the left hand that clinically corresponds to the reduction of metastasis in the right hemisphere brain.The use of the claimed method of treatment of malignant novoo the STN method of treatment and set for its implementation:
- to simplify the way of treatment by simultaneously injecting a complex preparation containing AFP and cytotoxic surfactants in the optimum ratio;
- to reduce the dose used components: AFP in 13-140 time, the cytotoxic component in 3-14 times;
to increase the effectiveness of treatment due to the high specificity of the drug in relation to growing cancer cells and the best part of the integrated product having a long shelf life (two years);
to reduce the cost of treatment due to malokomplektnoj declare integrated product and low doses used chemotherapy drugs.Thus, in the present method of treating malignant tumors implements two biological mechanism. The first is the targeted delivery of cytotoxic tools using AFP to tumor cells. The second is aimed at the destruction of tumor cells due to the destruction of intracellular structures, in particular the EPR and lysosomes. This can cause self-digestion of tumor cells at the expense contained in the lysosomes enzymes hydrolysis-type address-induced apoptosis. Directed reduction is much less than what I standard cancer chemotherapy. Declare comprehensive drug Reducin has high efficiency of antitumor action, malokomplektnoj, ease of preparation, storage duration. 1. The method of treatment of malignant tumors, including the introduction of alpha-fetoprotein, characterized in that the alpha-fetoprotein is administered as part of the integrated product, optionally containing polyene antibiotics and the filler in the ratio 1 : (60 - 100) : (50 - 70), when this drug is administered parenterally, a course of 10 injections every three days.2. Complex drug with antitumor activity, including alpha-fetoprotein, a cytotoxic agent and a filler, characterized in that the cytotoxic means it contains a polyene antibiotic, and as filler polysaccharide or sugar the next time quantitative ratio of the components, mg:
Alpha-fetoprotein - 0,07 - 0,15
Polyene antibiotic - 4,2 - 7,0
Filler - 3,5 - 5,0
3. Complex drug under item 2, characterized in that as a polyene antibiotic it contains amphotericin b or nystatin.4. Complex drug under item 2, characterized in that as napolnitel glucose.
FIELD: medicine, pediatrics.
SUBSTANCE: the present innovation deals with treating motor-autonomic disorders in children associated with affected function of central nervous system. For this purpose one should puncture perineural areas in the region of the main nervous trunks with alfetin dissolved in cerebrolysine. Additionally, one should puncture in projection area of cervical and lumbar spinal thickenings and areas that correspond to segmentary innervation of organs with affected function and, also, in scalp areas depending upon the character of patient's disorders. The method suggested provides improved autonomic-trophic impact of nervous system.
EFFECT: higher efficiency of therapy.